Research Paper
Difference of geographic distributions of the Chinese patients with prion diseases in the permanent resident places and referring places
Kang Xiao, Ming-Fan Pang, Yue-Qiao Zhao, Li-Ping Gao, Yue-Zhang Wu, Yuan Wang, show all Pages 58-65 | Received 08 Nov 2021, Accepted 13 May 2022, Published online: 30 May 2022
ABSTRACT
Human prion diseases (PrDs) are a group of transmissible neurodegenerative diseases that can be clarified as sporadic, genetic and iatrogenic forms. In this study, we have analysed the time and geographic distributions of 2011 PrD cases diagnosed by China National Surveillance for Creutzfeldt-Jakob disease (CNS-CJD) since 2006, including 1792 sporadic CJD (sCJD) cases and 219 gPrD cases. Apparently, the cases numbers of both sCJD and gPrD increased along with the surveillance years, showing a stepping up every five years. The geographic distributions of the PrDs cases based on the permanent residences were wide, distributing in 30 out of 31 provincial-level administrative divisions in Chinese mainland. However, the case numbers in the provincial level varied largely. The provinces in the eastern part of China had much more cases than those in the western part. Normalized the case numbers with the total population each province revealed higher incidences in six provinces. Further, the resident and referring places of all PrD cases were analysed, illustrating a clear concentrating pattern of referring in the large metropolises. Five provincial-level administrative divisions reported more PrD cases from other provinces than the local ones. Particularly, BJ reported not only more than one-fourth of all PrDs cases in Chinese mainland but also 3.64-fold more PrDs cases from other provinces than its local ones. We believed that good medical resources, well-trained programmes and knowledge of PrDs in the clinicians and the CDC staffs contributed to well-referring PrD cases in those large cities. Snip...
Discussion As a rare disease, less than 10 Chinese PrD or CJD cases had been described in the literatures in 1990ʹs. More and more PrD cases have been identified and diagnosed since 2006 we conducted CNS-CJD, particularly in the past recent years [15,20]. Small numbers of definite sCJD cases and overnumbered probable sCJD cases in CNS-CJD are closely related with the extremely low rate of autopsy in China. Moreover, more and more provinces actively refer PrD cases to CNS-CJD along with the surveillance years. Our data here propose that about half of the provinces in Chinese mainland continually reported PrD cases in the past 10 years. It reflects that the clinical recognition capacity for PrD in Chinese mainland has been improved markedly after the implementation of CNS-CJD. We have noticed the obvious diversity in geographic distribution of the PrD cases based on their permanent addresses among the provinces. The case numbers in the provinces locating at the western part of China are much less. After normalized with the total population of each province, the geographic patterns of PrD cases has changed in a certain degree. More referred cases are concentrated in the large metropolises, such as BJ, SH TJ and CQ, with higher ratio of urban population, better medical resources and economic situation, which is most likely reflecting the wide and good knowledge of PrD among the physicians in those large cities. Our data also figure out that five provincial-level administrative divisions, including BJ, SH, GD, CQ and SN, have referred more cases of PrDs coming from other provinces than those from locals. JL province has referred the same numbers of PrD cases as the local ones. The referred case numbers of the rest provinces in Chinese mainland are less than the local ones. This scenario demonstrates excessive contributions of those five provinces to identifying and referring PrD cases. As the capital of China, BJ city has unparalleled medical resources. Ordinarily, about half of the patients in the large hospitals in BJ come from other provinces [21], particularly the patients of rare and difficult-diagnosed diseases. Previously, we had analysed the CJD surveillance activity in BJ from 2006 to 2013, proposing that the ratio of the diagnosed PrD cases from local and other provinces is 1:3.07 [21]. Such ratio maintains unchanged, even slightly increases, by June 2020 from the data in this study (1:3.65), strongly indicating the continually great role of BJ in the recognition for PrDs in CNS-CJD. On the other point, the PrD cases reported from BJ show a wide geographic distribution covering 28 different provinces, despite of large amount of cases from the neighbour provinces. It reflects that the BJ’s medical system supplies the medical services not only for BJ’s people but also for the people outside of BJ. In addition to BJ, the other four provincial-level administrative divisions (SH, GD, CQ and SH) also contribute more PrD cases from other provinces. Unlike BJ, the outside PrD cases reported from those four provinces mainly locate at the neighbour provinces. Like BJ, SH and CQ are also metropolises with high level of medical resources, making them capable of receiving hundreds of patients from the neighbour provinces. Guangzhou and Xi’an cities are the capital cities of provinces GD and SN, respectively. There are more than two medical universities and dozens of large hospitals in those two large cities. Apparently, good medical resources in the large cities are one of the major elements for identifying and referring PrDs. During the implementation of CNS-CJD, different trainings from clinical to laboratory have been conducted by China CDC almost every surveillance year. The trainees come from both the CDC sections and the department of neurology in hospitals. In some places, e.g., BJ and SH, the provincial-level CDCs have also conducted further PrD trainings to more physicians from local hospitals. We believe that those training programs have enhanced the capacity of the clinicians for PrDs. Actually, the numbers of hospitals referring PrD cases in BJ and SH are much more than the other cities (data not shown). As a huge and developing countries, the medical resources in Chinese mainland is markedly unbalance. Both numbers of referred PrD cases and referring hospitals in the western part of China are less. Further practicable training programs for the staffs in those provinces are critical. Our data here has illustrated the similar profiles in referring sCJD and gPrD cases among the provinces that BJ city has referred more than one-third of all diagnosed gPrD cases in Chinese mainland. Besides of FFI [13,22], other types of gPrDs (gCJD and GSS) usually display undistinguishable clinical manifestations as sCJD, except that the onset-ages of gPrDs are usually young [23,24]. In fact, the vast majority of gCJD and GSS were referred as sCJD before PRNP sequencing. Notably, HA province referred obviously more FFI cases than other provinces, since more than one-third of Chinese FFI cases lived in HA [22]. Good knowledge of FFI possibly makes the local neurologists more sensitive for the patients with unexplainable sleeping problem.
