CREUTZFELDT JAKOB DISEASE: Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease

Subject: Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease

Of Grave Concern

Clare Fraser

Affiliations

Macquarie University Hospital, Sydney, Australia Save Sight Institute, University of Sydney, Australia

Corresponding author: Dr. Clare Fraser, Macquarie Ophthalmology, Suite 401, 2 Technology Place, Macquarie University, NSW, Australia.

Simon Taylor

Affiliations Macquarie University Hospital, Sydney, Australia Save Sight Institute, University of Sydney, Australia , FRANZCO

Kate Reid Affiliations The Canberra Hospital, Canberra, Australia , FRANZCO

Omar Ahmad Affiliations Macquarie University Hospital, Sydney, Australia , FRCAP

Mark L. Moster Affiliations Wills Eye Hospital and Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA , MD

DOI: http://dx.doi.org/10.1016/j.survophthal.2015.12.009

Publication History

Published Online: December 29, 2015Accepted: December 22, 2015; Received: December 21, 2015

Abstract

A 73-year-old woman presented with vision loss and recurrent proptosis with conjunctival chemosis 4 weeks after an uncomplicated fat-only orbital decompression for thyroid eye disease. Her Graves disease was biochemically “burnt out,” and she had diabetes mellitus. Initial neuro-imaging showed a straightened optic nerve and orbital apex fat streaking so a bilateral bony decompression of the orbital apex was performed for presumed compressive optic neuropathy. Vision failed to improve, and she experienced cognitive decline. She described metamorphopsia and insomnia. Examination showed a hemi-field loss of red sensitivity, difficulties with higher visual processing, and memory problems. Occipital cortical ribboning was seen on diffusion weighted MRI, CSF was positive for 14-3-3, and her EEG showed periodic complexes. A diagnosis of the Heidenhain variant of Creutzfeldt-Jakob disease was made. She became akinetic and mute, dying a few months later.

Key words: thyroid eye disease, proptosis, compressive optic neuropathy, visual fields, higher visual processing, Creutzfeldt Jacob Disease, Heidenhain variant, spongiform encephalopathy

http://www.surveyophthalmol.com/article/S0039-6257(15)30078-3/abstract

Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings

Article type: Research Article

Affiliations: [a] Dipartimento di Scienze Biomediche e Neuromotorie (DiBiNeM), Università di Bologna, Bologna, Italy | [b] IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy | [c] Dipartimento di Biologica Cellulare e Neuroscienze, Istituto Superiore di Sanità, Roma, Italy | [d] UOC di Neurologia, Ospedale Morgagni-Pierantoni, Forlì, Italy | [e] UOC di Neurologia, Ospedale Ramazzini, Carpi, Italy

Correspondence: [*] Correspondence to: Prof. Piero Parchi, MD, PhD, IRCCS Istituto delle Scienze Neurologiche, Via Altura 3, 40139 Bologna, Italy. Tel.: +39 051 4966740; Fax: +39 051 4966208; E-mail: piero.parchi@unibo.it.

Abstract: The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9% ) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-waved complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).

Keywords: Dementia, molecular typing, neurodegenerative diseases, occipital cortex, prion diseases, prion protein

DOI: 10.3233/JAD-150668

Journal: Journal of Alzheimer's Disease, vol. Preprint, no. Preprint, pp. 1-12, 2015

Accepted 21 October 2015 | Published 1 December 2015

http://content.iospress.com/articles/journal-of-alzheimers-disease/jad150668

Subject: visual variant of Alzheimer’s disease VVAD vs Heidenhain Variant Creutzfeldt Jakob Disease hvCJD

Research article

Visual signs and symptoms in patients with the visual variant of Alzheimer disease

Pierre-François Kaeser1, Joseph Ghika2 and François-Xavier Borruat1*

* Corresponding author: François-Xavier Borruat francois.borruat@fa2.ch

Author Affiliations

1 Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Avenue de France 15, Lausanne, CH-1004, Switzerland

2 Department of Neurology, University of Lausanne, CHUV, Lausanne, Switzerland

For all author emails, please log on.

BMC Ophthalmology 2015, 15:65 doi:10.1186/s12886-015-0060-9

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1471-2415/15/65

Received: 11 July 2014 Accepted: 19 June 2015 Published: 30 June 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Abstract Background

Prominent visual symptoms can present in the visual variant of Alzheimer’s disease (VVAD). Ophthalmologists have a significant role to play in the early diagnosis of VVAD.

Methods

We retrospectively reviewed the files of ten consecutive patients diagnosed with VVAD. All patients had a full neuro-ophthalmologic examination, a formal neurological and neuro-psychological testing, and cerebral MRI to confirm diagnosis. In addition, functional neuroimaging was obtained in seven patients.

Results

The common primary symptom at presentation with all patients was difficulty with near vision (reading difficulty n = 8, “visual blur” in near vision n = 2), and difficulty writing (n = 3). Following assessment, impaired reading and writing skills were evident in 9/10 and 8/10 patients respectively. Median distance visual acuity was 20/25 and at near the median visual acuity was J6. Partial homonymous visual field defect was detected in 80 % (8/10) of the patients. Color vision was impaired in all patients when tested with Ishihara pseudoisochromatic plates, but simple color naming was normal in 8/9 tested patients. Simultanagnosia was present in 8/10 patients. Vision dysfunction corresponded with cerebral MRI findings where parieto-occipital cortical atrophy was observed in all patients. PET scan (5 patients) or SPECT (2 patients) revealed parieto-occipital dysfunction (hypometabolism or hypoperfusion) in all 7 tested patients

Conclusions

Visual difficulties are prominent in VVAD. Dyslexia, incomplete homonymous hemianopia, preserved color identification with abnormal color vision on Ishihara, and simultanagnosia were all symptoms observed frequently in this patient series. Ophthalmologists should be aware of the possibility of neurodegenerative disorders such as VVAD in patients with unexplained visual complaints, in particular reading difficulties.

Keywords: Alzheimer; Reading difficulty; Homonymous hemianopsia; Simultanagnosia

http://www.biomedcentral.com/1471-2415/15/65

Journal of Neuro-Ophthalmology: March 2014 - Volume 34 - Issue 1 - p 4–9 doi: 10.1097/WNO.0b013e3182916155

Original Contribution

The Heidenhain Variant of Creutzfeldt-Jakob Disease—A Case Series

Parker, Sarah E. MD; Gujrati, Meena MD; Pula, John H. MD; Zallek, Sarah N. MD; Kattah, Jorge C. MD

Supplemental Author Material Collapse Box Abstract Background: To study the neuro-ophthalmologic characteristics of patients with the visual variant of Creuztfeldt-Jakob disease (CJD) predominantly affecting the occipital and parietal lobes, known as the Heidenhain variant (HvCJD). The initial symptoms and findings may overlap with other posterior cerebral degenerative disorders. We reviewed our experience with HvCJD including clinical course and results of neuroimaging, electroencephalography (EEG), and cerebrospinal fluid (CSF) studies. Neuropathological postmortem findings were reviewed when available to confirm the clinical impression.

Methods: Retrospective study of HvCJD patients examined in the past 15 years at a single tertiary referral university hospital. Rapid rate of visual and neurological deterioration and abnormal diffusion-weighted imaging (DWI) were characteristic for HvCJD.

Results: Three patients displayed abnormalities in DWI, EEG, and CSF and had rapid clinical progression, leading to a clinical diagnosis of HvCJD. None underwent diagnostic cerebral biopsy. In 2 patients, the diagnosis of sporadic CJD was confirmed by postmortem neuropathologic, immunohistochemical, and genetic studies.

Conclusions: The gold standard for establishing the diagnosis of HvCJD is based on the characteristic histopathologic findings and molecular confirmation. Concern with potential iatrogenic CJD, related to surgical instrumentation or operating room prion contamination, has limited the availability of confirmatory brain biopsy. Our case series illustrates how the combination of clinical neuroimaging and EEG studies and 14:3:3 protein and other neuronal protein marker levels can lead to the diagnosis of HvCJD. Immunohistochemical analysis and genetic testing at a specialized prion research center will assist in identifying the sporadic variant and genetic forms of CJD.

SNIP...

DISCUSSION

In 1998, Benson et al (11) described PCD as an unusual neurodegenerative disorder involving the posterior parietal and occipital lobes. Neuropathologic findings in PCD include senile plaques and neurofibrillary tangles, typical for Alzheimer disease in the majority of cases (7–9). Less frequently, subcortical gliosis as a variant of Pick disease and spongiform changes, neuronal loss and gliosis due to prion infection were reported (9). However, epidemiologic data are lacking. Clinical findings in PCD and HvCJD include combinations of visual field defects, cortical blindness, dyschromatopsia, visual agnosia, alexia, prosopagnosia, palinopsia, optical anosognosia, Balint and Gertsmann syndrome (12–16). Between 1998 and 2012, we evaluated 10 patients with PCD; 3 had sporadic HvCJD who were followed until their death. We are uncertain about the etiology in the remaining 7 patients who developed either a slowly progressive dementia (evolving over several years) and are still alive or were lost to follow-up. The largest published series of the HvCJD included 34 pathologically confirmed cases over a 51-month period (6). This study from the University of Göttingen in Germany is the geographic base of the “German National Creutzfeldt-Jakob Disease Surveillance Study.” Clinical findings were available in 25 cases and consisted of a combination of visual loss and higher visual deficits as found in previous studies. The rate of neurological deterioration was faster in the HvCJD group compared with other CJD variants and did not correlate with location or extent of neuropathologic findings. Homozygosis for methionine in codon 129, identified in 2 of our patients, was noted as a possible genetic indicator of an aggressive clinical course. We evaluated our patients by applying the diagnostic criteria used by Kropp et al (6) and endorsed by the World Health Organization (Table 1). Neuroimaging findings showed subtle increased intensity in the parieto-occipital region on T2 and FLAIR images only in case 2. Yet all 3 patients had striking visual deficits on examination. Therefore, HvCJD should be considered in any patient with visual field loss and a normal MRI or when imaging abnormalities fail to explain the clinical findings (15). Our imaging protocol included diffusion-weighted imaging (DWI) sequences (12,16). Restricted diffusion involving the gyri of the parieto-occipital cortex was observed in 2 of our cases (Fig. 3). The third patient (Case 2) was evaluated before the incorporation of DWI sequences in the MRI protocol at our institution. DWI was the most helpful ancillary test supporting the diagnosis of HvCJD, and to our knowledge, other PCD variants usually are not associated with DWI changes. Graphic Table 1

Initial EEG results showed nonspecific focal or generalized slowing, but follow-up EEG showed periodic sharp waves (Fig. 2) characteristic of CJD in later stages, correlating with the presence of myoclonus. SPECT scanning confirmed occipital hypoperfusion in one of our cases and should be part of PCD evaluation. SPECT largely has been replaced by PET that demonstrates focal cerebral hypometabolism in PCD (13,17). An important characteristic observation suggesting HvCJD in our patients was rapid clinical deterioration. The initial HvCJD diagnosis in Case 1 was supported by progressive neurological deterioration over 10 weeks after the onset of visual symptoms. Our other 2 patients were evaluated at an earlier stage of disease and were scheduled for additional testing over several days. Both patients failed to keep their 2-week follow-up appointments, and contact with their families revealed that they experienced rapid neurological deterioration with inability to perform activities of daily living. This prompted us to perform house calls to complete neurological evaluation and discussion with the family. Markers of massive neuronal loss (14:3:3 protein and neuronal-specific enolase) were elevated in 2 of our cases. These markers are deemed highly specific and sensitive (1). Their value must be interpreted with caution in individual cases, as increased neuronal protein levels (false positives) may be found in other rapidly progressive dementias and potential PCD mimics including autoimmune and paraneoplastic encephalitis, nonconvulsive status epilepticus, intravascular lymphoma, and vasculitis (2,5). Although characteristic histopathology of CJD remains the gold standard in establishing the diagnosis, the risk of instrument or surgical suite prion contamination during brain biopsy has limited the availability of brain biopsy (10). Until a specific serum or CSF prion marker is available, the premortem diagnosis of HvCJD in a patient with PCD continues to rely on close clinical monitoring, neuroimaging testing, serial EEG, and elevated CSF markers (18,19). We strongly recommend that specimens be sent to the National Prion Research Center at Case Western Reserve University in Cleveland, OH, and similar prion research centers for confirmatory, cerebral histopathology, immunohistochemical staining of abnormal protease-resistant prion protein, and genetic testing. This testing protocol establishes the diagnosis of sporadic, variant, and genetic forms of CJD and hopefully will prevent delay in establishing the correct diagnosis (20). In vitro, anti-prion agents have been found effective in controlling prion growth and progression. Unfortunately, these agents have failed to cure or slow CJD infection in humans (21–23).

http://journals.lww.com/jneuro-ophthalmology/pages/articleviewer.aspx?year=2014&issue=03000&article=00003&type=abstract

P07 Behavioral Neurology: Aging and Dementia MRI More Useful Than PET for Diagnosis of Heidenhain Variant Creutzfeldt-Jacob Disease (P07.163)

Jonathan Beary1 and Edward Manno2 1 General Neurology, Neurological Institute Cleveland Clinic Cleveland OH 2 Cerebrovascular Neurology, Neurological Institute Cleveland Clinic Cleveland OH

OBJECTIVE: To demonstrate that MRI detection of subtle focal cortical abnormalities can prove more useful than positron emission tomography (PET) in the diagnosis of Heidenhain variant Creutzfeldt-Jakob Disease (hvCJD).

BACKGROUND: hvCJD is a rare neurodegenerative, spongiform encephalopathy with an aggressive clinical course. PET brain imaging has been reported to detect focal cortical abnormalities in hvCJD with greater sensitivity than MRI. However, because PET is both more costly and less accessable than MRI, early diagnosis of this disease and subsequent prognostication may be unnecessarily delayed. The reliability of MRI over PET in detecting isolated occipital cortical changes suggestive of hvCJD has not been well studied.

DESIGN/METHODS: This is a case report with relevent neuroimaging review.

RESULTS: A 70 year-old right-handed male experienced visual hallucinations and visuospatial disorientation with worsening ataxia followed by progressive anterograde amnesia and cortical blindness. Six weeks later he was comatose with startle myoclonus. A sharply-contoured periodic pattern was evident posteriorly on continuous EEG monitoring with brain MRI revealing subtle bilateral occipital cortical diffusion restriction. PET brain imaging showed diffuse non-focal cortical hypometabolism. Both cerebrospinal fluid (CSF) 14-3-3 and tau protein studies were positive. EEG progressed to refractory status epilepticus and the patient died four days later. ***The presence of abnormal brain protease-resistant prion protein and MM1 genotype at autopsy supported the diagnosis of hvCJD.

CONCLUSIONS: hvCJD should be considered in patients with rapid-onset idiopathic visual disturbance and dementia. When combined with EEG and CSF analysis, isolated MRI visual cortex diffusion restriction is suggestive of this ultra-aggressive prion variant. MRI is able to efficiently facilitate valuable prognostication early in hvCJD and can be more useful than costly PET imaging.

