Daniel Todd Laskowitz
Professor of Neurology
Our laboratory uses molecular biology, cell culture, and animal modeling techniques to examine the CNS response to acute injury. In particular, our laboratory examines the role of microglial activation and the endogenous CNS inflammatory response in exacerbating secondary injury following acute brain insult. Much of the in vitro work in this laboratory is dedicated to elucidating cellular responses to injury with the ultimate goal of exploring new therapeutic interventions in the clinical setting of stroke, intracranial hemorrhage, and closed head injury.
In conjunction with the Multidisciplinary Neuroprotection Laboratories, we also focus on clinically relevant small animal models of acute CNS injury. For example, we have recently characterized murine models of closed head injury, subarachnoid hemorrhage, intracranial hemorrhage and perinatal hypoxia-ischemia, in addition to the standard rodent models of focal stroke and transient forebrain ischemia. Recently we have adapted several of these models from the rat to the mouse to take advantage of murine transgenic technology. The objective of these studies are two-fold: to gain better insight into the cellular responses and pathophysiology of acute brain injury, and to test novel therapeutic strategies for clinical translation. In both cell culture systems and animal models, our primary focus is on examining the role of oxidative stress and inflammatory mechanism in mediating brain injury following acute brain insult, and examining the neuroprotective effects of endogenous apolipoprotein E in the injured mammalian central nervous system.
Our laboratory is committed to translational research, and has several active clinical research protocols, which are designed to bring the research performed in the Multidisciplinary Research Laboratories to the clinical arena. These protocols are centered around patients following stroke and acute brain injury, and are primarily based out of the Emergency Room and Neurocritical Care Unit. For example, we are currently examining the role of inflammatory mediators for use as a point-of-care diagnostic marker following stroke, intracranial hemorrhage, and closed head injury. We have recently translated a novel apoE mimetic from the preclinical setting to a multi center Phase 2 trial evaluating efficacy in intracranial hemorrhage. We are also examining the functional role of different polymorphisms of of inflammatory cytokines in the setting of acute brain injury and neurological dysfunction following cardiopulmonary bypass.
Appointments and Affiliations
- Professor of Neurology
- Vice Chair for Academic Affairs in the Department of Neurology
- Director, Duke Clinical Research Institute in the Department of Neurology
- Professor in Neurobiology
- Professor in Anesthesiology
- Professor in Neurosurgery
- Affiliate, Duke Global Health Institute
- Associate of the Duke Initiative for Science & Society
- Member in the Duke Clinical Research Institute
- Office Location: 227B Bryan Res Bldg, Durham, NC 27710
- Office Phone: (919) 684-0056
- Email Address: firstname.lastname@example.org
- Duke University, 1997
- University of Pennsylvania, 1995
- M.D. Duke University, 1991
Awards, Honors, and Distinctions
- A.A. Bennet Award in Neuroscience. Brown University . 2017
- Chairman Award for Excellence. Duke University Medical Center. 2017
- Faculty inductee, AOA Medical Honor Society. AOA. 2011
- Annual Scientific Award, Society of Critical Care Medicine. SCCM. 2010
- Fellow, American Neurological Association. ANA. 2003
- Fellow, American Heart Association. AHA. 2001
- Paul Beeson Physician Faculty Scholar. American Foundation Aging Research. 1999
- Genentech Young Investigator Award in Stroke. AAN/Genentech. 1997
- National Stroke Association Fellowship. National Stroke Association . 1997
- Upjohn and Pharmacia Award for Outstanding CNS Research. Upjohn and Pharmacia/ Duke University Medical Center. 1997
- American Association of Neurology Resident Scholar Award. University of Pennsylvania. 1995
- Long Island Jewish Medical Center Intern of the Year. Long Island Jewish Medical Center. 1992
- Sandoz Award for Superior Academic Achievement. Duke University School of Medicine. 1991
- CRS 301B: CONTINUATION OF RESEARCH STUDY
- INTERDIS 312B: Research Ethics
- THESIS 301B: Thesis
In the News
- Can an ApoE Mimetic Peptide Reduce Rates of Secondary Brain Injury? (Jul 18, 2017 | Clinical Practice Today)
- Treating the Inflammation from Traumatic Brain Injury (Jan 10, 2017)
- Phillips, S; Stanley, L; Nicoletto, H; Burkman, M; Laskowitz, DT; Cairns, CB, Use of emergency department transcranial Doppler assessment of reperfusion after intravenous tPA for ischemic stroke., Journal of Emergency Medicine, vol 42 no. 1 (2012), pp. 40-43 [10.1016/j.jemermed.2008.06.028] [abs].