Conclusions According to our study, the cases numbers of both sCJD and gPrD increased along with the surveillance years, with a wide geographic distribution in Chinese mainland. However, the case numbers in the eastern provinces were much more than those in the western provinces. Our study indicated that good medical resources, well training programs and knowledge of PrDs in the clinicians and the CDC staffs contributed to well-referring PrD cases in those large cities.
KEYWORDS: Prion diseaseCreutzfeldt-Jakob diseasesurveillancecase referringgeographic difference
Original Article
Published: 06 September 2021
Genetic Prion Disease: Insight from the Features and Experience of China National Surveillance for Creutzfeldt-Jakob Disease
Qi Shi, Cao Chen, Kang Xiao, Wei Zhou, Li-Ping Gao, Dong-Dong Chen, Yue-Zhang Wu, Yuan Wang, Chao Hu, Chen Gao & Xiao-Ping Dong Neuroscience Bulletin volume 37, pages1570–1582 (2021)Cite this article
Abstract
Human genetic prion diseases (gPrDs) are directly associated with mutations and insertions in the PRNP (Prion Protein) gene. We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020. Nineteen different subtypes were identified and gPrDs accounted for 10.9% of all diagnosed PrDs within the same period. Some subtypes of gPrDs showed a degree of geographic association. The age at onset of Chinese gPrDs peaked in the 50–59 year group. Gerstmann–Sträussler–Scheinker syndrome (GSS) and fatal familial insomnia (FFI) cases usually displayed clinical symptoms earlier than genetic Creutzfeldt–Jakob disease (gCJD) patients with point mutations. A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients. None of the E196A gCJD patients reported a family history. The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD (sCJD). EEG examination was not sensitive for gPrDs. sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients. CSF 14-3-3 positivity was frequently detected in gCJD patients. Increased CSF tau was found in more than half of FFI and T188K gCJD cases, and an even higher proportion of E196A and E200K gCJD patients. 63.6% of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC. GSS and FFI cases had longer durations than most subtypes of gCJD. This is one of the largest studies of gPrDs in East Asians, and the illness profile of Chinese gPrDs is clearly distinct. Extremely high proportions of T188K and E196A occur among Chinese gPrDs; these mutations are rarely reported in Caucasians and Japanese.
Research Article
Analysis of Chinese patients with sporadic Creutzfeldt-Jakob disease
Jing Yang,Haiyan Kuang,Qiong Wang,Jiao Liu,Xueping Chen &Huifang Shang
Pages 137-142 | Received 18 Feb 2020, Accepted 22 Apr 2020, Published online: 07 May 2020
Download citation https://doi.org/10.1080/19336896.2020.1761515
ABSTRACT
Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, incurable, and fatal neurodegenerative disorder. The objective of this study was to describe the clinical features and survival time of Chinese sCJD patients, and to explore the associations between clinical data and survival. In this study, we analysed the clinical data of 21 sCJD patients in a tertiary care hospital and used all Chinese case material available from 152 patients with sCJD in literatures between 2008 and 2018. The mean age of onset of all 173 deceased patients was 61.44 year-olds (y), with the highest incidence in the population of 60 to 69 y. The most common manifestation at disease onset was progressive dementia. With the progression of the disease, the four main clinical symptoms and signs were developed, including myoclonus, visual or cerebella disturbance, pyramidal or extrapyramidal dysfunction, and akinetic mutism. Extrapyramidal symptoms were more frequently observed. The mean survival time was 7.34 months, and 82.10% of cases died within 1 year after disease onset. The follow-up showed that the survival time was longer and the myoclonus sign was more frequently presented in younger-onset sCJD patients. Patients with abnormalities only in cortical regions had a higher frequency of pyramidal dysfunction than patients having lesions in both cortex and basal ganglia. The findings of this study might provide some insight into the clinical characteristics of sCJD patients in China, but further studies could examine the presences of clinical features and survival time in patients with early age of onset in a prospective manner.
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In summary, this study showed the clinical manifestations and survival time of Chinese sCJD patients, and the differences in the survival time between younger-onset and older-onset patients. With the development of the clinical syndrome, younger-onset patients more frequently showed myoclonus sign, and patients having abnormalities only in cortical regions had a higher frequency of pyramidal dysfunction than patients with lesions in both cortex and basal ganglia. The high frequency of myoclonus and prolonged survival time in younger-onset sCJD patients might have some implications for clinical practice, and further studies could examine the presences of clinical features and survival time in patients with different ages of onset in a prospective manner.
