1. The Historical Significance of
Biomarkers in Prion Diseases
Biomarkers in Neurodegeneration Seminar
Johns Hopkins Bayview Medical Center
Presented by: Brian Appleby, M.D.
April 5, 2010
2. • History of prion diseases
One
• Spongiform encephalopathy and transmissibility
as biomarkers of prion disease
Two
• PrPres as a biomarker of prion disease
Three
• Describe biomarkers in different types of prion
Four diseases
8. “…this is a disease of middle and late life which begins
with…disturbances of the motor apparatus and of
sensation…the patient’s gait is strikingly
uncoordinated…striking mental changes appear, in the
form of apathy, negativism, and delirious and hallucinatory
confusional states…The course of the disease is subacutely
progressive…of several weeks to a year.”
Jakob A. Med Klin 1921
26. “…the evidence that no inactivation results from exposure
to a huge dose of ultraviolet light, of wave- length
specifically absorbed by nucleic acids, suggests that the
agent may be able to increase in quantity without itself
containing nucleic acid.”
Alper T, et al. Biochem Biophys Res Commun 1966
Alper T, et al. Nature 1967
27. S1 + G1 = S1
G G0
S2 + G2 = S2
G S
S1 + G2 = S2
S+G=S
S2 + G1 = 0
X M
M+G=S
P1 = normal
P2 = normal
P1 + P2 = scrapie
Griffith JS. Nature 1967
34. “Protein X”
A. PrPc (blue) and PrPSc
(red) undergo
endocytosis
B. Co-factor (yellow) on
lipid raft assists
conversion of PrPc to
PrPSc
Taylor D & Hooper N. Semin Cell Dev Biol, 2007
35. “These findings provide strong support for the protein-only
hypothesis of TSE diseases, as well as argue that
cofactors such as nucleic acids, other polyanions
or lipids are nonobligatory for prion protein
conversion to the infectious form.”
Kim J, et al. JBC [In Press]
53. Strain Individual variability
sCJD
gCJD
*connected circles represent animals inoculated at same time
with identical aliquots
Brown P, et al. Ann Neurol 1994
54. Incidence of iCJD cases from hGH
Huillard d’Aignaux J, et al. Neurology 1999
57. Summary
• Prion disease cause spongiform
encephalopathies and are transmissible*
• Prion disease are characterized by an
abnormal isomer of the native prion protein
that is incompletely digested by proteinase K
• Prion disease characteristics are affected by
PrPres strain and host genotype.
58. Acknowledgements
Patients and families CJD Foundation, CJD Insight, CJD Aware!
Florence Kranitz
Paul Brown (CEA/DSV/iMETI/SEPIA) Deana Simpson
Bob Will (National CJD Surveillance Unit, UK)
NPDPSC
Johns Hopkins Pierluigi Gambetti
Peter Rabins Sally Berri
Kostas Lyketsos
Barbara Crain FTD/YOD Clinic
Avi Nath Chiadi Onyike
Mary Anne Wylie
Rebecca Rye
Kate Hicks
Editor's Notes
SmartArt custom animation effects: vertical chevron list with dark colors(Basic)To reproduce the SmartArt effects on this slide, do the following:On the Home tab, in the Slides group, click Layout, and then click Blank. On the Insert tab, in the Illustrations group, click SmartArt. In the Choose a SmartArt Graphic dialog box, in the left pane, click List. In the List pane, click Vertical Chevron List (fourth row, fourth option from the left), and then click OK to insert the graphic into the slide. To create a fourth chevron, select the third chevron at the bottom of the graphic, and then under SmartArtTools, on the Design tab, in the CreateGraphic group, click the arrow next to AddShape, and select AddShapeAfter.To add bullets for the fourth chevron, select the fourth chevron, and then under SmartArtTools, on the Design tab, in the CreateGraphic group, click AddBullet.To enter text, select the SmartArt graphic, and then click one of the arrows on the left border. In the Type your text here dialog box, enter text for each level. (Note: In the example slide, the first-level text boxes contain “One,” “Two,” “Three,” and “Four.” The second-level text is “Supporting Text.”)On the slide, select the SmartArt graphic and drag the right center sizing handle to the right edge of the slide.With the SmartArt graphic still selected, on the DesignTab, in the Themes group, click Colors, and then under Built-In select Median. (Note: If this action is taken in a PowerPoint presentation containing more than one