- James, ML; Blessing, R; Phillips-Bute, BG; Bennett, E; Laskowitz, DT, S100B and brain natriuretic peptide predict functional neurological outcome after intracerebral haemorrhage., Biomarkers, vol 14 no. 6 (2009), pp. 388-394 [10.1080/13547500903015784] [abs].
- Mathew, JP; Mackensen, GB; Phillips-Bute, B; Grocott, HP; Glower, DD; Laskowitz, DT; Blumenthal, JA; Newman, MF; Neurologic Outcome Research Group (NORG) of the Duke Heart Center,, Randomized, double-blinded, placebo controlled study of neuroprotection with lidocaine in cardiac surgery., Stroke; a Journal of Cerebral Circulation, vol 40 no. 3 (2009), pp. 880-887 [10.1161/STROKEAHA.108.531236] [abs].
- Smith, SW; Ivancevich, NM; Lindsey, BD; Whitman, J; Light, E; Fronheiser, M; Nicoletto, HA; Laskowitz, DT, The ultrasound brain helmet: feasibility study of multiple simultaneous 3D scans of cerebral vasculature., Ultrasound Med Biol, vol 35 no. 2 (2009), pp. 329-338 [10.1016/j.ultrasmedbio.2008.08.016] [abs].
- James, ML; Sullivan, PM; Lascola, CD; Vitek, MP; Laskowitz, DT, Pharmacogenomic effects of apolipoprotein e on intracerebral hemorrhage., Stroke; a Journal of Cerebral Circulation, vol 40 no. 2 (2009), pp. 632-639 [10.1161/STROKEAHA.108.530402] [abs].
- Wang, H; Christensen, DJ; Vitek, MP; Sullivan, PM; Laskowitz, DT, APOE genotype affects outcome in a murine model of sepsis: implications for a new treatment strategy., Anaesthesia and Intensive Care, vol 37 no. 1 (2009), pp. 38-45 [10.1177/0310057X0903700111] [abs].
- Laskowitz, DT; Kasner, SE; Saver, J; Remmel, KS; Jauch, EC; BRAIN Study Group,, Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study., Stroke; a Journal of Cerebral Circulation, vol 40 no. 1 (2009), pp. 77-85 [10.1161/STROKEAHA.108.516377] [abs].
- James, ML; Blessing, R; Bennett, E; Laskowitz, DT, Apolipoprotein E modifies neurological outcome by affecting cerebral edema but not hematoma size after intracerebral hemorrhage in humans., J Stroke Cerebrovasc Dis, vol 18 no. 2 (2009), pp. 144-149 [10.1016/j.jstrokecerebrovasdis.2008.09.012] [abs].
- Takata, K; Sheng, H; Borel, CO; Laskowitz, DT; Warner, DS; Lombard, FW, Long-term cognitive dysfunction following experimental subarachnoid hemorrhage: new perspectives., Exp Neurol, vol 213 no. 2 (2008), pp. 336-344 [10.1016/j.expneurol.2008.06.009] [abs].
- Ivancevich, NM; Pinton, GF; Nicoletto, HA; Bennett, E; Laskowitz, DT; Smith, SW, Real-time 3-D contrast-enhanced transcranial ultrasound and aberration correction., Ultrasound in Medicine & Biology, vol 34 no. 9 (2008), pp. 1387-1395 [10.1016/j.ultrasmedbio.2008.01.015] [abs].
- Gump, W; Laskowitz, DT, Management of post-subarachnoid hemorrhage vasospasm., Curr Atheroscler Rep, vol 10 no. 4 (2008), pp. 354-360 [10.1007/s11883-008-0054-7] [abs].