Letter to the Editor
Assessment of the Sensitivity and Specificity of the Established Real-time Quaking-induced Conversion (RT-QuIC) Technique in Chinese CJD Surveillance*
XIAO Kang1 , YANG Xue Hua1 , ZOU Wen Quan1 , DONG Xiao Ping1,2,3,# , and SHI Qi1,#
Real-time quaking-induced conversion (RT-QuIC) assay is a newly established PrPSc-detecting method. The development of RT-QuIC improves the diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD), showing good sensitivity and specificity in many countries when the method was used in cerebrospinal fluid (CSF) samples. However, in China, the sensitivity and specificity of RT-QuIC has yet to be determined due to the lack of definitive diagnosis samples. Recently, 30 definitive sCJD and 30 non-CJD diagnoses were evaluated by RT-QuIC assay. In the 30 sCJD CSF samples, 29 showed positive results. By contrast, all the non-CJD samples were negative. The sensitivity and specificity of our RT-QuIC assay were 96.67% and 100%, respectively, and are comparable to other published data. Results can provide a fundamental basis for the usage of RT-QuIC assay in CJD surveillance in China.
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The CSF RT-QuIC reactivities among the sCJD patients show variation[7] . On the basis of the electrophoretic patterns of PrPSc in brains and the polymorphism of codon 129, sCJD can be divided into six different subtypes[8] . Studies have already proposed that compared with MM1 patients, the MM2 subtypes usually have a longer lag time and a lower rfu intensity in CSF RT-QuIC[7] . Coincidentally, the sCJD case that was negative in RT-QuIC was an MM2 subtype. This result is meaningful for Chinese CJD surveillance because absolute majorities of Han Chinese and Chinese sCJD patients are Met/Met homozygotes at codon 129[9] . In other words, the PrPSc subtypes of Chinese sCJD patients should be MM1 and MM2 predominately. The brain PrPSc subtypes of Chinese CJD patients remain unclear due to a limited implementation of brain autopsy and biopsy in China. The PrPSc subtypes of Japanese sCJD patients have been reported to be 56.82% MM1 and 22.73% MM2[10] . Under the assumption that the profiles of PrPSc subtypes among Chinese patients are similar to those of the Japanese, 22.73% of the probable Chinese sCJD patients may display low reactivity and may even test negative in CSF RTQuIC. Combining the data of CSF RT-QuIC and that of other routine clinical and laboratory examinations may help speculate the ratio of MM2 subtypes among the probable sCJD patients in China. Ethics Approval and Consent to Participate This study was approved by the Ethical Committee of National Institute for Viral Disease Control and Prevention, China CDC under protocol 2009ZX10004- 101.
The Features of Genetic Prion Diseases Based on Chinese Surveillance Program
Qi Shi,Wei Zhou,Cao Chen,Bao-Yun Zhang,Kang Xiao,Xiu-Chun Zhang,Xiao-Jing Shen,Qing Li,Li-Quan Deng,Jian-Hua Dong,Wen-Qing Lin,Pu Huang,Wei-Jia Jiang, [ ... ],Xiao-Ping Dong [ view all ]
Published: October 21, 2015
Abstract
Objective
To identify the features of Chinese genetic prion diseases.
Methods
Suspected Creutzfeldt-Jakob disease (CJD) cases that were reported under CJD surveillance were diagnosed and subtyped using the diagnostic criteria issued by the WHO. The general information concerning the patient, their clinical, MRI and EEG data, and the results of CSF 14-3-3 and PRNP sequencing were carefully collected from the database of the national CJD surveillance program and analyzed using the SPSS 11.5 statistical software program.
Results
Since 2006, 69 patients were diagnosed with genetic prion diseases and as having 15 different mutations. The median age of the 69 patients at disease onset was 53.5 years, varying from 19 to 80 years. The majority of patients displaying clinical symptoms were in the 50–59 years of age. FFI, T188K gCJD and E200K were the three most common subtypes. The disease appeared in the family histories of 43.48% of the patients. The clinical manifestations varied considerably among the various diseases. Patients who carried mutations in the N-terminus displayed a younger age of onset, were CSF 14-3-3 negative, had a family history of the condition, and experienced a longer duration of the condition. The clinical courses of T188K were significantly shorter than those of FFI and E200K gCJD, while the symptoms in the FFI group appeared at a younger age and for a longer duration. Moreover, the time intervals between the initial neurologist visit to the final diagnosis were similar among patients with FFI, T188K gCJD, E200K gCJD and other diseases.
Conclusion
The features of Chinese genetic prion diseases are different from those seen in Europe and other Asian countries.
CASE REPORT article
Front. Neurol., 28 July 2020 | https://doi.org/10.3389/fneur.2020.00763
Could Sporadic Creutzfeldt-Jakob Disease Be Underdiagnosed in China? Experience From Four Cases
Yi-Liu Zhang1, Xiao-Mei Wu1, Yang Chen1, Wen-Ping Gu2* and Wei Lu1*
1Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, China
2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
Background: Creutzfeldt-Jakob Disease (CJD) is a rapidly progressive neurodegenerative disease caused by the misfolded version of the cellular prion protein. Here we report four cases of sporadic CJD (sCJD) and describe the diagnostic methods available in order avoid missed or delayed recognition of CJD in China.
