• VG Khurana, I Meissner, YR Sohni, WR Bamlet, RL McClelland, JM Cunningham, FB Meyer. The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture. Journal of Neurosurgery. Volume 102. Pages 526-531. 2005.
  • Comment: This article reports a genetic predisposition towards brain aneurysm rupture, and was the culmination of three years of efforts to better understand this very special problem in neurosurgery. The concepts have been independently validated by three other North American groups of researchers. A simple genetic test to screen for rupture-prone aneurysms may one day be available to health care professionals and patients alike. The work also reports for the first time both anatomical and genetic evidence for rupture-resistant versus rupture-prone brain aneurysms.
• RF Spetzler, NA Martin. A proposed grading system for arteriovenous malformations. Journal of Neurosurgery. Volume 65. Pages 476-83. 1986.
  • Comment: This seminal article classifying brain AVMs according to risk of surgical treatment. The Spetzler-Martin AVM Grading Scale was thereafter adopted worldwide.
• DG Peters, AB Kassam, E Feingold, E Heidrich-O'Hare, H Yonas, RE Ferrell, A Brufsky. Molecular anatomy of an intracranial aneurysm: Coordinated expression of genes involved in wound healing and tissue remodeling. Stroke. Volume 32. Pages 1036-1042, 2001.
  • Comment: A preliminary glimpse into the protein molecules that may be dynamically expressed in an aneurysm.
• DG Piepgras, VG Khurana, DA Nichols. Occult rupture of a giant vertebral artery aneurysm following proximal occlusion and intrasaccular thrombosis. Journal of Neurosurgery. Volume 95. Pages 132-137. 2001.
  • Comment: An article reporting that brain aneurysms (in this case a giant one containing thrombus) may rupture occultly (i.e., subclinically, without the "classic" picture of subarachnoid hemorrhage).
• JB Bederson, IA Awad, DO Wiebers, et al. Recommendations for the management of patients with unruptured intracranial aneurysms. A statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation. Volume 102. Pages 2300-2308. 2000.
  • Comment: This important article relates to very controversial areas in neurosurgery: i.e., how and when to screen for, and treat patients with, unruptured brain aneurysms.
• HH Dietrich, RG Dacey Jr. Molecular keys to the problems of cerebral vasospasm. Neurosurgery. Volume 46. Pages 517-530. 2000.
  • Comment: The article reviews a variety of possible mechanisms underlying cerebral vasospasm which is a potentially life-threatening complication of aneurysm rupture. Vasospasm remains difficult to treat based on our limited understanding of its precise molecular basis.
• VG Khurana, FB Meyer. Translational paradigms in cerebrovascular gene transfer. Journal of Cerebral Blood Flow and Metabolism. Volume 23. Pages 1251-1962. 2003.
  • Comment: This is a review of fundamental concepts in gene transfer which is the science underlying gene therapy. The article summarizes the present research and development of this area related to the use of this technology in the brain circulation.
• MA Kay, JC Glorioso, L Naldini. Viral vectors for gene therapy: The art of turning infectious agents into vehicles of therapeutics. Nature Medicine. Volume 7. Pages 33-40. 2001.
  • Comment: The above article reviews the different types of viruses that can be genetically engineered for use in gene therapy models.

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In this section below, several references have been chosen as recommended reading for each topic. Of course, there are many other excellent books and articles that could have been included; the ones listed below were selected as a suitable introduction to, or overview of, the specific area.

• AJ Molyneux, RS Kerr, LM Yu, M Clarke, M Sneade, JA Yarnold, P Sandercock, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomized comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysmal occlusion. Lancet. Volume 366. Pages 809-817. 2005.
  • Comment: An important study comparing coiling vs. clipping of ruptured saccular brain aneurysms. This multicenter study is led by Drs. Molyneux & Kerr. Note that ISAT has very significant inclusion and exclusion criteria (see below)
• GW Britz. ISAT trial: coiling or clipping for intracranial aneurysms? Lancet. Volume 366. Pages 783-785. 2005.
  • Comment: The above article by Dr. Britz represents a balanced critique of the ISAT study and is also well worth reading.
• An overview of ISAT and a discussion of "coiling versus clipping" choices, including Frequently Asked Questions, is provided elsewhere. See below for a commentary:

Commentary: Main messages so far from the supporters and critics of ISAT (the following comments pertain to ruptured saccular/ruptured berry aneurysms, i.e., the kinds of aneurysms that featured exclusively in ISAT):