- Laskowitz, DT; Warner, DS, The use of S100B as a biomarker in subarachnoid hemorrhage: clarity in its promise and limits., Critical Care Medicine, vol 36 no. 8 (2008), pp. 2452-2453 [10.1097/ccm.0b013e3181810457] [abs].
- Glickman, SW; Anstrom, KJ; Lin, L; Chandra, A; Laskowitz, DT; Woods, CW; Freeman, DH; Kraft, M; Beskow, LM; Weinfurt, KP; Schulman, KA; Cairns, CB, Challenges in enrollment of minority, pediatric, and geriatric patients in emergency and acute care clinical research., Annals of Emergency Medicine, vol 51 no. 6 (2008), pp. 775-780.e3 [10.1016/j.annemergmed.2007.11.002] [abs].
- Laskowitz, DT; Warner, DS, Statins in acute brain injury: getting the cart before the horse., Neurocritical Care, vol 8 no. 1 (2008), pp. 3-5 [10.1007/s12028-007-9040-0] [abs].
- James, ML; Warner, DS; Laskowitz, DT, Preclinical models of intracerebral hemorrhage: a translational perspective., Neurocritical Care, vol 9 no. 1 (2008), pp. 139-152 [10.1007/s12028-007-9030-2] [abs].
- Laskowitz, DT; Vitek, MP, Apolipoprotein E and neurological disease: therapeutic potential and pharmacogenomic interactions., Pharmacogenomics, vol 8 no. 8 (2007), pp. 959-969 [10.2217/14622418.104.22.1689] [abs].
- Laskowitz, DT; McKenna, SE; Song, P; Wang, H; Durham, L; Yeung, N; Christensen, D; Vitek, MP, COG1410, a novel apolipoprotein E-based peptide, improves functional recovery in a murine model of traumatic brain injury., Journal of Neurotrauma, vol 24 no. 7 (2007), pp. 1093-1107 [10.1089/neu.2006.0192] [abs].
- Wang, H; Lynch, JR; Song, P; Yang, H-J; Yates, RB; Mace, B; Warner, DS; Guyton, JR; Laskowitz, DT, Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury., Experimental Neurology, vol 206 no. 1 (2007), pp. 59-69 [10.1016/j.expneurol.2007.03.031] [abs].
- Mace, BE; Wang, H; Lynch, JR; Moss, J; Sullivan, P; Colton, H; Morgan, K; Renauld, J-C; Laskowitz, DT, Apolipoprotein E modifies the CNS response to injury via a histamine-mediated pathway., Neurological Research, vol 29 no. 3 (2007), pp. 243-250 [10.1179/016164107X158974] [abs].
- Wang, H; Durham, L; Dawson, H; Song, P; Warner, DS; Sullivan, PM; Vitek, MP; Laskowitz, DT, An apolipoprotein E-based therapeutic improves outcome and reduces Alzheimer's disease pathology following closed head injury: evidence of pharmacogenomic interaction., Neuroscience, vol 144 no. 4 (2007), pp. 1324-1333 [10.1016/j.neuroscience.2006.11.017] [abs].
- Ely, EW; Girard, TD; Shintani, AK; Jackson, JC; Gordon, SM; Thomason, JWW; Pun, BT; Canonico, AE; Light, RW; Pandharipande, P; Laskowitz, DT, Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients., Critical Care Medicine, vol 35 no. 1 (2007), pp. 112-117 [10.1097/01.CCM.0000251925.18961.CA] [abs].
- Jauch, EC; Laskowitz, DT, Can D-dimer levels identify patients at risk for early neurological deterioration in acute ischemic stroke?, Nature Clinical Practice. Neurology, vol 2 no. 11 (2006), pp. 590-591 [10.1038/ncpneuro0321] [abs].
- McGirt, MJ; Blessing, R; Alexander, MJ; Nimjee, SM; Woodworth, GF; Friedman, AH; Graffagnino, C; Laskowitz, DT; Lynch, JR, Risk of cerebral vasopasm after subarachnoid hemorrhage reduced by statin therapy: A multivariate analysis of an institutional experience., Journal of Neurosurgery, vol 105 no. 5 (2006), pp. 671-674 [10.3171/jns.2006.105.5.671] [abs].