slide, the theme will be applied to all of the slides.)With the SmartArt graphic still selected, under SmartArtTools, on the Design tab, in the SmartArtStyles group, click MoreStyles, and then under 3-D select Inset (first row, second option from the left). Also under SmartArtTools, on the Design tab, in the SmartArtStyles group, click ChangeColors, and then under Colorful select Colorful -AccentColors (first option from the left). To reproduce the chevron effects on this slide, do the following:Press and hold CTRL, and select all four chevrons in the SmartArt graphic. On the Home tab, in the Font group, in the Font list select Franklin Gothic Medium Cond, and then in the FontSize box select 28.On the Home tab, in the bottom right corner of the Drawing group, click the FormatShape dialog box launcher. In the FormatShape dialog box, click TextBox in the left pane, and in the TextBox pane do the following:Under Textlayout, in the Verticalalignment list select Bottom.Under Internalmargin, do the following: In the Left box, enter 0”. In the Right box, enter 0”. In the Bottom box, enter 0”. In the Top box, enter 0.6”.To reproduce the rectangle effects on this slide, do the following:Press and hold CTRL, and the four of the rectangles (with bulleted text). On the Home tab, in the Font group, do the following:In the Font list, select FranklinGothicBook.In the FontSize box, enter 21.In the FontColor list, under ThemeColors select White, Background 1 (first row, first option from the left).On the Home tab, in the bottom right corner of the Drawing group, click the Format Shape dialog box launcher. In the Format Shape dialog box, click Fill in the left pane, select Gradientfill in the Fill pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Down (first row, second option from the left). Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under ThemeColors select Black, Text 1 (first row, second option from the left).In the Transparency box, enter 100%. Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under ThemeColors select Black, Text 1 (first row, second option from the left).In the Transparency box, enter 45%. Also in the FormatShape dialog box, click Shadow in the left pane, and in the Shadow pane, in the Presets list, select NoShadow.Also in the FormatShape dialog box, click 3-DFormat in the left pane, and in the 3-DFormat pane, under Bevel, in the Top list select NoBevel.Select the top rectangle with bulleted text.On the Home tab, in the bottom right corner of the Drawing group, click the FormatShape dialog box launcher. In the FormatShape dialog box, click LineColor in the left pane, select Gradientfill in the LineColor pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Down (first row, second option from the left). Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under ThemeColors select Orange, Accent 2 (first row, sixth option from the left).In the Transparency box, enter 100%. Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under ThemeColors select Orange, Accent 2 (first row, sixth option from the left).In the Transparency box, enter 0%. Select the second rectangle from the top with bulleted text.On the Home tab, in the bottom right corner of the Drawing group, click the FormatShape dialog box launcher. In the FormatShape dialog box, click LineColor in the left pane, select Gradientfill in the LineColor pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Down (first row, second option from the left). Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under ThemeColors select Olive Green, Accent 3 (first row, seventh option from the left).In the Transparency box, enter 100%. Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under ThemeColors select Olive Green, Accent 3 (first row, seventh option from the left).In the Transparency box, enter 0%. Select the third rectangle from the top with bulleted text.On the Home tab, in the bottom right corner of the Drawing group, click the FormatShape dialog box launcher. In the FormatShape dialog box, click LineColor in the left pane, select Gradient fill in the LineColor pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Down (first row, second option from the left). Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under ThemeColors select Gold, Accent 4 (first row, eighth option from the left).In the Transparency box, enter 100%. Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under ThemeColors select Gold, Accent 4 (first row, eighth option from the left).In the Transparency box, enter 0%. Select the fourth rectangle from the top with bulleted text.On the Home tab, in the bottom right corner of the Drawing group, click the FormatShape dialog box launcher. In the FormatShape dialog box, click LineColor in the left pane, select Gradient fill in the LineColor pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Down (first row, second option from the left). Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under ThemeColors select Green, Accent 5 (first row, ninth option from the left).In the Transparency box, enter 100%. Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under ThemeColors select Green, Accent 5 (first row, ninth option from the left).In the Transparency box, enter 0%. To reproduce the animation effects on this slide, do the following: On the Animations tab, in the Animations group, click CustomAnimation.Select the SmartArt graphic, and then in the CustomAnimation task pane do the following:Click AddEffect, point to Entrance, and select MoreEffects. In the AddEntranceEffect dialog box, under Moderate select Grow & Turn.Click the arrow to the right of the animation effect (grow & turn effect for the graphic), select EffectOptions, and then in the Grow & Turn dialog box, do the following:On the Timing tab, in the Speed list, select 0.5 seconds (Very Fast).On the SmartArtAnimation tab, in the Groupgraphic list, select Onebyone.Click the double arrow to expand the contents of the list in the CustomAnimation task pane.Press and hold CTRL, and select the second, fourth, sixth, and eighth effects (grow & turn entrance effects), and then do the following:Click Change, point to Entrance and select MoreEffects. In the ChangeEntranceEffect dialog box, under Moderate select EaseIn.With the four ease-in entrance effects still selected, under Modify: Ease In do the following:In the Start list, select WithPrevious.In the Speed list, select Fast.Select the grow & turn entrance effect (first effect in the list), and under Modify: Grow & Turn, in the Start list, select WithPrevious. To reproduce the background effects on this slide, do the following:Right-click the slide background area, and then click Format Background. In the Format Background dialog box, click Fill in the left pane, select Gradient fill in the Fill pane, and then do the following:In the Type list, select Radial.Click the button next to Direction, and then click From Center (third option from the left). Under Gradient stops, click Add or Remove until two stops appear in the drop-down list.Also under Gradient stops, customize the gradient stops that you added as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 20%.Click the button next to Color, and then under ThemeColors select White, Background 1, Darker 25% (fourth row, first option from the left). Select Stop 2 from the list, and then do the following: In the Stop position box, enter 100%.Click the button next to Color, and then under ThemeColors select Black, Text 1 (first row, second option from the left).
Known to exist since the 18th century. Occur in sheep and goat. No evidence of human transmission. Sx’s start with mildly impaired social behavior: unusual restlessness and signs of nervousness. Overt illness lasts 2 wks-6 mo. Scratch against objects, ataxia.
First described by Jakob in 1921, in which he referred to a case described by Creutzfeldt in 1920. Pathologic review of those specimens confirmed only 2/5 cases to be true CJD.
“spastic pseudosclerosis”
AD inheritance with various mutations, P102L most commonClinically characterized by dominant cerebellar syndrome, pyramidal signs, and cognitive decline. Onset 4th-6th decade of life. Duration of months to 6 years.Neuropathologically characterized by PrP-amyloid plaques in cerebellar cortex. Transmission studied first performed by Masters et al in 1981.