Disclosure: Dr. Beary has nothing to disclose. Dr. Manno has nothing to disclose.

http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/P07.163

Resident and Fellow Section

Mystery Case:

Heidenhain variant of Creutzfeldt-Jakob disease

Matthew Kalp, MD, PhD and Christopher H. Gottschalk, MD

A 75-year-old woman complained of a “scrambled brain” for 1 month. She endorsed poor depth perception and an inability to construct “mental maps” of her home and the grocery store. Examination revealed impaired delayed recall, ocular apraxia, optic ataxia, and simultanagnosia (Bálint syndrome). Diffusion-weighted MRI demonstrated cortical hyperintensities in the occipital lobes extending into the right parietal lobe, suggesting spongiform encephalopathy (figure). The 14-3-3 protein and elevated neuron-specific enolase were detected in the CSF. The patient was diagnosed with the Heidenhain variant of Creutzfeldt-Jakob disease.1 Early in the disease, this subgroup of patients with prion disease have isolated visual, not cognitive, symptoms and may be referred to an ophthalmologist.2

http://www.neurology.org/content/83/22/e187.extract?etoc

Heidenhain Variant Creutzfeldt Jakob Disease autopsy case report 'MOM'

DIVISION OF NEUROPATHOLOGY University of Texas Medical Branch 114 McCullough Bldg. Galveston, Texas 77555-0785

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Patient Account: 90000014-518 Med. Rec. No.: (0160)118511Q Patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Admitting Race: C

Attending Dr.: Date / Time Admitted : 12/14/97 1228 Copies to:

UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683 Pathology Report

FINAL AUTOPSY DIAGNOSIS Autopsy' Office (409)772-2858

Autopsy NO.: AU-97-00435

AUTOPSY INFORMATION: Occupation: Unknown Birthplace: Unknown Residence: Crystal Beach Date/Time of Death: 12/14/97 13:30 Date/Time of Autopsy: 12/15/97 15:00

Pathologist/Resident: Pencil/Fernandez Service: Private Restriction: Brain only

FINAL AUTOPSY DIAGNOSIS

I. Brain: Creutzfeldt-Jakob disease, Heidenhain variant.

***TYPE: Anatomic(A) or Clinical(C) Diagnosis. IMPORTANCE: 1-immediate cause of death (COD); 2.ureterlying COD; 3-contributory COD: 4.concomitant, significant; 5-incidental ***

Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed Date; Time: 01/30/98 - 0832

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UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683

Pathology Report

Autopsy NO,: AU-97-00435

MICROSCOPIC DESCRIPTION: The spongiform change is evident in all areas of neocortex, varying from mild to moderate in severity with only very mild neuronal loss and gliosis. In the bilateral occipital lobes, there is severe loss cortical neurons and gliosis, with a corresponding pallor of the underlying white matter. There is only minimal, focal spongiform change in corpus striatum, lentiform nuclei, thalamus, hippocampus, brainstem and cerebellum. There is no significant loss of neurons from the lateral geniculate nucleus, and the optic chiasm and tracts are well-myelinated.

SECTIONS TAKEN: N-l) Pituitary, N-2) Right frontal, N-3) Right inferior frontal, N-4) Right caudate putamen. N-5) Right lentiform nuclei, N-6) Right hippocampus, N-7) optic chiasm. N-8) Left inferior temporal lobe, N-9) Right inferior occipital, N-10} Cerabellum. N-l1) Midbrain, N-12) Pons, N-13) Medulla.

FINAL DIAGNOSES: BRAIN: 1. Clinical history of rapidly progressive dementia, clinically consistent with Creutzfeldt-Jakob Disease.

a. spongiform encephalopathy, most Severe in occipital lobes, consistent with Heidenhain variant of Creutzfeldt-Jakob disease.

b. Ventriculer enlargement, moderate, consistent with atrophy. 1. Communicating spherical enlargement of occipital horn of left lateral ventricle (possible incidental congenital anomaly).

DURA; Left subdural hemorrhage, recent, minimal.

PITUITARY: Severe capillary congestion.

COMMENTS; See also western blot report from Dr. Gambetti's lab Amyloid stains are not completed for this case as of this date. The results, which are not essential for the diagnosis, will be reported separately in an addendum.

(this was hand written notes) no amyloid evident in the special stains. no evidence of plaques.GAE

Gerald A. Campbell, M.D., Pathologist Division of Neuropathology

(Electronic Signature}. (Gross: 01/16/98 Final: 02/08/98

Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed Date: Time: 02/09/98 - 1120

Page 2 END OF REPORT -------

UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 fax (409) 772-5683 Pathology Report

Date/Time of Death: 12/14/97 Autopsy No.: AU-97-00435

NEUROPATHOLOGY CONSULTATION

CLINICAL HISTORY This patient was a 63-year-old white female with recent onset of progressive dementia. She was well until September of this year, when she noted a decrease in her visual activity and was found to have visual field defects as well. MRI revealed no lesions in the orbits or optic pathways. She was admitted to the hospital with the working diagnosis of bilateral optic neuropathy for a course of intravenous methylprednisolone, but her vision continued to deteriorate. She developed increasing memory and speech impairment, weakness and myoclonus. She died on 12/14/97, approximately three and one-half months after her symptoms started.

Date/Time of Death: 12/14/97 13:30 Date/Time Autopsy: 12/15/97 15:00 Pathologist Resident: PENCIL/FERNANDEZ

GROSS DESCRIPTION: Submitted are the brain, convexity dura and pituitary gland.

The pituitary gland is very dark and almost hemorrhagic in appearance, but has no obvious hematoma. It is submitted totally for histology.

The right convexity dura has diffuse but minimal subdura hemorrhage, and the dura is otherwise unremarkable.

The brain is normally developed with normal size for an adult and is symmetric externally. It does not have apparent sulcal widening. There is mild congestion of the leptomeninges, which are transparent. There is no evidence of inflammatory exudete. There is no evidence of internal softenings or other lesions externally. The cerebral arteries have focal atherosclerosis, but are without significant compromise of the vessels lumens. There is no evidence of aneurysms or malformations.

The hemispheres are sliced coronally revealing, a ventricular system which is mildly enlarged. The cortical ribbon is normal in thickness throughout most of the brain, except for the inferior and medial occipital lobes bilaterally, where the cortex is firm, thin and has a brownish discoloration, more severely so on the left than the right. In addition there is a spherical enlargement of the left occipital horn of the lateral ventricle which communicates with the remainder of the lateral ventricle. The tissue of the white matter around this enlargement is somewhat softer then in other areas. Other areas of the brain are grossly unremarkable. The brainstem and cerebellum are sliced transversely, revealing normal development and no evidence of gross changes or lesions.

DICTATED BY: GERALD A. CAMPBELL, M.D., PATHOLOGIST 01/16/98

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Patient Account: 90000014-518 Med. Rec. No,: (0160)118511Q

Patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex:F Race:C Admitting Dr.: Attending Dr: Date/Time Admitted: 12/14/97 1228

UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683 Pathology Report

FINAL AUTOPSY REPORT Autopsy Office (409)772-2858 Autopsy No.: AU-97-00435

CLINICAL SUMMARY:

This is a 63-year-old white female with a recent onset of progressive dementia. Her past medical history is significant for hypothyroidism. She was well until September of this year, when she noted visual difficulty. By mid-October, she could not read the newspaper. She was found to have a decrease in visual acuity and visual field defects. One week after her initial evaluation, a panel of blood tests showed no significant abnormalities and a MRI revealed some periventricular white matter "plaque-like" areas but no lesions in the orbits or optic pathways.

The patient had continued deterioration and distortion of her vision. The visual field defects increased, and she was found to have paracentral scotomas which were thought to be consistent with bilateral optic neuropathy. Early in November, she was admitted to the hospital for a course of intravenous methyl prednisolone.

During her hospital stay, she was noted to have short term memory and speech impairment; her vision did not improve. She was discharged with the diagnosis of Creutzfeldt-Jakob disease.

Later, the patient developed progressive dementia with marked impairment of speech and memory. She had complete visual loss, increased weakness and myoclonus. She died on December 14, 1997.

MF /AV 12/16/97

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Patient Account: 90000014-518 Med. Rec. No.: (0160)118511Q Patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.: Attending Dr.: Date / Time Admitted : 12/14/97 1228

UTMB University of Texas Medical Branch Galveston. Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683 Pathology Report

AU-97-00435

GROSS DESCRIPTION:

EXTERNAL EXAMINATION: The body is that of a 63-year-old well-nourished, well-developed white female. There is no rigor mortis present, and there is unfixed dependent lividity on the posterior surface. The head is normocephalic with a moderate amount of gray, medium length scalp hair. The irides are blue with equal pupils measuring 0.4 mm in diameter. The nares are patent with no exudate. Dentition is fair. Buccal membranes are normal. There is normal female hair distribution. The chest does not have increased anterior-posterior diameter. The abdomen is slightly protuberant. Lymph node enlargement is not present. The extremities are unremarkable. The genitalia are those of a normal female. Two well-healed remote scars are identified in the abdomen: one in the right upper quadrant and another in the superpubic area.

BRAIN: The brain weighs 1450 gm. The gyri and sulci display a normal pattern without edema or atrophy. The meninges show no abnormalities. The circle of Willis, basilar and vertebral arteries show no significant atherosclerosis. The brain is fixed in formalin for later examination by a neuropathologist (see neuropathology report). No indentation of the cingulate gyri, unci or molding of the cerebellar tonsils are noted.

SPINAL CORD: The spinal cord is not removed.

PITUITARY GLAND: The pituitary gland is removed and is fixed in formalin for subsequent examination by a neuropathologist.

MF /AV 12/16/97

Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed Date / Time: 01/30/98 - 0832

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Patient Account : 90000014-518 Med. Rec. No.: (0160)118511Q patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.: Attending Dr,: Date/Time Admitted: 12/14/97 1228

UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409) 772-5683

Pathology Report AU-97-00435

MICROSCOPIC DESCRIPTION:

BRAIN: Histologic examination of multiple sampled areas of the brain showed the characteristic features of Creutzfetdt-Jakob disease. These were present in most sections, but were particularly prominent in the occipital cortex. The spongiform degeneration was seen in the neuropil of the gray matter as multiple vacuoles amoung numerous reactive astrocytes and occasional neuronal cell bodies. These changes were most notable in the basal layer of the cortex. PAS and amyloid stains will be performed on selected sections to asses the presence of plaques.

MF /MF 01/28/98

Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed Date / Time: 01/30/98 - 0832

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Patient Account: 90000014-518 Med. Rec. No.: (0160}118511Q Patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.: Attending Dr.: Date / Time Admitted : 12/14/97 1228

UTMB University of Texas Medical Branch Galveston, Texas 775550-0543 (409) 772-1238 Fax (409) 772-5683 Pathology Report

Autopsy office (409)772-2858 Autopsy No.: AU-97-00435

FINAL AUTOPSY REPORT

CLINICOPATHOLOGIC CORRELATION:

The clinical findings in this case strongly suggest the diagnosis of Creutzfeldt-Jakob disease: progressive dementia, typical EEG changes, visual disturbances and myoclonus. These characteristics indicate this is a "probable case of CJD", according the criteria set by the EC Surveillance Group of Creutzfeldt-Jakob Disease in Europe (1).

The definitive diagnosis of Creutzfeldt-Jakob disease, however, is established by neuropathologic findings. There are three changes that are classically described and considered diagnostic: spongiform change, neuronal loss and astrocytic gliosis. The presence of these can vary significantly in proportion and distribution and often correlate with clinical symptoms. This permits classification of the disease into several variants.

Three variants of Creutzfeldt-Jakob disease have been proposed by Roos and Gajdusek (2): frontopyramidal, with pyramidal or lower motor neuron involvement; occipitoparietal {Heidenhain), characterized by disorders in higher cortical function and vision; and diffuse, with cerebral, cortical, basal ganglia, thalamic, cerebellar, midbrain and spinal cord involvement.

Histological examination from multiple samples of the brain in this case revealed astrocytic gliosis, spongiform degeneration and neuronal loss. Although these changes were seen in most sections, they were most prominent in the occipital cortex. This correlates very well with the clinical history of visual disturbances. Based on this finding, the present case corresponds to the Heidenhain variant. It is not uncommon for Creutzfeldt-Jakob disease to present with visual symptoms as the initial manifestation of the disease. Vargas et al (3) has reported three cases with these characteristics.

There have been numerous and significant advances in our understanding of Creutzfeldt-Jakob disease and prion diseases in general. These have been reviewed in several papers written recently, including one by Horowich and Weissman (4).

In summary, this 63 year old female with a history of visual disturbances and dementia of rapid progression was found to have the neuropathologic changes characteristic of Creutzfeldt-Jakob disease, predominantly in the occipital cortex. The occipital tropism and consequent visual symptoms indicate this case corresponds to the Heidenhain variant.

REFERENCES:

Patient Name: POULTER, BARBARA Patient location: AUTOPSY Room/Bed: Printed Date / Time: 01/30/98 * 0832

Page: 5 Continued ....

--------------

Patient Account: 90000014-518 Med. Rec. No.: (0160)118511Q Patient Name: POULTER, BARBARA Age: 63 YRS DOB: 10/17/34 Sex: F Race: C Admitting Dr.: Attending Dr.: Date / Time Admitted : 12/14/97 1228

UTMB University of Texas Medical Branch Galveston, Texas 77555-0543 (409) 772-1238 Fax (409} 772-5683 Pathology Report

Autopsy No.: AU-97-00435

FINAL AUTOPSY REPORT

CLINICOPATHOLOGIC CORRELATION:

1. Budka H, et al: Tissue handling in suspected Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases), Brain Pathology. 5:319-322,1995.

2. Roos R, Gajdusek DC, Gibbs CJ Jr: The clinical characteristics of transmissible Creutzfeldt-Jakob disease. Brain 96: 1-20, 1973.

3. Vargas ME, et al: Homonymous field defect as the first Manifestation of Creutzfeldt-Jakob disease. American Journal of Ophthalmology. 119:497-504, 1995.

4. Horowich AL, Weissman JS: Deadly conformations - protein misfolding in prion disease. Cell Vol.89, 499-510, 1997.

MF /MF 01/28/98

SCOT D. PENCIL, M.D., PATHOLOGIST MARTIN FERNANDEZ, M.D. 01/29/98 (Electronic Signature)

Patient Name: POULTER, BARBARA Patient Location: AUTOPSY Room/Bed: Printed Date / Time: 01/30/98 - 0832

Page: 6 END OF REPORT

--------------

The University of Texas Medical Branch at Galveston

Gerald A, Campbell, Ph.D., M.D, Associate Professor and Director Division of Neuropathology Department of Pathology

February 26, 1998

Pierluigi Gambetti, M.D. Professor Institute of Pathology Case Western Reserve University 2085 Adelbert Road Cleveland Ohio 44106

Dear Dr, Gambetti:

Enclosed please find the microscopic slides and autopsy report from our patient, Barbara Poulter (Hosp.# 11851lQ, Autopsy # AU97-435). These slides are being sent for consultation at the request of Mr. Singletary, Ms. Poulter's son and next of kin. We will also send frozen tissue from the brain on dry ice next week, and someone will call you on the day the tissue is shipped. Please return the slides when you have finished with your examination. If you need any further information, please do not hesitate to call me. Thanks for your assistance with this case.

Sincerely, Gerald A. Campbell

------------------

CASE WESTERN RESERVE UNIVERSITY

February 26, 1988

Gerald Campbell, M.D,, PhD. Division of Neuropathology, G85 University TX Medical Branch Galveston, TX 77555-0785

Dear Dr. Campbell,

As per our telephone conversation concerning a recent case of CJD, I Will be willing to examine slides and the frozen tissue on western blotting, I will issue a report to you about our conclusions. Below is my address, Our Fed Ex number is XXXXXXXXXXXXXXX.

Thank your for your assistance in this matter,

Best personal regards,

Pierluigi Gambetti, M.D.

PG:In

Division of Neuropathology Pierluigi Gambetti, M.D. Director Institute Of Neuropathology 2085 Adelbert Road Cleveland, Ohio 44106

Phone 216-368-0587 Fax 216-368-2546

------------------

CASE WESTERN RESERVE UNIVERSITY

February 27, 1998

Dr. Gerald A. Campbell The University of Texas Medical Branch at Galveston Division of Neuropathology, G85 Galveston. TX 77555-0785

Dear Dr. Campbell,

We are in receipt of the slides you sent on Mrs. Barbara Poulter (your #: AU97-435;our#098-28).

Best personal regards, Pierluigi Gambetti, M.D.

PG:sb

Division of Neuropathology Pierluigi Gambetti, M.D., Director

-----------------------------------

CASE WESTERN RESERVE UNIVERSITY

March 30, 1998

Dr. Gerald A, Campbell The University of Texas Medical Branch at Galveston Division of Neuropathology Department of Pathology Galveston, Texas

Dear Dr Campbell,

We performed Western immunoblot analysis on the frozen tissue from your case #AU97-435 (our #098-28). The Immunoblot reveals the presence of protease-resistant prion protein (PrPres) confirming the diagnosis of prion disease. The immunoblot pattern of PrPres is consistent with the diagnosis of Creutzfeldt-Jakob disease.

