Viral Coagulopathy in Patients With COVID-19: Treatment and Care.

COVID-19 has proven to be particularly challenging given the complex pathogenesis of SARS-CoV-2. Early data have demonstrated how the host response to this novel coronavirus leads to the proliferation of pro-inflammatory cytokines, massive endothelial damage, and generalized vascular manifestations. While SARS-CoV-2 primarily targets the upper and lower respiratory tract, other organ systems are also affected. SARS-CoV-2 relies on 2 host cell receptors for successful attachment: angiotensin-converting enzyme 2 and transmembrane protease serine 2. Clinicopathologic reports have demonstrated associations between severe COVID-19 and viral coagulopathy, resulting in pulmonary embolism; venous, arterial, and microvascular thrombosis; lung endothelial injury; and associated thrombotic complications leading to acute respiratory distress syndrome. Viral coagulopathy is not novel given similar observations with SARS classic, including the consumption of platelets, generation of thrombin, and increased fibrin degradation product exhibiting overt disseminated intravascular coagulation-like syndrome. The specific mechanism(s) behind the thrombotic complications in COVID-19 patients has yet to be fully understood. Parenteral anticoagulants, such as heparin and low-molecular-weights heparins, are widely used in the management of COVID-19 patients. Beyond the primary (anticoagulant) effects of these agents, they may exhibit antiviral, anti-inflammatory, and cytoprotective effects. Direct oral anticoagulants and antiplatelet agents are also useful in the management of these patients. Tissue plasminogen activator and other fibrinolytic modalities may also be helpful in the overall management. Catheter-directed thrombolysis can be used in patients developing pulmonary embolism. Further investigations are required to understand the molecular and cellular mechanisms involved in the pathogenesis of COVID-19-associated thrombotic complications.

Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing.

Grange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss-of-function variants in YY1AP1 have only recently been associated with Grange syndrome. YY1AP1 encodes for the transcription coactivator yin yang 1-associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno-occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound-heterozygosity in all affected siblings. RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. This is the first report of biallelic YY1AP1 variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome.

Artery of Percheron infarction: a case report.

BACKGROUND: The artery of Percheron is a rare anatomic variant of arterial supply to the paramedian thalamus and rostral midbrain, and occlusion of the artery of Percheron results in bilateral paramedian thalamic infarcts with or without midbrain involvement. Acute artery of Percheron infarcts represent 0.1 to 2% of total ischemic stroke. However, of thalamic strokes, occlusion of artery of Percheron is the cause in 4 to 35% of cases. Early diagnosis of artery of Percheron infarction can be challenging because it is infrequent and early computed tomography or magnetic resonance imaging may be negative. Thus, it can be confused with other neurological conditions such as tumors and infections. CASE PRESENTATION: This is a retrospective case study of a 56-year-old white man admitted to Umeå University Hospital and diagnosed with an artery of Percheron infarction. Medical records and the neuroradiological database were reviewed, and the diagnosis was made based on typical symptoms and radiological findings of artery of Percheron infarction. We report the case of a 56-year-old man with a history of overconsumption of alcohol who was found in his home unconscious and hypothermic. He had a Reaction Level Scale-85 score of 4. He developed ventricular fibrillation on arrival at our emergency department, and cardiopulmonary resuscitation successfully restored sinus rhythm within an estimated 2 minutes of onset. He was then put on cardiopulmonary bypass for rewarming. The initial head computed tomography performed on admission was wrongly assessed as unremarkable. Bilateral ischemia in the paramedian thalamic nuclei and pons were first documented on a follow-up computed tomography on day 24 after hospitalization. He died on day 35 after hospitalization. CONCLUSIONS: Artery of Percheron infarcts are rare. The radiological diagnosis can initially often be judged as normal and in combination with variability in the neurological symptoms it is a rather difficult condition to diagnose. For these reasons few clinicians have much experience with this type of infarct, which may delay diagnosis and initiation of appropriate treatment.

Shear-sensitive nanocapsule drug release for site-specific inhibition of occlusive thrombus formation.

