Thank you transfer a letter of James M. Howard to me. Here is my discussion.
In this clinical research, we mainly focus on the efficacy and safety of Ginkgo in combination with aspirin in acute ischemic stroke and its impact on the recurrence of vascular events. However, the underlying molecular mechanisms are worth to be explored because of their effectiveness.
Although there have been reviewed that cortisol levels are high for at least 7 days after stroke and elevated cortisol after stroke is associated with dependency, morbidity, and mortality [1] . There is insufficient evidence to relate the severity of ischemic stroke with cortisol because cortisol can be influenced by diurnal rhythm, food, life style and so on. There has been no evidence to ascribe cortisol both by Ginkgo and aspirin directly to improve cognitive and neurological function. There has been reported that lower levels of DHEAS were associated with an increased risk of ischemic stroke [2], but few literatures show that reductions in cortisol increase the positive effects of DHEA on brain functions.
The potential mechanisms of Ginkgo and aspirin have not been clear. Notably, it has been found that Ginkgo plus aspirin can enhance the expressions of LOX-1 and p-p38MAPK correlated with the inhibition of ROS production, LOX-1 expression and p38MAPK phosphorylation in human coronaryartery endothelial cells [3]....
Thank you transfer a letter of James M. Howard to me. Here is my discussion.
In this clinical research, we mainly focus on the efficacy and safety of Ginkgo in combination with aspirin in acute ischemic stroke and its impact on the recurrence of vascular events. However, the underlying molecular mechanisms are worth to be explored because of their effectiveness.
Although there have been reviewed that cortisol levels are high for at least 7 days after stroke and elevated cortisol after stroke is associated with dependency, morbidity, and mortality [1] . There is insufficient evidence to relate the severity of ischemic stroke with cortisol because cortisol can be influenced by diurnal rhythm, food, life style and so on. There has been no evidence to ascribe cortisol both by Ginkgo and aspirin directly to improve cognitive and neurological function. There has been reported that lower levels of DHEAS were associated with an increased risk of ischemic stroke [2], but few literatures show that reductions in cortisol increase the positive effects of DHEA on brain functions.
The potential mechanisms of Ginkgo and aspirin have not been clear. Notably, it has been found that Ginkgo plus aspirin can enhance the expressions of LOX-1 and p-p38MAPK correlated with the inhibition of ROS production, LOX-1 expression and p38MAPK phosphorylation in human coronaryartery endothelial cells [3]. Also, Ginkgo plus aspirin reduced transcription of TGF-β1, MMP-2 and MMP-9 genes and by the decreased expression of type I collagen,MMP-2 and MMP-9 proteins in myocardial cells [4]. We may investigate the novel mechanisms according to clues above.
Reference:
[1] Amanda Jayne Barugh, et al. Cortisol levels and the severity and outcomes of acute stroke: a systematic review [J]. J Neurol. 2014 March ; 261(3): 533–545.
[2] Monik C. Jiménez, ScD, Qi Sun, MD, ScD, et al. Low dehydroepiandrosterone sulphate is associated with increased risk of ischemic stroke among women: DHEAS and Risk of Ischemic Stroke in Women [J]. Stroke. 2013 July ; 44(7).
[3] Xianguan Zhua, Zhongdong Li, et al. Ginkgo biloba extract and Aspirin synergistically attenuate activated platelet-induced ROS production and LOX-1 expression in human coronary artery endothelial cells [J]. Phytomedicine. 2013. 20:114-119.
[4] Wei Li, Zhenhua Luo, Xingde Liu, Lingyun Fu, et al. Effect of Ginkgo biloba extract on experimental cardiac remodeling [J]. BMC Complementary and Alternative Medicine. 2015.15:277
I suggest the positive effect of combined aspirin and ginkgo post ischemic stroke is reduced cortisol. Aspirin and ginkgo both reduce cortisol. Increased reduction of cortisol by both produces more "improved cognitive and neurological functions" than aspirin alone. Furthermore, I suggest reductions in cortisol increase the positive effects of dehydroepiandrosterone (DHEA) on brain functions.