Thank you for referring to us this interesting case.

Sincerely,

Piero Parchi, M.D.

Pierluigi Gambetti, M.D.

PP:sb

Division of Neuropathology Pierluigi Gambetti, M.D., Director Case Western Reserve University

This Autopsy report is for the use of anyone, who is trying to understand this hideous disease CJD. I hope it can be beneficial for some in researching human TSE. Please remember, this was my Mom, and to use this with great respect.

thank you, kind regards,

Terry S. Singeltary Sr., Bacliff, Texas USA

-------------------------------

BARBARA FREDERICK POULTER

DIED 12-14-97

If I had one last thing I could tell you, it would be, I love you. I'm sorry for the stupid argument we had the last few months, BEFORE this hideous disease ROARED through your body. BUT, I PROMISE MOM, YOUR DEATH WILL NOT GO UNANSWERED!

HEIDENHAN VARIANT CREUTZFELDT JAKOB DISEASE

We got a call from my Mother around the end of Oct. saying "the damn'est thing has happened, I can't see, and if I'm talking to you and I don't make sense, bare with me, I'll come back". It was a shock to all of us. It seems that a few days before, she was crossing the ferry and became frightened because she was having problems seeing. She explained it as looking down a tunnel or not being able to see from the sides, and seeing brown spots.

We had NOT been talking, over something, we had NO control of, for a few months. So I did not know she had been having these visual problems, until she was blind. These were her first symptoms. From that point on, I was with her most everyday. I had to cross the Galveston/Bolivar ferry, and its about 30 minutes each way, so as the disease progressed, it gave me a great deal of time to think. When the visual problems started, it was about 2 weeks later, and she was blind. That led to coordination, and balance problems starting. But as this hideous disease progresses, it just GOES. You don't seem to catch up with it. It was like a fire in a hurricane. We would go out and get her things she needed one day, and the next day it would be obsolete, because the disease had gone to another stage. So you started over. Her coordination and balancing led to being in a wheel-chair. She was starting to get these trembles. I also noticed how her hands and feet started to go inward. Her speech was nothing more than jerble at this time, and this was probably about the 6th week, (at this point we had to tie her to the wheel chair, to keep her from falling out). The trembles had turned into SEVERE JERKS, that at times would take 3 of us to hold her down. I will never forget that....About her 8th week she became comatose....She died around the 10th week. I had spent the night, she had problems through the night, so the nurse came. She checked her out and comforted us, (HOSPICE IS A WONDERFUL ORGANIZATION). The nurse said she seemed to be alright and that it would probably be alright to go home for a few hours. I was on the Ferry, going back to Galveston, when I got the call, she was gone. What can you do, Mom was gone, and I was stuck on the Damn Ferry, going the wrong direction.

She knew what she had. I remember, before she had lost her speech completely. After a doctors conference, and CJD had come up. She heard us say CJD, and she screamed, SHE knew! At that point, I didn't know what was, much less, CREUTZFELDT JAKOB DISEASE.....I have learned a lot since. I have learned I truly miss my Mom and I am MAD as hell that she is gone!

Terry/MADSON!!!

SYMPTOMS:

VISION - BLIND IN ABOUT 10 TO 14 DAYS

COORDINATION AND MUSCLE CONTROL SWALLOWING DIFFICULTY CONFUSION AND DEMENTIA SPEECH PROBLEMS HALLUCINATIONS TREMBLES TOO SEVERE JERKING LOSS OF WEIGHT HANDS AND FEET GREW INWARD UPPER TRUNK STIFFNESS, SHOULDER, UPPER ARM

http://www.fortunecity.com/healthclub/cpr/798/terry.htm

Back to MANY FACES OF CJD

http://www.fortunecity.com/healthclub/cpr/798/cjd.htm

snip...

http://creutzfeldt-jakob-disease.blogspot.com/2008/07/heidenhain-variant-creutzfeldt-jakob.html

Thursday, December 24, 2015

Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings

Article type: Research Article

http://creutzfeldt-jakob-disease.blogspot.com/2015/12/revisiting-heidenhain-variant-of.html

***Saturday, January 16, 2016

***Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Products Guidance for Industry

http://creutzfeldt-jakob-disease.blogspot.com/2016/01/revised-preventive-measures-to-reduce.html

Saturday, December 12, 2015

CREUTZFELDT JAKOB DISEASE CJD TSE PRION REPORT DECEMBER 14, 2015

http://creutzfeldt-jakob-disease.blogspot.com/2015/12/creutzfeldt-jakob-disease-cjd-tse-prion.html

Friday, December 04, 2009

*** New guidance on decontamination of trial contact lenses and other contact devices has been revealed for CJD AND vCJD

http://creutzfeldt-jakob-disease.blogspot.com/2009/12/new-guidance-on-decontamination-of.html

Thursday, January 29, 2009

***Medical Procedures and Risk for Sporadic Creutzfeldt-Jakob Disease, Japan, 1999–2008 (WARNING TO Neurosurgeons and Ophthalmologists)

http://creutzfeldt-jakob-disease.blogspot.com/2009/01/medical-procedures-and-risk-for.html

Wednesday, August 20, 2008

***Tonometer disinfection practice in the United Kingdom: A national survey

http://creutzfeldt-jakob-disease.blogspot.com/2008/08/tonometer-disinfection-practice-in.html

Home / Science News

***Eye procedure raises CJD concerns***

By STEVE MITCHELL, Medical Correspondent | Nov. 18, 2004 at 4:01 PM

WASHINGTON, Nov. 18 (UPI) -- A New York man who died from a rare brain disorder similar to mad cow disease in May underwent an eye procedure prior to his death that raises concerns about the possibility of transmitting the fatal disease to others, United Press International has learned.

The development comes on the heels of the announcement Thursday by U.S. Department of Agriculture officials of a possible second case of mad cow disease in U.S. herds. Richard Da Silva, 58, of Orange County, N.Y., died from Creutzfeldt Jakob disease, an incurable brain-wasting illness that strikes about one person per million.

Richard's wife Ann Marie Da Silva told UPI he underwent a check for the eye disease glaucoma in 2003, approximately a year before his death. The procedure involves the use of a tonometer, which contacts the cornea -- an eye tissue that can contain prions, the infectious agent thought to cause CJD.

Ann Marie's concern is that others who had the tonometer used on them could have gotten infected.

A 2003 study by British researchers suggests her concerns may be justified. A team led by J.W. Ironside from the National Creutzfeldt-Jakob Disease Surveillance Unit at the University of Edinburgh examined tonometer heads and found they can retain cornea tissue that could infect other people -- even after cleaning and decontaminating the instrument.

"Retained corneal epithelial cells, following the standard decontamination routine of tonometer prisms, may represent potential prion infectivity," the researchers wrote in the British Journal of Ophthalmology last year. "Once the infectious agent is on the cornea, it could theoretically infect the brain."

Prions, misfolded proteins thought to be the cause of mad cow, CJD and similar diseases, are notoriously difficult to destroy and are capable of withstanding most sterilization procedures.

Laura Manuelidis, an expert on these diseases and section chief of surgery in the neuropathology department at Yale University, agreed with the British researchers that tonometers represent a potential risk of passing CJD to other people.

Manuelidis told UPI she has been voicing her concern about the risks of corneas since 1977 when her own study, published in the New England Journal of Medicine, showed the eye tissue, if infected, could transmit CJD.

At the time the procedure was done on Richard Da Silva, about a year before he died, she said it was "absolutely" possible he was infectious.

The CJD Incidents Panel, a body of experts set up by the U.K. Department of Health, noted in a 2001 report that procedures involving the cornea are considered medium risk for transmitting CJD. The first two patients who have a contaminated eye instrument used on them have the highest risk of contracting the disease, the panel said.

In 1999, the U.K. Department of Health banned opticians from reusing equipment that came in contact with patients' eyes out of concern it could result in the transmission of variant CJD, the form of the disease humans can contract from consuming infected beef products.

Richard Da Silva was associated with a cluster of five other cases of CJD in southern New York that raised concerns about vCJD.

None of the cases have been determined to stem from mad cow disease, but concerns about the cattle illness in the United States could increase in light of the USDA announcement Thursday that a cow tested positive on initial tests for the disease. If confirmed, this would be the second U.S. case of the illness; the first was detected in a Washington cow last December. The USDA said the suspect animal disclosed Thursday did not enter the food chain. The USDA did not release further details about the cow, but said results from further lab tests to confirm the initial tests were expected within seven days.

Ann Marie Da Silva said she informed the New York Health Department and later the eye doctor who performed the procedure about her husband's illness and her concerns about the risk of transmitting CJD via the tonometer.

The optometrist -- whom she declined to name because she did not want to jeopardize his career -- "didn't even know what this disease was," she said.

"He said the health department never called him and I called them (the health department) back and they didn't seem concerned about it," she added. "I just kept getting angrier and angrier when I felt I was being dismissed."

She said the state health department "seems to have an attitude of don't ask, don't tell" about CJD.

"There's a stigma attached to it," she said. "Is it because they're so afraid the public will panic? I don't know, but I don't think that the answer is to push things under the rug."

New York State Department of Health spokeswoman Claire Pospisil told UPI she would look into whether the agency was concerned about the possibility of transmitting CJD via tonometers, but she had not called back prior to story publication.

Disposable tonometers are readily available and could avoid the risk of transmitting the disease, Ironside and colleagues noted in their study. Ann Marie Da Silva said she asked the optometrist whether he used disposable tonometers and "he said 'No, it's a reusable one.'"

Ironside's team also noted other ophthalmic instruments come into contact with the cornea and could represent a source of infection as they are either difficult to decontaminate or cannot withstand the harsh procedures necessary to inactivate prions. These include corneal burrs, diagnostic and therapeutic contact lenses and other coated lenses.

Terry Singletary, whose mother died from a type of CJD called Heidenhain Variant, told UPI health officials were not doing enough to prevent people from being infected by contaminated medical equipment.

"They've got to start taking this disease seriously and they simply aren't doing it," said Singletary, who is a member of CJD Watch and CJD Voice -- advocacy groups for CJD patients and their families.

U.S. Centers for Disease Control and Prevention spokeswoman Christine Pearson did not return a phone call from UPI seeking comment. The agency's Web site states the eye is one of three tissues, along with the brain and spinal cord, that are considered to have "high infectivity."

The Web site said more than 250 people worldwide have contracted CJD through contaminated surgical instruments and tissue transplants. This includes as many as four who were infected by corneal grafts. The agency noted no such cases have been reported since 1976, when sterilization procedures were instituted in healthcare facilities.

Ironside and colleagues noted in their study, however, many disinfection procedures used on optical instruments, such as tonometers, fail. They wrote their finding of cornea tissue on tonometers indicates that "no current cleaning and disinfection strategy is fully effective."

Singletary said CDC's assertion that no CJD cases from infected equipment or tissues have been detected since 1976 is misleading.

"They have absolutely no idea" whether any cases have occurred in this manner, he said, because CJD cases often aren't investigated and the agency has not required physicians nationwide report all cases of CJD.

"There's no national surveillance unit for CJD in the United States; people are dying who aren't autopsied, the CDC has no way of knowing" whether people have been infected via infected equipment or tissues, he said.

Ann Marie Da Silva said she has contacted several members of her state's congressional delegation about her concerns, including Rep. Sue Kelly, R-N.Y., and Sen. Charles Schumer, D-N.Y.

"Basically, what I want is to be a positive force in this, but I also want more of a dialogue going on with the public and the health department," she said.

http://www.upi.com/Science_News/2004/11/18/Eye-procedure-raises-CJD-concerns/29741100811678/

Cadaver corneal transplants -- without family permission

Houston, Texas channel 11 news 28 Nov 99 Reported by Terry S. Singeltary Sr.son of CJD victim

http://www.mad-cow.org/~tom/dec99_news.html#bbb

http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf

Serologicals Corporation

Microsoft PowerPoint - 2005 Education Day BSE Presentation.ppt

ISPE Omaha, Nebraska April, 2005 Serologicals Corporation

Implications of Animal Derived Products and Processes on Manufacturing and Regulatory Systems Presented by Sue Sutton-Jones

• Serologicals Corporation is now comprised of 3 main

businesses: Celliance™, Chemicon™ and Upstate™. All 3

Companies provide animal derived products of different

species in their product offerings.

• Animal Blood Proteins

Celliance™ provides a wide range of approximately 90 distinct

animal protein products. These products, such as BSA, are

primarily supplied to life science companies for use in blood

typing and other diagnostic reagents. One of the primary uses

of bovine albumin is to enhance the detection of blood group

antibodies, a characteristic essential for the safe transfusion of

whole blood. The Company also provides a line of highly

purified animal proteins known as tissue culture media

components that are used by biotechnology and

biopharmaceutical companies as nutrient additives in cell

culture media. Examples of these media components are

Bovine EX-CYTE®, produced through a patented

manufacturing process, and transferrin.

• A British company preparing 40,000 heart valves a year from bovine pericardium, primarily for export, and they are not required to source this material from BSE-free herds even in peak epidemic years. It is amazing to watch health "authorities" groveling on their bellies to wring petty concessions from middle management at obscure little companies.

• The main worry is not the practice of using 800 potentially infected cows a week for human heart transplant material but that the press or recipients will get wind of it, hurting business. Sun, 3 Sep 2000. Unpublished Inquiry documents obtained by CJD activist Terry S. Singeltary Sr. of Bacliff, Texas

http://www.ispe.org/midwest/2005-education-day-implications-animal-derived-products-processes-manufacturing-regulatory-systems.pdf

40,000 human heart valves a year from BSE herds

Sun, 3 Sep 2000. Unpublished Inquiry documents obtained by CJD activist Terry S. Singeltary Sr. of Bacliff, Texas

Opinion (webmaster): Below are some shocking documents. Here is a British company preparing 40,000 heart valves a year from bovine pericardium, primarily for export, and they are not required to source this material from BSE-free herds even in peak epidemic years. It is amazing to watch health "authorities" grovelling on their bellies to wring petty concessions from middle management at obscure little companies. The main worry is not the practise of using 800 potentially infected cows a week for human heart transplant material but that the press or recipients will get wind of it, hurting business.

BSE wasn't the problem, it was awkward queries from importing countries like the US. The cows are stunned using brain penetration -- can't do anything about the chunks of bovine brain blasted into the circulatory system, it's the norm. Can't use younger lower-risk animals either, patch would not be big enough. It is fascinating to see the British government worrying about, but doing nothing, with pigs with BSE 10 years ago.

While scrapie was long used as an excuse for continuing with human use of BSE-tainted material, little sheep material was used medically. Bovine transplants, vaccines, insulin doeses, etc. are far more dangerous than dietary material as injections, and are done on a very wide scale. So scrapie was never a valid analogy to BSE, as MAFF knew full well.

The British government deferred to the manufacturer's rep for an opinion on how contaminated pericardium might be, just as this appeared showing that this tissue is extremely dangerous:

http://www.mad-cow.org/00/sep00_news.html#hhh

> COMMERCIAL IN CONFIDENCE

> Miss M Duncan From: Dr E Hoxey

> Date: 29 January 1990

> cc: Mr R Burton

> Dr N Richardson

> Ms K Turner

> Ms J Dhell

> Mr N Weatherhead

> BOVINE SPONGIFORM ENCEPHALOPATHY

> 1. In your absence on sick leave, I chaired the STD BSE group meeting

> on 26th January 1990.

> 2. The minutes of the meeting will be circulated shortly but I was asked

> to bring to your attention the concerns of the group regarding the BMS

> heart valve.

> 3. This concern arose from a number of points on the agenda:-

> i) the______________decision to source all raw material for sutures

> from Australasia from January 1990.