- Mesis, RG; Wang, H; Lombard, FW; Yates, R; Vitek, MP; Borel, CO; Warner, DS; Laskowitz, DT, Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage., Neurosurgical Focus, vol 21 no. 3 (2006) [10.3171/foc.2006.21.3.4] [abs].
- Li, F-Q; Sempowski, GD; McKenna, SE; Laskowitz, DT; Colton, CA; Vitek, MP, Apolipoprotein E-derived peptides ameliorate clinical disability and inflammatory infiltrates into the spinal cord in a murine model of multiple sclerosis., The Journal of Pharmacology and Experimental Therapeutics, vol 318 no. 3 (2006), pp. 956-965 [10.1124/jpet.106.103671] [abs].
- Newman, MF; Mathew, JP; Grocott, HP; Mackensen, GB; Monk, T; Welsh-Bohmer, KA; Blumenthal, JA; Laskowitz, DT; Mark, DB, Central nervous system injury associated with cardiac surgery., Lancet, vol 368 no. 9536 (2006), pp. 694-703 [10.1016/S0140-6736(06)69254-4] [abs].
- Warner, DS; Laskowitz, DT, Changing outcome from aneurysmal subarachnoid hemorrhage: another step closer., Anesthesiology, vol 104 no. 4 (2006), pp. 629-630 [10.1097/00000542-200604000-00002] [abs].
- Leinenweber, SB; Sheng, H; Lynch, JR; Wang, H; Batinić-Haberle, I; Laskowitz, DT; Crapo, JD; Pearlstein, RD; Warner, DS, Effects of a manganese (III) porphyrin catalytic antioxidant in a mouse closed head injury model., European Journal of Pharmacology, vol 531 no. 1-3 (2006), pp. 126-132 [10.1016/j.ejphar.2005.12.031] [abs].
- Laskowitz, DT; Fillit, H; Yeung, N; Toku, K; Vitek, MP, Apolipoprotein E-derived peptides reduce CNS inflammation: implications for therapy of neurological disease., Acta Neurologica Scandinavica, Supplement, vol 185 (2006), pp. 15-20 [10.1111/j.1600-0404.2006.00680.x] [abs].
- Gao, J; Wang, H; Sheng, H; Lynch, JR; Warner, DS; Durham, L; Vitek, MP; Laskowitz, DT, A novel apoE-derived therapeutic reduces vasospasm and improves outcome in a murine model of subarachnoid hemorrhage., Neurocritical Care, vol 4 no. 1 (2006), pp. 25-31 [10.1385/NCC:4:1:025] [abs].
- Wang, H; Gao, J; Lassiter, TF; McDonagh, DL; Sheng, H; Warner, DS; Lynch, JR; Laskowitz, DT, Levetiracetam is neuroprotective in murine models of closed head injury and subarachnoid hemorrhage., Neurocritical Care, vol 5 no. 1 (2006), pp. 71-78 [10.1385/NCC:5:1:71] [abs].
- Phillips-Bute, B; Mathew, JP; Blumenthal, JA; Grocott, HP; Laskowitz, DT; Jones, RH; Mark, DB; Newman, MF, Association of neurocognitive function and quality of life 1 year after coronary artery bypass graft (CABG) surgery., Psychosom Med, vol 68 no. 3 (2006), pp. 369-375 [10.1097/01.psy.0000221272.77984.e2] [abs].
- Moretti, EW; Morris, RW; Podgoreanu, M; Schwinn, DA; Newman, MF; Bennett, E; Moulin, VG; Mba, UU; Laskowitz, DT; Perioperative Genetics and Safety Outcomes Study (PEGASUS) Investigative Team,, APOE polymorphism is associated with risk of severe sepsis in surgical patients., Critical Care Medicine, vol 33 no. 11 (2005), pp. 2521-2526 [10.1097/01.ccm.0000186368.96146.fb] [abs].