Thanks so much for notifying us about the figure misalignment issue in the original article - “Artificial Intelligence in Healthcare: Past, Present and Future.”
We have now investigated the issue. The misalignment originated from a glitch during the production stage. We now have fixed the issue and updated the online version of the paper. The latest publication is attached for your reference. Please accept our sincere apology for the mistake.
It appears that the figures to not match their descriptive text: Figure 8 is not a stylised representation of an neural network - it is a stylised representation of a support vector machine and figure 9 is not a stylised representation of a deep learning network, the authors illustration is more of a conventional neural network with only one hidden layer.
We have reviewed your comments on our paper. For your opinion on the issue of penumbra not to be present in subacute phase of stroke, there are literature reporting its presence days after the initial stroke. Penumbra is a dynamic phenomenon without clear demarcation. For example, there is a zone of benign misery perfusion outside of penumbra with its CBF between 15 to 30ml/100g/min (1). This zone may not be viable if perfusion is not re-established. That is to say with a major cerebral arterial occlusion, even with the help of collaterals, brain tissue may die slowly over a period of time. In clinical practice and proven by imaging studies, the side of brain with a large arterial occlusion will significantly atrophy, a process perhaps related to cell apoptosis from chronic hypoxic state (2). Hence, re-opening the occluded artery may or may not help the immediate stroke, but likely help the large ipsilateral brain tissue in a long run. More longitudinal study is certainly needed to examine this issue.
You have questioned our equipment on its ability to detect penumbra. We have had over 10 years of experience in performing MR perfusion with MRI scanner manufactured by Siemens.
All of our patients have received guideline recommended best medical management including dual antiplatelet and statin therapy plus life style modificat...
We have reviewed your comments on our paper. For your opinion on the issue of penumbra not to be present in subacute phase of stroke, there are literature reporting its presence days after the initial stroke. Penumbra is a dynamic phenomenon without clear demarcation. For example, there is a zone of benign misery perfusion outside of penumbra with its CBF between 15 to 30ml/100g/min (1). This zone may not be viable if perfusion is not re-established. That is to say with a major cerebral arterial occlusion, even with the help of collaterals, brain tissue may die slowly over a period of time. In clinical practice and proven by imaging studies, the side of brain with a large arterial occlusion will significantly atrophy, a process perhaps related to cell apoptosis from chronic hypoxic state (2). Hence, re-opening the occluded artery may or may not help the immediate stroke, but likely help the large ipsilateral brain tissue in a long run. More longitudinal study is certainly needed to examine this issue.
You have questioned our equipment on its ability to detect penumbra. We have had over 10 years of experience in performing MR perfusion with MRI scanner manufactured by Siemens.
All of our patients have received guideline recommended best medical management including dual antiplatelet and statin therapy plus life style modification. However, our series was not a clinical trial, the compliance of patient with the treatment plan was not closely tracked.
Reference:
1. Powers WJ Stroke Misery perfusion in cerebrovascular disease—is it important? Nature Reviews Neurology 2012;8:479-480
2. Thanvi B, Robinson T. Complete occlusion of extracranial internal carotid artery: clinical features, pathophysiology, diagnosis and management Postgrad Med J. 2007; 83(976): 95–99.
The article by Dr. Chen and his colleagues1 raises an important issue of managing intracranial stenosis or occlusion during the subacute phase of ischemic stroke. The authors concluded that selective percutaneous transluminal angioplasty (PTA) or percutaneous transluminal angioplasty and stenting (PTAS) for intracranial severe stenosis or occlusion is safe and effective in patients with subacute or subacute/chronic stroke. It should be extremely precaution while applying this conclusion into clinical practice. A couple of concerns need to be addressed: (1) there is large body of evidences and publications demonstrated that the ischemic penumbra can exist for only few hours 2. The authors provided the perfusion study in case 1 and commended that there is large area of low perfusion which might be salvageable. However, the authors did not mention which vendor and software have been utilized in the perfusion study. A different vendor and/or software can have significant variability on the result of cerebral perfusion study. I doubt the penumbra (aka, the mismatch on a perfusion study) can last for days in patients with ischemic stroke. (2) American Heart Association/American Stroke Association recommended3 aggressive medical management including dual antiplatelets of aspirin and clopidogrel as well as high-intensity Statin (Class IIB; level of Evidence B) for patients with ischemic stroke caused by 50% to 99% stenosis of a major intracranial artery. Intracranial artery angiop...