> ii) the major cleandown and decontamination proposed for the

> factory and the possibility of press interest that this may generate.

> iii) the indication in the Tyrell Report on Research that the

> infective agent may be induced to cross the species barrier by

> intracerebral, intraperitoneal or intravenous injection.

> 4. As you are aware, the____________situation has been a model which we

> have observed closely.

> 5. Reviewing the BMS situatien, we considered the incidence of BSE in

> the herds used for materials, the processing received by the material

> and the age of the cattle used. Given the number of uncertainties and

> lack of definitive information on BSE, the_______________model was

> still considered as a good one. The group were uncomfortable with the

> position of BMS as the only company using UK sourced material.

> 6. The group considered that it may be worthwhile arranging a further

> meeting with___________to confidentially make them aware that they

> would now be the only company using UK sourced bovine material for

> products of this type.

> 7. Clearly, __________and__________ are now in an exposed position in

> this area and all the implications need te be considered. Could we have

> your news on this proposal please?

> Dr E V Hoxey

> PD STD PG1A

> 716 RSQ

> Ext 3356

> 90/01.29/19.1

> ==============

> B.S.E. GUIDELINES ON BOVINE IMPLANTS & BLOOD CONTACT DEVICES -

> MEETING WITH MANUFACTURERS

> DATE: 8 DECEMBER 1989

> DH REPRESENTATIVES Nigel Richardson

> Will Burton

> Eammon Hoxey

> Jeremy Tinkler

> Helen Campbell

> Carol Bleakley

> Bill Waine

> The main purpose of the meeeting is to discuss the companies current

> manufacturing procedures, future plans and their compliance with the

> BSE guidelines. Their views were also sought as to the practical

> feasibility of the guidelines with respect to the manufacturing

> process, and any improvements that could be suggested.

> The meetings were held separately with each company. Neither had

> received any queries concerning BSE from countries to which their

> products are exported.

> CURRENT POSITION

> 1.__________ have brought in a microbiologist as a technical scientific

> adviser, initially to inform them of the current understanding of

> BSE. He is still available to them and keeps them up to date with new

> developments.

> 2. At present they produce bovine pericardial heart valves, & (a sister

> company) produces heparin coated products (from a porcine source). In

> the future it is possible that they will introduce a bovine patch

> produced from bovine pericardium from the same source. They will keep

> the Department informed of any progress in this area.

> SOURCE MATERIAL

> 3. The source material for the manufacture of heart valves is bovine

> pericardial sacs. The cows used are 18-24 months old when slaughtered,

> the majority around 18 months. BMS have no knowledge of the actual

> age.

> 4. The cows are killed using brain penetration. Dr Bleakley made the

> point that as far as she was aware this was the only method used in

> this country. Meat inspectors are paid to obtain the bovine

> pericardium. They are paid a set rate but bonuses are given for

> increased yields. Mr Burton expressed concern as to the conflict of

> interests that may arise as a result of this. Dr Bleakley did not

> believe that this was the case because of the relationship BMS had

> developed with the inspectors.

> 89/12.12/8.1

> ============

> COMMENTS ON THE GUIDELINES

> 14. Dr. Bleakley believed that the pericardium would not allow the

> replication of the causative agent, and does not present a risk.

> 15. She suggested that the guidelines were impossible to implement

> from the point of view of the manufacturing process for the following

> reasons:-

> -It is not possible to use closed herds simply because of the numbers

> of cattle involved. This is up to 800 each week.

> -Calves under 6 months old cannot be used as the pericardium is too

> thin to be incorporated into a valve.

> -For cows this in the age group used brain penetration is the only

> method of slaughtering used in this country.

> PROPOSALS PUT FORWARD BY DR BLEAKLEY

> 16. The goverment should fund research in this area. For example,

> investigating the presence or absence of the infectious agent in

> other parts of the body, such as the pericardium. Also to look at how

> the slaughtering process affects the spread of the disease.

> 17. Ideally the answer would be to take random tissue samples in

> order to detect contaminated material. This is not currently feasible

> with the length of time required to conduct titre testing.

> COMMENTS ON THE REVIEW ON METHODS OF STERILIZATION FOR BSE

> 18. Everything present reflected the published material, but the

> validity of some of this is questionable. It was pointed out that:-

> -it was stated that different strains display different heat

> sensitivity, but this does not appear to be chemically related

> -the claim to be "effective' would depend on the type of material that

> was being used and the time involved.

> CURRENT POSITION

> 19.____________ manufacture porcine valves and bovine pericardial

> patches. The possibility of producing porcine conduits is currently

> being investigated. This has not yet progressed.

> 20. The material is obtained from 2 abattoires in this country:-

> -Dorchester, where veal calves under 18 weeks are slaughtered for

> sourcing pericardium for ________________. These are used to produce

> small patches of less than 90mm diameter, this may be divided into 4

> quadrants. This represents 80-90% of sales.

> -Fairham where cows between 5 and 10 years old are slaughtered to

> produce larger patches and strips of 100mm by 45mm.

> 89/12.12/8.2

> =============

> 32. As a result of the concern voiced of direct inoculation of BSE

> via sectioning instruments it was stated that it would be feasible to

> use new blades with each carcass.

> COMMENTS ON THE GUIDELINES

> 33. Dr Waine was not convinced of the need for sterile sectioning

> equipment and separate packaging from the abattoire. He felt that

> this would merely have a cosmetic effect.

> 34. He suggested that the possibility of bovine-human cross-infection

> was very remote.

> 35. He did not believe that it was possible for manufacturers to

> follow the guidelines as they stand.

> PROPOSALS

> 36. Dr Waine felt that the steps taken by the Government had been

> realistic to control the outbreak.

> REVIEW

> 37. Dr Waine did not believe that any sterilization treatment

> proposed would retain the surgical usage of the pericardium.

> VALVES

> 38. The response has been that this problem is restricted to the U.K.

> Thier material is obtained from the same Italian source as the

> patches. There is no age specification on the cows but the preference

> is for the larger valves which would therefore come from the older

> animals.

> PORCINE VALVES

> 39. There was a small discussion as to whether these products do fall

> under the issued guidelines. The assumption had been made by the

> company that they are not included as pigs are not known to be

> susceptible to infection by a Scrapie-like agent. This was confirmed

> by Dr Hoxey.

> 40. The pigs are electrocuted and the heart and pericardium obtained

> prior to inspection.

> 41. One abattoire supplies them with most of their porcine requirments.

> H Campbell

> PG2C

> Room 312 RSQ

> Ext. 3212

> 12 December 1989

> 89/12.12/8.3

> ============

> TIP740203/3 0241

> Bovine Spongiform Meeting Held On Friday 26th January 1990

> Present Dr E Hoxey {chairman)

> Mr W Burton

> Dr N Richardson

> Mrs J Dhell

> Ms K Turner

> MS H Cambell

> Mr N Weatherhead (secretary)

> copies: Miss Duncan

> 1.Apologies

> Apologies were received from Miss Duncan

> 2.Minutes of the last meeting.

> The previous minutes were accepted.

> 3.Matters arising not on the agenda.

> As agreed at the previous meeting the paper on "Inactivation of

> Scrapie-like Agents" was sent with a Covering letter drafted by

> Dr Hoxey to all companies that use Bovine or Porcine materiais.

> 4.Report on the STD meeting with ___________________

> The minutes of the meeting were discussed by the committee it was

> noted that:-

> a} _____________ now meet DH Guidelines as the devices produced from

> the calf material comply as that they are obtained from animals less

> than 6 months old.The company had written to confirm that they now

> source older animals from overseas.

> b) _____________ are unable to meet the DH Guidelines.

> and will not be doing so in the foreseeable future. The panel showed

> concern over the stance that BMS are taking. The committee felt that it

> was important to arrange a further meeting to inform them that they

> are now the only company using UK sourced material. [see minutes of the

> meeting dated 8/12/89 attached). Dr Hoxey agreed to write separatey

> to Miss Duncan on this issue.

> action: Dr Hoxey

> 5. Report on the CSM/MCA BSE working party meeting 10/1/90

> Mr Burton had produced a note of the above meeting as the minutes had

> as yet not been distributed. The committee noted that:-

> 90/01.26/20.1

> =============

> TIP740203/3 0242

> 1) _______________ has exceeded all expectations tn complying

> with DH Guidelines. They will be sourcing all raw material from

> Australasia from January 1990.

> 2) _______________ are using an international expert _______________

> to advise them on factory decontamination at the change over of source.

> 3) The use of Dr Taylor and the factory decontamination may qenerate

> press interest.

> 4) The offal ban has not yet been expanded to include Scotland.

> 5) The CSM/MCA BSE working group agrees with the approach that STD

> are taking to Tissue Harvesting and wished to be kept updated.

> The note of the meeting is attached for reference.

> 6. STD Database updating

> Mr Burton drafted a minute for signature by Mr Worroll.The object of

> the minute was to enable STD to keep a check on companies that use

> animal material in their products.

> The control manual committee amended the minute and agreed that the

> audit report procedure should include (if it does not already) a

> statement to the effect that the company information section should

> include details of raw materials used.

> The CMC suggested a sentence to the effect "Team leaders visiting

> Blue Guide companies should additionally take account of Mr Worroll's

> minute of Jan 1990." The committee agreed with this sentence and passed

> it back for inclusion in the Base-line Documents.

> action N Weatherhead

> 7. Review of the 'Interim Report of the Consultative Committee on

> Research into BSE" (Tyrell committee report.)

> Mrs Dhell presented a summarized Version of the above document to the

> committee. It was noted that only the research studies catorqorised

> high/medium priority would all somehow receive funding. The committee

> expressed a wish to find out:-

> 1) Areas which have not been prioritised which have relevance to

> STDS area of interest.

> 2) Has any party taken up the study "Investigation into the fate of

> bovine and ovine tissues and product that could lead to infection by

> as yet unrecognised routes."

> 90/01.26/20.2

> ==============

> TIP740203/3 0243

> 3. The protocol of work being carried out by the Clinical Research

> Laboratory in Harrow add proposed by the Neuropathogenesis unit in

> Edinburgh:

> a) Have they any plans to include pericardium. If not could PD suggest

> that they miqht include it.

> b) What controls are they using.

> c) Will it be possible to arrange a visit.

> 4) It was suggested that Dr Pickles be contacted as the DH

> representitive on the Tyrell committee, to enquire if comments on

> this document were being sought by the committee, as PD has a number

> of points it wishes to raise.

> 8. Incorporation of Guidance into Chemical Methods for the sterilization

> of animal tissue Used in medical Devices.

> The draft paper on methods of validation in chemical sterilization was

> shown to the BGRP for comments, these were later received. A copy was

> also forwarded to MCA and despite numerous reminders no reply had as

> yet been received.

> The committee recommended that the paper on "Chemical Methods for the

> Sterilization of Animal Tissue Used in Medical Devices" should be

> amended include Tissue Harvesting. The BGRP will be informed of this

> and a copy of tbe document will be presented to the next CMS/MCA BSE

> working group which is to be held on 4th July l99O.

> Mrs Dhell to arrange a meeting to draft this ammendment.

> Mrs Turner

> action:Hr Tinkler

> Mrs Dhell

> Dr Hoxey

> 9. Possibility of sending STD paper 'Inactivation of Scrapie-like

> Agents" to Dr Taylor and Dr Kimberlin for their comments.

> The committee felt that the paper should be sent to Dr Taylor and

> Dr Klmberlin and that they should be invited to comment. If they

> subsequently required payment for this work the committee felt that

> the Department should finance it if necessary.

> Mrs Dhell will draft a letter to accompany the report for Miss Duncan

> to sign.

> action: Mrs Dhell

> 90/01.26/20.3

> ==============

> TIP740203/3 0244

> 10. - presentation on current situation

> Miss Duncan's report was passed over until the next meeting.

> 1l. Oral discussion on relevant media interest and media reports.

> The discussion mainly revolved around _____________ and the exposed

> position PD would be in if the media became involved. The possible

> press coverage expected in relation to events at ___________ could also

> raise the profile of BSE in "medical" products.

> Mr Burton to obtain copies of any defensive briefings drafted

> by MCA in responce to the ______________ situation.

> N Weatherhead

> 90/01.26/20.4

> TSS

> "Terry S. Singeltary Sr." wrote:

> >

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

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

Subject: [CJDVoice] Re: Ophthalmic surgery and Creutzfeldt-Jakob disease

Date: Thu, 01 Jul 2004 21:11:58 -0500

From: "Terry S. Singeltary Sr."

Reply-To: cjdvoice@yahoogroups.com

To: Bovine Spongiform Encephalopathy

CC: cjdvoice@yahoogroups.com

References: <405b143f .1090808="" wt.net="">

UNCORRECTED PROOF

Sir,

CJD and intraocular surgery

We read with interest the clinical study by Leslie et al,1 in

the May (2003) issue of Eye. The authors eloquently

showed the contamination results before and after the

use of an automated rinsing system. They hypothesized

that the contamination may be the cause of

endophthalmitis found in their unit, but another

observation can be made from their results. The

contaminants noted by the authors included organisms,

lens capsule and cells. The question of whether these

organisms were viable or not is certainly significant but

the finding of lens material may pose a risk of

transmission of Creutzfeldt–Jakob disease (CJD).

CJD is a transmissible human spongioform

encephalopathy characterized by the presence of

abnormal prion protein. Different forms of the disease

exists, for example, sCJD (sporadic), iCJD (following

iatrogenic spread), fCJD (familial), and vCJD (variant,

following the consumption of infected beef). Several

authors have commented on CJD transmission from

ocular transplants, for example, cornea2 or sclera.3

However, intraocular surgical transmission is of concern

due to the sheer volume of cataract surgery performed.

Hogan et al showed a 10-fold increase in prion titres in

the lens in scrapie-infected hamsters once they had

become neurologically symptomatic. In fact, levels in the

lens were similar to levels in the cornea prior to the onset

of neurological symptoms but became significantly

higher than those in the cornea after the onset of

symptoms, retina having the highest titres.4 Intraocular

‘inoculation’ by phacoemulsification and irrigationaspiration

handpieces contaminated by lens material

certainly would provide a route for transmission.

The recent steps taken by the Department of Health in

reviewing sterilizing units probably triggered by the

outbreak of vCJD is certainly welcomed.5 The risk of

intraocular transmission in anterior segment surgery is

probably greater from sCJD than vCJD due to the age of

the patients affected by the respective conditions. Tissue

distribution of prion protein from human eyes has as yet

to show levels of prion in the cornea or lens,6,7 but the

authors concluded that the inability to detect prion

protein in the cornea or lens could not be taken as

evidence for the absence of infectivity in these tissues.7

Since prions adhere strongly to metal surfaces and are

resistant to many sterilization processes,8 the reduction

of contaminants as illustrated by this report in patients

with known or suspected CJD9 and the use of single-use

equipment5 (eg disposable simcoe) will reduce risks of

transmission further.

References

1 Leslie T, Aitken DA, Barrie T, Kirkness CM. Residual debris

as a potential cause of postphacoemulsification

endophthalmitis. Eye 2003; 7: 506–512.

2 Hogan RN, Brown P, Heck E, Cavanagh HD. Risk of prion

disease transmission from ocular donor tissue

transplantation. Cornea 1999; 18: 2–11.

3 Mehta JS, Franks WA. The sclera, the prion, and the

ophthalmologist. Br J Opthalmol 2002; 86: 587–592.

4 Hogan RN, Bowman KA, Baringer JR et al. Replication of

scrapie prions in hamster eyes precedes retinal degeneration.

Ophthalmic Res 1986; 18: 230–235.

5 Tullo AT. CJD and eye surgery-new disease old disease. J Cat

Refract Surg 2003; 29: 629–631.

6 Wadsworth JDF, Joiner S, Hill AF et al. Tissue distribution of

protease resitant prion protein in variant CJD disease using a

highly sensitive immunoblot analysis assay. Lancet 2001; 358:

171–180.

7 Head MW, Northcott V, Rennison K et al. Prion protein

accumulation in eyes of patients with sporadic and variant

CJD. IOVS 2003; 44(1): 342–346.

