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Amphetamines help restore speech after stroke
SCIENCE AND MEDICINE
Angiogenesis and functional recovery demonstrated after minor stroke esearchers have used a rat model to demonstrate that existing arteries widen and lengthen in the region surrounding the area of ischaemia caused by the induction of an experimental “mini-stroke”. “There is also evidence that angiogenesis occurs within 30 days, resulting in a network of new capillaries in the ischaemic border. We are now assessing how the vascular plasticity may affect neuronal connections”, says lead author Ling Wei (Washington University School of Medicine, St Louis, MO, USA). Wei and colleagues used an optical detection system and a 6–8 mm cranial window to identify three to six proximal and distal branches of the middle cerebral artery supplying the barrel cortex. A suture was then passed through the dura and under each arteriole. In the experimental group, the suture was tied; in controls it was left untied. Videomicroscopy was used in conjunction with fluorescein staining in each rat immediately after, and 30 days after, ligation to detect perfusion levels in the tissue; in another similarly prepared group, immunochemistry was used to detect angiogenesis. Just after ligation, there was an inner core with little observable perfusion, a surrounding ring of
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reduced perfusion and an outer ring of unchanged perfusion. 30 days later, the diameters and lengths of vessels in the ischaemic border had grown significantly and the fluorescein stain was able to enter occluded segments of the middle cerebral artery. Angiogenesis had occurred, but was confined to the ischaemic border (Stroke 2001; 32: 2179–84). “This study in rats makes an important contribution to the understanding of angiogenesis in the periinfarct tissue surrounding an ischemic infarct in cerebral cortex”, says Randolph Nudo (Center on Aging, University of Kansas Medical Center, KS, USA). Such chronic
studies of angiogenesis in animal models are rare; this is the first direct demonstration of post-stroke angiogenesis in surface collaterals and their supplied vascular beds in the same animal, he continues. Wei reports that the group now plan to explore ways to use drugs, gene therapy, rehabilitation, and other methods to enhance restoration of local blood supply, reduce stroke damage, and improve brain function. “This work is particularly provocative in light of recent studies showing substantial physiological and anatomical plasticity in neurons surrounding a cortical infarct”, comments Nudo. Kathryn Senior
Amphetamines help restore speech after stroke Delaina Walker-Batson (Stroke Center, Texas Women’s University, Dallas, TX, USA) and colleagues report that administration of dextroamphetamine, paired with ten 1-h sessions of language therapy, facilitated recovery from aphasia in 21 stroke patients. Patients were treated with 10 mg of the drug, or a placebo, between 16 and 45 days after an acute non-haemorrhagic infarction that resulted in loss of speech. 30 min later they received a 1-h speech therapy session; this treatment combination was repeated every 3–4 days for ten sessions. After 1 week, there was a significant difference in the gain scores between the groups (p=0·0153, with the greater gain in the drug-treated group). The difference was still significant when corrected for the severity of the initial aphasia, and age (Stroke 2001; 32: 2093–96). Kathryn Senior
Melanoma spread involves signals in cellular environment S scientists report that aggressive melanoma cells modify their environment by laying down molecular cues in the extracellular matrix. These cues, says Richard Seftor (University of Iowa, Iowa City, IA, USA) can be read by less aggressive cells causing them to become more aggressive. “Our results”, Seftor suggests, “should alert physicians to the possibility that cancer therapy may not stop with killing cancer cells. Other tissues in the body may also be altered and we should design therapies to address these alterations as well.” Seftor, part of a University of Iowa team led by Mary Hendrix, is working on a process called vasculogenic mimicry. In this, aggressive tumour cells, but not less aggressive cells, form tubular networks resembling embryonic vascular networks when grown in a three-dimensional matrix in vitro. In collaboration with researchers elsewhere in the USA, the Iowa team discovered that aggressive
U
THE LANCET • Vol 358 • September 8, 2001
melanoma cell lines express several proteins involved in tumour cell invasion, cell motility, and modification of the extracellular matrix. “When we asked whether these proteins were involved in vasculogenic mimicry”, says Seftor, “we found that their expression colocalised with the in-vitro networks”. Furthermore, antisense oligonucleotides to laminin 5 ␥2 chain and antibodies to matrix metalloproteinases 2 and 14—three of the proteins expressed specifically in aggressive cells—inhibited network formation (Cancer Res 2001; 61: 6322–27). Most importantly, says Seftor, “poorly aggressive melanoma cells seeded onto matrix preconditioned by aggressive cells formed tubular networks along the laminin 5 ␥2 tracks left by the aggressive cells”. Seftor speculates that vasculogenic mimicry may act in addition to angiogenesis to aid perfusion of rapidly growing tumours. “Pathologists have reported similar networks in patient
samples”, he explains, “and a correlation has been established between the presence of these networks and poor clinical outcome for uveal melanoma. Thus, our results could lead to new diagnostic tools as well as indicating new targets for antitumour therapies.” “These are extremely interesting results”, comments Rona MacKie (University of Glasgow, UK). “Clinically, they raise important considerations about tumour excision. The normal belief is that if you have excised all the visible tumour cells, you have succeeded, but what if you have left behind this network?” MacKie goes on to sound a slight note of caution about extrapolating from experiments done on cell lines in culture to patients. Nevertheless, she says: “I will certainly be re-examining sections taken from some of my patients with aggressive melanoma for these networks.” Jane Bradbury
