Saturday, April 20, 2013

Insight into the frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease in Japan

J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2012-304850 Neuroinfection

Research paper

Insight into the frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease in Japan

Tsuyoshi Hamaguchi1, Kenji Sakai1, Moeko Noguchi-Shinohara1, Ichiro Nozaki1, Ichiro Takumi2, Nobuo Sanjo3, Atsuko Sadakane4, Yosikazu Nakamura4, Tetsuyuki Kitamoto5, Nobuhito Saito6, Hidehiro Mizusawa3, Masahito Yamada1 + Author Affiliations

1Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan 2Department of Neurosurgery, Nippon Medical School Musashi Kosugi Hospital, Kawasaki, Kanagawa, Japan 3Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan 4Department of Public Health, Jichi Medical University, Shimotsuke, Japan 5Department of Prion Protein Research, Division of CJD Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan 6Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan Correspondence to Professor Masahito Yamada, Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan; Received 26 December 2012 Revised 28 February 2013 Accepted 26 March 2013 Published Online First 17 April 2013


Objective More than 60% of patients worldwide with Creutzfeldt-Jakob disease (CJD) associated with dura mater graft (dCJD) have been diagnosed in Japan. The remarkable frequency of dura mater grafts in Japan may possibly contribute to the elevated incidence of dCJD, but reasons for the disproportionate use of this procedure in Japan remain unclear. We investigated differences between dCJD patients in Japan and those elsewhere to help explain the more frequent use of cadaveric dura mater and the high incidence of dCJD in Japan.

Methods We obtained data on dCJD patients in Japan from the Japanese national CJD surveillance programme and on dCJD patients in other countries from the extant literature. We compared the demographic, clinical and pathological features of dCJD patients in Japan with those from other countries.

Results Data were obtained for 142 dCJD patients in Japan and 53 dCJD patients elsewhere. The medical conditions preceding dura mater graft transplantation were significantly different between Japan and other countries (p<0 .001="" and="" as="" cases="" cerebrovascular="" conditions="" countries.="" dcjd="" disease="" div="" dura="" for="" graft="" hemifacial="" in="" japan="" mater="" meningioma="" more="" neuralgia.="" neuralgia="" non-life-threatening="" of="" often="" or="" other="" patients="" received="" spasm="" such="" than="" there="" trigeminal="" were="" with="">

Conclusions Differences in the medical conditions precipitating dura mater graft may contribute to the frequent use of cadaveric dura mater and the higher incidence of dCJD in Japan.

Dura Mater

The worldwide tally of dura mater–associated cases is 228, and new cases still continue to occur here and there, the most recent being individual cases in Austria, South Korea, and the Netherlands in 2011. If the pharmaceutical industry (in contrast to government-sponsored laboratories) comes away from the growth hormone story with an almost untainted record—only 1 case has been attributed to industrially prepared hormone (11)—the same cannot be said about the private sector producing dura mater grafts. The source of almost all infections was a manufacturer in Germany, B. Braun Melsungen AG, which has a worldwide distribution network, and the incidence of CJD appears to have more or less paralleled the frequency with which this source of dura mater was used. In Japan, it is estimated that as many as 20,000 patches may have been used each year, and the 142 cases in that country constitute two thirds of the global total. Nevertheless, the overall attack rate in the at-risk patient population in Japan is <0 .03="" 1.3="" 12="" 2="" 30="" a="" agent="" an="" and="" approximately="" atypical="" blots="" cases="" cjd.="" clinical="" deposition="" different="" div="" dura="" electroencephalogram="" entire="" except="" features="" florid="" for="" from="" group="" had="" imaging="" in="" incubation="" infecting="" japan="" magnetic="" mater="" mean="" mimicking="" molecular="" neuropathologic="" noncharacteristic="" of="" on="" one="" patient="" patients="" periods="" plaque="" plaques="" possibility="" prion="" progression="" protein="" pulvinar="" ranged="" recipient="" resonance="" sign="" signature="" similar="" slow="" sporadic="" strains="" suggested="" the="" third="" those="" to="" tracings="" vcjd="" were="" western="" which="" worldwide="" years="">

Evaluation of the influence of the codon 129 genotype is complicated by the fact that the population in Japan, among whom most cases occurred, has a high frequency of the M allele (>90%), which dominated sporadic and dura mater–associated forms of CJD (Table 3) (6–9,14,15). Among the cases in persons not from Japan, the distribution of genotypes approximated that found among patients with sporadic CJD, and, as with growth hormone–associated cases, incubation periods were somewhat longer for persons with heterozygous than with homozygous genotypes.

Current Prevention Strategies

The best way to abolish secondary iatrogenic infections is, obviously, to prevent primary infections, but without a test to identify infected but asymptomatic persons, we cannot entirely eliminate the risk inherent in human-to-human tissue transfer. We are therefore obliged to rely on the default strategies of 1) identification and donor deferral of persons at higher than normal risk for CJD development and 2) inclusion of prion-reduction steps in the sterilization of penetrating instruments and the processing of therapeutic tissues and fluids.

Delineation of high-risk categories initially focused on precisely those groups of persons who were exposed to the known sources of iatrogenic disease: recipients of cadaveric dura mater grafts or pituitary-derived hormones. When vCJD started to occur, restrictions were also placed on donor time of residence in the most heavily infected regions—the United Kingdom and, to a lesser extent, continental Europe—and embargoes were placed on the importation of biological products from these regions. These deferral and import restrictions remain in place today and need some thoughtful reevaluation in view of the near extinction of all such sources of iatrogenic CJD. In the United States, there have been only 4 cases of dura mater–associated disease (the most recent in 2005) and no case of growth hormone–associated CJD for anyone who began treatment after 1977.

