most recent version of my CJD related presentation

4. Background The biggest TSE killer in humans is CJD, first identified in the 1920s by German neuropsychiatrists Alfons Jakob and Hans Creutzfeldt. Since then, painstaking detective work by scientists in the United States, Europe, Australia and Japan has followed the zigzag course of the disease. TSEs, or prion diseases, are not only infectious, they are also inheritable in a very small number of cases. They have no cure and no validated pre-mortem test, so absolute confirmation cannot be made until a post-mortem examination of the brain. However, developments over the last few years provide much encouragement. The most common form of the disease - Classical CJD - occurs at a rate of about one to two per million people in many countries annually, mainly (but not always) in older people. It has no known cause to date. As of Dec 2003 – vCJD has been proven to be transmitted via blood. Whatever the cause - a yet-to-be identified virus, Virino, or "prion" (a corrupted naturally occurring protein) - TSEs are among the worst diseases yet identified. The infective agent appears to bind to alcohol-based disinfectants and resists heating to phenomenal temperatures, freezing, burial underground for years, the strongest of chemicals and conventional surgical sterilisation.

5. Background and Current Day Issues CJD collectively was generally an “unheard of” condition until the advent of the emergence of vCJD in 1996 in the UK which “changed the landscape” of CJD Over the last few years, the level and depth of contact between a number of Support Groups has evolved, namely due to use of the Internet Many Support Groups are now linked to each other from their respective websites Sharing our experiences, knowledge, aspirations, concerns, achievements and goals should be encouraged Collaboration amongst researchers and scientists should be encouraged

6. Background and Current Day Issues Through the global unity that continues to grow, I firmly believe that by forming such a Global Alliance, these groups combined voice and strength for those who have lost, those current suffering from, and those sadly still to come in the future is and will always be really important. Graham Steel, 2005

9. FLAIR MR(I) IMAGING c CJD compared with v CJD Detection results on patient data. Left (1 and 2 ) a cCJD case with stronger hyperintensities in the head of caudate and putamen. Right (3 and 4) a vCJD case with stronger hyperintensities in the pulvinar. We present for each case an original cross-section of the FLAIR MR image with abnormal hyperintensities in the internal nuclei and next the same cross-section superimposed with the CJD detection map

12. Peripheral Nerve's (PN’s) and Dorsal Root Ganglion (DRG) Conditioned medium enhances axonal outgrowth from PN-DRGs. PN-DRGs after culture in collagen gels for 3 d, labeled with an antibody to PGP 9.5 (visualized with HRP conjugated avidin) taken using dark-ground illumination to make it easier to see fine axons at low magnification. In a control preparation ( A ) cultured in RPMI medium, only a few axons have grown out of the cut end of the peripheral nerve, whereas extensive axonal outgrowth has occurred from a preparation cultured inmedium conditioned by lesioned sciatic nerve segments ( B ). Scale bar, 200_m. DOI:10.1523/JNEUROSCI.5089-06.2007 Copyright©2007 Society for Neuroscience 0270-6474/07/271190-10$15.00/0

14. Neuropathologic characteristics of brainstem lesions in Classical Creutzfeldt-Jakob disease.

18. ORAL SCRAPIE SPREADS ALONG SPLANCHNIC AND VAGUS NERVES PATRICIA A. MCBRIDE,1* WALTER J. SCHULZ-SCHAEFFER,2† MAURA DONALDSON,1 MOIRA BRUCE,1 H. DIRINGER,3 HANS A. KRETZSCHMAR,2 AND MICHAEL BEEKES3

19. Blood Transfusion Sheep PrP d in brainstem after blood transfusion

23. Figure 4 | Initial pathways of transmissible spongiform encephalopathy (TSE) agent neuroinvasion from the intestine. Analysis of the progression of disease-specific prion protein (PrP) accumulation within the nervous system of experimentally inoculated rodents indicates that the scrapie agent spreads from the intestine to the central nervous system (CNS) through two distinct neuroanotomical pathways95. In each case, the initial spread occurs in a retrograde direction along efferent (motor) pathways in a stepwise manner between synaptically linked sets of nerves. One route to the CNS occurs along sympathetic fibres of the splanchnic nerve to the intermediolateral cell column (IML) of the mid-thoracic spinal cord. Subsequently, the agent spreads to the brain in a caudal-to-cranial direction along the spinal cord. Neuroinvasion from the intestine can also occur independently of the spinal cord. In this case, the agent spreads along parasympathetic fibres of the vagus nerve to the dorsal motor nucleus of the vagus nerve (DMNV) within the medulla oblongata of the brain. GALT, gut-associated lymphoid tissues. © 2006 Nature Publishing Group