Transition effect for timeline, slide 1(Basic)Recognized similarity in neuropathology between scrapie and kuruTip: This transition works well for graphics that horizontally span more than one slide. To reproduce the shape effects on this slide, do the following:On the Home tab, in the Slides group, click Layout, and then click Blank.On the Home tab, in the Drawing group, click Shapes, and then under Block Arrows click Chevron (second row, eighth option from the left). On the slide, drag to draw a long, horizontal chevron shape.Select the chevron. Under DrawingTools, on the Format tab, in the Size group, do the following:In the Shape Height box, enter 0.7”.In the Shape Width box, enter 9.48”.Drag the chevron until the right end is beyond the right edge of the slide, and the left end of the chevron is approximately one inch to the right of the left edge of the slide.Select the chevron. Under DrawingTools, on the Format tab, in the ShapeStyles group, click the arrow next to ShapeFill, point to Gradient, and then click MoreGradients. In the Format Shape dialog box, click Fill in the left pane, select Gradientfill in the Fill pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Up (second row, second option from the left).Under Gradient stops, click Add or Remove until a total of four gradient stops appear in the drop-down list. Also under Gradient stops, customize the gradient stops as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colors click White, Background 1 (first row, first option from the left)Select Stop 2 from the list, and then do the following:In the Stop position box, enter 36%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Select Stop 3 from the list, and then do the following:In the Stop position box, enter 73%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 178, Green: 190, Blue: 194. Select Stop 4 from the list, and then do the following:In the Stop position box, enter 100%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Also in the Format Shape dialog box, click LineColor in the left pane, and then select No line in the LineColor pane.Also in the Format Shape dialog box, click Shadow in the left pane, and then do the following in the Shadow pane: Click the button next to Presets, and then under Outer click OffsetBottom (first row, second option from the left).In the Transparency box, enter 60%.In the Size box, enter 100%.In the Blur box, enter 4 pt.In the Angle box, enter 90°.In the Distance box, enter 3 pt. Also in the Format Shape dialog box, click 3-DFormat in the left pane. In the 3-D Format pane, under Bevel,click the button next to Top, and then under Bevel click Circle (first row, first option from the left). Next to Top, in the Width box, enter 4 pt, and in the Height box, enter 4 pt.On the Insert tab, in the Text group, click Text Box, and then on the slide, drag to draw the text box.Enter text in the text box, select the text, and then on the Home tab, in the Font group, select Gill Sans MT Condensed from the Font list, enter 26 in the Font Size box, click Bold, click the arrow next to Font Color, and then under Theme Colors click White, Background 1, Darker 50% (sixth row, first option from the left).On the Home tab, in the Paragraph group, click Center to center the text in the text box.Select the text box. On the Home tab, in the Clipboard group, click the arrow under Paste, and then click Duplicate. Repeat this process to create a total of three text boxes.Click in each of the two duplicate text boxes, and then edit the text.Drag the text boxes onto the chevron shape to form a row. Press CTRL+A to select all the objects on the slide. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click AlignMiddle.Press and hold SHIFT, and then select all three text boxes. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click DistributeHorizontally.To reproduce the animation effects on this slide, do the following:On the Animations tab, in the TransitiontoThisSlide group, click More, and then under Pushand Cover click PushLeft.On the Animations tab, in the TransitionstoThisSlide group, in the Transition Speed list, select Slow.
Transition effect for timeline, slide 2(Basic)Tip: This transition works well for graphics that horizontally span more than one slide. To reproduce the shape effects on this slide, do the following:On the Home tab, in the Slides group, click Layout, and then click Blank.On the Home tab, in the Drawing group, click Shapes, and then under Block Arrows,click Chevron (second row, eighth option from the left). On the slide, drag to draw a long, horizontal chevron shape.Select the chevron. Under DrawingTools, on the Format tab, in the Size group, do the following:In the Shape Height box, enter 0.7”.In the Shape Width box, enter 11.03”.Drag the chevron until it extends past both the left and right edges of the slide. Select the chevron. Under DrawingTools, on the Format tab, in the ShapeStyles group, click the arrow next to ShapeFill, click Gradient, and then click MoreGradients.In the Format Shape dialog box, click Fill in the left pane, select Gradientfill in the Fill pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Up (second row, second option from the left).Under Gradient stops, click Add or Remove until a total of four gradient stops appear in the drop-down list. Also under Gradient stops, customize the gradient stops as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colors click White, Background 1 (first row, first option from the left).Select Stop 2 from the list, and then do the following:In the Stop position box, enter 36%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Select Stop 3 from the list, and then do the following:In the Stop position box, enter 73%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 178, Green: 190, Blue: 194. Select Stop 4 from the list, and then do the following:In the Stop position box, enter 100%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Also in the Format Shape dialog box, click LineColor in the left pane, and