Essentials Vessel stenosis due to large thrombus formation increases local shear 1-2 orders of magnitude. High shear at stenotic sites was exploited to trigger eptifibatide release from nanocapsules. Local delivery of eptifibatide prevented vessel occlusion without increased tail bleeding times. Local nanocapsule delivery of eptifibatide may be safer than systemic antiplatelet therapies. SUMMARY: Background Myocardial infarction and stroke remain the leading causes of mortality and morbidity. The major limitation of current antiplatelet therapy is that the effective concentrations are limited because of bleeding complications. Targeted delivery of antiplatelet drug to sites of thrombosis would overcome these limitations. Objectives Here, we have exploited a key biomechanical feature specific to thrombosis, i.e. significantly increased blood shear stress resulting from a reduction in the lumen of the vessel, to achieve site-directed delivery of the clinically used antiplatelet agent eptifibatide by using shear-sensitive phosphatidylcholine (PC)-based nanocapsules. Methods PC-based nanocapsules (2.8 × 1012 ) with high-dose encapsulated eptifibatide were introduced into microfluidic blood perfusion assays and into in vivo models of thrombosis and tail bleeding. Results Shear-triggered nanocapsule delivery of eptifibatide inhibited in vitro thrombus formation selectively under stenotic and high shear flow conditions above a shear rate of 1000 s-1 while leaving thrombus formation under physiologic shear rates unaffected. Thrombosis was effectively prevented in in vivo models of vessel wall damage. Importantly, mice infused with shear-sensitive antiplatelet nanocapsules did not show prolonged bleeding times. Conclusions Targeted delivery of eptifibatide by shear-sensitive nanocapsules offers site-specific antiplatelet potential, and may form a basis for developing more potent and safer antiplatelet drugs.

Investigation of the effect of safranal and crocin pre-treatment on hepatic injury induced by infrarenal aortic occlusion.

Ischemia-reperfusion (IR) injury of the liver is an unresolved problem that occurs during certain surgical approaches, including hepatic, cardiac and aortic operations. In this study we aimed to investigate whether crocin and safranal had protective effects on liver IR injury induced in an infrarenal aortic clamping (IRAC) model. Male Wistar-Albino rats (n=32) were divided into four groups with 8 animals each as follows: Sham, IR, IR+crocin, and IR+safranal. The infrarenal aorta (IRA) was clamped for 60min for the ischemic period and allowed to reperfuse for 120min. Blood and tissue samples were collected for biochemical, histological and immunohistological analysis. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were found to be significantly higher in the IR group than the sham group (respectively; p=0.015, p<0.001). There were significant differences between the IR group and the IR+crocin group or the IR+safranal group in AST levels (respectively; p=0.02, p<0.001). ALT showed a significant decrease in the IR+crocin group compared to the IR group (p<0.05). We also observed histopathological changes among the groups. Bax and Caspase-3 expression in the IR group was remarkably higher than in the other groups. Caspase-3 and Bax expression in the IR+crocin and the IR+safranal groups were significantly lower than in the IR group. Nevertheless, there were no significant differences in BCL2 expression among the groups. IRAC is a cause of IR injury in the liver. This study showed that crocin and safranal have protective effects on IR induced liver injury.

Study on cerebroprotective actions of Clerodendron glandulosumleaves extract against long term bilateral common carotid artery occlusion in rats.

Stroke is a major cause of death and disability worldwide. The resulting burden on the society continues to grow, with increase in the incidence of stroke. Oxidative stress has been involved in the pathogenesis of several neurological diseases including acute stroke.Focal and global cerebral ischemia represents diseases that are common in the human population.In recent years much attention is being paid towards the exploration of herbal preparation, antioxidant agents and combination therapies including COX-2 inhibitors in experimental model of stroke.Possible effect of a hydroalcoholic leaf extract of Clerodendron glandulosumColeb (C. glandulosum)on oxidant-antioxidant status in ischemia-hypoperfusion injury in the rat forebrain has been investigated.Healthy adult male Wistar albino rats were divided into five groups (n=8). Group I was served as Sham control (normal saline 1ml/kg, orally), group II was served hypoperfusion control (normal saline 1ml/kg, orally), group III, group IV were served as hydroalcoholic extract treated (200 and 400mg/kg, orally) and group V was treated with Quercetin (10mg/kg, orally) for 14days to assess preventive and curative effects of C. glandulosum. Flavonoid and phenolic compounds exhibit a broad spectrum of biological activity, including antioxidant. C. glandulosum extract (200 and 400mg/kg, p.o) was administered orally, once daily for a period of 2 weeks after the occlusion of BCCA. After 14th days rats were subjected to behavioral studies. After behavioral studies animals were sacrificed and brain was removed and homogenized. Estimation of Lipid peroxidation (LPO) Myeloperoxidase (MPO), estimation of protein levels and the activities of Superoxide dismutase (SOD), Catalase (CAT), were performed. Infarct size and histopathological changes were observed in treated groups.