Case presentation: We report four patients diagnosed with sCJD between March 2018 and December 2019 at Xiangya Hospital and the Second Xiangya Hospital of Central South University. All patients were admitted to the hospital because of a progressive cognitive decline. Although their routine tests and biochemical indicators in the cerebrospinal fluid (CSF), as well as computed tomography (CT) imaging, did not reveal any apparent abnormalities, the presence of “cortical ribboning” was incidentally found on diffusion-weighted imaging (DWI). The patients were subsequently diagnosed with CJD based on positive testing for 14-3-3 protein in their CSF, and the presence of periodic sharp and slow wave complexes (PSWCs) on their electroencephalograms (EEG). Additionally, two of patients was confirmed pathological examination of cerebral biopsies demonstrating neuronal loss, gliosis, and spongiform changes.
Conclusions: CJD is a rare disease and is easily misdiagnosed by clinician in China due to a lack of recognition and awareness of CJD. Based on our experience described in this report, enhanced vigilance for CJD is required for patients with rapidly progressive dementia in China and other developing countries. DWI, EEG and detection of 14-3-3 protein in CSF should be performed in order to achieve a timely diagnosis of CJD.
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Conclusion
CJD is a rare disease, but the limited availability of more advance diagnostic methods combined with a lack of awareness about CJD in China and other developing countries may be leading to a missed diagnoses, misdiagnoses and low diagnostic rate. New, less invasive and more accessible diagnostic techniques as an alternative to brain biopsy, including EEG, DWI, RT-QuIC, 14-3-3 protein, and other biomarkers, could improve the accuracy of diagnosing prion diseases. We diagnosed four cases within a <2-year period, which alerts us to CJD being a public health concern that requires greater attention. In China, awareness should be generated for patients with rapidly progressive dementia in clinical practice, and patients should be examined by methods such as DWI, testing for 14-3-3 proteins in the CSF, RT-QuIC, and so on, in order to ensure a correct diagnosis.
Published: 18 October 2008
Surveillance for Creutzfeldt-Jakob disease in China from 2006 to 2007
Qi Shi, Chen Gao, Wei Zhou, Bao-Yun Zhang, Jian-Ming Chen, Chan Tian, Hui-Ying Jiang, Jun Han, Ni-Juan Xiang, Xiao-Fang Wang, Yong-Jun Gao & Xiao-Ping Dong
BMC Public Health volume 8, Article number: 360 (2008) Cite this article
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Abstract
Background
Human transmissible spongiform encephalopathies (HTSE), or Creutzfeldt-Jakob disease (CJD), is a group of rare and fatal diseases in central nervous system. Since outbreak of bovine spongiform encephalopathy (BSE) and variant CJD, a worldwide CJD surveillance network has been established under the proposition of WHO. In China, a national CJD surveillance system has started since 2002. The data of CJD surveillance from 2006 to 2007 was analyzed.
Methods
Total 12 provinces are included in CJD surveillance system. The surveillance unit in each province consists of one or two sentinel hospitals and the provincial CDC. All suspected CJD cases reported from CJD surveillance were diagnosed and subtyped based on the diagnostic criteria for CJD issued by WHO.
Results
Total 192 suspected CJD cases were reported and 5 genetic CJD, 51 probable and 30 possible sporadic CJD (sCJD) cases were diagnosed. The collected sCJD cases distribute sporadically without geographical clustering and seasonal relativity and the highest incidences in both probable and possible sCJD cases appeared in the group of 60–69 year. The most common three foremost symptoms were progressive dementia, cerebellum and mental-related symptoms. The probable sCJD patients owning both typical EEG alteration and CSF protein 14-3-3 positive have more characteristic clinical syndromes than the ones having only one positive. The polymorphisms of codon 129 of all tested reported cases shows typical patterns of Han Chinese as previous reports, that M129M are predominant whereas M129V are seldom.
Conclusion
Chinese CJD patients possessed similar epidemiological and clinical characteristics as worldwide.
RESOLUTION No. 17
Recognition of the Bovine Spongiform Encephalopathy Risk Status of Members
3. The Director General publish the following List of Members with zones18 recognised as having a negligible BSE risk in accordance with Chapter 11.4. of the Terrestrial Code: China (People’s Rep. of): a zone designated by the Delegate of China (People’s Rep. of) in a document addressed to the Director General in November 2013, consisting of the People’s Republic of China with the exclusion of Hong Kong and Macau.
Chinese scientist elected chairman of OIE Regional Commission for Asia, the Far East and Oceania Source：MARA Date：2021-05-31 Dr. Huang Baoxu, World Organization for Animal Health (OIE) Delegate from China and a researcher with the China Animal Health and Epidemiology Center (CAHEC), was elected chairman of OIE Regional Commission for Asia, the Far East and Oceania (AFEO) on May 28, 2021.
The 88th General Session of the World Assembly of National Delegates to the OIE was held virtually on May 24–28. The Assembly unanimously approved maintaining the recognition of a negligible bovine spongiform encephalopathy (BES) risk status, and rinderpest-free, contagious bovine pleuropneumonia-free, and African horse sickness-free status for China. The Exotic Disease Watch and Research Center of CAHEC was designated as an OIE African Swine Fever Reference Laboratory. All these signify China’s achievements in animal diseases control are well received by the international community, and China’s research and diagnostic capabilities are up to globally advanced level.