then select No line in the LineColor pane.Also in the Format Shape dialog box, click Shadow in the left pane. In the Shadow pane, click the button next to Presets, under Outer click OffsetBottom (first row, second option from the left), and then do the following: In the Transparency box, enter 60%.In the Size box, enter 100%.In the Blur box, enter 4 pt.In the Angle box, enter 90°.In the Distance box, enter 3 pt. Also in the Format Shape dialog box, click 3-DFormat in the left pane. In the 3-D Format pane, under Bevel,click the button next to Top, and then under Bevel click Circle (first row, first option from the left). Next to Top, in the Width box, enter 4 pt, and in the Height box, enter 4 pt.On the Insert tab, in the Text group, click Text Box, and then on the slide, drag to draw the text box.Enter text in the text box, select the text, and then on the Home tab, in the Font group, select Gill Sans MT Cond from the Font list, enter 26 in the Font Size box, click Bold, click the arrow next to Font Color, and then under Theme Colors click White, Background 1, Darker 50% (sixth row, first option from the left).On the Home tab, in the Paragraph group, click Center to center the text in the text box.Select the text box. On the Home tab, in the Clipboard group, click the arrow under Paste, and then click Duplicate. Repeat this process to create a total of three text boxes.Click in each of the two duplicate text boxes, and then edit the text.Drag the text boxes onto the chevron shape to form a row. Press CTRL+A to select all the objects on the slide. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click AlignMiddle.Press and hold SHIFT, and then select all three text boxes. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click DistributeHorizontally.To reproduce the animation effects on this slide, do the following:On the Animations tab, in the TransitiontoThisSlide group, click More, and then under Pushand Cover click PushLeft.On the Animations tab, in the TransitionstoThisSlide group, in the Transition Speed list, select Slow.
Transition effect for timeline, slide 2(Basic)Tip: This transition works well for graphics that horizontally span more than one slide. To reproduce the shape effects on this slide, do the following:On the Home tab, in the Slides group, click Layout, and then click Blank.On the Home tab, in the Drawing group, click Shapes, and then under Block Arrows,click Chevron (second row, eighth option from the left). On the slide, drag to draw a long, horizontal chevron shape.Select the chevron. Under DrawingTools, on the Format tab, in the Size group, do the following:In the Shape Height box, enter 0.7”.In the Shape Width box, enter 11.03”.Drag the chevron until it extends past both the left and right edges of the slide. Select the chevron. Under DrawingTools, on the Format tab, in the ShapeStyles group, click the arrow next to ShapeFill, click Gradient, and then click MoreGradients.In the Format Shape dialog box, click Fill in the left pane, select Gradientfill in the Fill pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Up (second row, second option from the left).Under Gradient stops, click Add or Remove until a total of four gradient stops appear in the drop-down list. Also under Gradient stops, customize the gradient stops as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colors click White, Background 1 (first row, first option from the left).Select Stop 2 from the list, and then do the following:In the Stop position box, enter 36%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Select Stop 3 from the list, and then do the following:In the Stop position box, enter 73%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 178, Green: 190, Blue: 194. Select Stop 4 from the list, and then do the following:In the Stop position box, enter 100%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Also in the Format Shape dialog box, click LineColor in the left pane, and then select No line in the LineColor pane.Also in the Format Shape dialog box, click Shadow in the left pane. In the Shadow pane, click the button next to Presets, under Outer click OffsetBottom (first row, second option from the left), and then do the following: In the Transparency box, enter 60%.In the Size box, enter 100%.In the Blur box, enter 4 pt.In the Angle box, enter 90°.In the Distance box, enter 3 pt. Also in the Format Shape dialog box, click 3-DFormat in the left pane. In the 3-D Format pane, under Bevel,click the button next to Top, and then under Bevel click Circle (first row, first option from the left). Next to Top, in the Width box, enter 4 pt, and in the Height box, enter 4 pt.On the Insert tab, in the Text group, click Text Box, and then on the slide, drag to draw the text box.Enter text in the text box, select the text, and then on the Home tab, in the Font group, select Gill Sans MT Cond from the Font list, enter 26 in the Font Size box, click Bold, click the arrow next to Font Color, and then under Theme Colors click White, Background 1, Darker 50% (sixth row, first option from the left).On the Home tab, in the Paragraph group, click Center to center the text in the text box.Select the text box. On the Home tab, in the Clipboard group, click the arrow under Paste, and then click Duplicate. Repeat this process to create a total of three text boxes.Click in each of the two duplicate text boxes, and then edit the text.Drag the text boxes onto the chevron shape to form a row. Press CTRL+A to select all the objects on the slide. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click AlignMiddle.Press and hold SHIFT, and then select all three text boxes. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click DistributeHorizontally.To reproduce the animation effects on this slide, do the following:On the Animations tab, in the TransitiontoThisSlide group, click More, and then under Pushand Cover click PushLeft.On the Animations tab, in the TransitionstoThisSlide group, in the Transition Speed list, select Slow.