The article by Dr. Chen and his colleagues1 raises an important issue of managing intracranial stenosis or occlusion during the subacute phase of ischemic stroke. The authors concluded that selective percutaneous transluminal angioplasty (PTA) or percutaneous transluminal angioplasty and stenting (PTAS) for intracranial severe stenosis or occlusion is safe and effective in patients with subacute or subacute/chronic stroke. It should be extremely precaution while applying this conclusion into clinical practice. A couple of concerns need to be addressed: (1) there is large body of evidences and publications demonstrated that the ischemic penumbra can exist for only few hours 2. The authors provided the perfusion study in case 1 and commended that there is large area of low perfusion which might be salvageable. However, the authors did not mention which vendor and software have been utilized in the perfusion study. A different vendor and/or software can have significant variability on the result of cerebral perfusion study. I doubt the penumbra (aka, the mismatch on a perfusion study) can last for days in patients with ischemic stroke. (2) American Heart Association/American Stroke Association recommended3 aggressive medical management including dual antiplatelets of aspirin and clopidogrel as well as high-intensity Statin (Class IIB; level of Evidence B) for patients with ischemic stroke caused by 50% to 99% stenosis of a major intracranial artery. Intracranial artery angioplasty or stenting is not recommended and is investigational (Class III; level of Evidence B). The authors mentioned that the patient of case 1 received dual antiplatelet therapy of aspirin and clopidogrel. However, I cannot tell after reading the article whether the rest of patients in this case series received aggressive medical management. The purpose of medical treatment in patients with acute stroke is to save the ischemic tissue/penumbra. No doubt we can recanalize an occluded intracranial artery to restore normal flow with reaching TICI score 3 after an endovascular procedure, however, no convince rationale for pursuing interventional procedure if there is no or less than 20% mismatch on a perfusion study during the subacute phase of ischemic cerebral infarct without tried aggressive medical therapy. We pursue saving the tissue at risk not the vessel.
1. Chen K, Hou X, Zhou Z, et al. The efficacy and safety of endovascular recanalization of occluded large cerebral arteries during the subacute phase of cerebral infarction: a case series report. Stroke and Vasc Neurol 2017 0:e000086. doi:10.1136/svn-2017-000086.
2. Hakim AM. Ischemic penumbra: the therapeutic window. Neurology 1998; 51(Suppl 3): S44-S46
3. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Endorsed by the American Association of Neurological Surgeons and Congress of Neurological Surgeons. Stroke. Stroke 2014;45(7):2160-2236
The role of CSD in migraine is actually generally accepted as one of the pathophysiological process. In fact several novel CGRP targeted migraine medications are showing that CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression. Some of them are currently under review by FDA and expect to be on the market in late 2018. The research in rodents may not always be applicable to human with migraine and this theory has been in existence for over a decade. On your view of posterior cerebral circulation vulnerability to stroke, that was not quite relevant to the theme of current paper, which was about the association of migraine and stroke, not why stroke occurs more in posterior circulation. One fact of interest is that migraine sequelae related white matter changes would involve the entire brain, not limited to posterior circulation.
I read with interest the article by Zhang et al., (SVN, 2017, 2: e000077) [1] about "Migraine and stroke". At a time when the pathophysiology of migraine is poorly understood and the pathogenetic role of cortical spreading depression (CSD) is far from being generally accepted (Gupta, 2009) [2], Zhang et al. underscore the link between migraine with aura and ischemic stroke. With nosological splitting having been taken to the extreme end of the spectrum, Zhang et al., believe that migraine with aura (MwA) and migraine without aura (MwoA) are distinct entities.1 With the same epidemiology, the same clinical features (except the aura), and the same migraine preventive agents like propranolol, we have split wide the classification of the primary headache disorders, and maintain the belief-in-belief strategy at the cost of remaining confused at several levels, including the pathophysiology of primary headache disorders.