On the other hand, the possibility of iatrogenic infection resulting from transfer of tissues or fluids from persons who have contracted a prion disease from animals has not disappeared with the abating epidemics of bovine spongiform encephalopathy and vCJD. A few persons who may be experiencing a long incubation phase of vCJD still pose an obvious danger in the United Kingdom, but an underappreciated potential danger lies in 2 other animal diseases: scrapie and chronic wasting disease (CWD). Although scrapie-infected sheep tissues have been consumed for long enough (hundreds of years) to be considered harmless for humans, the same cannot be said about the atypical strains of scrapie that are beginning to displace the typical strains and with which we do not yet have enough experience to evaluate human pathogenicity. Similarly, we cannot declare with certainty that CWD poses no threat to humans, and CWD is continuing its unchecked spread across the United States and Canada with no guarantee that it will not become globally distributed in the years to come. One hunter has already put a group of unwitting persons at risk for infection by donating a deer, later found to have CWD, for consumption at a rural banquet in New York State (16); more such exposures are likely to occur as CWD continues its geographic expansion.

Future Prevention Strategies

The issue of reducing risk by taking steps to inactivate prions is always a work in progress as new therapeutic products come into production and new methods to inactivate prions are discovered. The tried-and-true laboratory method of prion sterilization (1-hour exposures to either undiluted bleach or 1 N sodium hydroxide followed by steam autoclaving at 3 atmospheres pressure for 20 minutes) is applicable only to nonfragile instruments and not at all to living tissues. The surprising resistance of dura mater to 0.1 N sodium hydroxide (17) and of growth hormone to 6 M urea (18) led to their incorporation into processing protocols before being replaced by nondural tissue or synthetic patches and recombinant hormone. To reduce infectivity, blood, blood products, and other fluids can be subjected to nanofiltration and prion-affinity ligands (19–22), which should also be applicable to other biological products, for example, vaccine and stem cell cultures, should they be susceptible to infection (23). Fragile instruments such as endoscopes and electrodes remain a challenge, but new and gentler methods— alkaline cleaning solutions, phenolics, and gaseous hydrogen peroxide—have proven harmless to instruments and give a high, if not always complete, degree of prion inactivation (24–26).

The ongoing refinement of a quaking-induced conversion detection of the misfolded prion protein holds the best prospect of evolving into a sensitive and practical tool, but it has yet to be validated in blind testing of plasma from symptomatic patients or in presymptomatic persons, even more rigorous but necessary (27,28). It may be necessary to use scrapie-infected animals for presymptomatic validation because only 1 group of humans could furnish appropriate samples—asymptomatic carriers of CJD-inducing mutations—and putting together and testing a reasonable number of such samples will take years to accomplish.

The total numbers of cases for the 2 major causes of iatrogenic CJD during the past 40 years (226 growth hormone cases and 228 dura mater cases) are amazingly close and are likely to remain so after the few additional long-incubating cases finally surface in the next few years. The combination of appropriate blood donor deferrals and the incorporation of tissue, fluid, and instrument infectivity–reduction steps should continue to hold the sources of potential iatrogenic disease to a minimum until such time as a practical screening test for inapparent infection is validated for human use.

Dr Brown spent his career at the National Institutes of Health in the Laboratory of Central Nervous System Studies conducting research on the transmissible spongiform encephalopathies, especially with respect to epidemiology, iatrogenic CJD, disinfection, and blood infectivity. He currently chairs a scientific advisory committee for the Laboratoire Français du Fractionnement et des Biotechnologies in Les Ulis, France, and advises the Centre à l’Energie Atomique in Fontenay-aux-Roses, France.


see full text ;

Thursday, May 17, 2012

Iatrogenic Creutzfeldt-Jakob Disease, Final Assessment

Volume 18, Number 6—June 2012

Monday, September 3, 2012


Asia-Oceania Symposium on Prion Disease AOSPD 2010

Poster 10

Human prion diseases in Japan: a prospective surveillance from 1999

Sakai, K, Nozaki, I., Hamaguchi, T., Noguchi-Shinohara, M., Nakamura Y., Sato, T,

Kitamot, T., Mizusawa, H., Sanjo, N., Moriwaka, F., Shiga, Y., Kuroiwa, Y.,

Nishizawa, M., Inuzuka, T., Takeda, M., Abe, K., Murai, H., Murayama, S., Tateishi, J., Shirabe, S., Takumi, I., Harada, M., Yamada, M.

Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School Science, Japan; 2) Creutzfeldt-Jakob disease Surveillance Committee, Japan


The current surveillance system of prion diseases by the Creutzfeldt-Jakob (CJD) Surveillance Committee, Japan, started in 1999. The purpose of this study is to describe the epidemiology and clinical features of human prion diseases in Japan.

[Materials and Methods]

The clinical, neuropathological, and molecular genetic data of patients suspected as having prion disease were prospectively collected and analyzed by the CJD Surveillance Committee, Japan, from 1999 to 2009.

[Results and Discussion]

We have obtained the information of 1,823 patients. A total of 1,421 cases of prion diseases was identified, including 1,088 cases of sporadic CJD (sCJD) (76.6%), 245 cases of genetic prion diseases (17.2%), 80 cases of dura mater graft-associated CJD (dCJD) (5.6%), 1 case of variant CJD (vCJD) (0.1 %), and 7 cases of unclassified CJD (0.5%). The overall annual incidence rate was 0.92 cases per million person­-year. In sCJD, codon 129 polymorphism of the prion protein (PrP) gene was Met/Met in 94.9%, Met/Val in 4.3%, and Val/Val 0.7%. MM2 type occupied the majority of atypical sCJD cases. In genetic prion diseases, the most frequent mutation of the PrP gene was V1801 (42.9%), followed by P102L (18.0%), E200K (16.3%), and M232R (13.9 %), and so on. Eighty cases of dCJD were found in this surveillance system; when combined with cases identified by previous surveillance systems, the total number of dCJD cases in Japan was 138. One case of vCJD with a history of a short stay in the UK was identified in 2005.