• Coiling appears safer in the short term at least for ruptured brain aneurysms.
• Coiling may be appropriate for many but not all ruptured brain aneurysms.
• Coiling may be a less permanent and/or more uncertain form of treatment depending on the ruptured aneurysm's size and extent of coiling.
• Some ruptured aneurysms that can appear "completely treated" by coiling can still rebleed, and this situation (although not commmon) tends to occur more often with apparently "completely coiled" aneurysms compared with apparently "completely clipped" aneurysms.
• Coiling and open surgery are good alternatives for ruptured aneurysms, but the outcomes may be to some extent "operator-dependent", and the treatment choice should be made on a case-by-case basis.
• Aneurysm clipping (ruptured and unruptured) has proven its long-term effectiveness and worthiness over several decades.
• It is a common misconception (and one that has been promoted effectively by certain self-interest groups) that the ISAT study compared all types of aneurysms and that the conclusions of ISAT are applicable to all types of saccular aneurysms. This is not so. In reality, the study (i) only included patients with ruptured saccular aneurysms and (ii) only included those ruptured saccular aneurysms whose radiological appearance suggested they could be treated "equally" effectively by either method (coiling or open surgery). That is, the study intentionally excluded patients with (i) unruptured aneurysms and (ii) ruptured aneurysms that appeared to be more effectively treatable by one technique over the other. In fact, the vast majority (almost 80%) of patients eligible for the study were actually excluded from enrollment and further analysis based on the above criteria, and therefore it is worth noting the potential impact of these "inclusion" and "exclusion" criteria on any conclusions drawn and promoted.
• From an ISAT Joint Position Statement issued by the American Association of Neurological Surgeons (AANS) in November, 2005 (Harbaugh et al.):
  • "Of 9,278 patients with ruptured intracranial aneurysms assessed for ISAT eligibility, only 2,143 were randomized [i.e., included in ISAT]. In those 7,135 patients not randomized [i.e., not included in ISAT], more patients underwent craniotomy for aneurysm clipping than endovascular aneurysm coiling. Over the course of the ISAT study, neurovascular teams in the participating centers felt that surgery was the best option for the majority of patients with ruptured aneurysms who were not randomized. Therefore, if an experienced vascular neurosurgeon thinks that craniotomy for aneurysm clipping is the best option for a patient with a ruptured intracranial aneurysm, the patient should continue to be offered surgery as the treatment of choice. The results of ISAT do not apply to this larger group of patients, as they were excluded from the randomized trial. Disappointingly, outcomes and follow-up were not provided for the non-randomized patients."

• Primer on Cerebrovascular Diseases (Textbook). Edited by KMA Welch, LR Caplan, DJ Reis, BK Siesjo, B Weir. Published by Academic Press (San Diego, CA). 1997.
• VG Khurana, JA Friedman, FB Meyer: Chapter 11: Biology of Cerebral Blood Vessels and Blood Flow. In Le Roux PD, Winn HR, Newell DW (eds), Management of Cerebral Aneurysms (Textbook), Philadelphia, WB Saunders, pp 139-167, 2003.
• RM Lee. Morphology of cerebral arteries. Pharmacology and Therapeutics. Volume 66. Pages 149-173. 1995.
• E Dahl. The ultrastructure of cerebral blood vessels in man. Cephalalgia. Volume 6. Pages 45-48. 1986.
• JE Brian Jr, FM Faraci, DD Heistad. Recent insights into the regulation of the cerebral circulation. Clinical & Experimental Pharmacology and Physiology. Volume 23. Pages 449-457. 1996.
• M Wahl, L Schilling. Regulation of cerebral blood flow - A brief review. Acta Neurochirurgica. Volume 59. Pages 3-10. 1993.

