Medical POSTGRADUATES No. 1, Vol. 37, 2009 Morphologic Findings of Myelodysplastic Syndrome with Isolated del(5q) Fig. 1 Fig. 2 Fig. 3 1

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1 Medical POSTGRADUATES Abstracts

2 Medical POSTGRADUATES No. 1, Vol. 37, 2009 Morphologic Findings of Myelodysplastic Syndrome with Isolated del(5q) Fig. 1 Fig. 2 Fig. 3 1

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4 Fig. 2. Fig. 3. REFERENCES 1. World Health Organization Classification of Tumors of 2. (2006) :.. E Public, pp Haematopoietic and Lymphoid Tissues. (2007) IARC 270 press:

5 Medical POSTGRADUATES No. 1, Vol.37, 2009 Crush Syndrome : The Fourth Pitfall 4

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11 Medical POSTGRADUATES No. 1, Vol.37, 2009 A Concise Review of Prion Biology Table 1 Fig. 1 10

12 Table 1. PrP c PrP Sc -helix -sheet (soluble) (insoluble) Proteinase KProteinase K (aggregation) (aggregation) Fig

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14 REFERENCES 1. Aguzzi A & Heikenwalder M (2005) : Prions, cytokines, and chemokines: a meeting in lymphoid organs. I m m u n i t y, 22 : Aguzzi A & Polymenidou M (2004) : Mammalian prion biology. One century of evolving concepts. C e l l, 116 : Aguzzi A & Sigurdson CJ (2004) : Antiprion immunotherapy: to suppress or to stimulate? N a t u r e Rev Immunol, 4 : Aguzzi A, Sigurdson C & Heikenwaelder M (2008) : Molecular mechanisms of prion pathogenesis. Annu Rev P a t h o l, 3 : Barmada SJ & Harris DA (2005) : Visualization of prion infection in transgenic mice expressing green fluorescent protein-tagged prion protein. J Neurosci, 25 : Beekes M & McBride PA (2000) : Early accumulation of pathological PrP in the enteric nervous system and gutassociated lymphoid tissue of hamsters orally infected with scrapie. Neurosci Lett, 278 : Brown KL et al. (1999) : Scrapie replication in lymphoid tissues depends on prion protein- expressing follicular dendritic cells. Nature Med, 5 : Bueler HR, Fischer M, Lang Y, Bluethmann H, Lipp HP et al. (1992) : Normal development and behavior of mice lacking the neuronal cell-surface PrP protein. N a t u r e, 356 : Clarke MC & Kimberlin RH (1984) : Pathogenesis of mouse scrapie: distribution of agent in the pulp and stroma of infected spleens. Vet Microbiol, 9 : Glatzel M, Abela E, Maissen M & Aguzzi A (2003) : Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease. N Engl J Med, 349 : Haik S et al. (2003) : The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease. N a t u r e M e d, 9 : Huang FP, Farquhar CF, Mabbott NA, Bruce ME & MacPherson GG (2002) : Migrating intestinal dendritic cells transport PrP Sc from the gut. J Gen Virol, 83 : Huang FP, Farquhar CF, Mabbott NA, Bruce ME & MacPherson GG (2002) : Migrating intestinal dendritic cells transport PrP Sc from the gut. J Gen Virol, 83 : Kimberlin RH & Walker CA (1989) : The role of the spleen in the neuroinvasion of scrapie in mice. V i r u s R e s, 12 : Klein MA et al. (1998) : PrP expression in B lymphocytes is not required for prion neuroinvasion. Nature Med, 4 : Ma J, Wollmann R & Lindquist S (2002) : Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. S c i e n c e, 298 : Mabbott NA & MacPherson GG (2006) : Prions and their lethal journey to the brain. Nature Rev Microbiol, 4 : Mould DL, Dawson AM & Rennie JC (1970) : Very early replication of scrapie in lymphocytic tissue. N a t u r e, 228 : Neutra MR, Frey A & Kraehenbuhl JP (1996) : Epithelial M cells: gateways for mucosal infection and immunization. C e l l, 86 : Prinz M et al. (2002) : Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells. Proc Natl Acad Sci USA, 99 : Prinz M et al. (2003) : Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. N a t u r e, 425 : Prusiner SB (1982) : Novel proteinaceous infectious particles cause scrapie. S c i e n c e, 216 :