Human prion diseases in Japan were characterized by frequent occurrence of dCJD relative commonness of MM2 among atypical sCJD cases, and unique PrP gene mutations in genetic prion diseases, which were different from those in countries.

Prospective 10-year surveillance of human prion diseases in Japan

Ichiro Nozaki1,2, Tsuyoshi Hamaguchi1, Nobuo Sanjo3,4, Moeko Noguchi-Shinohara1, Kenji Sakai1, Yosikazu Nakamura4,5, Takeshi Sato4,6, Tetsuyuki Kitamoto4,7, Hidehiro Mizusawa3,4, Fumio Moriwaka4,8, Yusei Shiga4,9, Yoshiyuki Kuroiwa4,10, Masatoyo Nishizawa4,11, Shigeki Kuzuhara4,12, Takashi Inuzuka4,13, Masatoshi Takeda4,14, Shigetoshi Kuroda4,15, Koji Abe4,16, Hiroyuki Murai4,17, Shigeo Murayama4,18, Jun Tateishi4,19, Ichiro Takumi4,20, Susumu Shirabe4,21, Masafumi Harada4,22, Atsuko Sadakane5 and Masahito Yamada1,4

+ Author Affiliations

1 Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

2 Department of Neurology, Noto General Hospital, Nanao, Japan

3 Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

4 Creutzfeldt–Jakob Disease Surveillance Committee, Japan

5 Department of Public Health, Jichi Medical University, Shimotsuke, Japan

6 Department of Neurology, Higashi Yamato Hospital, Higashiyamato, Japan

7 Department of Prion Protein Research, Division of CJD Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan

8 Department of Communication Disorders, Health Sciences University of Hokkaido Graduate School of Psychological Science, Ishikari, Japan

9 Department of Neurology, Aoba Neurosurgical Clinic, Sendai, Japan

10 Department of Neurology, Yokohama City University School of Medicine, Yokohama, Japan

11 Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan

12 Department of Neurology, National Center Hospital of Neurology and Psychiatry, Tokyo, Japan

13 Department of Neurology and Geriatrics, Gifu University Graduate School of Medicine, Gifu, Japan

14 Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan

15 Department of Neuropsychiatry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

16 Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama University, Okayama, Japan

17 Department of Neurology, Iizuka Hospital, Fukuoka, Japan

18 Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

19 Harukaze Healthcare Service Institution, Fukuoka, Japan

20 Department of Neurosurgery, Nippon Medical School Musashi Kosugi Hospital, Kawasaki, Japan

21 Centre of Health and Community Medicine, Nagasaki University, Nagasaki, Japan

22 Department of Medical Imaging, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan

Correspondence to: Masahito Yamada, Department of Neurology and Neurobiology of Ageing, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan E-mail: Received May 1, 2010. Revision received June 14, 2010. Accepted June 15, 2010.

Next Section Summary

We analysed the epidemiological data and clinical features of patients with prion diseases that had been registered by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, over the past 10 years, since 1999. We obtained information on 1685 Japanese patients suspected as having prion diseases and judged that 1222 patients had prion diseases, consisting of definite (n?=?180, 14.7%) and probable (n?=?1029, 84.2%) cases, except for dura mater graft-associated Creutzfeldt–Jakob disease which also included possible cases (n?=?13, 1.1%). They were classified into 922 (75.5%) with sporadic Creutzfeldt–Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt–Jakob disease and one case of variant Creutzfeldt–Jakob disease, and three cases of unclassified Creutzfeldt–Jakob disease (0.2%). The annual incidence rate of prion disease ranged from 0.65 in 1999 to 1.10 in 2006, with an average of 0.85, similar to European countries. Although methionine homozygosity at codon 129 polymorphism of the prion protein gene was reported to be very common (93%) in the general Japanese population, sporadic Creutzfeldt–Jakob disease in Japan was significantly associated with codon 129 homozygosity (97.5%), as reported in western countries. In sporadic Creutzfeldt–Jakob disease, MM1 type (Parchi’s classification) is the most common, as in western countries. Among atypical sporadic Creutzfeldt–Jakob disease cases, the MM2 type appeared most common, probably related to the very high proportion of methionine allele in the Japanese population. As for iatrogenic Creutzfeldt–Jakob disease, only dura mater graft-associated Creutzfeldt–Jakob disease cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt–Jakob disease was 138, comprising the majority of worldwide dura mater graft-associated Creutzfeldt–Jakob disease patients. Regarding genetic prion diseases, the most common mutation of prion protein gene was V180I (41.2%), followed by P102L (18.1%), E200K (17.1%) and M232R (15.3%), and this distribution was quite different from that in Europe. In particular, V180I and M232R were quite rare mutations worldwide. Patients with V180I or M232R mutations rarely had a family history of prion diseases, indicating that a genetic test for sporadic cases is necessary to distinguish these from sporadic Creutzfeldt–Jakob disease. In conclusion, our prospective 10-year surveillance revealed a frequent occurrence of dura mater graft-associated Creutzfeldt–Jakob disease, and unique phenotypes of sporadic Creutzfeldt–Jakob disease and genetic prion diseases related to the characteristic distribution of prion protein gene mutations and polymorphisms in Japan, compared with those in western countries.