8 Rutala WA, Weber DJ. Creutzfeldt-Jakob disease:

recommendations for disinfection and sterilization. Clin

Infect Dis 2001; 32: 1348–1356.

9 Weber DJ, Rutala WA. Managing the risk of nosocomial

transmission of prion diseases. Curr Opin Infect Dis 2002; 15:

421–425.

JS Mehta and R Osborne

The Western Eye Hospital

Marylebone Road, London, UK

Correspondence: JS Mehta

9 Sandringham Court

King & Queen Wharf,

Rotherhithe Street,

London SE16 5SQ, UK

Tel: þ44 7980691396

Fax: þ44 8701316622

E-mail: jodmehta@hotmail.com

Eye (2003) 0, 000–000. doi:10.1038/sj.eye.6701401

Journal: IJO Disk used Despatch Date: 31/12/2003

Article: npg_eye_6701401 Pages:1--1 Op: HNM Ed: Naganjana

Eye (2004) 00, 1–1

www.nature.com/eye

CORRESPONDANCE

TSS

Terry S. Singeltary Sr. wrote:

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

> #########

> April 2004; Vol. 88, No. 4

> URL: http://www.bjophthalmol.com/content/vol88/issue4/index.shtml?etoc

> Series editor: David Taylor

> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

> . . . . . . . . . . . . . . .

> Ophthalmic surgery and Creutzfeldt-

> Jakob disease

> P S-Juan, H J T Ward, R De Silva, R S G Knight, R G Will

> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

> . . . . . . . . . . .

> Although the evidence does not suggest that contaminated

> ophthalmic instruments represent a risk of onward transmission of

> sporadic CJD, this conclusion should be treated with caution

> The occurrence of variant

> Creutzfeldt-Jakob disease (vCJD)

> and the probable causal link with

> bovine spongiform encephalopathy

> (BSE) in cattle have increased interest

> in the search for possible environmental

> sources of sporadic CJD (sCJD).

> Presumed iatrogenic CJD is rare. Up to

> the year 2000 there had been 267 cases

> reported worldwide: three cases secondary

> to human corneal grafting (one

> confirmed, one probable, and one possible

> case), 114 related to human dura

> mater grafts, 139 related to human

> growth hormone treatment, four related

> to human pituitary gonadotrophin therapy,

> and seven linked to neurosurgical

> procedures or stereotactic EEG electrodes.

> 1 Because of the marked resistance

> of the infectious agent of CJD to

> conventional sterilisation techniques,

> there is concern about the possibility of

> transmission of infection via surgical

> instruments in contact with infected

> tissue, especially in neurosurgery or

> ophthalmic surgery.

> The presence of infection in the eye

> in sCJD was first demonstrated following

> the intracerbral inoculation of

> pooled sCJD eye tissue in non-human

> primates.2 Recently the infectious form

> of prion protein (PrPSc) has been identified

> in the neural retina, optic nerve,

> and in retinal pigmented epithelium

> in variant and sporadic CJD using

> immunohistochemistry or western

> blot,3 4 with comparable levels to those

> found in brain. PrPSc was not detected

> in other ocular tissues. Although this

> suggests that there may be a greater

> risk of contaminating surgical instruments

> in procedures involving the

> posterior segment of the eye, infectivity

> has been demonstrated in animal

> and human cornea,5 and circumstantial

> evidence has implicated corneal

> transplantation as a mechanism of

> transmission of iatrogenic CJD.6 Experimental

> infection has been achieved

> following conjunctival installation of

> scrapie infectivity in mice7 and by

> inoculation of an adapted agent into

> the anterior chamber of the eye in

> guinea pigs.8

> Recently it has been shown that the

> experimental transmission of metallic

> suface bound prions is highly efficient.9

> Steel wires in contact with the brain of

> pre-symptomatic mice needed only

> 5 minutes to acquire an infectious load

> equivalent to the injection of a 1%

> homogenate of brain. Infected wires

> were inserted transiently into the brains

> of healthy mice and only 30 minutes of

> exposure was sufficient to result in

> infection. The same wires remained

> infective when reintroduced into

> another set of healthy mice. Although,

> to our knowledge, there have been no

> documented cases of CJD secondary to

> ophthalmic surgery other than corneal

> transplantation, there is a possibility

> that ophthalmic surgery might be a risk

> procedure for the accidental iatrogenic

> transmission of CJD.

> Precautions to minimise the risks of

> iatrogenic transmission of CJD are vital

> and the Department of Health has

> established an incidents panel to provide

> advice in cases of all forms of

> human prion diseases in which there is

> the possibility for cross infection.

> However, an important question is

> whether the concerns raised by experimental

> work translate into an actual

> risk in the clinical setting. This commentary

> reviews the data on ophthalmic

> surgery in sCJD and vCJD from the

> archives of the UK National CJD

> Surveillance Unit from 1990 to 2002,

> including information on both sCJD and

> vCJD.

> We analysed the surgical history of

> sCJD and vCJD cases with specific

> reference to ophthalmic surgery. Cases

> of CJD were identified in the current

> prospective UK national surveillance

> project (1990-October 2002) by direct

> notification or from death certificates,10

> and were classified as definite, probable,

> or possible cases of sCJD or vCJD

> according to published diagnostic criteria.

> Only definite or probable cases

> were included in this analysis. All cases

> with a history of ophthalmic surgery

> were identified from the database,

> which has a specific code for this type

> of surgery. Information on past ophthalmic

> surgery was obtained from relatives,

> general practitioner records, and/or

> copies of case notes. Case files were

> examined to identify the type of surgery,

> date of surgery, and hospital in which

> the surgery had taken place. In cases in

> which the surgery was carried out after

> the onset of clinical symptoms of CJD

> detailed information on the clinical

> course was extracted.

> The frequency of a history of eye

> surgery in sCJD and vCJD was compared

> with data on the frequency of past

> eye surgery in age and sex matched

> control groups. During the period of the

> study the case-control study has

> evolved. Between 1990 and 1998 a

> single hospital control was obtained for

> the sCJD cases and from 1999 2002 a

> single community based control was

> identified. From 1996 2002 a single

> hospital control was obtained for vCJD

> cases and since 1998 attempts have been

> made to obtain four community based

> controls per case of vCJD. Because of the

> limited numbers of controls and the

> infrequency of past eye surgery this

> study reports on unmatched comparisons

> of the frequency of past eye

> surgery.

> Fifty eight cases of sCJD (11%) out of

> 510 with information available had a

> history of intraocular surgery, with an

> average of 1.34 interventions per

> patient. The types of operation (n=78)

> in the total of 58 cases having undergone

> any form of ocular surgery are

> listed in table 1 and the years of

> operation in figure 1. Ten cases of

> sCJD underwent eye surgery during

> Table 1 Types of operation on cases of sporadic CJD

> Number of operations

> on sCJD cases

> Number of

> operations on

> hospital controls

> Number of operations

> on community controls

> (n = 78) (n = 39) (n = 20)

> Intraocular surgery* 55 (70%) 29 (74%) 17 (85%)

> Extraocular surgery 17 (22%) 6 (16%) 3 (15%)

> Laser therapy 4 (5%) 2 (5%)

> Information not available 2 (3%) 2 (5%)

> *Cataract, trauma, and glaucoma.

> 446 COMMENTARY

> www.bjophthalmol.com

> the prodromal (within 3 months of

> onset) or early symptomatic phase of

> the disease, the majority cataract operations.

> Four out of these 10 patients had

> the Heidenhain variant of sCJD, with

> visual onset and early development of

> cortical blindness (table 2). Figure 2

> shows the time interval between last eye

> surgery and the onset of symtoms in

> sCJD patients.

> The frequency of past eye surgery was

> compared with the control groups in

> sCJD (table 3) and vCJD. In the hospital

> control group for sCJD, 31 (14%) out of

> 226 had a history of ophthalmic surgery,

> with an average of 1.26 procedures per

> patient and in the community control

> group for sCJD 14 (13%) out of 106,

> with an average of 1.43 procedures per

> patient. Eight patients with vCJD (6%)

> out of 125 with information available

> had a history of eye surgery and all were

> squint corrections in childhood, with

> the exception of one case with a history

> of open surgery for retinal detachment

> carried out 15, 17, and 20 months before

> the development of symptoms (this case

> predated the establishment of the CJD

> incidents panel). In the hospital control

> group for vCJD (15%) 10 out of 67 had a

> history of ophthalmic surgery and in the

> community control group for vCJD five

> (3%) out of 155 had had eye surgery.

> There were no significant (at the 5%

> level) differences between the frequencies

> of past eye surgery in the cases and

> any of the control groups.

> Details of the year and hospital of

> each surgical procedure were listed and

> in the great majority there was no

> temporal or geographic link between

> operations. A group of six cases of sCJD

> had been operated on in one hospital

> and in two pairs of cases the procedures

> had been carried out in the same year.

> Inquiry about the specific dates of these

> procedures, however, indicated that the

> operations had been carried out months

> apart.

> The aim of this article is to document

> the frequency of past eye surgery in CJD

> and to determine whether there is

> evidence of transmission of CJD

> through contaminated ophthalmic

> instruments. About 10% of cases of

> sCJD have a history of eye surgery, of

> which about 70% involved open surgery

> on the anterior chamber of the eye. In

> the great majority of cases the surgical

> instruments were reused on subsequent

> patients, usually because CJD developed

> years after the original procedure.

> Despite this, the evidence in this paper

> does not suggest that there is onward

> iatrogenic transmission of sCJD through

> eye surgery, a finding consistent with

> some previous studies.11 12

> An important question is whether

> cases of CJD caused by this type of

> Figure 1 Year of eye surgery in sCJD.

> Table 2 sCJD patients with ophthalmic surgery after clinical onset

> Case Date of surgery Intervention

> Heidenhain

> variant Diagnosis

> 1 1992 Cataract Definite

> 2 1992 Laser therapy * Definite

> 3 1992 Cataract * Definite

> 4 1993 Cataract Definite

> 5 1996 Cataract Definite

> 6 1998 Dacryocystorhinostomy Definite

> 7 1998 Cataract Definite

> 8 1999 Cataract * Definite

> 9 1999 Laser therapy * Definite

> 10 2000 Cataract Definite

> *Heidenhain variant: cases with isolated cortical visual symptoms at

> onset.

> Figure 2 Interval between last eye surgery and onset of symptoms in sCJD

> (n = 54).

> Table 3 Past ophthalmic surgery in sCJD compared with control groups

> Cases Hospital controls Community controls

> (n = 510) (n = 226) (n = 106)

> Patients with eye operations 58 (11%) 31 (14%) 14 (13%)

> Total number of operations 78 39 20

> Average per patient 1.34 1.26 1.43

> COMMENTARY 447

> www.bjophthalmol.com

> transmission would be identified by this

> study. The clinicopathological features

> and incubation period of iatrogenic CJD

> vary according to the route of transmission

> with, for example, a cerebellar

> syndrome and only limited cognitive

> impairment in human growth hormone

> related CJD. In CJD caused by corneal

> transplantation the clinical and pathological

> phenotype is similar to sCJD and

> the incubation periods in the three cases

> reported to date were 15 months,

> 18 months, and 30 years.6 13 The surveillance

> system for CJD in the United

> Kingdom is efficient at identifying cases

> as judged by annual incidence rates of

> sCJD of around one case per million,

> and it is likely that cases with a typical

> phenotype would be identified. The

> period of observation of CJD from 1990

> to 2002, with additional information

> from 1980 9, suggests that there is the

> potential to identify case to case transmission

> through past eye surgery, with

> the assumption that the incubation

> period of such cases would be months

> or years rather than decades. It is,

> however, important to emphasise that

> a significant proportion of the eye

> operations were carried out relatively

> recently and, if the incubation period

> were extended, onward transmission

> may not have been identified by this

> study.

> Evidence of transmission of sCJD

> through contaminated neurosurgical

> instruments rests on the close temporal

> relation between operations carried out

> on CJD cases and unaffected individuals

> who subsequently developed CJD.14 15

> An analysis of the dates and sites of

> eye operations in cases of sCJD in this

> study showed no such relation. The

> elegant experiments by Weismann et

> al9 raise the possibility that surgical

> instruments contaminated during neurosurgery

> might pose a significant risk

> of iatrogenic transmission. In this context

> it is of interest that a number of

> cases of sporadic (and iatrogenic) CJD

> have undergone brain surgery (12/400

> cases in the European study), but there

> is no evidence from case-control studies

> that previous neurosurgery increases the

> risk of developing sporadic CJD. This is

> despite the fact that potentially contaminated

> neurosurgical instruments

> have inadvertently been reused on other

> patients on a number of occasions.

> The 10 cases of sCJD undergoing eye

> surgery in the early clinical stages of the

> illness may represent the greatest risk of

> onward transmission of infection,

> because there are probably higher levels

> of infection in the eye late in the

> incubation period as a result of centrifugal

> spread of infection along the optic

> nerve.4 The diagnosis of sCJD can be

> very difficult in the early stages of the

> clinical illness and this is particularly

> true of cases with isolated cortical visual

> symptoms (the Heidenhain variant of

> sCJD), which affected four of these 10

> cases. The presence of confusion, memory

> impairment, or other neurological

> signs may raise the suspicion of a

> neurodegenerative disorder.

> The data on vCJD are limited and the

> period of observation is shorter than in

> sCJD. Although there is currently no

> evidence of transmission of vCJD

> through contaminated ophthalmic

> instruments, this possibility cannot be

> excluded, not least because the incubation

> period in vCJD is unknown.

> Furthermore, in vCJD the presence of

> prion protein (PrP) immunostaining in

> systemic lymphoreticular tissues suggests

> that the risk from contaminated

> surgical instruments may be greater

> than in sCJD, in which these tissues

> do not stain for PrP, using comparable

> methods.

> The data from our case-control study

> show no significant risk related to a

> history of eye surgery in sCJD in

> comparison with two control groups.

> The methodology of the case-control

> study in our analysis is not ideal. There

> is a deficit in the numbers of controls in

> comparison with the numbers of cases

> and an unmatched analysis was undertaken.

> The results of our study are,

> however, consistent with the results of

> a previous case-control study in

> Europe,12 but contrast with the results

> of an Australian study in which previous

> cataract/eye surgery was associated with

> a more than sixfold increase in the risk

> of sCJD.16 The studies used different

> types of control group, the European

> study hospital controls and the

> Australian study community controls.

> However, in a reanalysis of the

> European data using a community control

> group, eye surgery was again found

> not to increase the risk of sporadic

> CJD.11 The disparity in outcome in the

> two studies relates primarily to the

> frequency of previous eye surgery in

> the control groups (European studies

> 34/406, 8% , 37/325, 11%: Australian 24/

> 784, 3%) rather than the cases

> (European studies 33/401, 8%, 37/328,

> 11%: Australian 24/241, 10%). Although

> this type of study cannot exclude the

> possibility of rare instances of iatrogenic

> transmission of CJD through eye

> surgery, the balance of evidence does

> not support the hypothesis that exposure

> to potentially contaminated

> ophthalmic instruments has, hitherto,

> been associated with the risk of developing

> CJD.

> Although the evidence in this paper

> does not suggest that contaminated

> ophthalmic instruments represent a

> risk of onward transmission of sporadic

> CJD, this conclusion should be treated

> with caution. The eye contains significant

> levels of infection in sCJD and

> vCJD, and even limited exposures can

> result in the iatrogenic transmission of

> CJD.17

> This paper confirms that ophthalmologists

> may be involved in treating

> patients in the early stages of CJD and

> it is essential to follow current guidelines

> in relation to surgical, including

> ophthalmic and neurosurgical, instruments

> used in suspect cases of CJD of all

> types.18 Such instruments should be

> destroyed or quarantined until a definitive

> diagnosis is available and the

> development of single use devices and

> instruments in eye surgery has been

> advocated,19 provided these do not prejudice

> clinical outcome. All cases of

> suspect CJD should be reported to the

> local consultant in communicable disease

> control in order that appropriate

> measures to protect public health

> are instituted, including a review of

> previous surgery. Advice on specific

> cases which raise concern is available

> fromthe CJD incidents panel (www.doh.