The concept of CSD is maintained by key omissions and assumptions (see Box 1, p. 1601, reference No. 2). The fact that atenolol, a hydrophilic pharmacologic agent, that does not cross the blood-brain barrier and does not influence any brain neuronal function including the CSD in unconscious experimental animals and prevents both MwA and MwoA equally efficiently is a pharmacologic absolute known since 1980, [3,4,] that is by itself sufficient to eliminate the concept of CSD from migraine pathophysiology.
I read with interest the article by Zhang et al., (SVN, 2017, 2: e000077) [1] about "Migraine and stroke". At a time when the pathophysiology of migraine is poorly understood and the pathogenetic role of cortical spreading depression (CSD) is far from being generally accepted (Gupta, 2009) [2], Zhang et al. underscore the link between migraine with aura and ischemic stroke. With nosological splitting having been taken to the extreme end of the spectrum, Zhang et al., believe that migraine with aura (MwA) and migraine without aura (MwoA) are distinct entities.1 With the same epidemiology, the same clinical features (except the aura), and the same migraine preventive agents like propranolol, we have split wide the classification of the primary headache disorders, and maintain the belief-in-belief strategy at the cost of remaining confused at several levels, including the pathophysiology of primary headache disorders.
The concept of CSD is maintained by key omissions and assumptions (see Box 1, p. 1601, reference No. 2). The fact that atenolol, a hydrophilic pharmacologic agent, that does not cross the blood-brain barrier and does not influence any brain neuronal function including the CSD in unconscious experimental animals and prevents both MwA and MwoA equally efficiently is a pharmacologic absolute known since 1980, [3,4,] that is by itself sufficient to eliminate the concept of CSD from migraine pathophysiology.
The rodent model of migraine does not mimic migraine closely as we do not know whether rodents suffer aura or headache. What we do know is that rodents (rats and mice) cannot vomit. [5] Nausea and/or vomiting is a pathognomonic feature of migraine (both MwA and MwoA) that can remit the headache attack -- a fact that even struck Hippocrates. Nausea and /or vomiting have a distinct brain pathophysiology that is adaptive in migraine (but is unavailable to the rodent). [6, 7, 8]
Migraine is a lateralizing disorder, with the headache typically presenting as a unllateral, bilateral, side-locked or side-shifting feature. [9] No feature of CSD permits to rationalize lateralization of headache of migraine.
The rarity of stroke complicating migraine, does not allow the hypercoagulability or the endothelial dysfunction to be the final or common arbiter for development of stroke. A shift of focus to thrombophilia and hypercoagulation, as suggested by Zhang et al., [1] would be far less productive than a re-focus of the optimal prevention of migraine attacks as well as the determination of the optimal blood pressure for migraine patients (as migraine patients generally maintain a low systemic blood pressure [10], and, migraine prophylactic agents like propranolol, atenolol, nadolol, metoprolol, flunarizine, verapamil, and clonidine commonly lower the systemic blood pressure.
Zhang et al,, [1] do not consider the particular anatomical vulnerability of the posterior cerebral circulation. [11]
1. Zhang Y, Parikh A, Qian S. Migraine and stroke. Stroke and Vascular Neurology 2017;2: e000077.
2. Gupta VK. CSD, BBB and MMP-9 elevations. Exp Rev Neurother 2009; 9: 1595-1614,
3. Stensrud P, Sjaastad O. Comparative trial of tenormin (atenolol) and inderal (propranolol) in migraine. Headache 1980; 20: 204-207.
4. Gupta VK (ed). Stress and Migraine: Brain Autonomic Function, BP, IOP, and BBB. (Chapter 5). In: Adaptive Mechanisms in Migraine. A Comprehensive Synthesis in Evolution. Breaking the Migraine Code. New York: Nova Science Publishers, Inc., 2009, pp 25-37.