Key words prion disease dura mater graft-associated Creutzfeldt–Jakob disease 14-3-3 protein periodic synchronous wave complexes codon 129 or 219 polymorphism


Sporadic Creutzfeldt–Jakob disease

The very high frequency of PSWCs in sporadic Creutzfeldt–Jakob disease (97%), compared with the data of western countries (Collins et al., 2006), is related to the application of the diagnostic criteria by Masters et al. (1979) and the low autopsy rate in Japan. Regarding the subtypes according to Parchi’s classification (Parchi et al., 1999), the MM1 type was the most common (25/44, 56.8%), characterized by typical Creutzfeldt–Jakob disease features: rapid clinical course, positive PSWCs and CSF 14-3-3 protein and typical MRI findings (Table 4). Among atypical cases other than the MM1 type, the proportion of the MM2 type was relatively high (10/44, 22.7%) compared with Europe, the USA (12/300, 4.0%) (Parchi et al., 1999) and Germany (12/243, 4.9%) (Heinemann et al., 2007). MM2 type cases included cortical (50%), thalamic (40%) and combined (cortical and thalamic) forms (10%). Our results were influenced by the bias that atypical cases might have been more selectively autopsied to confirm the diagnosis; however, the relatively high proportion of the MM2 type in Japanese patients with sporadic Creutzfeldt–Jakob disease reflected the high proportion of the methionine homozygote genotype in the Japanese population.

Clinical characteristics of each sporadic Creutzfeldt–Jakob disease subtype (MM1, MM2-cortical, MM2-thalamic, MV2 and VV2) were almost the same as in previous reports (Parchi et al., 1999; Collins et al., 2006), except for the higher frequency of extrapyramidal signs (72%) in the MM1 type [7% in a previous report (Parchi et al., 1999)] and the lower frequency of pyramidal signs (0%) in MM2-cortical subtype [83% in previous reports (Parchi et al., 1999; Krasnianski et al., 2006)]. The deficiency of pyramidal or other neurological signs in the MM2-cortical subtype would lead to difficulties in the clinical diagnosis of MM2-type sporadic Creutzfeldt–Jakob disease on the basis of the current sporadic Creutzfeldt–Jakob disease criteria, although cortical hyperintensities on MRI suggest the diagnosis (Hamaguchi et al., 2005). In this study, the age at onset of the MM2-thalamic subtype was younger with a longer duration than the MM1 type, and neither PSWCs on EEG nor hyperintensities on MRI were identified in the MM2-thalamic subtype.

Prospective 10-year surveillance of human prion diseases in Japan

Table 2

Classification of each type of prion disease according to accuracy of diagnosis

Sporadic Creutzfeldt–Jakob disease Variant Creutzfeldt–Jakob disease Dura mater graft-associated Creutzfeldt–Jakob disease Genetic prion disease Total (%)


111 1 33 35 180 (13.6)


811 0 34 181 1026 (77.7)


97 0 13 4 114 (8.6)

Total (%)

1019 (77.2) 1 (0.1) 80 (6.1)

Intraspecies transmission of L-type-like bovine spongiform encephalopathy detected in Japan

Shigeo Fukuda 1*, Yoshifumi Iwamaru 2*, Morikazu Imamura 2 , Kentarou Masujin 2 , Yoshihisa Shimizu 2 , Yuichi Matsuura 2 , Yujing Shu 2 , Megumi Kurachi 2 , Kazuo Kasai 2 , Yuichi Murayama 2 , Sadao Onoe 1 , Ken'ichi Hagiwara 3 , Tetsutaro Sata 4 , Shirou Mohri 2 , Takashi Yokoyama 2 and Hiroyuki Okada 2 1 Molecular Biotechnology Laboratory, Hokkaido Animal Research Center, Shintoku, Hokkaido 081-0038, Japan 2 Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kan-nondai, Tsukuba, Ibaraki 305-0856, Japan 3 Departments of Biochemistry and Cell Biology , and 4 Pathology, National Institute of Infectious Diseases, Toyama 1-23-1 Shinjuku-ku, Tokyo, 162-8640, Japan Correspondence Hiroyuki Okada, Prion Disease Research Center, National Institute of Animal Health, Kannonndai 3-1-5, Tsukuba, Ibaraki 305-0856, Japan. Tel & fax: +81-29-838-7757; email:

*These authors contributed equally to this work.

Copyright © 2009 Japanese Society for Bacteriology, Japanese Society for Virology, Japanese Society for Host Defense Research, and Blackwell Publishing Asia Pty Ltd KEYWORDS atypical bovine spongiform encephalopathy • cattle • L-type-like • transmission


It has been assumed that the agent causing BSE in cattle is a uniform strain (classical BSE); however, different neuropathological and molecular phenotypes of BSE (atypical BSE) have been recently reported. We demonstrated the successful transmission of L-type-like atypical BSE detected in Japan (BSE/JP24 isolate) to cattle. Based on the incubation period, neuropathological hallmarks, and molecular properties of the abnormal host prion protein, the characteristics of BSE/JP24 prion were apparently distinguishable from the classical BSE prion and closely resemble those of bovine amyloidotic spongiform encephalopathy prion detected in Italy.


Received 7 May 2009; revised 2 August 2009; accepted 4 August 2009.