15 Medical POSTGRADUATES No. 1, Vol.37, 2009 Pathology of the Prion Disease and Prion Decontamination Table 1. Term or acronym & definition CJD: Creutzfeldt-Jacob disease scjd: sporadic Creutzfeldt-Jacob disease fcjd: familial Creutzfeldt-Jacob disease icjd: iatrogenic Creutzfeldt-Jacob disease vcjd: variant Creutzfeldt-Jacob disease BSE: Bovine spongiform encephalitis GSS: Gerstmann Straussler Scheinker disease FFI: fatal familial insomnia PrP: Prion protein PRNP: Gene encoding prion protein in humans PrP c : normal cellular isoform of prion protein PrP Sc : abnormal disease-associated form of prion protein 14

16 Table 2 Table 2. scjd * Spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter * Encephalopathy with PrP immunoreactivity (plaque and/or diffuse synaptic-like and/or patchy/perivacuolar types) 15

17 Table 3 Table 3. * Familial CJD - spongiform degeneration of the brain, with variable neuronal loss and gliosis. Kuru-type amyloid plaques in minority of cases.. * Gerstmann-Straussler-Scheinker disease(gss) - Widespread multicentric PrP amyloid plaques in the brain, often in the absence of spongiform change * Fatal familial insomnia(ffi) - Severe neuronal loss and gliosis in the anterior and medial thalamus, often with minimal spongiform degeneration in the brain * Prion protein cerebral amyloid angiopathy(prp-caa) - PrP amyloid deposition in small and medium-sized vessels, tau-positive neurofibrillary tangle, neuropil threads and dystrophic neuritis in the cerebrum 16

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19 Table 4 Table 4. Cerebral and cerebellar cortex Caudate nucleus and putamen Posterior thalamic nuclei Brainstem and spinal cord accumulation Biochemistry Multiple florid plaques in routine stained sections Numerous small cluster plaques in PrP immunohistochemistry Amorphous and pericapillary PrP accumulation Severe spongiform change Perinueronal & periaxonal PrP accumulation Marked neuronal loss and gliosis Patchy spongiform change Perineuronal and reticular PrP Type 2B PrP Sc on Western blot analysis 18

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21 Table 5 Table 5. * Samples should be labeled biohazard. * Single-use protective clothing is preferred. * Use disposable equipment wherever possible, and dispose by incineration. * Fixatives and waste fluids should be decontaminated before disposal. * Effective chemicals and physical agents to reduce prion infectivity include: Hypochlorite (20,000ppm free chlorine) NaOH (1-2N for 1h) Formic acid (100% for 1h) Steam heat (>134for at least 18 min.) REFERENCES 1. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG (2003) : Sporadic and familial CJD: classification and characterisation. Br Med Bull, 66 : Gambetti P, Parchi P, Chen SG (2003) : Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia. Clin Lab Med, 23(1) : Liberski PP, Sikorska B, Hauw JJ, Kopp N, Streichenberger N, Giraud P, Budka H, Boellaard JW, Brown P (2008) : Tubulovesicular structures are a consistent (and unexplained) finding in the brains of humans with prion diseases. Virus Res. 132(1-2) : Epub 2008 Jan Brandner S, Whitfield J, Boone K, Puwa A, O'Malley C, Linehan JM, Joiner S, Scaravilli F, Calder I, P Alpers M, Wadsworth JD, Collinge J (2008) : Central and peripheral pathology of kuru: pathological analysis of a recent case and comparison with other forms of human prion disease. Philos Trans R Soc Lond B Biol Sci, 27;363(1510) : Vital A, Canron MH, Gil R, Hauw JJ, Vital C (2007) : A sporadic case of Creutzfeldt-Jakob disease with betaamyloid deposits and alpha-synuclein inclusions. N e u r o p a t h o l o g y, 27(3) : Liberski PP (2004) : Amyloid plaques in transmissible spongiform encephalopathies (prion diseases). F o l i a N e u r o p a t h o l, 42(Suppl B) : Piao YS, Kakita A, Watanabe H, Kitamoto T, Takahashi H (2005) : Sporadic fatal insomnia with spongiform degeneration in the thalamus and widespread PrP S c deposits in the brain. N e u r o p a t h o l o g y, 25(2) : Liberski PP, Streichenberger N, Giraud P, Soutrenon M, Meyronnet D, Sikorska B, Kopp N (2005) : Ultrastructural pathology of prion diseases revisited: brain biopsy studies. Neuropathol Appl Neurobiol, 31(1) : Heath CA, Barker RA, Esmonde TF, Harvey P, Roberts R, Trend P, Head MW, Smith C, Bell JE, Ironside JW, Will RG, Knight RS (2006) : Dura mater-associated Creutzfeldt-Jakob disease: experience from surveillance in the UK. J Neurol Neurosurg Psychiatry, 77(7) : Noguchi-Shinohara M, Hamaguchi T, Kitamoto T, Sato T, Nakamura Y, Mizusawa H, Yamada M (2007) : Clinical features and diagnosis of dura mater graft associated Creutzfeldt Jakob disease. N e u r o l o g y, 69(4) : Ironside JW, Head MW (2004) : Neuropathology and 20