The OIE’s recognition is of great significance in increasing China’s voice in animal health and enabling China’s leading role in the region. It will also boost the process of standard-setting and sound development of veterinary service in China.
The OIE, an intergovernmental organization, plays an important role in global animal health and food safety. Its animal health standards are recognized as international standards or guidelines by the Agreement on the Application of Sanitary and Phytosanitary Measures (SPS measures) of the World Trade Organization. The OIE has set up five regional commissions to coordinate and promote cooperation among its members, and address policy and technical issues related with animal diseases control in respective region.
No.11 Nongzhanguan Nanli,Chaoyang District,Beijing China (100125)
PEOPLE’S REPUBLIC OF CHINA ("CHINA")
Questions from the United States to China
concerning Sanitary and Phytosanitary Measures
The following communication, dated 2 October 2009, is being circulated at the request of the Delegation of the United States. _______________
Restrictions on trade in beef
1. China continues to impose bovine spongiform encephalopathy (BSE) related restrictions on imports of beef and beef products from the United States, contrary to the guidelines of the World Organization for Animal Health (OIE) . The OIE classified the United States as "controlled risk" for BSE in May 2007. The OIE Code provides for conditions under which beef and beef products can be safely traded from all countries. In the case of "controlled risk" countries, the OIE recognizes that trade in beef and beef products and cattle of all ages from a "controlled risk" country is safe, provided that certain slaughter and beef processing conditions are met, including the removal of appropriate specified risk materials (SRMs) in a manner that avoids cross-contamination of meat. The United States has satisfied these conditions by taking the following steps to mitigate BSE risk: (a) appropriate removal of SRMs; (b) implementation of an appropriate feed ban that has been effectively enforced; (c) an active surveillance program that has exceeded OIE requirements, and (d) thorough epidemiological investigations of all BSE cases. Since the May 2007 OIE classification of the United States as a "controlled risk" country, the governments of Canada, the Philippines, Indonesia, Malaysia, Ghana, Costa Rica and Belize, among others, have opened their markets to the full range of US beef and beef products consistent with OIE guidelines, recognizing that US BSE measures are effective. To date, however, China has only offered to accept products from animals that are under 30 months of age.
(a) In connection with last year’s transitional review before this Committee, the United States asked China whether it had performed a risk assessment relevant to its BSE-related restrictions on imports of beef and beef products from the United States. China stated that it had "conducted the necessary risk assessments on beef imported from the United States and there had been many technical communications on numerous occasions". However, no additional information was provided. Please provide additional information on the risk assessment, including an explanation of how that risk assessment supports the measures that China is applying to US-origin beef and beef products.
(b) Please explain China’s plans for opening its market to the full range of US beef and beef products consistent with OIE guidelines.
BSE-related restrictions on other products
2. China continues to impose additional BSE-related import restrictions on protein-free tallow. The OIE’s BSE chapter specifies that protein-free tallow should be traded regardless of the BSE status of the exporting country without BSE-related restrictions. However, China continues to insist that the United States certify that the tallow not be processed from certain SRMs, and that certain tallow processing methods commonly used in the United States be prohibited. Additionally, China insists that the United States certify that materials used to produce tallow were not sourced from farms where a BSE-positive animal has been detected. China’s position is not aligned with OIE guidelines and has effectively blocked imports of US-origin protein-free tallow. The United States has provided China with several quantitative risk assessments that demonstrate that any BSE-related risks associated with protein-free tallow are too small to calculate.
(a) In connection with last year’s transitional review before this Committee, the United States asked China whether it had performed a risk assessment relevant to its BSE-related restrictions on imports of protein-free tallow from the United States. At last year’s transitional review before this Committee, China stated that it had "conducted the necessary risk assessments on beef imported from the United States and there had been many technical communications on numerous occasions". However, no additional information was provided, and China’s response was unclear as to whether it has also conducted a risk assessment relevant to protein-free tallow. Please provide additional information on any risk assessment that China has conducted which is relevant to its BSE-related restrictions on imports of US-origin protein-free tallow.
2.2.2. Maintenance of a negligible BSE risk status The OIE Status Department reviewed all annual reconfirmations for negligible BSE risk status including those in section 2.1. and reported the outcome of its analysis to the Commission.
11 A zone designated by the Delegate of China in a document addressed to the Director General in November 2013, consisting of the People’s Republic of China with the exclusion of Hong Kong and Macau.
Scrapie, CWD, TSE, Prion, China ???
ORIGINAL ARTICLE
Open Access
Concordance of CSF RT-QuIC across the European Creutzfeldt-Jakob Disease surveillance network
Neil McKenzie,Gabriele Piconi,Audrey Culeux,Anna-Lena Hammarin,Christos Stergiou,Socrates Tzartos,Alexandra A. M. Versleijen,Jacqueline van de Geer,Patrick Cras,Franco Cardone,Anna Ladogana,Angela Mammana,Marcello Rossi,Matilde Bongianni,Daniela Perra,Guenther Regelsberger,Sigrid Klotz,Simone Horneman,Adriano Aguzzi,Schmitz Matthias,Mary Andrews,Kimberley Burns,Stéphane Haïk,Raquel Ruiz-García,Jenny Verner-Carlsson,John Tzartos,Marcel M. Verbeek,Bart De Vil,Anna Poleggi,Piero Parchi,Gianluigi Zanusso,Ellen Gelpi,Karl Frontzek,Regina Reiman,Peter Hermann,Inga Zerr,Suvankar Pal,Alison Green …
First published: 07 May 2022 https://doi.org/10.1111/ene.15387
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi:10.1111/ene.15387
Background
Cerebrospinal fluid (CSF) Real Time-Quaking Induced Conversion (RT-QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt-Jakob Disease (sCJD) and this has led to it being included in revised European CJD Surveillance network diagnostic criteria for sCJD. As CSF RT-QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring-trial was to ascertain the degree of concordance between European countries undertaking CSF RT-QuIC.