> gov.uk/cjd/incidentspanel.htm), which

> has published a consultation document

> (www.doh.gov.uk/cjd/consultation).

> ACKNOWLEDGEMENTS

> We would like to thank Dr JF Geddes and

> Miss Gillian Adams, FRCS, for their help in

> confirming some of the clinical details. PS-J

> was supported by the postMIR grant

> Wenceslao Lopez Albo from the IFIMAV

> Institute of the Fundacio´n Pu´blica Marque´s

> de Valdecilla. The National CJD Surveillance

> Unit is funded by the Department of

> Health and the Scottish Executive Health

> Department.

> Br J Ophthalmol 2004;88:446 449.

> doi: 10.1136/bjo.2003.028373

> Authors affiliations

> . . . . . . . . . . . . . . . . . . . . . .

> P S-Juan, H J T Ward, R S G Knight, R G Will,

> The National CJD Surveillance Unit, Western

> General Hospital, Edinburgh EH4 2XU, UK

> R De Silva, Oldchurch Hospital, Romford, UK

> Correspondence to: R G Will, The National CJD

> Surveillance Unit, Western General Hospital,

> Edinburgh EH4 2XU, UK; r.g.will@ed.ac.uk

> Accepted for publication 19 August 2003

> REFERENCES

> 1 Brown P, Preece M, Brandel JP, et al. Creutzfeldt-

> Jakob disease at the millennium. Neurology

> 2000;55:1075 81.

> 2 Brown P, Gibbs CJ, Rodgers-Johnson P, et al.

> Human spongiform encephalopathy: The

> National Institutes of Health Series of 300 cases of

> experimentally transmitted disease. Ann Neurol

> 1994;35:513 29.

> 3 Wadsworth JD, Joiner S, Hill AF, et al. Tissue

> distribution of protease resistant prion protein in

> variant Creutzfeldt-Jakob disease using a highly

> sensitive immunoblotting assay. Lancet

> 2001;358:171 80.

> 448 COMMENTARY

> www.bjophthalmol.com

> 4 Head MW, Northcott V, Rennison K, et al. Prion

> protein accumulation in eyes of patients with

> sporadic and variant Creutzfeldt-Jakob disease.

> Invest Ophthalmol Vis Sci 2002;44:342 6.

> 5 Lueck CJ, McIlwaine GG, Zeidler M. Creutzfeldt-

> Jakob disease and the eye. I Background and

> patient management. Eye 2000;14:263 90.

> 6 Hogan RN, Brown P, Heck E, et al. Risk of prion

> disease transmission from ocular donor tissue

> transplantation. Cornea 1999;18:2 11.

> 7 Scott JR, Foster JD, Fraser H. Conjunctival

> instillation of scrapie in mice can produce disease.

> Vet Microbiol 1993;34:305 9.

> 8 Manuelidis EE, Angelo JN, Gorgacz EJ, et al.

> Experimental Creutzfeldt-Jakob disease

> transmitted via the eye with infected cornea.

> N Eng J Med 1977;296:1334 6.

> 9 Weissmann C, Enari M, Klohn P-C, et al.

> Transmission of prions. J Infect Dis

> 2002;186:S157 65.

> 10 Cousens SN, Zeidler M, Esmonde TF, et al.

> Sporadic Creutzfeldt-Jakob disease in the United

> Kingdom: analysis of epidemiological

> surveillance data for 1970 76. BMJ

> 1997;315:389 95.

> 11 Ward HJT, Everington D, Croes EA, et al.

> Sporadic Creutzfeldt-Jakob disease and surgery:

> a case control study using community controls.

> Neurology 2002;59:543 8.

> 12 Van Duijn CM, Delasnerie-LaupreÆtre N,

> Masullo C, et al. Case control study of risk factors

> of Creutzfeldt-Jakob disease in Europe during

> 1993 95. Lancet 1998;351:1081 5.

> 13 Heckmann JG, Lang CJG, Petruch F, et al.

> Transmission of Creutzfeldt-Jakob disease via

> corneal transplant. J Neurol Neurosurg Psychiatry

> 1997;63:388 90.

> 14 Will RG, Matthews WB. Evidence for case-tocase-

> transmission of Creutzfeldt-Jakob disease.

> J Neurol Neurosurg Psychiatry 1982;45:235 8.

> 15 Foncin JF, Gaches J, Cathala F, et al. Transmission

> iatrogene interhumaine possible de maladie

> de Creutzfeldt-Jakob avec atteinte des grains de

> cervelet. Rev Neurol (Paris) 1980;136:280.

> 16 Collins S, Law MG, Fletcher A, et al. Surgical

> treatment and risk of sporadic Creutzfeldt-Jakob

> disease: a case-control study. Lancet

> 1999;353:693 7.

> 17 Croes EA, Roks CMAA, Jansen GH, et al.

> Creutzfeldt-Jakob disease 38 years after

> diagnostic use of human growth hormone.

> J Neurol Neurosurg Psychiatry 2002;72:792 3.

> 18 Department of Health. Transmissible spongiform

> encephalopathy agents: safe working and the

> prevention of infection: publication of revised

> ACDP/SEAC guidance. London: DoH, June 2003

> (www.doh.gov.uk/cjd/tseguidance).

> 19 Tullo A. Creutzfeldt-Jakob disease and eye

> surgery new disease, old disease. J Cataract

> Refract Surg 2003;29:629 31.

> The lighter

> side...................................................................................

> EMichael Balis.

> COMMENTARY 449

> www.bjophthalmol.com

> =====================

> Subject: RE-The Eyes Have It (cjd) and they could be stealing them from

> your loved one... "pay back time"

> Date: Sat, 16 Sep 2000 10:04:26 -0700

> From: "Terry S. Singeltary Sr."

> Reply-To: Bovine Spongiform Encephalopathy

> To: BSE-L

> Greetings List Members,

> I hate to keep kicking a madcow, but this still is very disturbing

> to me. Not only for the recipient of the cornea's, but as well, for

> the people whom would be operated on, using the same tools that

> were used to put those stolen cornea's in the recipient with.

> No history of this donor or his family (re-ffi), or anything

> would be known, using stolen organs and or tissue's. I just think

> this is not only wrong, but very dangerous to a great many other

> people, as this is one of the most infectious tissues of TSE's. It seems

> that this practice of stealing organ/tissue happens more than we think.

> Anyway, the family of the victim which had their cornea's stolen, are

> now suing. In the example I used with my Mother, if 3 months before, she

> would have been in a catastrophic accident (car wreck, whatever), no

> autopsy (for whatever reason), no family (for whatever reason), she lay

> in the morgue, and after 4 hours, they come steal the cornea's, lot of

> people could have been infected, just because of lack of medical history

> of donor/family. It may be hypothetical, but very real. We need to stop

> the spread of this disease.

> kind regards,

> Terry S. Singeltary Sr., Bacliff, Texas USA

> ===========================================

> Previous story--

> Cadaver corneal transplants -- without family permission...

> http://www.mad-cow.org/~tom/dec99_news.html#bbb

> ===============================================

> Sept. 15, 2000, 11:39PM

> Slain woman's family sues over

> missing eyes

> By BILL MURPHY

> The family of a woman who was stabbed to death last year has

> filed a lawsuit accusing the Lions Eye Bank of Houston of

> removing the woman's eyes without permission and inserting

> plastic discs in their place.

> Daisy Diaz's relatives were horrified when they saw her body

> and noticed her eyes were missing, said their lawyer, Duncan

> Neblett III.

> "They're a Catholic family," Neblett said. "They have strong

> beliefs about the body and burial. They were really upset by

> this."

> Dorey Zidrow, the eye bank's spokeswoman, said she could

> not specifically discuss the Diaz case because it was in litigation.

> But Zidrow said a state law allows doctors to remove corneas

> -- the dime-sized lens near the eye's surface -- from a corpse

> without the family's permission.

> The eye bank's usual procedure calls for removing the corneas,

> Zidrow said, but not the entire eyes.

> "There are an awful lot of people who benefit from this program

> in the state of Texas," she said.

> Diaz, 25, was stabbed to death in her apartment in the 400

> block of Thornton in October. Her brother-in-law, 30-year-old

> Raudel Quiroz, is charged in the killing but has not been caught.

> Neblett said authorities have told him Quiroz may have returned

> to his native Guatemala.

> Neither Diaz nor her family had given permission to donate any

> of her organs, Neblett said.

> Although state law allows corneas to be removed from corpses

> without first gaining the family's permission, they cannot be

> removed over the family's stated objection.

> The eye bank is located at, and staffed by, the Baylor College

> of Medicine, and receives part of its funding from the Lions

> Club.

> The Diaz lawsuit is the second such suit to be filed against the

> eye bank in recent years.

> The family of Levi Perry Jr., a Houston teacher shot to death in

> MacGregor Park in 1994, also alleged in their suit that Perry's

> eyes were removed. The family was awarded $345,000 from

> the eye bank in April 1999.

> http://www.chron.com/cs/CDA/story.hts/metropolitan/669555

> ==========================================================

> THE LEGALITY OF STEALING ORGAN/TISSUE...

> TEXAS STATUTES

> Sec. 693.012. Removal of Corneal Tissue Permitted Under Certain

> Circumstances.

> snip...

> Search 1999 Legislation for: 693.014

> [[[as you can see, they knew it was wrong when they wrote the laws. or

> they would not have covered the rear-ends so well...TSS]]]

> ---------------------------------------------------------

> thanks again,

> kind regards,

> Terry S. Singeltary Sr.

United States Senate

HEALTH, EDUCATION, LABOR, AND PENSIONS COMMITTEE

Patty Murray, Ranking Member

Minority Staff Report January 13, 2016

Thursday, January 14, 2016

*** Preventable Tragedies: Superbugs and How Ineffective Monitoring of Medical Device Safety Fails Patients REPORT ***

*** how can it be, HOW CAN IT BE $$$ not a word about CJD GSS FFI VPSPR TSE Prions that I saw...absolutely crazy, WE ARE MISSING THE BIGGER PICTURE!

how many victims that will never be reported ???

http://transmissiblespongiformencephalopathy.blogspot.com/2016/01/preventable-tragedies-superbugs-and-how.html

Sunday, October 18, 2015

World Organisation for Animal Health (OIE) and the Institut Pasteur Cooperating on animal disease and zoonosis research

http://bovineprp.blogspot.com/2015/10/world-organisation-for-animal-health.html

Saturday, December 12, 2015

*** BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION REPORT DECEMBER 14, 2015

http://bovineprp.blogspot.com/2015/12/bovine-spongiform-encephalopathy-bse.html

Thursday, December 17, 2015

Annual report of the Scientific Network on BSE-TSE 2015 EFSA-Q-2015-00738 10 December 2015

http://efsaopinionbseanimalprotein.blogspot.com/2015/12/annual-report-of-scientific-network-on.html

Friday, January 1, 2016

South Korea Lifts Ban on Beef, Veal Imports From Canada

http://usdavskorea.blogspot.com/2016/01/south-korea-lifts-ban-on-beef-veal.html

US CONGRESS, another failed entity...tss

Tuesday, December 29, 2015

*** Congress repeals country-of-origin labeling rule for beef and pork

http://naiscoolyes.blogspot.com/2015/12/congress-repeals-country-of-origin.html

December 28, 2015 at 2:21am

*** Australian government assessing risk of importing beef from US, Japan and the Netherlands

http://justgroundsonline.com/profiles/blogs/australian-government-assessing-risk-of-importing-beef-from-us?xg_source=msg_appr_blogpost

Thursday, December 24, 2015

Infectious disease spread is fueled by international trade

http://transmissiblespongiformencephalopathy.blogspot.com/2015/12/infectious-disease-spread-is-fueled-by.html

*** you can find some history of the BSE cases in Canada and Klein’s BSE SSS policy comment here ;

http://usdavskorea.blogspot.com/2016/01/south-korea-lifts-ban-on-beef-veal.html

Thursday, January 14, 2016

*** EMERGING ANIMAL DISEASES Actions Needed to Better Position USDA to Address Future Risks Report to the Chairman, Committee on Energy and Commerce, House of Representatives December 2015 GAO-16-132

GAO

http://animalhealthreportpriontse.blogspot.com/2016/01/emerging-animal-diseases-actions-needed_14.html

Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html

07 02:27 AM

Terry S. Singeltary Sr. said:

re-Evidence for human transmission of amyloid-? pathology and cerebral amyloid angiopathy

Nature 525, 247?250 (10 September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14 August 2015 Published online 09 September 2015 Updated online 11 September 2015 Erratum (October, 2015)

http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html

*** I would kindly like to comment on the Nature Paper, the Lancet reply, and the newspaper articles.

snip...see full text ;

http://www.nature.com/nature/journal/v525/n7568/full/nature15369.html#/comments

Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN

BSE101/1 0136

IN CONFIDENCE

CMO

From: . Dr J S Metiers DCMO

4 November 1992

TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES

1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have recognised the public sensitivity of these findings and intend to report them in their proper context. 'This hopefully will avoid misunderstanding and possible distortion by the media to portray the results as having more greater significance than the findings so far justify.

2. Using a highly unusual route of transmission (intra-cerebral injection) the researchers have demonstrated the transmission of a pathological process from two cases one of severe Alzheimer's disease the other of Gerstmann-Straussler disease to marmosets. However they have not demonstrated the transmission of either clinical condition as the "animals were behaving normally when killed". As the report emphasises the unanswered question is whether the disease condition would have revealed itself if the marmosets had lived longer. They are planning further research to see if the conditions, as opposed to the partial pathological process, is transmissible.

what are the implications for public health?

3. The route 'of transmission is very specific and in the natural state of things highly unusual. However it could be argued that the results reveal a potential risk, in that brain tissue from these two patients has been shown to transmit a pathological process. Should therefore brain tissue from such cases be regarded as potentially infective? Pathologists, morticians, neuro surgeons and those assisting at neuro surgical procedures and others coming into contact with "raw" human brain tissue could in theory be at risk. However, on a priori grounds given the highly specific route of transmission in these experiments that risk must be negligible if the usual precautions for handling brain tissue are observed.

92/11.4/1.1

BSE101/1 0137

4. The other dimension to consider is the public reaction. To some extent the GSS case demonstrates little more than the transmission of BSE to a pig by intra-cerebral injection. If other prion diseases can be transmitted in this way it is little surprise that some pathological findings observed in GSS were also transmissible to a marmoset. But the transmission of features of Alzheimer's pathology is a different matter, given the much greater frequency of this disease and raises the unanswered question whether some cases are the result of a transmissible prion. The only tenable public line will be that "more research is required’’ before that hypothesis could be evaluated. The possibility on a transmissible prion remains open. In the meantime MRC needs carefully to consider the range and sequence of studies needed to follow through from the preliminary observations in these two cases. Not a particularly comfortable message, but until we know more about the causation of Alzheimer's disease the total reassurance is not practical.

J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832 llllYc!eS 2 92/11.4/1.2

http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf

>>> The only tenable public line will be that "more research is required’’ <<<

>>> possibility on a transmissible prion remains open<<<

O.K., so it’s about 23 years later, so somebody please tell me, when is "more research is required’’ enough time for evaluation ?