Transition effect for timeline, slide 3(Basic)Tip: This transition works well for graphics that horizontally span more than one slide. To reproduce the shape effects on this slide, do the following:On the Home tab, in the Slides group, click Layout, and then click Blank.On the Home tab, in the Drawing group, click Shapes, and then under Block Arrows,click Chevron (second row, eighth option from the left). On the slide, drag to draw a long, horizontal chevron shape.Select the chevron. Under DrawingTools, on the Format tab, in the Size group, do the following:In the Shape Height box, enter 0.7”.In the Shape Width box, enter 9.48”.Drag the chevron so that the left end is beyond the left edge of the slide, and the right end is approximately one inch left of the right edge of the slide. Select the chevron. Under DrawingTools, on the Format tab, in the ShapeStyles group, click the arrow next to ShapeFill, click Gradient, and then click MoreGradients. In the Format Shape dialog box, click Fill in the left pane, select Gradientfill in the Fill pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Up (second row, second option from the left).Under Gradient stops, click Add or Remove until a total of four gradient stops appear in the drop-down list. Also under Gradient stops, customize the gradient stops as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colors click White, Background 1 (first row, first option from the left).Select Stop 2 from the list, and then do the following:In the Stop position box, enter 36%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Select Stop 3 from the list, and then do the following:In the Stop position box, enter 73%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 178, Green: 190, Blue: 194. Select Stop 4 from the list, and then do the following:In the Stop position box, enter 100%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Also in the Format Shape dialog box, click LineColor in the left pane, and then select No line in the LineColor pane.Also in the Format Shape dialog box, click Shadow in the left pane. In the Shadow pane, click the button next to Presets, under Outer click OffsetBottom (first row, second option from the left), and then do the following: In the Transparency box, enter 60%.In the Size box, enter 100%.In the Blur box, enter 4 pt.In the Angle box, enter 90°.In the Distance box, enter 3 pt. Also in the Format Shape dialog box, click 3-DFormat in the left pane. In the 3-D Format pane, under Bevel,click the button next to Top, and then under Bevel click Circle (first row, first option from the left). Next to Top, in the Width box, enter 4 pt, and in the Height box, enter 4 pt.On the Insert tab, in the Text group, click Text Box, and then on the slide, drag to draw the text box.Enter text in the text box, select the text, and then on the Home tab, in the Font group, select Gill Sans MT Cond from the Font list, enter 26 in the Font Size box, click Bold, click the arrow next to Font Color, and then under Theme Colors click White, Background 1, Darker 50% (sixth row, first option from the left).On the Home tab, in the Paragraph group, click Center to center the text in the text box.Select the text box. On the Home tab, in the Clipboard group, click the arrow under Paste, and then click Duplicate. Repeat this process to create a total of three text boxes.Click in each of the two duplicate text boxes, and then edit the text.Drag the text boxes onto the chevron shape to form a row. Press CTRL+A to select all the objects on the slide. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click AlignMiddle.Press and hold SHIFT, and then select all three text boxes. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click DistributeHorizontally.To reproduce the animation effects on this slide, do the following:On the Animations tab, in the TransitiontoThisSlide group, click More, and then under Pushand Cover click PushLeft.On the Animations tab, in the TransitionstoThisSlide group, in the Transition Speed list, select Slow.
