hey bse-tester,
bse-tester wrote;
(Incubation periods can be such a pain!!)
amen, and what a lot of folks don't understand is the friendly fire from consumption of BSE/TSE tainted products.
have you seen this one BSE-tester;
Re: Predicting susceptibility and incubation time of human-to-human
transmission of vCJD
Subject: Predicting susceptibility and incubation time of human-to-human transmission of vCJD
Date: March 27, 2006 at 6:24 am PST
Lancet Neurology DOI:10.1016/S1474-4422(06)70413-6
Predicting susceptibility and incubation time of human-to-human transmission of vCJD
MT Bishop a, P Hart b, L Aitchison b, HN Baybutt b, C Plinston b, V Thomson b, NL Tuzi b, MW Head a, JW Ironside a, RG Will a and JC Manson b
Summary
Background
Identification of possible transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion has caused concern over spread of the disease within the human population. We aimed to model iatrogenic spread to enable a comparison of transmission efficiencies of vCJD and bovine spongiform encephalopathy (BSE) and an assessment of the effect of the codon-129 polymorphism on human susceptibility.
Methods
Mice were produced to express human or bovine prion protein (PrP) by direct replacement of the mouse PrP gene. Since the human PrP gene has variation at codon 129, with MM, VV, and MV genotypes, three inbred lines with an identical genetic background were produced to express human PrP with the codon-129 MM, MV, and VV genotypes. Mice were inoculated with BSE or vCJD and assessed for clinical and pathological signs of disease.
Findings
BSE was transmitted to the bovine line but did not transmit to the human lines. By contrast, vCJD was transmitted to all three human lines with different pathological characteristics for each genotype and a gradation of transmission efficiency from MM to MV to VV.
Interpretation
Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue.
Affiliations
a. National CJD Surveillance Unit, Bryan Matthews Building, Western General Hospital, Edinburgh, UK
b. Institute for Animal Health, Neuropathogenesis Unit, King's Buildings, Edinburgh, UK
Correspondence to: Prof J C Manson, Institute for Animal Health, Neuropathogenesis Unit, Ogston Building, King's Buildings, West Mains Road, Edinburgh EH9 3JF, UK
further into this study;
SNIP...
Discussion
Although the cattle BSE epidemic in the UK has
amounted to more than 180 000 cases since the 1980s,
the extent of the human vCJD epidemic has so far
remained limited with the total number of cases
worldwide currently at 190. One explanation for this
apparent discrepancy is that there exists a significant
species barrier between cattle and human beings, which
limits the susceptibility of the human population to
BSE. The data shown here suggest that this could
indeed be the case since BSE was readily transmissible
to the bovine transgenic mice but not to the human
transgenic mice. However, once BSE has passed
through human beings in the form of vCJD, the
transmissibility of this TSE strain is altered for the
human population.
All the human transgenic lines inoculated with BSE
were negative for TSE transmission, which suggests that
either the human transgenic lines are relatively resistant
to transmission of BSE or the incubation time is longer
than the length of the experiment (approximately
700 days). BSE transmission previously observed by
others, in human transgenic lines overexpressing the
human prion protein, could be due to overexpression of
the PrP gene and may not therefore give a true reflection
of the species barrier between BSE and human
beings.15,25,26 This apparent resistance of human transgenic
mice to BSE could be explained by a large species barrier
and this in turn could explain the low number of vCJD
cases in the human population.
vCJD was transmitted to all three human lines with
different pathological characteristics for each genotype,
and a gradation of transmission efficiency from MM to
MV to VV. The greater transmission efficiency in HuMM
mice suggests that homozygosity for methionine at
codon 129 leads to earlier onset of TSE-related
pathological features and clinical disease than for the
other two genotypes. The differences in PrPSc deposition
in the HuMM and HuMV lines suggest that the codon-
129 polymorphism in human beings is likely to affect
the distribution of PrPSc deposition in the brain.
Moreover, the similar numbers that scored positive for
PrP deposition in each of the MM and MV groups (11/15
and 11/13 respectively) suggest that the two genotypes
might be equally susceptible to vCJD, but with different
incubation periods. Titration experiments are needed to
fully compare the susceptibility of each line. The single
HuVV mouse positive for PrPSc shows that VV
individuals may be susceptible to vCJD with very long
incubation times, including a lengthy subclinical phase.