DIGITAL OBJECT IDENTIFIER (DOI) 10.1111/j.1348-0421.2009.00169.x About DOI


In Japan, two atypical BSE cases have been identified to date. The first case showed an L-type-like electrophoretic mobility of the unglycosylated PrPSc on western blot analysis (9). The second casewas identified in an aged beef cattle, Japanese Black (BSE/JP24), and showed PrP-positive amyloid plaques in histopathological examination of the brain and a distinct glycoformprofile (10). Although such properties seem to be similar to those reported in a BASE case (7), unlike with the BASE prion, shortening of the incubation periods was observed in bovinized mice serially passaged with the BSE/JP24 prion (11). Thus, it remains controversial whether the BSE/JP24 prion is identical to the BASE prion. These observations prompted us to characterize the phenotypes of the BSE/JP24 prion propagated in its natural host by comparison with those of the classical BSE prion. Hence, we have inoculated with brain homogenates from classical BSE and BSE/JP24 isolates into Holstein cattle and assessed their risk against cattle species.


In summary, we demonstrated the successful transmission of the BSE/JP24 prion to cattle. The BSE/JP24 prion-affected cattle sustained the molecular properties of PK-treated PrPSc as those of the original BSE/JP24 isolate. Although most brain regions except for the medulla oblongata of the original BSE/JP24 isolate were unable to be investigated due to inadequate specimen collection, in comparison to experimentally BSE/JP24 prion-affected cattle, both neuropathological features, such as severe vacuolation in the medulla oblongata at the obex level and the presence of PrPSc plaques, closely resembled each other. Based on molecular properties of PK-treated PrPSc and a detailed comparison of the immunohistochemical and neuropathological properties, the BSE/JP24 prion was distinguishable from those in the classical BSE prion, and appear to be rather similar to the BASE prion (8). Of interest, experimental transmission of the BSE/JP24 prion to cattle induced a shorter incubation period and more severe neuropathological changes compared to the classical BSE prion, suggesting that the BASE and BSE/JP24 prion might be more virulent in cattle species. However, such speculation conflicts with reports that atypical BSE field cases have been mainly found in adult and aged cattle (5). The reason for this discrepancy in incubation periods between experimentally and naturally affected cattle is unknown. These observations may imply that atypical BSE are sporadic forms of BSE. Alternatively, the route of infection and/or prion titer may be attributed to the relatively long incubation period in natural atypical cases. Further studies using orally BSE/JP24 prion-affected cattle will be needed to address this issue.

These observations may imply that atypical BSE are sporadic forms of BSE.


"So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE."

Prions: Protein Aggregation and Infectious Diseases


Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland


3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion diseases are sporadic forms of CJD. For sCJD, there is no association with a mutant PRNP allele, nor is there any epidemiological evidence for exposure to a TSE agent through contact with people or animals infected with TSEs. sCJD cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant prion protein identified on western blot (type 1 or type 2) (174). Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower risk (378) and/or prolonged incubation time (119, 387). The lack of routine laboratory testing for preclinical diagnosis makes the search for agent sources and other risk factors extremely difficult. At present, the means of acquisition of a TSE agent in these patients remains a mystery. So far, there is no evidence for spontaneous PrPSc formation in any animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60 years. However, if spontaneous misfolding were the primary event, one might expect a continuously increasing incidence with age because more time would allow more opportunity for rare misfolding events.



Subject: Importation of Whole Cuts of Boneless Beef from Japan [Docket No. 05-004-1] RIN 0579-AB93 TSS SUBMISSION

Date: August 24, 2005 at 2:47 pm PST

August 24, 2005

Importation of Whole Cuts of Boneless Beef from Japan [Docket No. 05-004-1] RIN 0579-AB93 TSS SUBMISSION

Greetings APHIS ET AL,

My name is Terry S. Singeltary Sr.

YEAR 2000

-------- Original Message --------

Subject: Biotechnology for growth hormone deficiency CJD, FRANCE

Date: Wed, 23 Feb 2005 15:11:02 –0600

From: "Terry S. Singeltary Sr."

Reply-To: Bovine Spongiform Encephalopathy

##################### Bovine Spongiform Encephalopathy #####################

Biotechnology for growth hormone deficiency Growth hormone Philippe Cramer, MD France Biotech Julien Martinet, D pham France Biotech Text reviewed by Pr Raja Brauner (Hôpital Saint-Joseph, Paris) and Pr Pierre Thomopoulos (Hôpital Cochin, Paris)

N O V E M B R E 2 0 0 4


TREATMENT OF GH DEFICIENCY BEFORE BIOTECHNOLOGY The first replacement therapies were used in the United States in the 1950 s and in Europe at the beginning of the 1970 s. At that time GH was obtained by extraction from the pituitary glands of human cadavers. Unlike insulin (where insulins of porcine and bovine origin were used until the early 1980 s), it is not possible to use a hormone of animal origin in humans because hormones are species specific.

The only indication for this treatment was pituitary dwarfism. The growing need for growth hormone was such that it led to the use of pituitary glands from various sources. In France, for instance, Bulgarian pituitaries were imported from 1982. Between 1983 and1988, around half of all pituitaries were imported. The dramatic side effect of pituitary-derived GH was the appearance of Creutzfeldt- Jakob disease (CJD). The first reported death from CJD in a patient undergoing growth hormone therapy was in 1984, but it was not until two other deaths from CJD in 1985 that the American FDA envisaged the possibility of a correlation between CJD and pituitary-derived GH (see Appendix). Approximately one hundred cases of CJD have been reported in France. The first response to this infection was the treatment of pituitary extract with urea 8M to deactivate the prions.