Methods
Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non-CJD cases, were sent to 13 laboratories from 11 countries for RT-QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative.
Results
All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories; one had a disease duration greater than 26 months with a negative 14-3-3, whilst the remaining case had a 4 month disease duration and a positive 14-3-3. A single false positive CSF RT-QuIC result was observed in this study.
Conclusions
This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, rPrP substrates and CSF volumes. We recommend the adoption of CSF RT-QuIC by all CJD surveillance centres.
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Conclusions:
CSF RT-QuIC has been incorporated in the diagnostic criteria since Jan 2017 but has not been uniformly adopted by all surveillance centres . Many studies have shown that CSF RT-QuIC is a very accurate test for sCJD with a high degree of sensitivity and specificity. This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, different rPrP substrates and a range of CSF volumes to seed the reaction. We recommend the adoption of CSF RT-QuIC by all CJD surveillance centres.
References: snip...see full text;
***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***
Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.
https://www.nature.com/articles/srep11573
O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases).
Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases.
We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic cases***
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***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
==============
https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice.
***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.
***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20
Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases).
Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases.
We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic cases***
===============
***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
==============
https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf
***Transmission data also revealed that several scrapie prions propagate in HuPrP-Tg mice with efficiency comparable to that of cattle BSE. While the efficiency of transmission at primary passage was low, subsequent passages resulted in a highly virulent prion disease in both Met129 and Val129 mice.
***Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.
***These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20
PRION 2016 TOKYO
Saturday, April 23, 2016
SCRAPIE WS-01: Prion diseases in animals and zoonotic potential 2016
Prion. 10:S15-S21. 2016 ISSN: 1933-6896 printl 1933-690X online
Taylor & Francis
Prion 2016 Animal Prion Disease Workshop Abstracts
WS-01: Prion diseases in animals and zoonotic potential
Transmission of the different scrapie isolates in these mice leads to the emergence of prion strain phenotypes that showed similar characteristics to those displayed by MM1 or VV2 sCJD prion.
These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.
http://www.tandfonline.com/doi/abs/10.1080/19336896.2016.1163048?journalCode=kprn20
Title: Transmission of scrapie prions to primate after an extended silent incubation period)
*** In complement to the recent demonstration that humanized mice are susceptible to scrapie, we report here the first observation of direct transmission of a natural classical scrapie isolate to a macaque after a 10-year incubation period. Neuropathologic examination revealed all of the features of a prion disease: spongiform change, neuronal loss, and accumulation of PrPres throughout the CNS.
*** This observation strengthens the questioning of the harmlessness of scrapie to humans, at a time when protective measures for human and animal health are being dismantled and reduced as c-BSE is considered controlled and being eradicated.
*** Our results underscore the importance of precautionary and protective measures and the necessity for long-term experimental transmission studies to assess the zoonotic potential of other animal prion strains.
http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=313160
GAME FARM INDUSTRY WANTS TO COVER UP FINDINGS OF INCREASE RISK TO CJD FROM CERVID
BSE INQUIRY
CJD9/10022
October 1994
Mr R.N. Elmhirst Chairman British Deer Farmers Association Holly Lodge Spencers Lane
BerksWell Coventry CV7 7BZ
Dear Mr Elmhirst,
CREUTZFELDT-JAKOB DISEASE (CJD) SURVEILLANCE UNIT REPORT
Thank you for your recent letter concerning the publication of the third annual report from the CJD Surveillance Unit. I am sorry that you are dissatisfied with the way in which this report was published.
The Surveillance Unit is a completely independant outside body and the Department of Health is committed to publishing their reports as soon as they become available. In the circumstances it is not the practice to circulate the report for comment since the findings of the report would not be amended.. In future we can ensure that the British Deer Farmers Association receives a copy of the report in advance of publication.
The Chief Medical Officer has undertaken to keep the public fully informed of the results of any research in respect of CJD. This report was entirely the work of the unit and was produced completely independantly of the the Department.
The statistical results regarding the consumption of venison was put into perspective in the body of the report and was not mentioned at all in the press release. Media attention regarding this report was low key but gave a realistic presentation of the statistical findings of the Unit. This approach to publication was successful in that consumption of venison was highlighted only once by the media ie. in the News at one television proqramme.
I believe that a further statement about the report, or indeed statistical links between CJD and consumption of venison, would increase, and quite possibly give damaging credence, to the whole issue. From the low key media reports of which I am aware it seems unlikely that venison consumption will suffer adversely, if at all.
http://web.archive.org/web/20030511010117/http://www.bseinquiry.gov.uk/files/yb/1994/10/00003001.pdf
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasized by the finding that some strains of scrapie produce lesions identical to the once which characterize the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the scrapie problem urgent if the sheep industry is not to suffer grievously.
snip...