• Pathology of the Cerebral Blood Vessels (Textbook). Written by WE Stehbens. Published by CV Mosby (St. Louis, MO). 1972.
• J Suzuki, H Ohara. Clinicopathological study of cerebral aneurysms: Origin, rupture, repair, and growth. Journal of Neurosurgery. Volume 48. Pages 505-514. 1978.
• Aneurysms Affecting the Nervous System (Textbook). Written by B Weir. Published by Williams & Wilkins (Baltimore, MD). 1987.
• Giant Intracranial Aneurysms (Textbook). Edited by IA Awad, D Barrow. Published by the American Association of Neurological Surgeons (AANS) Publications Committee (Park Ridge, IL). 1995.
• MT Lawton, RF Spetzler. Surgical strategies for giant intracranial aneurysms. Neurosurgery Clinics of North America. Volume 9. Pages 725-742. 1998.
• SP Javedan SP, VR Deshmukh, RF Spetzler, JM Zabramski. The role of cerebral revascularization in patients with intracranial aneurysms. Neurosurgery Clinics of North America. Volume 12. Pages 541-555. 2001.
• JJ Evans, LN Sekhar, R Rak, D Stimac. Bypass grafting and revascularization in the management of posterior circulation aneurysms. Neurosurgery. Volume 55. Pages 1036-1049. 2004.
• VG Khurana, I Meissner, FB Meyer. Update on genetic evidence for rupture-prone compared with rupture-resistant intracranial saccular aneurysms. Neurosurgical Focus. Volume 17. E7. 2004.
• WI Schievink. Intracranial aneurysms. New England Journal of Medicine. Volume 336. Pages 28-40. 1997.
• GJ Rinkel, M Djibuti, A Algra, J van Gijn. Prevalence and risk of rupture of intracranial aneurysms: A systematic review. Stroke. Volume 29. Pages 251-256. 1998.

• International Study of Unruptured Intracranial Aneurysms (ISUIA) Investigators. Unruptured intracranial aneurysms: Risks of rupture and risks of surgical intervention. New England Journal of Medicine. Volume 339. Pages 1725-1733. 1998.
• DO Wiebers, JP Whisnant, WM O'Fallon. The natural history of unruptured intracranial aneurysms. New England Journal of Medicine. Volume 304. Pages 696-698. 1981.
• DO Wiebers, JP Whisnant, TM Sundt Jr, et al. The significance of unruptured intracranial saccular aneurysms. Journal of Neurosurgery. Volume 66. Pages 23-29. 1987.
• LR Caplan. Should intracranial aneurysms be treated before they rupture? New England Journal of Medicine. Volume 339. Pages 1774-1775. 1998.
• JB Bederson, IA Awad, DO Wiebers, et al. Recommendations for the management of patients with unruptured intracranial aneurysms. A statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation. Volume 102. Pages 2300-2308. 2000.
• VG Khurana, I Meissner, YR Sohni, WR Bamlet, RL McClelland, JM Cunningham, FB Meyer. The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture. Journal of Neurosurgery. Volume 102. Pages 526-531. 2005.

• TM Sundt Jr, JP Whisnant. Subarachnoid hemorrhage from intracranial aneurysms: Surgical management and natural history of disease. New England Journal of Medicine. Volume 299. Pages 116-122. 1978.
• NF Kassell, JC Torner. Aneurysmal rebleeding: A preliminary report from the Cooperative Aneurysm Study. Neurosurgery. Volume 13. Pages 479-481. 1983.
• VG Khurana, DG Piepgras, JP Whisnant JP. Ruptured giant intracranial aneurysms. Part I. A study of rebleeding. Journal of Neurosurgery. Volume 88. Pages 425-429. 1998.
• J Hillman, C von Essen, W Leszniewski, I Johansson. Significance of “ultra-early” rebleeding in subarachnoid hemorrhage. Journal of Neurosurgery. Volume 68. Pages 901-907. 1988.
• RD Verweij, EFM Wijdicks, J van Gijn. Warning headache in aneurysmal subarachnoid hemorrhage: A case-control study. Archives of Neurology. Volume 45. Pages 1019-1020. 1988.

• B Weir. The pathophysiology of cerebral vasospasm. British Journal of Neurosurgery. Volume 9. Pages 375-390. 1995.
• B Weir, L Macdonald. Cerebral vasospasm. Clinical Neurosurgery. Volume 40. Pages 40-55. 1993.
• NWC Dorsch, MT King. A review of cerebral vasospasm in aneurysmal subarachnoid haemorrhage. Part I. Incidence and effects. Journal of Clinical Neuroscience. Volume 1. Pages 19-26. 1994.
• VG Khurana, M Besser. Pathophysiological basis of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. Journal of Clinical Neuroscience. Volume 4. Pages 122-131. 1997.
• HH Dietrich, RG Dacey Jr. Molecular keys to the problems of cerebral vasospasm. Neurosurgery. Volume 46. Pages 517-530. 2000.
• VG Khurana, YR Sohni, WI Mangrum, RL McClelland, DJ O'Kane, FB Meyer, I Meissner. Endothelial nitric oxide synthase gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage and cerebral vasospasm. Journal of Cerebral Blood Flow and Metabolism. Volume 24. Pages 291-297. 2004.
• IA Awad, LP Carter, RF Spetzler, M Medina, FC Williams Jr. Clinical vasospasm after subarachnoid hemorrhage: response to hypervolemic hemodilution and arterial hypertension. Stroke. Volume 18. Pages 365-72. 1987.