A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease.

Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.

Characteristics of chronic pain associated with sleep difficulty in older adults: the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston study.

OBJECTIVES: To evaluate pain severity and distribution in relation to sleep difficulty in older adults. DESIGN: Population-based cross-sectional study. SETTING: Community within a 5-mile radius of the study center at the Institute for Aging Research, Hebrew SeniorLife (HSL), Boston. PARTICIPANTS: Seven hundred sixty-five participants of the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston Study aged 64 and older. MEASUREMENTS: Pain severity was measured using the Brief Pain Inventory (BPI) Pain Severity Subscale. Musculoskeletal pain distribution was grouped according to no pain, single site, two or more sites, and widespread pain (upper and lower extremities and back pain). Three aspects of sleep difficulty were measured using items from the Center for Epidemiologic Studies Depression Scale, Revised (trouble getting to sleep, sleep more than usual, and restless sleep). RESULTS: Prevalence of trouble getting to sleep according to BPI severity was 17.8%, 19.7%, 32.0%, and 37.0% for the lowest to highest pain severity quartiles, respectively. Similar relationships between pain and sleep were observed across sleep measures according to pain severity and distribution. Adjusted for sociodemographic characteristics, chronic conditions, and health behaviors, chronic pain was strongly associated with trouble sleeping (≥ 1 d/wk) (single-site pain, odds ratio (OR)=1.77, 95% confidence interval (CI)=1.10-2.87; multisite pain, OR=2.38, 95% CI=1.48-3.83; widespread pain, OR=2.55, 95% CI=1.43-4.54, each compared with no pain). Similar associations were observed for restless sleep and sleeping more than usual. For specific pain sites alone or in combination with other sites of pain, only modest associations were observed with sleep problems. CONCLUSION: Widespread or other multisite pain and moderate to severe pain are strongly associated with sleep difficulty in older adults. Further research is needed to better understand the burden and consequences of pain-related sleep problems in older adults.

[Therapy of chronic ischemic pain in peripheral arterial disease. A survey among physicians]. / Therapie chronischer Ischämieschmerzen bei peripherer arterieller Verschlusskrankheit. Eine Arztebefragung.

BACKGROUND: The intention of this study was to determine the status quo of commonly used pain therapies amongst treating physicians of different specialties and to examine their view on the problem of chronic ischemic pain. METHODS: A total of 281 physicians treating patients with chronic ischemic pain were surveyed. The surveyed physicians were mainly specialists in the fields of surgery, pain therapy, and internal medicine. RESULTS: Mainly a pharmacological therapy (metamizol/paracetamol, weak and strong opioids) was used in the treatment of chronic ischemic pain. We found differences between the specialties, for instance pain specialists used antidepressants and anticonvulsants more often than others. Therapeutic options were also evaluated differently by surgeons, pain therapists, and internal specialists: 57% of the surgeons considered the available symptomatic treatment options as sufficient whereas only 21% of the pain specialists agreed with that opinion. CONCLUSION: The differences among the specialties and the fact that the majority of physicians characterized the available symptomatic treatment options as insufficient point towards a need to review the treatment of ischemic pain in an interdisciplinary approach.

[Relationship between syndrome differentiation of traditional Chinese medicine and vascular endothelial function in patients with diabetic arterial occlusion of lower extremities].