22 molecular biology of variant Creutzfeldt-Jakob disease. Curr Top Microbiol Immunol, 284 : Centers for Disease Control and Prevention (CDC) 13. (2004) : Bovine spongiform encephalopathy in a dairy cow--washington state, MMWR Morb Mortal Wkly Rep, 52(53) : Love S, Louis DN, Ellison DW (2008) : Greenfield s neu-ropathology. 8th ed. pp Baxter HC, Campbell GA, Whittaker AG, Jones AC, Aitken A, Simpson AH, Casey M, Bountiff L, Gibbard L, Baxter RL (2005) : Elimination of transmissible spongiform encephalopathy infectivity and decontamination of surgical instruments by using radio-frequency gas-plasma treatment. J Gen Virol, 86(Pt 8) :

23 Medical POSTGRADUATES No. 1, Vol.37, 2009 Prion Disease : Classification, Clinical Features and Diagnosis Fig. 1 Fig. 2 Table 1 Fig

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25 Table 1. Clinical Features Diagnostic Tests Postmortem Neuropathologic E x a m i n a t i o n Age at D i s e a s e Human O n s e t D u r a t i o n, L e a d i n g G e n e t i c s H i s t o - Prion ( R a n g e ) Mean C l i n i c a l C S F P R N P p a t h o l o g i c B i o c h e m i c a l D i s e a s e y ( R a n g e ) S y m p t o m s E E G M R I B i o p s y Codon 129 M u t a t i o n F e a t u r e s T e s t s S p o r a d i c mo P r o g r e s s i v e Positive in P S W C Brain ( B r a i n ) MM, 70% N o t Spongiform P r P S c C J D (1-35 mo) dementia and > 90% % a t r o p h y m u s c l e MV, 14% o b s e r v e d c h a n g e s, t y p i n g Inherited CJD neurologic h y p e r i n t e n - VV, 16% neuronal ( W B ) signs(eg. myoclonus, sities loss, astrogliosis, cerebellar ataxia, in basal ganglia P r P visual problems, and/or cortical d e p o s i t i o n extrapyramidal 6 7 % (various patterns) s y m p t o m s ) Genetic mo Clinical Positive in PSWC, similar to More than similar to P r P S c C J D (2-41 mo) s y m p t o m s > 90% 7 5 % s C J D 2 5 s C J D t y p i n g similar to d i s e a s e - ( W B ) s C J D associated mutations (eg. E200K) G S S y C e r e b e l l a r U s u a l l y N o n s p e c i f i c N o r m a l M (on the P102L S p o n g i f o r m P r P S c (3 mo to d y s f u n c t i o n n e g a t i v e a l t e r a t i o n s o r m u t a t e d ( p l u s c h a n g e s, t y p i n g 13 y) (ataxia, n o n s p e c i f i c a l l e l e ) 7 less n e u r o n a l ( W B ) nystagmus, c e r e b e l l a r c o m m o n l o s s, d y s a r t h r i a ) atrophy m u t a t i o n s )a s t r o g l i o s i s, PrP deposition (multicentric plaques) F F I I n s o m n i a, N e g a t i v e N o n s p e c i f i c Normal or M (on the D N I n v o l v e m e n t P r P S c Acquired C J D ( ) mo a u t o m a t i c a l t e r a t i o n s n o n s p e c i f i c mutated of thalami t y p i n g (6-42 mo) d y s f u n c t i o n cerebral or a l l e l e ) ( W B ) cerebellar atrophy Variant mo Early P o s i t i v e N o n s p e c i f i c H y p e r i n t e n - ( B r a i n ) MM, 100% Not S p o n g i f o r m P r P S c C J D ( ) (6-24 mo) p s y c h i a t r i c in 50% a l t e r a t i o n s, s i t i e s t o n s i l s o b s e r v e d c h a n g e s, t y p i n g symptoms no PSWC in the n e u r o n a l ( W B ) (depression, p o s t e r i o r l o s s, anxiety, social t h a l a m u s a s t r o g l i o s i s, withdrawal), (pulvinar sign) P r P dysesthesia, later 7 8 % d e p o s i t i o n neurologic deficits and cognitive decline (florid plaques) I a t r o g e n i c S i m i l a r C l i n i c a l Positive in Similar to MM, 57% N o t Similar to P r P S c CJD to CJD symptoms 7 7 % s C J D MV, 20% o b s e r v e d s C J D t y p i n g similar to VV, 23% ( W B ) scjd Abbreviation : CJD, Creutzfeldt-Jacob disease; CSF, cerebrospinal fluid; EEG, electoencephalography; FFI, fatal familial insomnia; GSS, Gerstmann- Straussler-Scheinker - syndrome; M, methionine; MRI, magnetic resonance imaging; PrP, prion protein; PrP S c, protease-resistant form of host-derived prion protein; PSWC, periodic sharp wave complexes; scjd, sporadic Creutzfeldt-Jacob disease; V, valine; WB, Western blot. * Age at onset depended on the iatrogenic exposure; incubation period was 1 to 30 years 24