• RF Spetzler, NA Martin. A proposed grading system for arteriovenous malformations. Journal of Neurosurgery. Volume 65. Pages 476-83. 1986.
• RF Spetzler, PW Detwiler, HA Riina, RW Porter. Modified classification of spinal cord vascular lesions. Journal of Neurosurgery Spine. Volume 96. Pages 145-56. 2002.
• MK Morgan, AM Rochford, A Tsahtsarlis, N Little, KC Faulder. Surgical risks associated with the management of Grade I and Grade II brain arteriovenous malformations. Neurosurgery. Volume 54. Pages 832-837. 2004.
• RD Ferch, MK Morgan. High-grade arteriovenous malformations and their management. Journal of Clinical Neuroscience. Volume 9. Pages 37-40. 2002.
• RD Ferch, MK Morgan, WR Sears. Spinal arteriovenous malformations: a review with case illustrations. Journal of Clinical Neuroscience. Volume 8. Pages 299-304. 2001.
• PW Detweiler, RW Porter, RF Spetzler. Spinal arteriovenous malformations. Neurosurgery Clinics of North America. Volume 10. Pages 89-100. 1999.
• MT Lawton MT, MG Hamilton, RF Spetzler. Multimodality treatment of deep arteriovenous malformations: thalamus, basal ganglia, and brain stem. Neurosurgery. Volume 37. Pages 29-36. 1995
• MG Hamilton, RF Spetzler. The prospective application of a grading system for arteriovenous malformations. Neurosurgery. Volume 34. Pages 2-7. 1994.
• VG Khurana, CM Perez-Terzic, RC Petersen, WE Krauss. Singing paraplegia: A distinctive manifestation of a spinal dural arteriovenous fistula. Neurology. Volume 58. Pages 1279-1281. 2002.

• Cerebral Blood Flow and Metabolism (Textbook). Written by L Edvinsson, ET Mackenzie, J McCulloch. Published by Raven Press (New York, NY). 1993.
• VG Khurana, EE Benarroch, ZS Katusic, FB Meyer: Chapter 86: Cerebral Blood Flow and Metabolism. In Winn HR (ed), Youmans Neurological Surgery, 5^th Edition, Vol. 2, Philadelphia, WB Saunders, pp 1467-1494, 2003.
• Brain Energy Metabolism (Textbook). Written by BK Siesjo. Published by John Wiley & Sons (New York, NY). 1978.
• Neurosurgery Clinics of North America: Cerebral Blood Flow (Serial-Text). Volume 7. Edited by FB Meyer. Published by WB Saunders (Philadelphia, PA). 1996.
• FM Faraci, JE Brian. Nitric oxide and the cerebral circulation. Stroke. Volume 25. Pages 692-703. 1994.
• SS Kety. The circulation, metabolism, and functional activity of the human brain. Neurochemical Research. Volume 16. Pages 1073-1078. 1991.

• S Moncada, RMJ Palmer, EA Higgs. Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacological Reviews. Volume 43. Pages 109-142. 1991.
• S Moncada, A Higgs. The L-arginine-nitric oxide pathway. New England Journal of Medicine. Volume 329. Pages 2002-2012. 1993.
• E Anggard. Nitric oxide: Mediator, murderer, and medicine. Lancet. Volume 343: 1199-1206. 1994.
• PA Marsden, HHQ Heng, SW Scherer, RJ Stewart, AV Hall, XM Shi, LC Tsui, KT Schappert. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. Journal of Biological Chemistry. Volume 268. Pages 17478-17488. 1993.
• T Dalkara, MA Moskowitz. Nitric oxide and the cerebral circulation. In: KMA Welch, LR Caplan, DJ Reis, BK Siesjo, B Weir (editors): Primer on Cerebrovascular Diseases. San Diego, CA. Academic Press. Pages 96-98. 1997.
• XL Wang, J Wang. Endothelial nitric oxide synthase gene sequence variations and vascular disease. Molecular Genetics and Metabolism. Volume 70. Pages 241-251. 2000.