Self-Propagative Replication of Ab Oligomers Suggests Potential Transmissibility in Alzheimer Disease

Received July 24, 2014; Accepted September 16, 2014; Published November 3, 2014

http://www.plosone.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pone.0111492&representation=PDF

*** Singeltary comment PLoS ***

*** Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion disease, Iatrogenic, what if ?

Posted by flounder on 05 Nov 2014 at 21:27 GMT

http://www.plosone.org/annotation/listThread.action?root=82860

please see ;

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***

===============

https://prion2015.files.wordpress.com/2015/05/prion2015abstracts.pdf

snip...see ;

Monday, November 16, 2015

*** Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats Terry Singeltary Sr. Submission ***

http://www.regulations.gov/#!documentDetail;D=APHIS-2007-0127-0032

http://scrapie-usa.blogspot.com/2015/11/docket-no-aphis-2007-0127-scrapie-in.html

==========================================

***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.

==========================================

PRION 2015 CONFERENCE FT. COLLINS CWD RISK FACTORS TO HUMANS

*** LATE-BREAKING ABSTRACTS PRION 2015 CONFERENCE ***

O18

Zoonotic Potential of CWD Prions

Liuting Qing1, Ignazio Cali1,2, Jue Yuan1, Shenghai Huang3, Diane Kofskey1, Pierluigi Gambetti1, Wenquan Zou1, Qingzhong Kong1 1Case Western Reserve University, Cleveland, Ohio, USA, 2Second University of Naples, Naples, Italy, 3Encore Health Resources, Houston, Texas, USA

*** These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.

==================

***These results indicate that the CWD prion has the potential to infect human CNS and peripheral lymphoid tissues and that there might be asymptomatic human carriers of CWD infection.***

==================

P.105: RT-QuIC models trans-species prion transmission

Kristen Davenport, Davin Henderson, Candace Mathiason, and Edward Hoover Prion Research Center; Colorado State University; Fort Collins, CO USA

Conversely, FSE maintained sufficient BSE characteristics to more efficiently convert bovine rPrP than feline rPrP. Additionally, human rPrP was competent for conversion by CWD and fCWD.

***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.

================

***This insinuates that, at the level of protein:protein interactions, the barrier preventing transmission of CWD to humans is less robust than previously estimated.***

================

https://prion2015.files.wordpress.com/2015/05/programguide1.pdf

CWD TSE Prion in cervids to hTGmice, Heidenhain Variant Creutzfeldt-Jacob Disease MM1 genotype, and iatrogenic CJD ???

P07 Behavioral Neurology: Aging and Dementia MRI More Useful Than PET for Diagnosis of Heidenhain Variant Creutzfeldt-Jacob Disease (P07.163)

Jonathan Beary1 and Edward Manno2 1 General Neurology, Neurological Institute Cleveland Clinic Cleveland OH 2 Cerebrovascular Neurology, Neurological Institute Cleveland Clinic Cleveland OH

DESIGN/METHODS: This is a case report with relevent neuroimaging review.

Disclosure: Dr. Beary has nothing to disclose. Dr. Manno has nothing to disclose.

http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/P07.163

> The presence of abnormal brain protease-resistant prion protein and MM1 genotype at autopsy supported the diagnosis of hvCJD.

Wednesday, January 01, 2014

Molecular Barriers to Zoonotic Transmission of Prions

*** chronic wasting disease, there was no absolute barrier to conversion of the human prion protein.

*** Furthermore, the form of human PrPres produced in this in vitro assay when seeded with CWD, resembles that found in the most common human prion disease, namely sCJD of the MM1 subtype.

http://wwwnc.cdc.gov/eid/article/20/1/13-0858_article.htm

http://chronic-wasting-disease.blogspot.com/2014/01/molecular-barriers-to-zoonotic.html

Subtype 1: (sCJDMM1 and sCJDMV1)

This subtype is observed in patients who are MM homozygous or MV heterozygous at codon 129 of the PrP gene (PRNP) and carry PrPSc Type 1. Clinical duration is short, 3‑4 months.32 The most common presentation in sCJDMM1 patients is cognitive impairment leading to frank dementia, gait or limb ataxia, myoclonic jerks and visual signs leading to cortical blindness (Heidenhain’s syndrome)...

https://www.landesbioscience.com/pdf/06Ahmad_Liberski.pdf

Animals injected with iatrogenic Creutzfeldt–Jakob disease MM1 and genetic Creutzfeldt–Jakob disease MM1 linked to the E200K mutation showed the same phenotypic features as those infected with sporadic Creutzfeldt–Jakob disease MM1 prions...

http://brain.oxfordjournals.org/content/early/2010/09/07/brain.awq234.full.pdf

*** our results raise the possibility that CJD cases classified as VV1 may include cases caused by iatrogenic transmission of sCJD-MM1 prions or food-borne infection by type 1 prions from animals, e.g., chronic wasting disease prions in cervid. In fact, two CJD-VV1 patients who hunted deer or consumed venison have been reported (40, 41). The results of the present study emphasize the need for traceback studies and careful re-examination of the biochemical properties of sCJD-VV1 prions. ***

http://www.jbc.org/cgi/content/abstract/M704597200v1?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=Cross-sequence+transmission+of+sporadic+Creutzfeldt-Jakob+disease+creates+a+new+&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

snip...see full text ;

http://transmissiblespongiformencephalopathy.blogspot.com/2011/01/agent-strain-variation-in-human-prion.html

Wednesday, June 16, 2010

Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties

The epidemiological findings in sCJD demonstrate that approximately 80% of patients are diagnosed with “classic CJD” types MM1 and MV1, which might intriguingly suggest an infectious rather than genetic origin for the majority of sCJD cases.

snip...

Therefore if sCJD(MV2) and sCJD(VV2) were to become iatrogenic sources of human infection, the host response may be indistinguishable from sCJD(MM1) and more transmissible with respect to further infection.

END...TSS

http://creutzfeldt-jakob-disease.blogspot.com/2010/06/defining-sporadic-creutzfeldt-jakob.html

*** Needless conflict ***

Nature 485, 279–280 (17 May 2012) doi:10.1038/485279b

Published online 16 May 2012

Terry S. Singeltary Sr. said:

I kindly wish to submit the following please ;

http://www.nature.com/nature/journal/v485/n7398/full/485279b.html

Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

Title: Transmission of scrapie prions to primate after an extended silent incubation period

Authors

item Comoy, Emmanuel - item Mikol, Jacqueline - item Luccantoni-Freire, Sophie - item Correia, Evelyne - item Lescoutra-Etchegaray, Nathalie - item Durand, Valérie - item Dehen, Capucine - item Andreoletti, Olivier - item Casalone, Cristina - item Richt, Juergen item Greenlee, Justin item Baron, Thierry - item Benestad, Sylvie - item Hills, Bob - item Brown, Paul - item Deslys, Jean-Philippe -

Submitted to: Scientific Reports Publication Type: Peer Reviewed Journal Publication Acceptance Date: May 28, 2015 Publication Date: June 30, 2015 Citation: Comoy, E.E., Mikol, J., Luccantoni-Freire, S., Correia, E., Lescoutra-Etchegaray, N., Durand, V., Dehen, C., Andreoletti, O., Casalone, C., Richt, J.A., Greenlee, J.J., Baron, T., Benestad, S., Brown, P., Deslys, J. 2015. Transmission of scrapie prions to primate after an extended silent incubation period. Scientific Reports. 5:11573.

Interpretive Summary:

The transmissible spongiform encephalopathies (also called prion diseases) are fatal neurodegenerative diseases that affect animals and humans. The agent of prion diseases is a misfolded form of the prion protein that is resistant to breakdown by the host cells. Since all mammals express prion protein on the surface of various cells such as neurons, all mammals are, in theory, capable of replicating prion diseases. One example of a prion disease, bovine spongiform encephalopathy (BSE; also called mad cow disease), has been shown to infect cattle, sheep, exotic undulates, cats, non-human primates, and humans when the new host is exposed to feeds or foods contaminated with the disease agent. The purpose of this study was to test whether non-human primates (cynomologous macaque) are susceptible to the agent of sheep scrapie. After an incubation period of approximately 10 years a macaque developed progressive clinical signs suggestive of neurologic disease. Upon postmortem examination and microscopic examination of tissues, there was a widespread distribution of lesions consistent with a transmissible spongiform encephalopathy. This information will have a scientific impact since it is the first study that demonstrates the transmission of scrapie to a non-human primate with a close genetic relationship to humans. This information is especially useful to regulatory officials and those involved with risk assessment of the potential transmission of animal prion diseases to humans.

Technical Abstract:

Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the past decades, c-BSE's zoonotic potential has been the driving force in establishing extensive protective measures for animal and human health. In 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

*** Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats Terry Singeltary Sr. Submission ***

Monday, November 16, 2015

*** Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats Terry Singeltary Sr. Submission ***

http://www.regulations.gov/#!documentDetail;D=APHIS-2007-0127-0032

http://scrapie-usa.blogspot.com/2015/11/docket-no-aphis-2007-0127-scrapie-in.html

98 | Veterinary Record | January 24, 2015

EDITORIAL

Scrapie: a particularly persistent pathogen

Cristina Acín

Resistant prions in the environment have been the sword of Damocles for scrapie control and eradication. Attempts to establish which physical and chemical agents could be applied to inactivate or moderate scrapie infectivity were initiated in the 1960s and 1970s,with the first study of this type focusing on the effect of heat treatment in reducing prion infectivity (Hunter and Millson 1964). Nowadays, most of the chemical procedures that aim to inactivate the prion protein are based on the method developed by Kimberlin and collaborators (1983). This procedure consists of treatment with 20,000 parts per million free chlorine solution, for a minimum of one hour, of all surfaces that need to be sterilised (in laboratories, lambing pens, slaughterhouses, and so on). Despite this, veterinarians and farmers may still ask a range of questions, such as ‘Is there an official procedure published somewhere?’ and ‘Is there an international organisation which recommends and defines the exact method of scrapie decontamination that must be applied?’

From a European perspective, it is difficult to find a treatment that could be applied, especially in relation to the disinfection of surfaces in lambing pens of affected flocks. A 999/2001 EU regulation on controlling spongiform encephalopathies (European Parliament and Council 2001) did not specify a particular decontamination measure to be used when an outbreak of scrapie is diagnosed. There is only a brief recommendation in Annex VII concerning the control and eradication of transmissible spongiform encephalopathies (TSE s).

Chapter B of the regulation explains the measures that must be applied if new caprine animals are to be introduced to a holding where a scrapie outbreak has previously been diagnosed. In that case, the statement indicates that caprine animals can be introduced ‘provided that a cleaning and disinfection of all animal housing on the premises has been carried out following destocking’.

Issues around cleaning and disinfection are common in prion prevention recommendations, but relevant authorities, veterinarians and farmers may have difficulties in finding the specific protocol which applies. The European Food and Safety Authority (EFSA ) published a detailed report about the efficacy of certain biocides, such as sodium hydroxide, sodium hypochlorite, guanidine and even a formulation of copper or iron metal ions in combination with hydrogen peroxide, against prions (EFSA 2009). The report was based on scientific evidence (Fichet and others 2004, Lemmer and others 2004, Gao and others 2006, Solassol and others 2006) but unfortunately the decontamination measures were not assessed under outbreak conditions.

The EFSA Panel on Biological Hazards recently published its conclusions on the scrapie situation in the EU after 10 years of monitoring and control of the disease in sheep and goats (EFSA 2014), and one of the most interesting findings was the Icelandic experience regarding the effect of disinfection in scrapie control. The Icelandic plan consisted of: culling scrapie-affected sheep or the whole flock in newly diagnosed outbreaks; deep cleaning and disinfection of stables, sheds, barns and equipment with high pressure washing followed by cleaning with 500 parts per million of hypochlorite; drying and treatment with 300 ppm of iodophor; and restocking was not permitted for at least two years. Even when all of these measures were implemented, scrapie recurred on several farms, indicating that the infectious agent survived for years in the environment, even as many as 16 years after restocking (Georgsson and others 2006).

In the rest of the countries considered in the EFSA (2014) report, recommendations for disinfection measures were not specifically defined at the government level. In the report, the only recommendation that is made for sheep is repopulation with sheep with scrapie-resistant genotypes. This reduces the risk of scrapie recurrence but it is difficult to know its effect on the infection.

Until the EFSA was established (in May 2003), scientific opinions about TSE s were provided by the Scientific Steering Committee (SSC) of the EC, whose advice regarding inactivation procedures focused on treating animal waste at high temperatures (150°C for three hours) and high pressure alkaline hydrolysis (SSC 2003). At the same time, the TSE Risk Management Subgroup of the Advisory Committee on Dangerous Pathogens (ACDP) in the UK published guidance on safe working and the prevention of TSE infection. Annex C of the ACDP report established that sodium hypochlorite was considered to be effective, but only if 20,000 ppm of available chlorine was present for at least one hour, which has practical limitations such as the release of chlorine gas, corrosion, incompatibility with formaldehyde, alcohols and acids, rapid inactivation of its active chemicals and the stability of dilutions (ACDP 2009).

In an international context, the World Organisation for Animal Health (OIE) does not recommend a specific disinfection protocol for prion agents in its Terrestrial Code or Manual. Chapter 4.13 of the Terrestrial Code, General recommendations on disinfection and disinsection (OIE 2014), focuses on foot-and-mouth disease virus, mycobacteria and Bacillus anthracis, but not on prion disinfection. Nevertheless, the last update published by the OIE on bovine spongiform encephalopathy (OIE 2012) indicates that few effective decontamination techniques are available to inactivate the agent on surfaces, and recommends the removal of all organic material and the use of sodium hydroxide, or a sodium hypochlorite solution containing 2 per cent available chlorine, for more than one hour at 20ºC.

The World Health Organization outlines guidelines for the control of TSE s, and also emphasises the importance of mechanically cleaning surfaces before disinfection with sodium hydroxide or sodium hypochlorite for one hour (WHO 1999).

Finally, the relevant agencies in both Canada and the USA suggest that the best treatments for surfaces potentially contaminated with prions are sodium hydroxide or sodium hypochlorite at 20,000 ppm. This is a 2 per cent solution, while most commercial household bleaches contain 5.25 per cent sodium hypochlorite. It is therefore recommended to dilute one part 5.25 per cent bleach with 1.5 parts water (CDC 2009, Canadian Food Inspection Agency 2013).

So what should we do about disinfection against prions? First, it is suggested that a single protocol be created by international authorities to homogenise inactivation procedures and enable their application in all scrapie-affected countries. Sodium hypochlorite with 20,000 ppm of available chlorine seems to be the procedure used in most countries, as noted in a paper summarised on p 99 of this issue of Veterinary Record (Hawkins and others 2015). But are we totally sure of its effectiveness as a preventive measure in a scrapie outbreak? Would an in-depth study of the recurrence of scrapie disease be needed?

What we can conclude is that, if we want to fight prion diseases, and specifically classical scrapie, we must focus on the accuracy of diagnosis, monitoring and surveillance; appropriate animal identification and control of movements; and, in the end, have homogeneous and suitable protocols to decontaminate and disinfect lambing barns, sheds and equipment available to veterinarians and farmers. Finally, further investigations into the resistance of prion proteins in the diversity of environmental surfaces are required.

References

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98 | Veterinary Record | January 24, 2015

http://veterinaryrecord.bmj.com/content/176/4/97.extract

*** These results suggest that AA fibrils are relatively heat stable and that similar to prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA fibrils.

*** These findings may contribute to the prevention of AA fibril transmission through food materials to different animals and especially to humans.