In 1974, Ignazio Roiter, an Italian doctor,whose wife’s aunt died with depression and insomnia, despite appearing to sleep all the time. In 1979 a second aunt became ill. Then they noticed a pattern in the family. Then an uncle became ill in 1984 and was sent to Elio Lugaresi, a sleep expert who sent the brain to Gambetti
Transition effect for timeline, slide 2(Basic)Tip: This transition works well for graphics that horizontally span more than one slide. To reproduce the shape effects on this slide, do the following:On the Home tab, in the Slides group, click Layout, and then click Blank.On the Home tab, in the Drawing group, click Shapes, and then under Block Arrows,click Chevron (second row, eighth option from the left). On the slide, drag to draw a long, horizontal chevron shape.Select the chevron. Under DrawingTools, on the Format tab, in the Size group, do the following:In the Shape Height box, enter 0.7”.In the Shape Width box, enter 11.03”.Drag the chevron until it extends past both the left and right edges of the slide. Select the chevron. Under DrawingTools, on the Format tab, in the ShapeStyles group, click the arrow next to ShapeFill, click Gradient, and then click MoreGradients.In the Format Shape dialog box, click Fill in the left pane, select Gradientfill in the Fill pane, and then do the following:In the Type list, select Linear.Click the button next to Direction, and then click Linear Up (second row, second option from the left).Under Gradient stops, click Add or Remove until a total of four gradient stops appear in the drop-down list. Also under Gradient stops, customize the gradient stops as follows:Select Stop 1 from the list, and then do the following:In the Stop position box, enter 0%.Click the button next to Color, and then under Theme Colors click White, Background 1 (first row, first option from the left).Select Stop 2 from the list, and then do the following:In the Stop position box, enter 36%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Select Stop 3 from the list, and then do the following:In the Stop position box, enter 73%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 178, Green: 190, Blue: 194. Select Stop 4 from the list, and then do the following:In the Stop position box, enter 100%.Click the button next to Color, click More Colors, and then in the Colors dialog box, on the Custom tab, enter values for Red: 213, Green: 219, Blue: 221. Also in the Format Shape dialog box, click LineColor in the left pane, and then select No line in the LineColor pane.Also in the Format Shape dialog box, click Shadow in the left pane. In the Shadow pane, click the button next to Presets, under Outer click OffsetBottom (first row, second option from the left), and then do the following: In the Transparency box, enter 60%.In the Size box, enter 100%.In the Blur box, enter 4 pt.In the Angle box, enter 90°.In the Distance box, enter 3 pt. Also in the Format Shape dialog box, click 3-DFormat in the left pane. In the 3-D Format pane, under Bevel,click the button next to Top, and then under Bevel click Circle (first row, first option from the left). Next to Top, in the Width box, enter 4 pt, and in the Height box, enter 4 pt.On the Insert tab, in the Text group, click Text Box, and then on the slide, drag to draw the text box.Enter text in the text box, select the text, and then on the Home tab, in the Font group, select Gill Sans MT Cond from the Font list, enter 26 in the Font Size box, click Bold, click the arrow next to Font Color, and then under Theme Colors click White, Background 1, Darker 50% (sixth row, first option from the left).On the Home tab, in the Paragraph group, click Center to center the text in the text box.Select the text box. On the Home tab, in the Clipboard group, click the arrow under Paste, and then click Duplicate. Repeat this process to create a total of three text boxes.Click in each of the two duplicate text boxes, and then edit the text.Drag the text boxes onto the chevron shape to form a row. Press CTRL+A to select all the objects on the slide. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click AlignMiddle.Press and hold SHIFT, and then select all three text boxes. On the Home tab, in the Drawing group, click Arrange, point to Align, and then do the following:Click Align to Slide.Click DistributeHorizontally.To reproduce the animation effects on this slide, do the following:On the Animations tab, in the TransitiontoThisSlide group, click More, and then under Pushand Cover click PushLeft.On the Animations tab, in the TransitionstoThisSlide group, in the Transition Speed list, select Slow.
FFI=19kdal, CJD=21 kdalBrain vs brainstem
Excludes known iatrogenic and inherited cases. tEngland and Wales only for theperiod 1970-84. *Numbers in brackets indicate patients alive. Died before May1990.