Transmission studies from all three genotype mice are
now underway to examine the infectious nature of the
disease and determine any alterations in the strain
characteristics on passage through human transgenic
mice. By contrast with published data suggesting that
VV individuals cannot propagate the vCJD biochemical
phenotype,15 the data presented here suggest that the
PrPSc type will remain a useful diagnostic feature of
secondary vCJD infection irrespective of codon-129
genotype, as has been observed for the two extant cases
of transfusion-associated vCJD infection. 5,27
Transmission of vCJD to the three lines of human
transgenic mice indicates that the human population
could be at significantly heightened risk of developing
disease after iatrogenic exposure to vCJD. Secondary
transmission of vCJD has partly removed the cattle-to-
human species barrier and has resulted in an agent that
can be transmitted from human to human with relative
efficiency. Transmission studies in cynomolgus macaques
provide further evidence for this agent adaptation as they
show reduction in incubation times after serial passage
of BSE.28 Our BSE inoculation at 10-1 dilution was
compared with vCJD inoculation at 10-2 because the latter
inoculum was found to be toxic to the mice at 10-1. Use of
a higher dose ofvCJD inoculum would have maintained
or increased the transmission efficiency of vCJD and
enhanced the current findings.
Our findings raise concerns relevant to the possibility
of secondary transmission of vCJD through blood
transfusion, fractionated blood products, or contaminated
surgical instruments. For this study mice were injected
intracerebrally, whereas the probable human exposure to
these agents is by peripheral routes (eg, oral or
intravenous), and thus human-to-human exposures
might be significantly less efficient. However, it is difficult
to know for sure what the practical implications might be
in human beings. Peripheral route challenge is in
progress; however, BSE transmission studies in primates
have shown the intravenous route to be as efficient as the
intracerebral route, with an extension of the incubation
time.28
Although all cases of vC]D up to now have been
observed in the MM genotype, this model of human-to-
human vCJD transmission suggests that other genotypes
are also susceptible. In our experimental setting, all
PRNP codon-129 genotypes are susceptible to vCJD
infection; however, progressive development of
pathological TSE features (vacuolation and PrP
deposition) is more rapid in the MM-genotype mice. An
explanation for this finding might be provided by in-vitro
conversion of recombinant human PrP by BSE and vCJD
agents, which has shown that PrP with methionine at
position 129 is more efficiently converted than PrP with
valine, and that conversion by vCJD is significantly more
efficient than by BSE.29 Long incubation periods during
which PrPSc is deposited predicts that, in human beings,
infection could be present in all genotypes for a significant
period before clinical onset. Incubation periods of more
than 30 years have been reported in the human TSE
disease kuru.30
The possibility that an MV or VV genotype could result
in a phenotype distinct from that recognised in vCJD
draws attention to the importance of systematic
assessment of the clinical, genetic, pathological, and
biochemical features of all human prion diseases. Our
findings indicate that for human-to-human vCJD infection
it should be assumed that all codon-129
genotype individuals (not just MM) can be infected, that
long incubation times can occur, and that a significant
level of subclinical disease might be present in the population.
Contributors
MTB, PH, and CP did immunocytochemical and western blot analysis;
JCM, NT, HNB, and LA produced the transgenic mouse lines; JWI
supplied vCJD case material and reviewed the neuropathology; VT did
the mouse inoculations; and MTB, PH, MWH, RGW, JWI, and JCM
prepared the manuscript.
Conflicts of interest
We have no conflicts of interest.
Acknowledgments
snip...