- Lynch, JR; Wang, H; McGirt, MJ; Floyd, J; Friedman, AH; Coon, AL; Blessing, R; Alexander, MJ; Graffagnino, C; Warner, DS; Laskowitz, DT, Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial., Stroke; a Journal of Cerebral Circulation, vol 36 no. 9 (2005), pp. 2024-2026 [10.1161/01.STR.0000177879.11607.10] [abs].
- Laskowitz, DT; Blessing, R; Floyd, J; White, WD; Lynch, JR, Panel of biomarkers predicts stroke., Annals of the New York Academy of Sciences, vol 1053 (2005) [10.1196/annals.1344.051] [abs].
- Lynch, JR; Wang, H; Mace, B; Leinenweber, S; Warner, DS; Bennett, ER; Vitek, MP; McKenna, S; Laskowitz, DT, A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury., Experimental Neurology, vol 192 no. 1 (2005), pp. 109-116 [10.1016/j.expneurol.2004.11.014] [abs].
- McGirt, MJ; Woodworth, GF; Pradilla, G; Legnani, F; Warner, D; Tamargo, R; Clatterbuck, R; Lynch, JR; Laskowitz, DT, Galbraith Award: simvastatin attenuates experimental cerebral vasospasm and ameliorates serum markers of neuronal and endothelial injury in patients after subarachnoid hemorrhage: a dose-response effect dependent on endothelial nitric oxide synthase., Clinical Neurosurgery, vol 52 (2005), pp. 371-378 [abs].
- Lynch, JR; Blessing, R; White, WD; Grocott, HP; Newman, MF; Laskowitz, DT, Novel diagnostic test for acute stroke., Stroke; a Journal of Cerebral Circulation, vol 35 no. 1 (2004), pp. 57-63 [10.1161/01.STR.0000105927.62344.4C] [abs].
- Lynch, JR; Tang, W; Wang, H; Vitek, MP; Bennett, ER; Sullivan, PM; Warner, DS; Laskowitz, DT, APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response., The Journal of Biological Chemistry, vol 278 no. 49 (2003), pp. 48529-48533 [10.1074/jbc.M306923200] [abs].
- McGirt, MJ; Mavropoulos, JC; McGirt, LY; Alexander, MJ; Friedman, AH; Laskowitz, DT; Lynch, JR, Leukocytosis as an independent risk factor for cerebral vasospasm following aneurysmal subarachnoid hemorrhage., Journal of Neurosurgery, vol 98 no. 6 (2003), pp. 1222-1226 [10.3171/jns.2003.98.6.1222] [abs].
- Aono, M; Bennett, ER; Kim, KS; Lynch, JR; Myers, J; Pearlstein, RD; Warner, DS; Laskowitz, DT, Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures., Neuroscience, vol 116 no. 2 (2003), pp. 437-445 [10.1016/s0306-4522(02)00709-1] [abs].
- McGirt, MJ; Lynch, JR; Parra, A; Sheng, H; Pearlstein, RD; Laskowitz, DT; Pelligrino, DA; Warner, DS, Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage., Stroke; a Journal of Cerebral Circulation, vol 33 no. 12 (2002), pp. 2950-2956 [10.1161/01.str.0000038986.68044.39] [abs].
- McGirt, MJ; Lynch, JR; Blessing, R; Warner, DS; Friedman, AH; Laskowitz, DT, Serum von Willebrand factor, matrix metalloproteinase-9, and vascular endothelial growth factor levels predict the onset of cerebral vasospasm after aneurysmal subarachnoid hemorrhage., Neurosurgery, vol 51 no. 5 (2002), pp. 1128-1134 [10.1097/00006123-200211000-00005] [abs].
- Aono, M; Lee, Y; Grant, ER; Zivin, RA; Pearlstein, RD; Warner, DS; Bennett, ER; Laskowitz, DT, Apolipoprotein E protects against NMDA excitotoxicity., Neurobiology of Disease, vol 11 no. 1 (2002), pp. 214-220 [10.1006/nbdi.2002.0541] [abs].