5. Horn CC, Kimball BA, Wang H, Kaus J, Dienel S, Nagy A, Gathright GR, Yates BJ, Andrews PLR. Why can’t rodents vomit? A comparative behavioral, anatomical, and physiological Study. PLOS One Published: April 10, 2013 http://dx.doi.org/10.1371/journal.pone.0060537
6. Gupta VK. A clinical review of the adaptive potential of vasopressin in migraine. Cephalalgia 1997; 17: 561-569.
7. Gupta VK. Conceptual divide between adaptive and pathogenetic phenomena in migraine: nausea and vomiting. Brain 2004; 127: E 18. Published online 18 October 2004.
8. Gupta VK (ed). Nausea/Vomiting _vasopressin Nexus in migraine (Chapter 3). In: Adaptive Mechanisms in Migraine. A Comprehensive Synthesis in Evolution. Breaking the Migraine Code. New York: Nova Science Publishers, Inc., 2009, pp 11-19.
9. Gupta VK. Non-lateralizing brain PET changes in migraine: phenomenology versus pharmacology? Brain 2004; 127: E 12. Published online 30 June 2004)
10. .Seçil Y, Ünde C, Beckmann YY, Bozkaya YT, Özerkan F, Başoğlu M. Blood pressure changes in migraine patients before, during and after migraine attacks. Pain Practice 10, 222-227, 2010.
11. Gupta VK. Regional cerebral blood flow patterns in migraine: wht is the contribution to insight into disease mechanism? Eur J Neurology 1995; 2: 586-587.
Dear Editor，
Thank you transfer a letter of James M. Howard to me. Here is my discussion.
In this clinical research, we mainly focus on the efficacy and safety of Ginkgo in combination with aspirin in acute ischemic stroke and its impact on the recurrence of vascular events. However, the underlying molecular mechanisms are worth to be explored because of their effectiveness.
Although there have been reviewed that cortisol levels are high for at least 7 days after stroke and elevated cortisol after stroke is associated with dependency, morbidity, and mortality [1] . There is insufficient evidence to relate the severity of ischemic stroke with cortisol because cortisol can be influenced by diurnal rhythm, food, life style and so on. There has been no evidence to ascribe cortisol both by Ginkgo and aspirin directly to improve cognitive and neurological function. There has been reported that lower levels of DHEAS were associated with an increased risk of ischemic stroke [2], but few literatures show that reductions in cortisol increase the positive effects of DHEA on brain functions.
The potential mechanisms of Ginkgo and aspirin have not been clear. Notably, it has been found that Ginkgo plus aspirin can enhance the expressions of LOX-1 and p-p38MAPK correlated with the inhibition of ROS production, LOX-1 expression and p38MAPK phosphorylation in human coronaryartery endothelial cells [3]....
Show MoreI suggest the positive effect of combined aspirin and ginkgo post ischemic stroke is reduced cortisol. Aspirin and ginkgo both reduce cortisol. Increased reduction of cortisol by both produces more "improved cognitive and neurological functions" than aspirin alone. Furthermore, I suggest reductions in cortisol increase the positive effects of dehydroepiandrosterone (DHEA) on brain functions.
Dear Reader:
Thanks so much for notifying us about the figure misalignment issue in the original article - “Artificial Intelligence in Healthcare: Past, Present and Future.”
We have now investigated the issue. The misalignment originated from a glitch during the production stage. We now have fixed the issue and updated the online version of the paper. The latest publication is attached for your reference. Please accept our sincere apology for the mistake.
Yours sincerely,
Haipeng Shen
Professor and Area Coordinator
Innovation and Information Management
Faculty of Business and Economics
University of Hong Kong
It appears that the figures to not match their descriptive text: Figure 8 is not a stylised representation of an neural network - it is a stylised representation of a support vector machine and figure 9 is not a stylised representation of a deep learning network, the authors illustration is more of a conventional neural network with only one hidden layer.
By Shugui Shi, MD & Kangning Chen, MD.