http://www.thelancet.com/journals/laneur/article/PIIS1474442206704136/abstra
ct?isEOP=true
TSS
----- Original Message -----
From: "Terry S. Singeltary Sr." <
[email protected]>
To: <
[email protected]>
Cc: <
[email protected]>
Sent: Monday, March 27, 2006 12:35 PM
Subject: [CJDVoice] Fw: Predicting susceptibility and incubation time of
human-to-human transmission of vCJD
>
> ----- Original Message -----
> From: "Terry S. Singeltary Sr." <
[email protected]>
> To: "Bovine Spongiform Encephalopathy" <
[email protected]>
> Sent: Monday, March 27, 2006 11:34 AM
> Subject: Re: Predicting susceptibility and incubation time of
human-to-human
> transmission of vCJD
>
>
> >
> > RECALLS AND FIELD CORRECTIONS: BIOLOGICS -- CLASS I
> >
> > _______________________________
> > PRODUCT
> > Human Tissue for Transplantation, Recall # B-0432-6:
> > a) Tricortical Wedge (R) 1.5 x 2.5 cm,
> > Freeze Dried Irradiated;
> > b) Tricortical Wedge ( L ) 1.7 x 3.0 cm,
> > Fresh Frozen Irradiated;
> > c) Cancellous Crushed 60.0 cc, Freeze Dried,
> > Irradiated;
> > d) Cancellous Crushed 30.0 cc Freeze Dried,
> > Irradiated;
> > e) Achilles Tendon OA ( R ) Fresh Frozen
> > Irradiated;
> > f) Achilles Tendon OA ( L ) Fresh Frozen
> > Irradiated;
> > g) Lumbar;
> > h) Cancellous Crushed 30.0 cc Fresh Frozen,
> > Irradiated
> > CODE
> > a) Tissue 04091-002;
> > b) Tissue 04113-003;
> > c) Tissues 04091-008, 04101-008, 04103-002,
> > 04103-003, 04105-003;
> > d) Tissues 04091-005, 04091-006, 04091-007,
> > 04101-006, 04101-007, 04102-004, 04102-005,
> > 04104-003, 04104-004, 04104-005, 04105-002,
> > 04109-003, 04109-004, 04120-004, 04124-003,
> > 04124-004, 04138-002, 04138-003, 04140-002,
> > 04143-002, 04143-003, 04146-001, 04152-001;
> > e) Tissues 04101-003, 04123-004;
> > f) Tissues 04101-004, 04123-003;
> > g) Tissues 03049-001, 03051-001, 04091-001,
> > 04102-001, 04103-001, 04104-001, 04105-001,
> > 04106-001, 04107-001, 04108-001, 04109-001,
> > 04113-001, 04120-001, 04122-001, 04123-001,
> > 04124-001;
> > h) Tissue 04108-002
> > RECALLING FIRM/MANUFACTURER
> > Recalling Firm: Central Texas Regional Blood & Tissue Center, Austin,
TX,
> by
> > telephone on October 4, 2005, and by letter dated October 11, 2005.
> > Manufacturer: Biomedical Tissue Services, Fort Lee, NJ, firm initiated
> > recall is ongoing.
> > REASON
> > Human tissues, procured from donors without adequate donor eligibility
> > determinations, were distributed.
> > VOLUME OF PRODUCT IN COMMERCE
> > 51 allografts
> > DISTRIBUTION
> > TX and CO
> >
> > PRODUCT
> > Human Corneal Tissues for Transplantation, Recall # B-0380-6
> > CODE
> > Tissues: CI044108 OD and CI044108 OS
> > RECALLING FIRM/MANUFACTURER
> > Michigan Eye Bank, Ann Arbor, MI, by letter dated November 22, 2005, and
> by
> > facsimile dated November 28, 2005. Firm initiated recall is complete.
> > REASON
> > Human Corneas, collected from an ineligible donor, were distributed.
> > VOLUME OF PRODUCT IN COMMERCE
> > 2 tissues
> > DISTRIBUTION
> > MI, CA and Germany
> >
> > _______________________________
> >
> > PRODUCT
> > a) Red Blood Cells Leukocytes Reduced,
> > Recall # B-0617-6;
> > b) Red Blood Cells (Apheresis) Leukocytes Reduced
> > (distributed as split product), Recall # B-0618-6;
> > c) Platelets Leukocytes Reduced, Recall # B-0619-6;
> > d) Fresh Frozen Plasma, Recall # B-0620-6;
> > e) Cryoprecipitated AHF, Recall # B-0621-6;
> > f) Plasma Cryoprecipitate Reduced, Recall # B-0622-6;
> > g) Recovered Plasma, Recall # B-0623-6
> > CODE
> > a) Unit numbers: 1136792, 1040212, 1011245;
> > b) Unit numbers: 1048247-1, 1048247-2;
> > c) Unit numbers: 1040212, 1011245;
> > d) Unit number: 1136792;
> > e) Unit numbers: 1040212, 1011245;
> > f) Unit number: 1040212;
> > g) Unit number: 1011245
> > RECALLING FIRM/MANUFACTURER
> > Hoxworth Blood Center, Cincinnati, OH, by letter dated September 6,
2005.
> > Firm initiated recall is complete.