BIOIMPACT CREUTZFELDT-JAKOB DISEASE (CJD) Creutzfeldt-Jakob disease (CJD) is a rare and fatal neuro-degenerative disease, described for the first time in 1920, classified amongst the transmissible spongiform encephalopathies which can affect several species of animal. It leads to dementia, myoclonic jerks and ataxia. The disease normally affects adults between 50 and 75, but all generations are concerned when transmission is iatrogenic. Its distribution is sporadic, with an incidence of one case per million inhabitants. The majority of cases are sporadic (80%), 15% are of genetic origin, predominantly by transmission, and 5% are iatrogenic in origin (of which more than 90% of cases are associated with pituitary-derived growth hormone). There is currently no cure for this disease. According to the national network monitoring CJD in France, from January 1992 to October 2003, 8.3% of deaths from CJD originated from growth hormone therapy (86 cases out of 1037). Out of a total of 1361 patients studied who were treated with batches of pituitary-derived growth hormone suspected to be tainted, the average incubation time observed in the 55 patients who contracted CJD was 9 to 10 years, with a probability that 95% of cases were declared after ages 14 to 16 years. In addition, it was observed that 80% of patients infected were homozygous for codon 129 of gene PRNP (met-met or val-val), and this gene is therefore considered to indicate predisposition to CJD. These homozygous patients present an incubation time which is shorter than that for heterozygous individuals with the same gene. A new variant of this disease (nvCJD) appeared in Britain in 1996 under the name mad cow disease . After having studied other possibilities, scientists have adopted the theory of contamination of food by the agent causing bovine spongiform encephalopathy, BSE.




Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth hormone

E A Croes, G Roks, G H Jansen, P C G Nijssen, C M van Duijn ...............................................................

J Neurol Neurosurg Psychiatry 2002;72:792-793

A 47 year old man is described who developed pathology proven Creutzfeldt-Jakob disease (CJD) 38 years after receiving a low dose of human derived growth hormone (hGH) as part of a diagnostic procedure. The patient presented with a cerebellar syndrome, which is compatible with iatrogenic CJD. This is the longest incubation period described so far for iatrogenic CJD. Furthermore, this is the first report of CJD after diagnostic use of hGH. Since the patient was one of the first in the world to receive hGH, other cases of iatrogenic CJD can be expected in the coming years.

Prion diseases are potentially transmissible. Human to human transmission was first reported in 1974, when a 55 year old woman was described who developed symptoms of Creutzfeldt-Jakob disease (CJD) 18 months after a corneal transplant.1 Since then, transmission has been reported after stereotactic electroencephalographic (EEG) depth recording, human growth hormone (hGH) and gonadotrophin treatment, and dura mater transplantation.2-5 More than 267 patients with iatrogenic CJD are known today and their number is growing.6 The most important iatrogenic cause of CJD is still contaminated cadaveric hGH. Exposure to contaminated hGH occurred before 1985, when recombinant growth hormone became available. In a recent study, incubation periods in 139 patients with hGH associated CJD were found to range from 5-30 years, with a median of 12 years.6 One of the factors influencing incubation time is genotype on polymorphic codon 129 of the prion protein gene.7 The incubation time is significantly shorter in people who are homozygous for either methionine or valine on this polymorphism.7

We describe the second patient with hGH related CJD in the Netherlands. The patient developed the disease 38 years after hGH injections. To our knowledge, this is the longest incubation period described for any form of iatrogenic CJD. Further-more, our patient was not treated with hGH but only received a low dose as part of a diagnostic procedure.


This patient presented at the age of 47 years with paraesthesia in both arms for six months, difficulty with walking for four weeks, and involuntary movements of mainly the upper extremities of two weeks' duration. He did not notice any change in cognitive function, although his twin sister had noticed minor memory disturbances. There was no family history of neurological disease. During childhood the patient had experienced a growth delay compared with his twin sister and with the average in the Netherlands. When he was 9 years old, a nitrogen retention test with 6 IU hGH over five days was performed to exclude growth hormone deficiency. Since the result was not decisive, a quantitative amino acid test was performed, which measures 30 amino acids during fasting and one, two, and three hours after growth hormone injection. No abnormal amino acid concentrations were found making the diagnosis of primordial dwarfism most likely. Therefore, no treatment with hGH was given.

On neurological examination we found a slight dysarthria without aphasia. Cranial nerve function was normal. Walking was unstable and wide based. During movements of the upper extremities myoclonic jerks were present. Sensation, muscle tone, and strength were normal. Co-ordination was impaired in all four limbs with a disturbed balance. Tendon reflexes were brisk at the arms and increased at the legs with a clonus in the ankle reflex. Plantar responses were both normal. On the mini mental state examination, the patient scored 30/30. Routine laboratory investigation, thyroid function, vitamin concentrations (B-1, B-6, B-12, and E), and copper metabolism were normal. Admission EEG examination showed generalised arrhythmic slow activity with diffuse spikes and spike waves. EEG examination two months later showed a further slowing of the rhythm with bilateral diphasic sharp waves but was not typical for CJD. Cerebral magnetic resonance imaging was normal. Cerebrospinal fluid examination showed 1 cell/3 µl, normal glucose and protein concentrations, and a strongly positive 14-3-3 protein test. The patient was homozygous for methionine on the PRNP codon 129 polymorphism. On clinical grounds, CJD was diagnosed. Within one month the patient's condition deteriorated rapidly and because of severe disturbances in coordination and progressive myoclonus he became bedridden. An eye movement disorder developed with slow saccadic and dysmetric eye movements. Temperature became unstable with peaks of 39°C without an infectious focus, for which a disorder of autoregulation was presumed. Until a very advanced stage, cognitive function was intact. The patient died five months after admission. The diagnosis of CJD was confirmed at necropsy. The brain weighed 990 g and showed clear cortical and cerebellar atrophy. Spongiosis, neuronal loss, and gliosis were found predominantly in the putamen, caudate nucleus, and basotemporal and cerebellar cortex; the cerebellum was the most severely affected of these. Vacuoles ranged from 2-12 µm. No amyloid or Kuru plaques were found. Immunohistochemical staining (3F4 antibody 1:1000, Senetek, USA) was clearly positive for prion protein accumulation in a "synaptic" distribution. Most deposition was found in the stratum moleculare of the cerebellum.