24. The Nature of TSE Disease Transmission Although critical to the understanding of TSE diseases, the most fundamental aspect of such is still controversial: i.e. What is the nature of the agent that transmits these debilitating diseases? The scientific community is divided namely between two possibilities * : * Other theories also exist (Prof Laura Manuelidis, Prof Alan Ebringer, Mark Purdey etc)

30. Polyanions and the Proteome From the Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-3729 “Polyanions and the Proteome” (2004) Molecular & Cellular Proteomics 3.8 doi:10.1074/mcp.R400008-MCP200

31. Polyanions and the Proteome “Crowded House” From the Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-3729 “Polyanions and the Proteome” (2004) Molecular & Cellular Proteomics 3.8 doi:10.1074/mcp.R400008-MCP200 The very crowded environment of the cell. Actin ( red ), macromolecules, primarily ribosomes ( green ), and membranes ( blue ) are represented. Reprinted with permission from Medalia, O., Weber, I., Frangakis, A. S., Nicastro, D., Gerisch, G. and Baumeister, W. (2002) Macromolecular architecture in eukaryotic cells visualized by cryoelectron topography. Science 298, 1209–1213. Copyright 2002, AAAS.

33. Prions and their partners in crime From: Caughey B & Baron GS (2006) “Prions and their partners in crime” Nature 443 doi:10.1038/nature05294 PrPc

34. Prions and their partners in crime From: Caughey B & Baron GS (2006) “Prions and their partners in crime” Nature 443 doi:10.1038/nature05294

35. Prions and their partners in crime From: Caughey B & Baron GS (2006) “Prions and their partners in crime” Nature 443 doi:10.1038/nature05294 Transport of PrP d within neurones

36. From extracellular matrix into the “Crowded House” The Journal of Infectious Diseases 2006; 194:702–9 0022-1899/2006/19405-0024 Sabine Gauczynski, Daphne Nikles, Susanne El-Gogo, Dulce Papy-Garcia, Clemence Rey, Susanne Alban, Denis Barritault, Corinne Ida Lasmezas, and Stefan Weiss

38. Polyanions It is in terms of proteomics that the global role of polyanions both within and without cells might have its greatest immediate consequences. What at first appears to be a series of unrelated phenomena whose only common features are the involvement of polyanionic substances, may actually reflect a broad underlying role for highly negatively charged macromolecules in diverse cellular functions and environments. The elucidation of these roles will require that polyanions be taken into account as they relate to the spatial, structural, and temporal behavior of the proteome. Tools now exist to begin to ask to what extent protein/polyanion interactions are present in cells and to probe their biological roles. From the Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-3729 “Polyanions and the Proteome” (2004) Molecular & Cellular Proteomics 3.8 doi:10.1074/mcp.R400008-MCP200 D , microtubule. Reprinted with permission from Baker, N. A., Sept, D., Joseph, S., Holst, M. J., and McCammon, J. A. (2001) Electrostatics of nanosystems: Applications to microtubules and the ribosome. Proc. Natl. Acad. Sci. U. S. A. 98, 10037–10041. Copyright 2001, National Academy of Sciences, U.S.A. E , 50S ribosome. Reprinted with permission from Baker, N. A., Sept, D., Joseph, S., Holst, M. J., and McCammon, J. A. (2001) Electrostatics of nanosystems: Applications to microtubules and the ribosome. Proc. Natl. Acad. Sci. U. S. A. 98, 10037–10041. Copyright 2001, National Academy of Sciences, U.S.A.

42. Age of onset Illness duration (survival) Individuals in this study have had some form of Pentosan inducement (mainly i.c.) Human Prion Disease: Natural history. From Lesley Stewart et al .2006. 36m(a) 42m(a) 61m(a) 16m(d) 2 145 6-40m 14m 2 145 12-74yrs 28yrs vCJD 30m(a) 29m(d) 3 111 3-30m 16m 3 121 10-37yrs 26yrs iCJD (HGH) 52m(d) 60m(a) 6 21 2-84m 48m 7 38 22-71yrs 44yrs GSS P102L PPS Patients. Duration of illness studies N range Median Duration of illness studies N range Median Age of onset Type

47. Heart Rate Variability (HRV) measurements on CJD patients Chris Pomfrett Lecturer in Neurophysiology applied to Anaesthesia (Clinical Scientist) The University of Manchester Manchester Royal Infirmary M13 9WL Co-Workers: Professor Brian Pollard M.D., FRCA, David Glover, B.Sc. vCJD study DoH funded 2002 - June 04 BSE study funded by UK Dept. of Health (£112,000)

50. Diagnosis of asymptomatic individuals Prophylactic treatment An in-vivo test will be essential once anti-prion prophylactic treatments are discovered Prophylactic treatments will only be useful in the presence of a simple and efficient in-vivo test.

51. Effective treatment of prion diseases - Is it possible? Clinical symptoms diagnosis Treatment partially ineffective due to already established brain damage Screening of population at risk Diagnosis of asymptomatic individuals Prophylactic treatment