New studies on the heat resistance of hamster-adapted scrapie agent: Threshold survival after ashing at 600°C suggests an inorganic template of replication

The infectious agents responsible for transmissible spongiform encephalopathy (TSE) are notoriously resistant to most physical and chemical methods used for inactivating pathogens, including heat. It has long been recognized, for example, that boiling is ineffective and that higher temperatures are most efficient when combined with steam under pressure (i.e., autoclaving). As a means of decontamination, dry heat is used only at the extremely high temperatures achieved during incineration, usually in excess of 600°C. It has been assumed, without proof, that incineration totally inactivates the agents of TSE, whether of human or animal origin.

http://www.pnas.org/content/97/7/3418.full

Prion Infected Meat-and-Bone Meal Is Still Infectious after Biodiesel Production

Histochemical analysis of hamster brains inoculated with the solid residue showed typical spongiform degeneration and vacuolation. Re-inoculation of these brains into a new cohort of hamsters led to onset of clinical scrapie symptoms within 75 days, suggesting that the specific infectivity of the prion protein was not changed during the biodiesel process. The biodiesel reaction cannot be considered a viable prion decontamination method for MBM, although we observed increased survival time of hamsters and reduced infectivity greater than 6 log orders in the solid MBM residue. Furthermore, results from our study compare for the first time prion detection by Western Blot versus an infectivity bioassay for analysis of biodiesel reaction products. We could show that biochemical analysis alone is insufficient for detection of prion infectivity after a biodiesel process.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493038/

Detection of protease-resistant cervid prion protein in water from a CWD-endemic area

The data presented here demonstrate that sPMCA can detect low levels of PrPCWD in the environment, corroborate previous biological and experimental data suggesting long term persistence of prions in the environment2,3 and imply that PrPCWD accumulation over time may contribute to transmission of CWD in areas where it has been endemic for decades. This work demonstrates the utility of sPMCA to evaluate other environmental water sources for PrPCWD, including smaller bodies of water such as vernal pools and wallows, where large numbers of cervids congregate and into which prions from infected animals may be shed and concentrated to infectious levels.

http://www.landesbioscience.com/journals/prion/NicholsPRION3-3.pdf

A Quantitative Assessment of the Amount of Prion Diverted to Category 1 Materials and Wastewater During Processing

Keywords:Abattoir;bovine spongiform encephalopathy;QRA;scrapie;TSE

In this article the development and parameterization of a quantitative assessment is described that estimates the amount of TSE infectivity that is present in a whole animal carcass (bovine spongiform encephalopathy [BSE] for cattle and classical/atypical scrapie for sheep and lambs) and the amounts that subsequently fall to the floor during processing at facilities that handle specified risk material (SRM). BSE in cattle was found to contain the most oral doses, with a mean of 9864 BO ID50s (310, 38840) in a whole carcass compared to a mean of 1851 OO ID50s (600, 4070) and 614 OO ID50s (155, 1509) for a sheep infected with classical and atypical scrapie, respectively. Lambs contained the least infectivity with a mean of 251 OO ID50s (83, 548) for classical scrapie and 1 OO ID50s (0.2, 2) for atypical scrapie. The highest amounts of infectivity falling to the floor and entering the drains from slaughtering a whole carcass at SRM facilities were found to be from cattle infected with BSE at rendering and large incineration facilities with 7.4 BO ID50s (0.1, 29), intermediate plants and small incinerators with a mean of 4.5 BO ID50s (0.1, 18), and collection centers, 3.6 BO ID50s (0.1, 14). The lowest amounts entering drains are from lambs infected with classical and atypical scrapie at intermediate plants and atypical scrapie at collection centers with a mean of 3 × 10−7 OO ID50s (2 × 10−8, 1 × 10−6) per carcass. The results of this model provide key inputs for the model in the companion paper published here.

http://onlinelibrary.wiley.com/doi/10.1111/j.1539-6924.2012.01922.x/abstract

*** Infectious agent of sheep scrapie may persist in the environment for at least 16 years ***

Gudmundur Georgsson1, Sigurdur Sigurdarson2 and Paul Brown3

http://jgv.sgmjournals.org/content/87/12/3737.full

PL1

Using in vitro prion replication for high sensitive detection of prions and prionlike proteins and for understanding mechanisms of transmission.

Claudio Soto

Mitchell Center for Alzheimer's diseases and related Brain disorders, Department of Neurology, University of Texas Medical School at Houston.

Prion and prion-like proteins are misfolded protein aggregates with the ability to selfpropagate to spread disease between cells, organs and in some cases across individuals. I n T r a n s m i s s i b l e s p o n g i f o r m encephalopathies (TSEs), prions are mostly composed by a misfolded form of the prion protein (PrPSc), which propagates by transmitting its misfolding to the normal prion protein (PrPC). The availability of a procedure to replicate prions in the laboratory may be important to study the mechanism of prion and prion-like spreading and to develop high sensitive detection of small quantities of misfolded proteins in biological fluids, tissues and environmental samples. Protein Misfolding Cyclic Amplification (PMCA) is a simple, fast and efficient methodology to mimic prion replication in the test tube. PMCA is a platform technology that may enable amplification of any prion-like misfolded protein aggregating through a seeding/nucleation process. In TSEs, PMCA is able to detect the equivalent of one single molecule of infectious PrPSc and propagate prions that maintain high infectivity, strain properties and species specificity. Using PMCA we have been able to detect PrPSc in blood and urine of experimentally infected animals and humans affected by vCJD with high sensitivity and specificity. Recently, we have expanded the principles of PMCA to amplify amyloid-beta (Aβ) and alphasynuclein (α-syn) aggregates implicated in Alzheimer's and Parkinson's diseases, respectively. Experiments are ongoing to study the utility of this technology to detect Aβ and α-syn aggregates in samples of CSF and blood from patients affected by these diseases.

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***Recently, we have been using PMCA to study the role of environmental prion contamination on the horizontal spreading of TSEs. These experiments have focused on the study of the interaction of prions with plants and environmentally relevant surfaces. Our results show that plants (both leaves and roots) bind tightly to prions present in brain extracts and excreta (urine and feces) and retain even small quantities of PrPSc for long periods of time. Strikingly, ingestion of prioncontaminated leaves and roots produced disease with a 100% attack rate and an incubation period not substantially longer than feeding animals directly with scrapie brain homogenate. Furthermore, plants can uptake prions from contaminated soil and transport them to different parts of the plant tissue (stem and leaves). Similarly, prions bind tightly to a variety of environmentally relevant surfaces, including stones, wood, metals, plastic, glass, cement, etc. Prion contaminated surfaces efficiently transmit prion disease when these materials were directly injected into the brain of animals and strikingly when the contaminated surfaces were just placed in the animal cage. These findings demonstrate that environmental materials can efficiently bind infectious prions and act as carriers of infectivity, suggesting that they may play an important role in the horizontal transmission of the disease.

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Since its invention 13 years ago, PMCA has helped to answer fundamental questions of prion propagation and has broad applications in research areas including the food industry, blood bank safety and human and veterinary disease diagnosis.

https://prion2015.files.wordpress.com/2015/05/programguide1.pdf

Wednesday, December 16, 2015

Objects in contact with classical scrapie sheep act as a reservoir for scrapie transmission

Timm Konold1*, Stephen A. C. Hawkins2, Lisa C. Thurston3, Ben C. Maddison4, Kevin C. Gough5, Anthony Duarte1 and Hugh A. Simmons1

1 Animal Sciences Unit, Animal and Plant Health Agency Weybridge, Addlestone, UK, 2 Pathology Department, Animal and Plant Health Agency Weybridge, Addlestone, UK, 3 Surveillance and Laboratory Services, Animal and Plant Health Agency Penrith, Penrith, UK, 4 ADAS UK, School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, UK, 5 School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, UK

Classical scrapie is an environmentally transmissible prion disease of sheep and goats. Prions can persist and remain potentially infectious in the environment for many years and thus pose a risk of infecting animals after re-stocking. In vitro studies using serial protein misfolding cyclic amplification (sPMCA) have suggested that objects on a scrapie affected sheep farm could contribute to disease transmission. This in vivo study aimed to determine the role of field furniture (water troughs, feeding troughs, fencing, and other objects that sheep may rub against) used by a scrapie-infected sheep flock as a vector for disease transmission to scrapie-free lambs with the prion protein genotype VRQ/VRQ, which is associated with high susceptibility to classical scrapie. When the field furniture was placed in clean accommodation, sheep became infected when exposed to either a water trough (four out of five) or to objects used for rubbing (four out of seven). This field furniture had been used by the scrapie-infected flock 8 weeks earlier and had previously been shown to harbor scrapie prions by sPMCA. Sheep also became infected (20 out of 23) through exposure to contaminated field furniture placed within pasture not used by scrapie-infected sheep for 40 months, even though swabs from this furniture tested negative by PMCA. This infection rate decreased (1 out of 12) on the same paddock after replacement with clean field furniture. Twelve grazing sheep exposed to field furniture not in contact with scrapie-infected sheep for 18 months remained scrapie free. The findings of this study highlight the role of field furniture used by scrapie-infected sheep to act as a reservoir for disease re-introduction although infectivity declines considerably if the field furniture has not been in contact with scrapie-infected sheep for several months. PMCA may not be as sensitive as VRQ/VRQ sheep to test for environmental contamination.

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Discussion

Classical scrapie is an environmentally transmissible disease because it has been reported in naïve, supposedly previously unexposed sheep placed in pastures formerly occupied by scrapie-infected sheep (4, 19, 20). Although the vector for disease transmission is not known, soil is likely to be an important reservoir for prions (2) where – based on studies in rodents – prions can adhere to minerals as a biologically active form (21) and remain infectious for more than 2 years (22). Similarly, chronic wasting disease (CWD) has re-occurred in mule deer housed in paddocks used by infected deer 2 years earlier, which was assumed to be through foraging and soil consumption (23).

Our study suggested that the risk of acquiring scrapie infection was greater through exposure to contaminated wooden, plastic, and metal surfaces via water or food troughs, fencing, and hurdles than through grazing. Drinking from a water trough used by the scrapie flock was sufficient to cause infection in sheep in a clean building. Exposure to fences and other objects used for rubbing also led to infection, which supported the hypothesis that skin may be a vector for disease transmission (9). The risk of these objects to cause infection was further demonstrated when 87% of 23 sheep presented with PrPSc in lymphoid tissue after grazing on one of the paddocks, which contained metal hurdles, a metal lamb creep and a water trough in contact with the scrapie flock up to 8 weeks earlier, whereas no infection had been demonstrated previously in sheep grazing on this paddock, when equipped with new fencing and field furniture. When the contaminated furniture and fencing were removed, the infection rate dropped significantly to 8% of 12 sheep, with soil of the paddock as the most likely source of infection caused by shedding of prions from the scrapie-infected sheep in this paddock up to a week earlier.

This study also indicated that the level of contamination of field furniture sufficient to cause infection was dependent on two factors: stage of incubation period and time of last use by scrapie-infected sheep. Drinking from a water trough that had been used by scrapie sheep in the predominantly pre-clinical phase did not appear to cause infection, whereas infection was shown in sheep drinking from the water trough used by scrapie sheep in the later stage of the disease. It is possible that contamination occurred through shedding of prions in saliva, which may have contaminated the surface of the water trough and subsequently the water when it was refilled. Contamination appeared to be sufficient to cause infection only if the trough was in contact with sheep that included clinical cases. Indeed, there is an increased risk of bodily fluid infectivity with disease progression in scrapie (24) and CWD (25) based on PrPSc detection by sPMCA. Although ultraviolet light and heat under natural conditions do not inactivate prions (26), furniture in contact with the scrapie flock, which was assumed to be sufficiently contaminated to cause infection, did not act as vector for disease if not used for 18 months, which suggest that the weathering process alone was sufficient to inactivate prions.

PrPSc detection by sPMCA is increasingly used as a surrogate for infectivity measurements by bioassay in sheep or mice. In this reported study, however, the levels of PrPSc present in the environment were below the limit of detection of the sPMCA method, yet were still sufficient to cause infection of in-contact animals. In the present study, the outdoor objects were removed from the infected flock 8 weeks prior to sampling and were positive by sPMCA at very low levels (2 out of 37 reactions). As this sPMCA assay also yielded 2 positive reactions out of 139 in samples from the scrapie-free farm, the sPMCA assay could not detect PrPSc on any of the objects above the background of the assay. False positive reactions with sPMCA at a low frequency associated with de novo formation of infectious prions have been reported (27, 28). This is in contrast to our previous study where we demonstrated that outdoor objects that had been in contact with the scrapie-infected flock up to 20 days prior to sampling harbored PrPSc that was detectable by sPMCA analysis [4 out of 15 reactions (12)] and was significantly more positive by the assay compared to analogous samples from the scrapie-free farm. This discrepancy could be due to the use of a different sPMCA substrate between the studies that may alter the efficiency of amplification of the environmental PrPSc. In addition, the present study had a longer timeframe between the objects being in contact with the infected flock and sampling, which may affect the levels of extractable PrPSc. Alternatively, there may be potentially patchy contamination of this furniture with PrPSc, which may have been missed by swabbing. The failure of sPMCA to detect CWD-associated PrP in saliva from clinically affected deer despite confirmation of infectivity in saliva-inoculated transgenic mice was associated with as yet unidentified inhibitors in saliva (29), and it is possible that the sensitivity of sPMCA is affected by other substances in the tested material. In addition, sampling of amplifiable PrPSc and subsequent detection by sPMCA may be more difficult from furniture exposed to weather, which is supported by the observation that PrPSc was detected by sPMCA more frequently in indoor than outdoor furniture (12). A recent experimental study has demonstrated that repeated cycles of drying and wetting of prion-contaminated soil, equivalent to what is expected under natural weathering conditions, could reduce PMCA amplification efficiency and extend the incubation period in hamsters inoculated with soil samples (30). This seems to apply also to this study even though the reduction in infectivity was more dramatic in the sPMCA assays than in the sheep model. Sheep were not kept until clinical end-point, which would have enabled us to compare incubation periods, but the lack of infection in sheep exposed to furniture that had not been in contact with scrapie sheep for a longer time period supports the hypothesis that prion degradation and subsequent loss of infectivity occurs even under natural conditions.

In conclusion, the results in the current study indicate that removal of furniture that had been in contact with scrapie-infected animals should be recommended, particularly since cleaning and decontamination may not effectively remove scrapie infectivity (31), even though infectivity declines considerably if the pasture and the field furniture have not been in contact with scrapie-infected sheep for several months. As sPMCA failed to detect PrPSc in furniture that was subjected to weathering, even though exposure led to infection in sheep, this method may not always be reliable in predicting the risk of scrapie infection through environmental contamination. These results suggest that the VRQ/VRQ sheep model may be more sensitive than sPMCA for the detection of environmentally associated scrapie, and suggest that extremely low levels of scrapie contamination are able to cause infection in susceptible sheep genotypes.

Keywords: classical scrapie, prion, transmissible spongiform encephalopathy, sheep, field furniture, reservoir, serial protein misfolding cyclic amplification

http://journal.frontiersin.org/article/10.3389/fvets.2015.00032/full

Wednesday, December 16, 2015

*** Objects in contact with classical scrapie sheep act as a reservoir for scrapie transmission

http://scrapie-usa.blogspot.com/2015/12/objects-in-contact-with-classical.html

Monday, January 4, 2016

Long live the OIE, or time to close the doors on a failed entity?

http://transmissiblespongiformencephalopathy.blogspot.com/2016/01/long-live-oie-or-time-to-close-doors-on.html

Saturday, December 12, 2015

CHRONIC WASTING DISEASE CWD TSE PRION REPORT DECEMBER 14, 2015

http://chronic-wasting-disease.blogspot.com/2015/12/chronic-wasting-disease-cwd-tse-prion.html

Sunday, January 17, 2016

Wisconsin Captive CWD Lotto Pays Out Again indemnity payment of $298,770 for 228 white-tailed deer killed on farm

http://chronic-wasting-disease.blogspot.com/2016/01/wisconsin-captive-cwd-lotto-pays-out.html

TEXAS MONTHLY CHRONIC WASTING DISEASE CWD JANUARY 2016 DEER BREEDERS STILL DON'T GET IT $

Chronic Wasting Unease

The emergence of a deadly disease has wildlife officials and deer breeders eyeing each other suspiciously.

http://chronic-wasting-disease.blogspot.com/2015/12/texas-monthly-chronic-wasting-disease.html

Sunday, January 17, 2016

Texas 10,000 deer in Texas tested for deadly disease CWD TSE, but not tested much in the most logical place, the five-mile radius around the Medina County captive-deer facility where it was discovered

http://chronic-wasting-disease.blogspot.com/2016/01/texas-10000-deer-in-texas-tested-for.html

December 28, 2015 at 2:21am

Australian government assessing risk of importing beef from US, Japan and the Netherlands

http://justgroundsonline.com/profiles/blogs/australian-government-assessing-risk-of-importing-beef-from-us?xg_source=msg_appr_blogpost

Terry S. Singeltary Sr.