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From: TSS ()
Subject: Conversion of the BASE Prion Strain into the BSE Strain: The Origin of BSE?
Date: March 20, 2007 at 8:20 am PST

Conversion of the BASE Prion Strain into the BSE Strain: The Origin of BSE?
Raffaella Capobianco1, Cristina Casalone2, Silvia Suardi1, Michela Mangieri1, Claudia Miccolo1, Lucia Limido1, Marcella Catania1, Giacomina Rossi1, Giuseppe Di Fede1, Giorgio Giaccone1, Maria Grazia Bruzzone1, Ludovico Minati1, Cristiano Corona2, Pierluigi Acutis2, Daniela Gelmetti3, Guerino Lombardi3, Martin H. Groschup4, Anne Buschmann4, Gianluigi Zanusso5, Salvatore Monaco5, Maria Caramelli2, Fabrizio Tagliavini1*

1 Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milan, Italy, 2 Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Torino, Italy, 3 Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Brescia, Italy, 4 Friedrich-Loeffler-Institut, Institute for Novel and Emerging Infectious Diseases, Greifswald, Insel Riems, Germany, 5 Department of Neurological and Visual Science, Section of Clinical Neurology, Policlinico G. B. Rossi, Verona, Italy

Atypical neuropathological and molecular phenotypes of bovine spongiform encephalopathy (BSE) have recently been identified in different countries. One of these phenotypes, named bovine “amyloidotic” spongiform encephalopathy (BASE), differs from classical BSE for the occurrence of a distinct type of the disease-associated prion protein (PrP), termed PrPSc, and the presence of PrP amyloid plaques. Here, we show that the agents responsible for BSE and BASE possess different biological properties upon transmission to transgenic mice expressing bovine PrP and inbred lines of nontransgenic mice. Strikingly, serial passages of the BASE strain to nontransgenic mice induced a neuropathological and molecular disease phenotype indistinguishable from that of BSE-infected mice. The existence of more than one agent associated with prion disease in cattle and the ability of the BASE strain to convert into the BSE strain may have important implications with respect to the origin of BSE and spongiform encephalopathies in other species, including humans.

full text ;

http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.ppat.0030031

Greetings, how might the above study relate to the below studies ??? ...tss

Personal Communication


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

Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD

Date: Thu, 28 Nov 2002 10:23:43

-0000 From: "Asante, Emmanuel A" To: "'flounder@wt.net'"

Dear Terry,

I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead
author on the paper. I have attached a pdf copy of the paper for your attention.

Thank you for your interest in the paper.

In respect of your first question, the simple answer is, yes. As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD. It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version. It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting. The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc.


I hope reading the paper will enlighten you more on the subject. If I can be of any further assistance please to not hesitate to ask.

Best wishes.

Emmanuel Asante

<> ____________________________________

Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics
Dept. Imperial

College School of Medicine (St. Mary's) Norfolk Place,
LONDON W2 1PG

Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email:

e.asante@ic.ac.uk (until 9/12/02)

New e-mail: e.asante@prion.ucl.ac.uk (active from now)

____________________________________


EMBO J. 2002 December 2; 21(23): 6358–6366.
doi: 10.1093/emboj/cdf653.

Copyright © 2002 European Molecular Biology Organization


BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein
Emmanuel A. Asante, Jacqueline M. Linehan, Melanie Desbruslais, Susan Joiner, Ian Gowland, Andrew L. Wood, Julie Welch, Andrew F. Hill, Sarah E. Lloyd, Jonathan D.F. Wadsworth, and John Collinge1

MRC Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College, Queen Square, London WC1N 3BG, UK 1Corresponding author e-mail: j.collinge@prion.ucl.ac.uk

Received August 1, 2002; Revised September 24, 2002; Accepted October 17, 2002.

Abstract

Variant Creutzfeldt–Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrPSc type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.


Keywords: BSE/Creutzfeldt–Jakob disease/prion/transgenic

snip...FULL TEXT ;

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12456643

Originally published in Science Express on 11 November 2004
Science 3 December 2004:
Vol. 306. no. 5702, pp. 1793 - 1796
DOI: 10.1126/science.1103932
Prev | Table of Contents | Next


Reports
Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype
Jonathan D. F. Wadsworth, Emmanuel A. Asante, Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner, Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd, Andrew F. Hill,* Sebastian Brandner, John Collinge

Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)–like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.

Medical Research Council (MRC) Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.


* Present address: Department of Biochemistry and Molecular Biology and Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.


To whom correspondence should be addressed. E-mail: j.collinge@prion.ucl.ac.uk

snip...