• JM Rusnak, RM Kisabeth, DP Herbert, DM McNeil. Pharmacogenomics: A clinician's primer on emerging technologies for improved patient care. Mayo Clinic Proceedings. Volume 76. Pages 299-309. 2001.
• WE Evans, MV Relling. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science. Volume 286. Pages 487-491. 1999.
• AD Roses. Genetic susceptibility to cardiovascular diseases. American Heart Journal. Volume 140. Pages S45-S47. 2000.
• EM Rubin, A Tall. Perspectives for vascular genomics. Nature. Volume 407. Pages 265-269. 2000.
• CP Lorentz, ED Wieben, A Tefferi, DA Whiteman, GW Dewald. Primer on medical genomics. Part I: History of genetics and sequencing of the human genome. Mayo Clinic Proceedings. Volume 77. Pages 773-782. 2002.
• A Pardanani, ED Wieben, TC Spelsberg, A Tefferi. Primer on medical genomics. Part IV: Expression proteomics. Mayo Clinic Proceedings. Volume 77. Pages 1185-1196. 2002.
• SM Ansell, MJ Ackerman, JL Black, LR Roberts, A Tefferi. Primer on medical genomics. Part VI: Genomics and molecular genetics in clinical practice. Mayo Clinic Proceedings. Volume 78. Pages 307-317. 2003.

• HM Blau, ML Springer. Gene therapy - A novel form of drug delivery. New England Journal of Medicine. Volume 333. Pages 1204-1207. 1995.
• MR Dyer, PL Herrling. Progress and potential for gene-based medicines. Molecular Therapy. Volume 1. Pages 213-224. 2000.
• DD Heistad, FM Faraci. Gene therapy for cerebral vascular disease. Stroke. Volume 27. Pages 1688-1693. 1996.
• AFY Chen, T O'Brien, ZS Katusic. Transfer and expression of recombinant nitric oxide synthase genes in the cardiovascular system. Trends in Pharmacological Sciences. Volume 19. Pages 276-286. 1998.
• VG Khurana, FB Meyer. Translational paradigms in cerebrovascular gene transfer. Journal of Cerebral Blood Flow and Metabolism. Volume 23. Pages 1251-1262. 2003.
• VG Khurana, LA Smith, TA Baker, D Eguchi, T O’Brien, ZS Katusic. Protective vasomotor effects of in vivo recombinant endothelial nitric oxide synthase gene expression in a canine model of cerebral vasospasm. Stroke. Volume 33. Pages 782-789. 2002.

• VG Khurana, DA Weiler, TA Witt, LA Smith, LS Kleppe, JE Parisi, RD Simari, T O’Brien, SJ Russell, ZS Katusic. A direct mechanical method for accurate and efficient adenoviral vector delivery to tissues. Gene Therapy. Volume 10. Pages 443-452. 2003.
  • Comment: This paper was the seminal article describing a new mechanical technique for intraoperative gene delivery that resulted in significantly improved accuracy and efficiency of gene transfer.
• United States Patent and Trademark Office (USPTO). Website URL: http://www.USPTO.gov [U.S. Pat. search term: 6,821,264.]
  • Comment: This patent describes the device affectionately known as The Genebrush.
• VG Khurana, FB Meyer: Translational paradigms in cerebrovascular gene transfer. Journal of Cerebral Blood Flow and Metabolism. Volume 23. Pages 1251-1962. 2003.
  • Comment: This article also describes gene therapy in general, focuses on cerebrovascular gene transfer studies, and describes and depicts the use of the surgical paintbrush (Genebrush).
• JI Rotmans, HJ Verhagen, E Velema, DP de Kleijn, M van den Heuvel, JJ Kastelein, G Pasterkamp, ES Stroes. Local overexpression of C-type natriuretic peptide ameliorates vascular adaptation of porcine hemodialysis grafts. Kidney International. Volume 65. Pages 1897-1905. 2004.
  • Comment: This article from a group in the Netherlands was the first to independently validate the safety and efficacy of the surgical paintbrush technique.
• K Kikuchi, AD McDonald, T Sasano, JK Donahue JK. Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer. Circulation. Volume 111. Pages 264-270. 2005.
  • Comment: This group from Johns Hopkins in Baltimore carried out a very comprehensive and landmark study using the surgical paintbrush, again validating its safety, effectiveness and potential for clinical use.

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