To the Reader,
We have reviewed your comments on our paper. For your opinion on the issue of penumbra not to be present in subacute phase of stroke, there are literature reporting its presence days after the initial stroke. Penumbra is a dynamic phenomenon without clear demarcation. For example, there is a zone of benign misery perfusion outside of penumbra with its CBF between 15 to 30ml/100g/min (1). This zone may not be viable if perfusion is not re-established. That is to say with a major cerebral arterial occlusion, even with the help of collaterals, brain tissue may die slowly over a period of time. In clinical practice and proven by imaging studies, the side of brain with a large arterial occlusion will significantly atrophy, a process perhaps related to cell apoptosis from chronic hypoxic state (2). Hence, re-opening the occluded artery may or may not help the immediate stroke, but likely help the large ipsilateral brain tissue in a long run. More longitudinal study is certainly needed to examine this issue.
You have questioned our equipment on its ability to detect penumbra. We have had over 10 years of experience in performing MR perfusion with MRI scanner manufactured by Siemens.
All of our patients have received guideline recommended best medical management including dual antiplatelet and statin therapy plus life style modificat...
Show MoreThe article by Dr. Chen and his colleagues1 raises an important issue of managing intracranial stenosis or occlusion during the subacute phase of ischemic stroke. The authors concluded that selective percutaneous transluminal angioplasty (PTA) or percutaneous transluminal angioplasty and stenting (PTAS) for intracranial severe stenosis or occlusion is safe and effective in patients with subacute or subacute/chronic stroke. It should be extremely precaution while applying this conclusion into clinical practice. A couple of concerns need to be addressed: (1) there is large body of evidences and publications demonstrated that the ischemic penumbra can exist for only few hours 2. The authors provided the perfusion study in case 1 and commended that there is large area of low perfusion which might be salvageable. However, the authors did not mention which vendor and software have been utilized in the perfusion study. A different vendor and/or software can have significant variability on the result of cerebral perfusion study. I doubt the penumbra (aka, the mismatch on a perfusion study) can last for days in patients with ischemic stroke. (2) American Heart Association/American Stroke Association recommended3 aggressive medical management including dual antiplatelets of aspirin and clopidogrel as well as high-intensity Statin (Class IIB; level of Evidence B) for patients with ischemic stroke caused by 50% to 99% stenosis of a major intracranial artery. Intracranial artery angiop...
Show MoreThe role of CSD in migraine is actually generally accepted as one of the pathophysiological process. In fact several novel CGRP targeted migraine medications are showing that CGRP-mAb can prevent the activation and sensitization of high-threshold (central) trigeminovascular neurons by cortical spreading depression. Some of them are currently under review by FDA and expect to be on the market in late 2018. The research in rodents may not always be applicable to human with migraine and this theory has been in existence for over a decade. On your view of posterior cerebral circulation vulnerability to stroke, that was not quite relevant to the theme of current paper, which was about the association of migraine and stroke, not why stroke occurs more in posterior circulation. One fact of interest is that migraine sequelae related white matter changes would involve the entire brain, not limited to posterior circulation.
I read with interest the article by Zhang et al., (SVN, 2017, 2: e000077) [1] about "Migraine and stroke". At a time when the pathophysiology of migraine is poorly understood and the pathogenetic role of cortical spreading depression (CSD) is far from being generally accepted (Gupta, 2009) [2], Zhang et al. underscore the link between migraine with aura and ischemic stroke. With nosological splitting having been taken to the extreme end of the spectrum, Zhang et al., believe that migraine with aura (MwA) and migraine without aura (MwoA) are distinct entities.1 With the same epidemiology, the same clinical features (except the aura), and the same migraine preventive agents like propranolol, we have split wide the classification of the primary headache disorders, and maintain the belief-in-belief strategy at the cost of remaining confused at several levels, including the pathophysiology of primary headache disorders.
The concept of CSD is maintained by key omissions and assumptions (see Box 1, p. 1601, reference No. 2). The fact that atenolol, a hydrophilic pharmacologic agent, that does not cross the blood-brain barrier and does not influence any brain neuronal function including the CSD in unconscious experimental animals and prevents both MwA and MwoA equally efficiently is a pharmacologic absolute known since 1980, [3,4,] that is by itself sufficient to eliminate the concept of CSD from migraine pathophysiology.
The rodent model of...
Show More