Although caution must be exercised in extrapolating from animal models, even where, as here, faithful recapitulation of molecular and pathological phenotypes is possible, our findings argue that primary human BSE prion infection, as well as secondary infection with vCJD prions by iatrogenic routes, may not be restricted to a single disease phenotype. These data, together with the recent recognition of probable iatrogenic transmission of vCJD prions to recipients of blood (21, 22), including a PRNP codon 129 Met/Val heterozygous individual (22), reiterate the need to stratify all human prion disease patients by PrPSc type. This surveillance will facilitate rapid recognition of novel PrPSc types and of any change in relative frequencies of particular PrPSc subtypes in relation to either BSE exposure patterns or iatrogenic sources of vCJD prions.

http://www.sciencemag.org/cgi/content/abstract/306/5702/1793

J Neuropsychiatry Clin Neurosci 17:489-495, November 2005
doi: 10.1176/appi.neuropsych.17.4.489
© 2005 American Psychiatric Publishing, Inc.


Psychiatric Manifestations of Creutzfeldt-Jakob
Disease: A 25-Year Analysis
Christopher A. Wall, M.D., Teresa A. Rummans, M.D.,
Allen J. Aksamit, M.D.,
Lois E. Krahn, M.D. and V. Shane Pankratz, Ph.D.
Received April 20, 2004; revised September 9, 2004;
accepted September 13,
2004. From the Mayo Clinic, Department of Psychiatry
and Psychology,
Rochester, Minnesota; Mayo Clinic, Department of
Neurology, Rochester,
Minnesota. Address correspondence to Dr. Wall, Mayo
Clinic, Department of
Psychiatry and Psychology, Mayo Building-W11A, 200
First St., SW, Rochester,
MN 55905; wall.chris@mayo.edu (E-mail).

This study characterizes the type and timing of
psychiatric manifestations
in sporadic Creutzfeldt-Jakob disease (sCJD).
Historically, sCJD has been
characterized by prominent neurological symptoms, while
the variant form
(vCJD) is described as primarily psychiatric in
presentation and course: A
retrospective review of 126 sCJD patients evaluated at
the Mayo Clinic from
1976-2001 was conducted. Cases were reviewed for
symptoms of depression,
anxiety, psychosis, behavior dyscontrol, sleep
disturbances, and
neurological signs during the disease course. Eighty
percent of the cases
demonstrated psychiatric symptoms within the first 100
days of illness, with
26% occurring at presentation. The most commonly
reported symptoms in this
population included sleep disturbances, psychotic
symptoms, and depression.
Psychiatric manifestations are an early and prominent
feature of sporadic
CJD, often occurring prior to formal diagnosis.


snip...


CONCLUSIONS

Historically, psychiatric manifestations have been
described as a relatively
infrequent occurrence in the sporadic form of
creutzfeldt-Jakob disease.
However, our findings suggest otherwise. In this study,
a vast majority of
the cases were noted to have at least one psychiatric
symptom during the
course of illness, with nearly one-quarter occurring in
the prodromal or
presenting phase of the illness. After comparing the
frequency of
neuropsychiatric symptoms in sporadic CJD to studies
describing the variant
form of CJD, we found that there are fewer clinical
differences than
previously reported.5-7 While the age of patients
with vCJD presentation
is significantly younger and the course of illness is
longer, the type and
timing of psychiatric manifestations appear similar
between these two
diseases. ...snip...


http://neuro.psychiatryonline.org/cgi/content/abstract/17/4/489

Coexistence of multiple PrPSc types in individuals with

Creutzfeldt-Jakob disease


Magdalini Polymenidou, Katharina Stoeck, Markus
Glatzel, Martin Vey, Anne Bellon, and Adriano Aguzzi


Summary


Background The molecular typing of sporadic
Creutzfeldt-Jakob disease (CJD) is based on the size
and glycoform

ratio of protease-resistant prion protein (PrPSc), and
on PRNP haplotype. On digestion with proteinase K, type
1 and

type 2 PrPSc display unglycosylated core fragments of
21 kDa and 19 kDa, resulting from cleavage around amino

acids 82 and 97, respectively.

Methods We generated anti-PrP monoclonal antibodies to
epitopes immediately preceding the differential proteinase

K cleavage sites. These antibodies, which were
designated POM2 and POM12, recognise type 1, but not
type 2, PrPSc.

Findings We studied 114 brain samples from 70 patients
with sporadic CJD and three patients with variant CJD.

Every patient classified as CJD type 2, and all variant
CJD patients, showed POM2/POM12 reactivity in the

cerebellum and other PrPSc-rich brain areas, with a
typical PrPSc type 1 migration pattern.

Interpretation The regular coexistence of multiple
PrPSc types in patients with CJD casts doubts on the
validity of

electrophoretic PrPSc mobilities as surrogates for
prion strains, and questions the rational basis of
current CJD

classifications.


snip...