76/10.12/4.6
IN CONFIDENCE
SCRAPIE TRANSMISSION TO CHIMPANZEES
IN CONFIDENCE
reference...
RB3.20
TRANSMISSION TO CHIMPANZEES
1. Kuru and CJD have been successfully transmitted to chimpanzees but scrapie and TME have not.
2. We cannot say that scrapie will not transmit to chimpanzees. There are several scrapie strains and I am not aware that all have been tried (that would have to be from mouse passaged material). Nor has a wide enough range of field isolates subsequently strain typed in mice been inoculated by the appropriate routes (i/c, ilp and i/v) :
3. I believe the proposed experiment to determine transmissibility, if conducted, would only show the susceptibility or resistance of the chimpanzee to infection/disease by the routes used and the result could not be interpreted for the predictability of the susceptibility for man. Proposals for prolonged oral exposure of chimpanzees to milk from cattle were suggested a long while ago and rejected.
4. In view of Dr Gibbs' probable use of chimpazees Mr Wells' comments (enclosed) are pertinent. I have yet to receive a direct communication from Dr Schellekers but before any collaboration or provision of material we should identify the Gibbs' proposals and objectives.
5. A positive result from a chimpanzee challenged severely would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
6. A negative result would take a lifetime to determine but that would be a shorter period than might be available for human exposure and it would still not answer the question regarding mans' susceptibility. In the meantime no doubt the negativity would be used defensively. It would however be counterproductive if the experiment finally became positive. We may learn more about public reactions following next Monday' s meeting.
R. Bradley
23 September 1990
CVO (+Mr Wells' comments)
Dr T W A Little
Dr B J Shreeve
90/9.23/1.1.
http://web.archive.org/web/20090506041740/http://www.bseinquiry.gov.uk/files/yb/1990/09/23001001.pdf
IN CONFIDENCE CHIMPANZEES
CODE 18-77 Reference RB3.46
Some further information that may assist in decision making has been gained by discussion with Dr Rosalind Ridley.
She says that careful study of Gajdusek's work shows no increased susceptibility of chimpanzees over New World Monkeys such as Squirrel Monkeys. She does not think it would tell you anything about the susceptibility to man. Also Gajdusek did not, she believes, challenge chimpanzees with scrapie as severely as we did pigs and we know little of that source of scrapie. Comparisons would be difficult. She also would not expect the Home Office to sanction such experiments here unless there was a very clear and important objective that would be important for human health protection. She doubted such a case could be made. If this is the case she thought it would be unethical to do an experiment abroad because we could not do it in our own country.
Retrospectively she feels they should have put up more marmosets than they did. They all remain healthy. They would normally regard the transmission as negative if no disease resulted in five years.
We are not being asked for a decision but I think that before we made one we should gain as much knowledge as we can. If we decided to proceed we would have to bear any criticisms for many years if there was an adverse view by scientists or media. This should not be undertaken lightly. There is already some adverse comment here, I gather, on the pig experiment though that will subside.
The Gibbs' (as' distinct from Schellekers') study is somewhat different. We are merely supplying material for comparative studies in a laboratory with the greatest experience of human SEs in the world and it has been sanctioned by USDA (though we do not know for certain yet if chimpanzees specifically will be used). This would keep it at a lower profile than if we conducted such an experiment in the UK or Europe.
I consider we must have very powerful and defendable objectives to go beyond Gibbs' proposed experiments and should not initiate others just because an offer has been made.
Scientists have a responsibility to seek other methods of investigative research other than animal experimentation. At present no objective has convinced me we need to do research using Chimpanzees - a species in need of protection. Resisting such proposals would enable us to communicate that information to the scientist and the public should the need arise. A line would have been drawn.
CVO cc Dr T Dr B W A Little Dr B J Shreeve
R Bradley
26 September 1990
90/9.26/3.2
http://web.archive.org/web/20090506041605/http://www.bseinquiry.gov.uk/files/yb/1990/09/26003001.pdf
this is tse prion political theater here, i.e. what i call TSE PRION POKER...tss
3. Prof. A. Robertson gave a brief account of BSE. The US approach was to accord it a very low profile indeed. Dr. A Thiermann showed the picture in the ''Independent'' with cattle being incinerated and thought this was a fanatical incident to be avoided in the US at all costs.
snip...
PAGE 26
Transmission Studies
Mule deer transmissions of CWD were by intracerebral inoculation and compared with natural cases {the following was written but with a single line marked through it ''first passage (by this route)}....TSS
resulted in a more rapidly progressive clinical disease with repeated episodes of synocopy ending in coma. One control animal became affected, it is believed through contamination of inoculum (?saline). Further CWD transmissions were carried out by Dick Marsh into ferret, mink and squirrel monkey. Transmission occurred in ALL of these species with the shortest incubation period in the ferret.
The occurrence of CWD must be viewed against the contest of the locations in which it occurred. It was an incidental and unwelcome complication of the respective wildlife research programmes. Despite its subsequent recognition as a new disease of cervids, therefore justifying direct investigation, no specific research funding was forthcoming. The USDA viewed it as a wildlife problem and consequently not their province! ...page 26.
snip...see;
IN CONFIDENCE
PERCEPTIONS OF UNCONVENTIONAL SLOW VIRUS DISEASE OF ANIMALS IN THE USA
GAH WELLS
REPORT OF A VISIT TO THE USA
APRIL-MAY 1989
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man.