OBJECTIVE: To investigate the relationship between syndrome differentiation of traditional Chinese medicine (TCM) and characteristic changes of vascular endothelial function in patients with diabetic arterial occlusion (DAO) of lower extremities. METHODS: Forty patients with DAO were selected as trial group. Twenty patients among them were attributed to blood stasis syndrome (group A1), and the others were attributed to syndrome of pathogenic dampness-heat attacking the lower limb (group A2) according to syndrome differentiation type of TCM. Patients with diabetes (group B), arteriosclerosis obliterans (group C) and healthy people (group D) were observed as the control groups, respectively. There were 20 cases in each group. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) were measured by high resolution ultrasound in the 100 subjects and the changes of vascular tension factors were also studied. RESULTS: The results showed that EDD in group A was reduced significantly as compared with that in the groups B, C and D. The levels of vascular contractile factors such as endothelin-1 (ET-1) and thromboxane B2 (TXB2) in group A were higher than those in the groups B, C and D, while the levels of vascular dilatory factors such as nitric oxide (NO) and 6-keto-prostaglandin F1alpha(6-Keto-PGF1alpha) were declined significantly as compared with those in the groups B and D. Linear correlation analysis showed that EDD was correlated positively with the levels of NO and 6-Keto-PGF1alpha, while the levels of ET-1 and TXB2 had negative correlation with EDD. EDD and EID in group A2 were declined significantly as compared with those in group A1. CONCLUSION: Our findings indicate that endothelial dysfunction may play an important role in the pathogenesis of DAO and may be associated with syndrome differentiation of TCM.

[Experimental study on effect of Tongxinluo on nerve cell apoptosis after cerebral ischemia in middle cerebral arterial obstructive model rats].

OBJECTIVE: To explore the action mechanism of Tongxinluo Capsule (TXL) in protecting brain from ischemic damage. METHODS: SD rats were divided into five groups randomly, the sham operation group, the model group, the MK-801 group, the large and low dosage TXL groups (TXLL and TXLS). After the middle cerebral arterial obstructive (MCAO) model was established, peritoneal injection of MK-801 0.5 mg/kg per day was given to the MK-801 group, and 1.0 g/(kg x d) and 0.5 g/(kg x d) of TXL powder was administered in twice via gastrogavage to the two TXL groups respectively. The nerve cell apoptosis rate, protein and mRNA expressions of Caspase-3, p53 and heat shock protein (HSP70) were observed using flow cytometry, Western blot and RT-PCR technique. RESULTS: Both TXL and MK-801 could obviously lower the apoptosis rate in model rat (P < 0.05, P < 0.01), TXLL showed the optimal effect. Caspase-3, p53 protein and mRNA expression in the model group were obviously higher than those in the sham operated group. As compared with the model group, the expressions of Caspase-3 and p53 were lower and those of HSP70 and mRNA were higher in the two TXL and MK-801 groups (P < 0.05 or P < 0.01). CONCLUSION: TXL displays it brain protective effect through reducing nerve cell apoptosis rate in MCAO model rats, the mechanism may be related to its actions in inhibiting apoptosis related factors Caspase-3 and p53, and promoting stress protecting factor HSP70.

HBO and gas embolism.

Gas embolism, which occurs with the entry of gas into the circulatory system from the vein, artery or both, is a potentially serious even fatal condition. The two main causes of gas embolism are iatrogenic and diving. The site of entry and the signs and symptoms distinguish between arterial and venous embolism. The entering gas may be air, but may also be CO(2) or other gases, especially in iatrogenic embolism. Supportive care is the primary therapy for venous gas embolism, while hyperbaric oxygen therapy in addition to supportive care is the first line of treatment for arterial gas embolism. In this article, we will review the pathophysiology, etiology, diagnosis and treatment of gas embolism.

Effects of acupressure on lower limb blood flow for the treatment of peripheral arterial occlusive diseases.