817
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Angiogenesis and functional recovery demonstrated after minor stroke esearchers have used a rat model to demonstrate that existing arteries widen and lengthen in the region surrounding the area of ischaemia caused by the induction of an experimental “mini-stroke”. “There is also evidence that angiogenesis occurs within 30 days, resulting in a network of new capillaries in the ischaemic border. We are now assessing how the vascular plasticity may affect neuronal connections”, says lead author Ling Wei (Washington University School of Medicine, St Louis, MO, USA). Wei and colleagues used an optical detection system and a 6–8 mm cranial window to identify three to six proximal and distal branches of the middle cerebral artery supplying the barrel cortex. A suture was then passed through the dura and under each arteriole. In the experimental group, the suture was tied; in controls it was left untied. Videomicroscopy was used in conjunction with fluorescein staining in each rat immediately after, and 30 days after, ligation to detect perfusion levels in the tissue; in another similarly prepared group, immunochemistry was used to detect angiogenesis. Just after ligation, there was an inner core with little observable perfusion, a surrounding ring of
R
reduced perfusion and an outer ring of unchanged perfusion. 30 days later, the diameters and lengths of vessels in the ischaemic border had grown significantly and the fluorescein stain was able to enter occluded segments of the middle cerebral artery. Angiogenesis had occurred, but was confined to the ischaemic border (Stroke 2001; 32: 2179–84). “This study in rats makes an important contribution to the understanding of angiogenesis in the periinfarct tissue surrounding an ischemic infarct in cerebral cortex”, says Randolph Nudo (Center on Aging, University of Kansas Medical Center, KS, USA). Such chronic
studies of angiogenesis in animal models are rare; this is the first direct demonstration of post-stroke angiogenesis in surface collaterals and their supplied vascular beds in the same animal, he continues. Wei reports that the group now plan to explore ways to use drugs, gene therapy, rehabilitation, and other methods to enhance restoration of local blood supply, reduce stroke damage, and improve brain function. “This work is particularly provocative in light of recent studies showing substantial physiological and anatomical plasticity in neurons surrounding a cortical infarct”, comments Nudo. Kathryn Senior
Amphetamines help restore speech after stroke Delaina Walker-Batson (Stroke Center, Texas Women’s University, Dallas, TX, USA) and colleagues report that administration of dextroamphetamine, paired with ten 1-h sessions of language therapy, facilitated recovery from aphasia in 21 stroke patients. Patients were treated with 10 mg of the drug, or a placebo, between 16 and 45 days after an acute non-haemorrhagic infarction that resulted in loss of speech. 30 min later they received a 1-h speech therapy session; this treatment combination was repeated every 3–4 days for ten sessions. After 1 week, there was a significant difference in the gain scores between the groups (p=0·0153, with the greater gain in the drug-treated group). The difference was still significant when corrected for the severity of the initial aphasia, and age (Stroke 2001; 32: 2093–96). Kathryn Senior
Melanoma spread involves signals in cellular environment S scientists report that aggressive melanoma cells modify their environment by laying down molecular cues in the extracellular matrix. These cues, says Richard Seftor (University of Iowa, Iowa City, IA, USA) can be read by less aggressive cells causing them to become more aggressive. “Our results”, Seftor suggests, “should alert physicians to the possibility that cancer therapy may not stop with killing cancer cells. Other tissues in the body may also be altered and we should design therapies to address these alterations as well.” Seftor, part of a University of Iowa team led by Mary Hendrix, is working on a process called vasculogenic mimicry. In this, aggressive tumour cells, but not less aggressive cells, form tubular networks resembling embryonic vascular networks when grown in a three-dimensional matrix in vitro. In collaboration with researchers elsewhere in the USA, the Iowa team discovered that aggressive
U
THE LANCET • Vol 358 • September 8, 2001
melanoma cell lines express several proteins involved in tumour cell invasion, cell motility, and modification of the extracellular matrix. “When we asked whether these proteins were involved in vasculogenic mimicry”, says Seftor, “we found that their expression colocalised with the in-vitro networks”. Furthermore, antisense oligonucleotides to laminin 5 ␥2 chain and antibodies to matrix metalloproteinases 2 and 14—three of the proteins expressed specifically in aggressive cells—inhibited network formation (Cancer Res 2001; 61: 6322–27). Most importantly, says Seftor, “poorly aggressive melanoma cells seeded onto matrix preconditioned by aggressive cells formed tubular networks along the laminin 5 ␥2 tracks left by the aggressive cells”. Seftor speculates that vasculogenic mimicry may act in addition to angiogenesis to aid perfusion of rapidly growing tumours. “Pathologists have reported similar networks in patient
samples”, he explains, “and a correlation has been established between the presence of these networks and poor clinical outcome for uveal melanoma. Thus, our results could lead to new diagnostic tools as well as indicating new targets for antitumour therapies.” “These are extremely interesting results”, comments Rona MacKie (University of Glasgow, UK). “Clinically, they raise important considerations about tumour excision. The normal belief is that if you have excised all the visible tumour cells, you have succeeded, but what if you have left behind this network?” MacKie goes on to sound a slight note of caution about extrapolating from experiments done on cell lines in culture to patients. Nevertheless, she says: “I will certainly be re-examining sections taken from some of my patients with aggressive melanoma for these networks.” Jane Bradbury
817
For personal use. Only reproduce with permission from The Lancet Publishing Group.