***> I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough.
***> Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
snip...
Sunday, January 10, 2021
APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087] Singeltary Submission June 17, 2019
APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087] Singeltary Submission
Greetings APHIS et al,
I would kindly like to comment on APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087], and my comments are as follows, with the latest peer review and transmission studies as references of evidence.
THE OIE/USDA BSE Minimal Risk Region MRR is nothing more than free pass to import and export the Transmissible Spongiform Encephalopathy TSE Prion disease. December 2003, when the USDA et al lost it's supposedly 'GOLD CARD' ie BSE FREE STATUS (that was based on nothing more than not looking and not finding BSE), once the USA lost it's gold card BSE Free status, the USDA OIE et al worked hard and fast to change the BSE Geographical Risk Statuses i.e. the BSE GBR's, and replaced it with the BSE MRR policy, the legal tool to trade mad cow type disease TSE Prion Globally. The USA is doing just what the UK did, when they shipped mad cow disease around the world, except with the BSE MRR policy, it's now legal.
Also, the whole concept of the BSE MRR policy is based on a false pretense, that atypical BSE is not transmissible, and that only typical c-BSE is transmissible via feed. This notion that atypical BSE TSE Prion is an old age cow disease that is not infectious is absolutely false, there is NO science to show this, and on the contrary, we now know that atypical BSE will transmit by ORAL ROUTES, but even much more concerning now, recent science has shown that Chronic Wasting Disease CWD TSE Prion in deer and elk which is rampant with no stopping is sight in the USA, and Scrapie TSE Prion in sheep and goat, will transmit to PIGS by oral routes, this is our worst nightmare, showing even more risk factors for the USA FDA PART 589 TSE PRION FEED ban.
The FDA PART 589 TSE PRION FEED ban has failed terribly bad, and is still failing, since August 1997. there is tonnage and tonnage of banned potential mad cow feed that went into commerce, and still is, with one decade, 10 YEARS, post August 1997 FDA PART 589 TSE PRION FEED ban, 2007, with 10,000,000 POUNDS, with REASON, Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement. you can see all these feed ban warning letters and tonnage of mad cow feed in commerce, year after year, that is not accessible on the internet anymore like it use to be, you can see history of the FDA failure August 1997 FDA PART 589 TSE PRION FEED ban here, but remember this, we have a new outbreak of TSE Prion disease in a new livestock species, the camel, and this too is very worrisome.
WITH the OIE and the USDA et al weakening the global TSE prion surveillance, by not classifying the atypical Scrapie as TSE Prion disease, and the notion that they want to do the same thing with typical scrapie and atypical BSE, it's just not scientific.
WE MUST abolish the BSE MRR policy, go back to the BSE GBR risk assessments by country, and enhance them to include all strains of TSE Prion disease in all species. With Chronic Wasting CWD TSE Prion disease spreading in Europe, now including, Norway, Finland, Sweden, also in Korea, Canada and the USA, and the TSE Prion in Camels, the fact the the USA is feeding potentially CWD, Scrapie, BSE, typical and atypical, to other animals, and shipping both this feed and or live animals or even grains around the globe, potentially exposed or infected with the TSE Prion. this APHIS Concurrence With OIE Risk Designation for Bovine Spongiform Encephalopathy [Docket No. APHIS-2018-0087], under it's present definition, does NOT show the true risk of the TSE Prion in any country. as i said, it's nothing more than a legal tool to trade the TSE Prion around the globe, nothing but ink on paper.
AS long as the BSE MRR policy stays in effect, TSE Prion disease will continued to be bought and sold as food for both humans and animals around the globe, and the future ramifications from friendly fire there from, i.e. iatrogenic exposure and transmission there from from all of the above, should not be underestimated. ...
Control of Chronic Wasting Disease OMB Control Number: 0579-0189 APHIS-2021-0004 Singeltary Submission
Docket No. APHIS-2018-0011 Chronic Wasting Disease Herd Certification
*** The potential impact of prion diseases on human health was greatly magnified by the recognition that interspecies transfer of BSE to humans by beef ingestion resulted in vCJD. While changes in animal feed constituents and slaughter practices appear to have curtailed vCJD, there is concern that CWD of free-ranging deer and elk in the U.S. might also cross the species barrier. Thus, consuming venison could be a source of human prion disease. Whether BSE and CWD represent interspecies scrapie transfer or are newly arisen prion diseases is unknown. Therefore, the possibility of transmission of prion disease through other food animals cannot be ruled out. There is evidence that vCJD can be transmitted through blood transfusion. There is likely a pool of unknown size of asymptomatic individuals infected with vCJD, and there may be asymptomatic individuals infected with the CWD equivalent. ***These circumstances represent a potential threat to blood, blood products, and plasma supplies.
Published: 06 September 2021
***> Chronic wasting disease: a cervid prion infection looming to spillover
Alicia Otero, Camilo Duque Velásquez, Judd Aiken & Debbie McKenzie
Veterinary Research volume 52, Article number: 115 (2021)
Terry S. Singeltary Sr.