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27 REFERENCES 1. Glatzel M, Stoeck K, Seeger H, Luhrs T, Aguzzi A (2005) 2. Wadsworth J, Hill AF, Collinge J (2003) : Molecular and : Human Prion Diseases Molecular and Clinical Aspects. clinical classification of human prion disease. B r i t i s h Arch Neurol, 62 : Medical Bulletin, 66 :

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29 Table 1. Disease Host Mechanism of Pathogenesis Bovine Spongiform Encephalopathy (BSE) Cattle Infection through BSE contaminated meat and bone meal Scrapie sheep Vertical and horizontal infections through milk, Chronic Wasting Disease (CWD) Mule deer, elk Saliva and blood blood, living in same cage and BSE infected feed Transmissible Mink Encephalopathy (TME) Mink Infection with prions from sheep or cattle Feline Spongiform Encephalopathy (FSE) Cats Infection through BSE contaminated beef Exotic ungulate encephalopathy kudu, nyala, oryx Infection through BSE contaminated MBM Sporadic Creutzfeldt-Jakob disease (scjd) Human Somatic mutation orspontaneous conversion of PrPcinto PrP Sc? Iatrogenic CJD (icjd) Human Infections from prion-contaminated human growth hormone, dura mater grafts, blood transfusions Varient CJD (vcjd) Human Infection through BSE infected meat Familial CJD (fcjd) Human Germline mutations in PrP gene.. Gerstmann-Straussler-Scheinker disease (GSS) Human Germline mutations in PrP gene Fatal Familial Insomnia (FFI) Human Germline mutation in PrP gene (D178N, M129) Fatal Sporadic Insomnia (FSI) Human Somatic mutation or spontaneous conversion of PrPcinto PrP Sc? Kuru Fore people Infection through ritualistic cannibalism 28

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52 Abstracts Medical POSTGRADUATES No. 1, Vol.37, 2009 Disparities in Liver Transplantation Before and After Introduction of the MELD Score Cynthia A Moylan et al. JAMA, 300(20) : , 2008 Benazepril plus Amlodipine or Hydrochlorothiazide for Hypertension in High-Risk Patients Kenneth Jamerson et al. N Eng J Med, 359 : ,

53 Inhaled Corticosteroids in Patients with Stable Chronic Obstructive Pulmonary Disease - A Systematic Review and Meta-analysis M Bradley Drummond et al. JAMA, 300(20) : ,

54 Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B Patrick Marcellin et al. N Eng J Med, 359 : , 2008 Diagnostic Performance of Coronary Angiography by 64-Row CT Julie M Miller et al. N Eng J Med, 359 : ,

55 Antihistamine Therapy and Bone Mineral Density : Analysis in a Population-Based US Sample Mitsuyo Kinjo et al. Ame J Med, 121 : , 2008 Effect of Tesofensine on Bodyweight Loss, Body Composition and Quality of Life in Obese Patients : A Randomised, Double-Blind, Placebo-Controlled Trial Arne Astrup et al. Lancet, 372 : ,

56 Association of Three Genetic loci with Uric Acid Concentration and Risk of Gout : a Genome-wide Association Study Abbas Dehghan et al. Lancet, 372 : ,

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