We describe a 47 year old patient who developed pathology proven CJD 38 years after hGH injections. The patient was never treated with hGH but received a small dose as part of a diagnostic procedure. The onset of CJD was signalled by prodromal symptoms of paraesthesia followed by a rapidly progressive ataxia. The disease presentation and course with predominantly cerebellar and eye movement disorders are compatible with iatrogenic CJD caused by hGH treatment.6 8

Growth hormone treatment was first described in 1958 but hGH was not produced on a larger scale from human pituitary glands until the beginning of the 1960s. In the Netherlands growth hormone extraction started in 1963 and was soon centrally coordinated. Until 1979 growth hormone was extracted non-commercially from pituitaries by a pharmaceutical company. In 1971 commercial products also became available. Our patient was one of the first to receive hGH in the Netherlands but the origin of this product was not recorded. A causal relation can therefore not be established with full certainty, but coincidentally receiving growth hormone and developing this very rare disease is unlikely. Since the clinical course in this relatively young patient is in accordance with an iatrogenic cause, we think the probability is high that the hGH injections explain the development of CJD in this patient.

The first Dutch patient with hGH related CJD died in 1990. 9 During several periods from 1963 to 1969 she received intramuscular injections of hGH. During an unknown period the hGH was derived from South America. At age 39, 27 years after starting the treatment, she developed an ataxic gait, slurred speech, sensory disorders, and myoclonus, but her cognitive function remained normal. Postmortem examination of the brain confirmed the diagnosis of CJD.9 Following the identification of this patient, a retrospective study was started to trace all 564 registered hGH recipients who were treated before May 1985. Until January 1995, none of these was suspected of having CJD.10 Since 1993 prospective surveillance for all forms of human prion disease has been carried out in the Netherlands and, apart from the patient described above, a further two patients with iatrogenic CJD have been identified, who developed the disease after dura mater transplantation.11

An incubation period as long as 38 years had never been reported for iatrogenic CJD. Huillard d'Aignaux et al7 studied the incubation period in 55 patients with hGH related CJD in a cohort of 1361 French hGH recipients. The median incubation period was between 9 and 10 years. Under the most pessimistic model, the upper limit of the 95% confidence interval varied between 17 and 20 years. Although the infecting dose cannot be quantified, it can be speculated that the long incubation period in our patient is partly explained by the administration of a limited amount of hGH. This hypothesis is supported by experimental models, in which higher infecting doses usually produce shorter incubation periods.6 Since our patient was one of the first in the world to receive hGH, this case indicates that still more patients with iatrogenic CJD can be expected in the coming years. Another implication of our study is that CJD can develop even after a low dose of hGH. This case once more testifies that worldwide close monitoring of any form of iatrogenic CJD is mandatory.


We are grateful to M Jansen PhD MD for his search for the origin of the growth hormone and P P Taminiau MD. CJD surveillance in the Netherlands is carried out as part of the EU Concerted Action on the Epidemiology of CJD and the the EU Concerted Action on Neuropathology of CJD, both funded through the BIOMED II programme, and is supported by the Dutch Ministry of Health. This surveillance would not have been possible without the cooperation of all Dutch neurologists and geriatricians. ........................................

Authors' affiliations

E A Croes, G Roks*, C M van Duijn, Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus University Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands

P C G Nijssen, Department of Neurology, St Elisabeth Hospital, PO Box 90151, 5000 LC Tilburg, Netherlands

G H Jansen, Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX Utrecht, Netherlands

*Also the Department of Neurology, St Elisabeth Hospital

Correspondence to: Professor C M van Duijn, Genetic Epidemiology Unit, Department of Epidemiology and Biostatistics, Erasmus University Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, Netherlands;

Received 27 December 2001 In revised form 1 March 2002 Accepted 12 March 2002

Competing interests: none declared


1 Duffy P, Wolf J, Collins G, et al. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974;290:692-3.

2 Bernoulli C, Siegfried J, Baumgartner G, et al. Danger of accidental person-to-person transmission of Creutzfeldt-Jakob disease by surgery. Lancet 1977;i:478-9.

3 Koch TK, Berg BO, De Armond SJ, et al. Creutzfeldt-Jakob disease in a young adult with idiopathic hypopituitarism: possible relation to the administration of cadaveric human growth hormone. N Engl J Med 1985;313:731-3.

4 Cochius JI, Burns RJ, Blumbergs PC, et al. Creutzfeldt-Jakob disease in a recipient of human pituitary-derived gonadotrophin. Aust NZ J Med 1990;20:592-3.

5 Thadani V, Penar PL, Partington J, et al. Creutzfeldt-Jakob disease probably acquired from a cadaveric dura mater graft: case report. J Neurosurg 1988;69:766-9.

6 Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2000;55:1075-81.

7 Huillard d'Aignaux J, Costagliola D, Maccario J, et al. Incubation period of Creutzfeldt-Jakob disease in human growth hormone recipients in France. Neurology 1999;53:1197-201.

8 Billette de Villemeur T, Deslys JP, Pradel A, et al. Creutzfeldt-Jakob disease from contaminated growth hormone extracts in France. Neurology 1996;47:690-5.

9 Roos RA, Wintzen AR, Will RG, et al. Een patiënt met de ziekte van Creutzfeldt-Jakob na behandeling met humaan groeihormoon. Ned Tijdschr Geneeskd 1996;140:1190-3.