- Lynch, JR; Pineda, JA; Morgan, D; Zhang, L; Warner, DS; Benveniste, H; Laskowitz, DT, Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema., Annals of Neurology, vol 51 no. 1 (2002), pp. 113-117 [10.1002/ana.10098] [abs].
- Misra, UK; Adlakha, CL; Gawdi, G; McMillian, MK; Pizzo, SV; Laskowitz, DT, Apolipoprotein E and mimetic peptide initiate a calcium-dependent signaling response in macrophages., Journal of Leukocyte Biology, vol 70 no. 4 (2001), pp. 677-683 [abs].
- Grocott, HP; Newman, MF; El-Moalem, H; Bainbridge, D; Butler, A; Laskowitz, DT, Apolipoprotein E genotype differentially influences the proinflammatory and anti-inflammatory response to cardiopulmonary bypass., The Journal of Thoracic and Cardiovascular Surgery, vol 122 no. 3 (2001), pp. 622-623 [10.1067/mtc.2001.115152] [abs].
- Lynch, JR; Morgan, D; Mance, J; Matthew, WD; Laskowitz, DT, Apolipoprotein E modulates glial activation and the endogenous central nervous system inflammatory response., Journal of Neuroimmunology, vol 114 no. 1-2 (2001), pp. 107-113 [10.1016/s0165-5728(00)00459-8] [abs].
- Laskowitz, DT; Thekdi, AD; Thekdi, SD; Han, SK; Myers, JK; Pizzo, SV; Bennett, ER, Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides., Experimental Neurology, vol 167 no. 1 (2001), pp. 74-85 [10.1006/exnr.2001.7541] [abs].
- Laskowitz, DT; Lee, DM; Schmechel, D; Staats, HF, Altered immune responses in apolipoprotein E-deficient mice., Journal of Lipid Research, vol 41 no. 4 (2000), pp. 613-620 [abs].
- Mahaffey, KW; Harrington, RA; Simoons, ML; Granger, CB; Graffagnino, C; Alberts, MJ; Laskowitz, DT; Miller, JM; Sloan, MA; Berdan, LG; MacAulay, CM; Lincoff, AM; Deckers, J; Topol, EJ; Califf, RM, Stroke in patients with acute coronary syndromes: incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina. Receptor suppression using integrilin therapy (PURSUIT) trial. The PURSUIT Investigators., Circulation, vol 99 no. 18 (1999), pp. 2371-2377 [10.1161/01.cir.99.18.2371] [abs].
- Laskowitz, DT; Horsburgh, K; Roses, AD, Apolipoprotein E and the CNS response to injury., Journal of Cerebral Blood Flow and Metabolism, vol 18 no. 5 (1998), pp. 465-471 [10.1097/00004647-199805000-00001] [abs].
- Sheng, H; Laskowitz, DT; Bennett, E; Schmechel, DE; Bart, RD; Saunders, AM; Pearlstein, RD; Roses, AD; Warner, DS, Apolipoprotein E isoform-specific differences in outcome from focal ischemia in transgenic mice., Journal of Cerebral Blood Flow and Metabolism, vol 18 no. 4 (1998), pp. 361-366 [10.1097/00004647-199804000-00003] [abs].
- Laskowitz, DT; Matthew, WD; Bennett, ER; Schmechel, D; Herbstreith, MH; Goel, S; McMillian, MK, Endogenous apolipoprotein E suppresses LPS-stimulated microglial nitric oxide production., Neuroreport, vol 9 no. 4 (1998), pp. 615-618 [10.1097/00001756-199803090-00010] [abs].
- Laskowitz, DT; Sheng, H; Bart, RD; Joyner, KA; Roses, AD; Warner, DS, Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia., Journal of Cerebral Blood Flow and Metabolism, vol 17 no. 7 (1997), pp. 753-758 [10.1097/00004647-199707000-00005] [abs].
- Laskowitz, DT; Goel, S; Bennett, ER; Matthew, WD, Apolipoprotein E suppresses glial cell secretion of TNF alpha., Journal of Neuroimmunology, vol 76 no. 1-2 (1997), pp. 70-74 [10.1016/s0165-5728(97)00021-0] [abs].