> > REASON
> > Blood products, collected from a donor considered to be at increased
risk
> > for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
> > VOLUME OF PRODUCT IN COMMERCE
> > 12 units
> > DISTRIBUTION
> > OH and FL
> >
> > _______________________________
> >
> > END OF ENFORCEMENT REPORT FOR MARCH 1, 2006
> >
> > ###
> >
> > http://www.fda.gov/bbs/topics/enforce/2006/ENF00941.html
> >
> >
> > PRODUCT
> > Recovered Plasma, Recall # B-0643-6
> > CODE
> > Unit numbers: R170537, R165863, and R158308
> > RECALLING FIRM/MANUFACTURER
> > Puget Sound Blood Center, Seattle, WA, by facsimile on October 7, 2003.
> Firm
> > initiated recall is complete.
> > REASON
> > Blood products, which were collected from an unsuitable donor based on
> risk
> > factors for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
> > VOLUME OF PRODUCT IN COMMERCE
> > 3 units
> > DISTRIBUTION
> > Austria
> >
> >
> > END OF ENFORCEMENT REPORT FOR FEBRUARY 22, 2006
> >
> > ###
> >
> > http://www.fda.gov/bbs/topics/enforce/2006/ENF00940.html
> >
> >
> > PRODUCT
> > a) Product is 1.0 cc Regenaform® RT. SINGLE PATIENT
> > USE ONLY. Recall # Z-0481-06;
> > b) OPTEFORM Allografts of varying sizes. SINGLE PATIENT
> > USE ONLY. Recall # Z-0482-06;
> > c) Product is OPTEFORM Allograft Paste of varying sizes.
> > SINGLE PATIENT USE ONLY. Recall # Z-0483-06;
> > d) OPTEFORM® RT Moldable Allograft of varying sizes.
> > SINGLE PATIENT USE ONLY. Recall # Z-0484-06;
> > e) Osteofil + RT Allograft Paste in varying sizes.
> > SINGLE PATIENT USE ONLY. Recall # Z-0485-06;
> > f) Osteofil Allograft Paste (Bio) of varying sizes.
> > SINGLE PATIENT USE ONLY. Recall # Z-0486-06;
> > g) Osteofil IC Syringeable of varying sizes. SINGLE
> > PATIENT USE ONLY. Recall # 0487-06;
> > h) Osteofil ICM Moldable Strip of varying sizes.
> > SINGLE PATIENT USE ONLY. Recall # Z-0488-06;
> > i) Osteofil RT, ICM Allograft Paste of varying sizes.
> > SINGLE PATIENT USE ONLY. Recall # Z-0489-06;
> > j) OSTEOFIL® DBM Paste of varying sizes. SINGLE
> > PATIENT USE ONLY. Recall # Z-0490-06;
> > k) OsteoPack 3 FZ 22cc. SINGLE PATIENT USE ONLY.
> > Recall # Z-0491-06;
> > l) Regenafil IC. SINGLE PATIENT USE ONLY.
> > Recall # Z-0492-06;
> > m) REGENAFORM RT Allograft Paste, 1cc. SINGLE
> > PATIENT USE ONLY. Recall # Z-0493-06;
> > n) Product is REGENAFORM® Allograft Moldable Blocks,
> > of varying sizes. SINGLE PATIENT USE ONLY.
> > Recall # Z-0494-06;
> > o) Product is RTI Allograft Paste of varying sizes.
> > SINGLE PATIENT USE ONLY. Recall # Z-0495-06;
> > p) Product is REGENAFIL® Allograft Paste, Syringe,
> > 0.5cc. SINGLE PATIENT USE ONLY. Recall # 0496-06;
> > q) Product is 1.0cc flowable paste from donor
> > approved for distribution in Italy. SINGLE
> > PATIENT USE ONLY. Recall # Z-0497-06;
> > r) Product is OPTEFIL Allograft Paste of varying
> > sizes. SINGLE PATIENT USE ONLY. Recall
> > # Z-0498-06;
> > s) Product is OPTEFIL Allograft Paste, Syringe
> > of varying sizes. SINGLE PATIENT USE ONLY.
> > Recall # Z-0499-06;
> > t) Product is OPTEFORM® Allograft Full Disc,
> > 5 x 90mm, 32cc, Frozen. SINGLE PATIENT USE
> > ONLY, Recall # Z-0500-06;
> > u) Product is 2.0 cc Opteform® RT. SINGLE
> > PATIENT USE ONLY. Recall # Z-0501-06
> > CODE
> > 2879130 2879131 2879132 2879133 2879134 2879135 2879136 2879137 2879138
> > 2879139 2879350 2879351 2879352 2879353 2879354 2879355 2879440 2879441
> > 2879442 2879443 2879444 2879445 2879446 2879447 2879448 2879449 2879450
snip...end (to long and to many to post here...TSS)
TSS