The above results set the existing CJD classifications

into debate and introduce interesting questions about

human CJD types. For example, do human prion types

exist in a dynamic equilibrium in the brains of affected

individuals? Do they coexist in most or even all CJD

cases? Is the biochemically identified PrPSc type simply

the dominant type, and not the only PrPSc species?


Published online October 31, 2005


http://neurology.thelancet.com


18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7
December 2006 are now available.


snip...

64. A member noted that at the recent Neuroprion meeting, a study was
presented showing that in transgenic mice BSE passaged in sheep may be more
virulent and infectious to a wider range of species than bovine derived BSE.

Other work presented suggested that BSE and bovine amyloidotic spongiform
encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the
prion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO A
MUTATION FOUND IN CASES OF SPORADIC CJD.


snip...

http://www.seac.gov.uk/minutes/95.pdf


3:30 Transmission of the Italian Atypical BSE (BASE) in Humanized Mouse

Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve
University

Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain
discovered recently in Italy, and similar or different atypical BSE cases
were also reported in other countries. The infectivity and phenotypes of
these atypical BSE strains in humans are unknown. In collaboration with
Pierluigi Gambetti, as well as Maria Caramelli and her co-workers, we have
inoculated transgenic mice expressing human prion protein with brain
homogenates from BASE or BSE infected cattle. Our data shows that about half
of the BASE-inoculated mice became infected with an average incubation time
of about 19 months; in contrast, none of the BSE-inoculated mice appear to
be infected after more than 2 years.

***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent than
classical BSE in humans.***


6:30 Close of Day One


http://www.healthtech.com/2007/tse/day1.asp


SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...


http://www.cjdsurveillance.com/resources-casereport.html

There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance
collection.

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf


Subject: [Docket No. 03-025IFA] FSIS Prohibition of the Use of Specified Risk Materials for Human Food and Requirements for the Disposition of Non-Ambulatory Disabled Cattle

snip...

>> Differences in tissue distribution could require new regulations

>> regarding specific risk material (SRM) removal.

snip...end

full text 33 PAGES ;

http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf

http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf

It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture. 33 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre. 34 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle, did not produce the same clinical signs of brain lesions characteristic of BSE.

http://www.bseinquiry.gov.uk/

1: J Infect Dis. 1994 Apr;169(4):814-20.

Intracerebral transmission of scrapie to cattle.

Cutlip RC, Miller JM, Race RE, Jenny AL, Katz JB, Lehmkuhl HD, DeBey BM, Robinson MM.

USDA, Agriculture Research Service, National Animal Disease Center, Ames, IA 50010.

To determine if sheep scrapie agent(s) in the United States would induce a disease in cattle resembling bovine spongiform encephalopathy, 18 newborn calves were inoculated intracerebrally with a pooled suspension of brain from 9 sheep with scrapie. Half of the calves were euthanatized 1 year after inoculation. All calves kept longer than 1 year became severely lethargic and demonstrated clinical signs of motor neuron dysfunction that were manifest as progressive stiffness, posterior paresis, general weakness, and permanent recumbency. The incubation period was 14-18 months, and the clinical course was 1-5 months. The brain from each calf was examined for lesions and for protease-resistant prion protein. Lesions were subtle, but a disease-specific isoform of the prion protein was present in the brain of all calves. Neither signs nor lesions were characteristic of those for bovine spongiform encephalopathy.

MeSH Terms: Animals Brain/microbiology* Brain/pathology Cattle Cattle Diseases/etiology* Cattle Diseases/pathology Encephalopathy, Bovine Spongiform/etiology* Encephalopathy, Bovine Spongiform/pathology Immunoblotting/veterinary Immunohistochemistry Male Motor Neurons/physiology Prions/analysis Scrapie/pathology Scrapie/transmission* Sheep Sleep Stages Time Factors

Substances: Prions

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8133096&dopt=Citation

9/13/2005

Page 16 of 17

Intracerebral transmission of scrapie to cattle FULL TEXT PDF;

SNIP...

Discussion

WE conclude that American sources of sheep scrapie are transmissible to cattle by direct intracerebral inoculation but the disease induced is NOT identical to BSE as seen in the United Kingdom. While there were similarities in clinical signs between this experimental disease and BSE, there was no evidence of aggressiveness, hyperexcitability, hyperesthesia (tactile or auditory), or hyperemetria of limbs as has been reported for BSE (9). Neither were there extensive neurologic lesions, which are primary for BSE, such as severe vacuolation of neurons and neuropil or neuronal necrosis and gliosis. Although some vacuolation of neuropil, chromotolysis in neurons, and gliosis were seen in the brains of some affected calves, these were industinguishable from those of controls. Vacuolated neurons in the red nucleus of both challenged and normal calves were considered normal for the bovines as previously described (50).