10 Wientjens DP, Rikken B, Wit JM, et al. A nationwide cohort study on Creutzfeldt-Jakob disease among human growth hormone recipients. Neuroepidemiology 2000;19:201-5.

11 Croes EA, Jansen GH, Lemstra AF, et al. The first two patients with dura mater associated Creutzfeldt-Jakob disease in the Netherlands. J Neurol 2001;248:877-81.


Possible iatrogenic Creutzfeldt-Jakob Disease in an adult male 50 years after treatment with human chorionic gonadotrophin

Brian Appleby1, Paul Brown2 1Johns Hopkins University School of Medicine, USA; 2CEA/DSV/iMETI/SEPIA, France

Background: Known causes of iatrogenic Creutzfeldt-Jakob disease (iCJD) include cadaverous corneal transplants, dural mater grafts, human growth hormone (hGH), neurosurgical depth electrodes, and neurosurgical instrument contamination. Four cases of iCJD from human gonadotrophin have been described to date, all of whom have been women.

Objectives: To present a case of possible iCJD from human chorionic gonadotrophin (hCG) and review data from four other cases Methods: Case report and descriptive analysis

Results: A 62-year-old Caucasian man developed ataxia that resulted in frequent falls and an initial diagnosis of benign positional vertigo. Further workup including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and a lumbar puncture were unrevealing. A cerebrospinal 14-3-3 protein analysis was indeterminate. At the end of the third month of his illness, he developed short-term amnesia, disorientation, and confabulation. A repeat EEG showed generalized slowing without evidence of periodic sharp wave complexes and a repeat 14-3-3 analysis was positive. A second brain MRI showed hyperintensity in the basal ganglia on diffusion- weighted images. He died following a four-month illness. Severe vacuolization was noted on microscopic examination and Western blot analyses detected type II prion proteins. Genomic analyses detected a silent polymorphism at codon 117 and valine homozygousity at codon 129 of the prion protein gene. Further review of his medical records revealed a history of cryptorchidism and treatment with hCG as a child in the 1940’s-1950’s.

Discussion: This case report describes a possible case of iCJD from hCG injections and is unique in that the patient was male and the incubation period approached 50 years. His clinical presentation, EEG findings, and codon 129 homozygousity are similar to previously described cases.

Tuesday, November 23, 2010

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S. Korea confirms first death caused by Creutzfeldt-Jakob disease ?


She is believed to have been infected during her brain surgery 23 years ago when she had dead brain tissue replaced with a graft of a dura mater product named Lyodura. The victim did not show symptoms until the occurrence of paralysis in her face and toe in June last year.

The KCDC said the transplanted dura mater originated from the body of a CJD patient. The center said it will track down potential patients who received similar transplants with Lyoduras around 1987.

Some 400 cases of iCDJ have been reported in 20 countries, 200 of which were caused after dura mater transplant operations. KCDC, meanwhile, stressed that there is no correlation between this case and the Variant Creutzfeldt-Jakob disease, which is often referred to as human mad cow disease.


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*** Current limitations about the cleaning of luminal endoscopes and TSE prion risk factors there from

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11 patients may have been exposed to fatal disease Creutzfeldt-Jakob Disease CJD Greenville Memorial Hospital

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FDA believes current regulation protects the public from BSE but reopens comment period due to new studies

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Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle -- an update 5 December 2012

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GAO-13-244, Mar 18, 2013 Dietary Supplements FDA May Have Opportunities to Expand Its Use of Reported Health Problems to Oversee Product

From: Terry S. Singeltary Sr.

Sent: Tuesday, March 19, 2013 2:46 PM


Cc: ; ;

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Statement from Agriculture Secretary Tom Vilsack:

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Creutzfeldt Jakob Disease and Human TSE Prion Disease in Washington State, 2006–2011-2012

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Creutzfeldt Jakob Disease Human TSE report update North America, Canada, Mexico, and USDA PRION UNIT as of May 18, 2012

type determination pending Creutzfeldt Jakob Disease (tdpCJD), is on the rise in Canada and the USA

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*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.


OR-10: Variably protease-sensitive prionopathy is transmissible in bank voles

Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1 Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve University; Cleveland, OH USA

Background. Variably protease-sensitive prionopathy (VPSPr) is a recently described “sporadic”neurodegenerative disease involving prion protein aggregation, which has clinical similarities with non-Alzheimer dementias, such as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is the electrophoretic pattern of PrPSc after digestion with proteinase K (PK). After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern similar to that described in GSS cases. The clinical and pathological features of VPSPr raised the question of the correct classification of VPSPr among prion diseases or other forms of neurodegenerative disorders. Here we report preliminary data on the transmissibility and pathological features of VPSPr cases in bank voles.

Materials and Methods. Seven VPSPr cases were inoculated in two genetic lines of bank voles, carrying either methionine or isoleucine at codon 109 of the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical diagnosis in voles was confirmed by brain pathological assessment and western blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.

Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission in BvM109. Overall, 3 voles were positive with survival time between 290 and 588 d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form of the typical PrP27–30, which was indistinguishable to that previously observed in BvM109 inoculated with sCJDMM1 cases.

In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until now. Overall, 5 voles were positive with survival time between 281 and 596 d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern, characterized by low molecular weight PrPres. These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus and the N-terminus. Second passages are in progress from these first successful transmissions.

Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109.

The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.

Wednesday, March 28, 2012


Thursday, April 4, 2013

Variably protease-sensitive prionopathy in the UK: a retrospective review 1991–2008

Brain (2013) 136 (4): 1102-1115. doi: 10.1093/brain/aws366

Sunday, March 31, 2013

Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years old, shall we pray


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