1. Neuroprotection Trials in Traumatic Brain Injury -2011 Ross Bullock, MD, PhD. Director, Neurotrauma,- University of Miami /Jackson Memorial Hospital, Miami.

3. Blast injury….Pathomechanism poorly understood.. Fulminant brain swelling, and delayed “Vasospasm”…. The DOD Effect on TBI research..2007-~$120m 2008 ~$90m…

4. “ Per Ardua ad Virtutam” 8 Major Consortia for TBI trials….Over 300 centers… NICHD TBI trials Cosortium…CDP choline trial-8 centers NETT…… progesterone “Protect “ trial-~17major centers.. NHLBI ….Hypertonic saline, prehospital DOD new PTSD/TBI Consortium.. 10 centers… LABIC—Latin American Brain Injury Centers.. ANZICS consortium….DECRA..17 centers ABIC…~50 centers.. EBIC….

6. “ Those who do not learn from the lessons of History, are Doomed to repeat the mistakes of the past” Winston Churchill

9. Nelfinavir - study 506 Mean changes from Baseline in CD4 cell cycle Clinical Trials in HIV/AIDS…600 trials, to get to HAART …

10. Hand-held battlefield ready and EMT use Point-of-Care Clinical laboratory platforms Biomarker Assay for CNS injury The Banyan vision… In Collaboration with Device Manufacturers TBI Biomarker Diagnostic

11. Kobeissy, et al. Wang . Differential proteomic analysis of traumatic brain injury biomarker study using CAX-PAGE/RPLC-MSMS method. Mol. Cell. Proteomics 5: 1887-1898. Neuroproteomic Biomarker Discovery ”high throughput screening”… Naïve vs. Injured

12. Time Post Injury (hours) SBDP120 (ng/ml) Time Post Injury (hours) CSF Serum SBDP120 in TBI.. SBDP120 (ng/ml)

14. Bcl-2 Bax Human CEREBRAL CONTUSIONS LOW POWER NNZ 2566— active against delayed apoptotic mechanisms, in Human TBI?—Neurotrophin? T B I HIGH POWER

15. N = Neuronal cell body V = Blood vessel Blk arrow = Astrocyte Dbl arrow = normal oligo Blk pointer = unraveled myelin Arrowhead = swollen axonal figures Open arrow = microglia Star = amorphous crystallized material 3d 15d 3mo 9mo 12mo Control Bramlett, et al.—apoptotic cell death delayed up to I year, after TBI..

16. 1 hour post injury.. GCS 13 6 hours after injury.. GCS 6 ICP High.. Delayed intracerebral hemorrhage due to coagulopathy..the Nemesis of “Polytrauma”

17. Schematic representation of PFC emulsion particle distribution within the capillary increasing the surface area for O2 transport to the entire blood volume. Can PFC’s increase Brain oxygenation, by Non Erythrocyte Oxygen transport, in compressed, deformed capillaries? RBC’s PFC Emulsion Particles

18. Effect of Hyperoxia on Regional Oxygenation and Metabolism after severe Human TBI … Nortje et al, Crit Care Med 2008 :36, 273-281

19. Results of a prospective randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. Rockswold GL , Ford SE , Anderson DC , Bergman TA , Sherman RE . Division of Neurosurgery, Hennepin County Medical Center, Minneapolis, Minnesota. The authors enrolled 168 patients with closed-head trauma into a prospective trial to evaluate the effect of hyperbaric oxygen in the treatment of brain injury.. Hyperbaric oxygen was administered to the treatment group in a monoplace chamber every 8 hours for 1 hour at 1.5 atm absolute; this treatment course continued for 2 weeks or until the patient was either brain dead or awake. An average of 21 treatments per patient was given. Outcome was assessed by blinded independent examiners. The entire group of 168 patients was followed for 12 months, with two patients lost to follow-up study. The mortality rate was 17% for the 84 hyperbaric oxygen-treated patients and 32% for the 82 control patients (chi-squared test, 1 df, p = 0.037). Among the 80 patients with an initial GCS score of 4, 5, or 6, the mortality rate was 17% for the hyperbaric oxygen-treated group and 42% for the controls (chi-squared test, 1 df, p = 0.04). Analysis of the 87 patients with peak intracranial pressures (ICP) greater than 20 mm Hg revealed a 21% mortality rate for the hyperbaric oxygen-treated patients, as opposed to 48% for the control group (chi-squared test, 1 df, p = 0.02 ). J Neurosurg. 1992 Jun;76(6):929-34

20. The NIH-NINDS Trial of ICP Monitoring, in Bolivia,LABIC… 4 hospitals, PRCT..~350 pts

21. Human TBI …and COSBID.. suppression of large amplitude delta activity (e.g. PLEDs) EEG DC 1 s 1 min Chi-square p<0.001 N=72, MIA= 2 nd highest enroller 68% 25% >38.0 23% 58% 35.0-38.0 10% 17% < 35.0 Temp during CSD All temps during monitoring Temperature ranges

22. Explained Variance Nagelkerke’s R 2 Univariate Analysis-outcome * * * * Significance at p<0.05

25. Cambridge – 34 Leeds – 20 Royal London – 12 Newcastle – 11 Southampton – 10 Singapore – 8 Milan, Italy – 6 Manchester – 6 Saudi Arabia – 5 Edmonton, Canada – 5 Calgary, Canada – 4 Hong-Kong – 4 Old Church – 4 Plymouth – 4 Hurstwood Park – 3 Kings College – 3 Pavia, Italy – 3 Barcelona, Spain – 2 Livorno, Italy – 1 Malaysia – 1 Oxford – 1 Queen’s Square – 1 Swansea – 1 Ulm, Germany - 1 The study has recruited 150 patients to date! Well done everyone!! The top five recruiting centres are Cambridge, Leeds, Royal London, Newcastle and Southampton. Please continue recruiting all 150 patients recruited, by june 2008! www.RESCUEicp.com DECRA Study…Melbourne,Australia, 210 pts, ~70 entered…J Cooper, G Rosenfeld

26. Photothera …the Allure of the Laser..

27. Alvarez-Buylla, et al, Nature,427, feb 2004,740-744

28. Cell proliferation at the site of injury Chirumamilla et al., 2002,J Neurotrauma

29. Age-related cell proliferation Underlying mechanisms

31. Nestin—marker of progenitor cells Tuj1-- MAP 2.. SPION labelling… Human “Neural stem cells” after TBI....n=31 Mouse NPC’s..SOX 2 positive cells..