PrP-res was found in ALL CHALLENGED CALVES REGARDLESS OF CLINCIAL SIGNS, and the amount of PrP-res positively related to the length of the incubation. ...

snip...

WE also conclude from these studies that scrapie in cattle MIGHT NOT BE RECOGNIZED BY ROUTINE HISTOPATHOLOGICAL EXAMINATION OF THE BRAIN AND SUGGEST THAT DETECTION OF PrP-res by immunohistochemistry or immunoblotting is necessary to make a definitive diagnosis. THUS, undiagnosed scrapie infection could contribute to the ''DOWNER-COW'' syndrome and could be responsible for some outbreaks of transmissible mink encephalopathy proposed by Burger and Hartsough

(8) and Marsh and harsough (52). ...

snip...

Multiple sources of sheep affected with scrapie and two breeds of cattle from several sources were used inthe current study in an effort to avoid a single strain of either agent or host. Preliminary results from mouse inoculations indicate multiple strains of the agent were present in the pooled inoculum (unpublished data). ...

Transmission of the sheep scrapie to cattle was attempted in 1979 by using intracerebral, intramuscular, subcutaneous, and oral routes of inoculation of 5, 8- to 11-month old cattlw with a homologous mixture of brain from 1 affected sheep (61, 62). ONE of the 5 cattle develped neurologic signs 48 months after inoculation. Signs were disorientation, incoordination, a stiff-legged stilted gait, progressive difficulty in rising, and finally in terminal recumbency. The clinical course was 2.5 months. TWO of the 5 cattle similarly inoculated with brain tissue from a goat with scrapie exhibited similar signs 27 and 36 months after incoluation. Clinical courses were 43 an 44 days. Brain lesions of mild gliosis and vacuolation and mouse inoculation data were insufficient to confirm a diagnosis of scrapie. This work remained controversial until recent examination of the brains detected PrP-res in all 3 cattle with neurologic disease but in none of the unaffected cattle (62). Results of these studies are similar to ours and underscore the necessity of methods other than histopathology to diagnose scrapie infection in cattle. We believe that immunologic techniques for detecting PrP-res currently provide the most sensitive and reliable way to make a definitive diagnosis...

http://www.bseinquiry.gov.uk/files/sc/seac17/tab03.pdf

Visit to USA ... info on BSE and Scrapie

http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf

http://www.ngpc.state.ne.us/cgi-bin/ultimatebb.cgi?ubb=get_topic;f=12;t=000385

12/10/76 AGRICULTURAL RESEARCH COUNCIL REPORT OF THE ADVISORY COMMITTE ON SCRAPIE

Office Note CHAIRMAN: PROFESSOR PETER WILDY

snip...

A The Present Position with respect to Scrapie A] The Problem

Scrapie is a natural disease of sheep and goats. It is a slow and inexorably progressive degenerative disorder of the nervous system and it ia fatal. It is enzootic in the United Kingdom but not in all countries.

The field problem has been reviewed by a MAFF working group (ARC 35/77). It is difficult to assess the incidence in Britain for a variety of reasons but the disease causes serious financial loss; it is estimated that it cost Swaledale breeders alone $l.7 M during the five years 1971-1975. A further inestimable loss arises from the closure of certain export markets, in particular those of the United States, to British sheep.

9/13/2005

Page 17 of 17

It is clear that scrapie in sheep is important commercially and for that reason alone effective measures to control it should be devised as quickly as possible.

Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"

Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.

snip...

76/10.12/4.6

http://www.bseinquiry.gov.uk/files/yb/1976/10/12004001.pdf

THE infamous USA SPORADIC CJDs, something to ponder;

IF the USA TSE in cattle all does not look like UK BSE, why would all USA human TSE look like UK nvCJD???

over 20 strains of scrapie documented to date with new atypical strains now being documented in sheep and goat i.e. BSE.

atypical strains of BSE/TSE showing up in cattle in different countries?

ALL animals for human/animal consumption must be tested for TSE.

ALL human TSEs must be made reportable Nationally and Internationally, OF ALL AGES...

IN a time when FSIS/APHIS/USDA/FDA et al should be strengthening the TSE regulations, it seems corporate interest has won out again over sound science and consumer protection from an agent that is 100% fatal for the ones that go clinical. With the many different atypical TSEs showing up in different parts of the world, and with GWs BSE MRR policy (the legal policy of trading all strains of TSEs), the battle that has waged for the last 25 years to eradicate this agent from this planet will be set back decades, if not lost for good. ...

Terry S. Singeltary Sr.

P.O. Box 42

Bacliff, Texas USA 77518

9/13/2005

kind regards,

terry

FULL TEXT ;

http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf

tss



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