PURPOSE: To investigate the effects of acupressure on lower limb blood flow for the treatment of peripheral arterial occlusive diseases (PAOD). METHODS: From February 2004 to February 2005, 30 patients with stage II PAOD underwent measurements of the lower limb blood flow. Six patients (group A) were assigned as controls without any acupoint stimulation, while 24 (group B) underwent stimulation at acupoints by acupressure. The acupoints Yanglingquan (GB34), Zusanli (ST36), Yinlingquan (SP9), and Sanyinjiao (SP6) of the symptomatic lower limbs were stimulated for 3 min. Transcutaneous oximetry (tcPO2) was used to determine the blood flow of the chest wall, bilateral distal crura, and bilateral dorsa of the foot before and during the stimulations at the acupoints. RESULTS: Group A showed no significant change in the lower limb blood flow. In group B, the tcPO2 values of chest wall, bilateral distal crura, and the dorsum of foot of the stimulated lower limb increased significantly during acupressure (P < 0.01), whereas no significant change was shown in the dorsum of the foot of the non-stimulated lower limb. Moreover, the blood flow of the lower limbs that had undergone an ipsilateral sympathectomy increased significantly (P < 0.01). CONCLUSIONS: Acupressure was found to cause significant increases in the lower limb blood flow of stage II PAOD patients. This treatment modality may therefore be effective for improving the symptoms of such patients.

Preclinical models of human peripheral arterial occlusive disease: implications for investigation of therapeutic agents.

Peripheral arterial occlusive disease (PAOD) is now recognized as a combination of clinical syndromes that are associated with significant morbidity and mortality. The primary pathophysiology of PAOD is impaired perfusion to the lower extremity. Effective pharmacotherapy designed to increase perfusion in PAOD is lacking, and revascularization options are suboptimal. New and more efficacious therapies that improve blood flow are definitely needed, and thus designing, describing, and validating these new therapies in preclinical PAOD models will be essential. This study describes the various preclinical PAOD models presently in use, correlates the models to human PAOD, and reviews the available end points that can be used to detect a response to therapy.

[Reflexotherapy in patients with ischemic angiopathies of the lower extremities]. / Primenenie metodov refleksoterapii u bol'nykh s ishemicheskimi angiopatiiami nizhnikh konechnostei.

Comparative assessment of different methods of reflexotherapy - RT (acupuncture, electroacupuncture, pharmacopuncture and the termopuncture) in treatment of ischemic angiopathies of the lower extremities is presented. One hundred and twenty-four patients with ischemic angiopathies were treated, 86 of them had I - II stage of the disease, 38 - III stage. Diagnosis of the disease and assessment of treatment efficacy were based on clinical, laboratory and special instrumental examinations. Functional examinations revealed equal reaction of peripheral blood flow to different RT methods. Moderate hypocoagulation compared with the baseline was demonstrated. Clinical symptoms (improvement of the general condition, decrease of pain syndrome) and improvement of biochemical and physiological parameters were criteria of successful treatment. The results of the study helped to develop methods of treatment with different variants of RT and to recommend them in clinical practice for combined treatment of this disease.

Endovascular intervention of aortoiliac occlusive disease in high-risk patients using the kissing stents technique: long-term results.

Endovascular intervention deploying a kissing stents (KS) technique has been used as an alternative to surgical intervention in treating symptomatic aortoiliac occlusive disease. However, the long-term results on high-risk patients are unknown. We retrospectively analyzed data on high-risk patients who underwent endovascular intervention using the KS technique at our institution. Fifty high-risk patients aged 62 +/- 6.4 years with severe aortoiliac stenosis underwent stent-supported angioplasty using the KS technique. Thirty percent of the patients had total occlusion of the distal aorta and/or the iliac arteries. Twelve patients received thrombolytics prior to stenting. The procedure was successful in all 50 patients. There was a 4% acute complication rate (distal embolization). However, there were no vascular complications, myocardial infarction, or perioperative death. Primary patency during follow-up of 20 +/- 12.3 months was 92%, while secondary patency rate was 100%. Amputation-free survival was 100%. Ninety-two percent remained free of lifestyle-limiting claudication.

Collateral growth: cells arrive at the construction site.

Coronary artery disease (CAD) and peripheral artery occlusion disease are the most common diseases in the Western world which are treated by pharmacological and surgical therapies. However, patients in the endstage of the disease are not suitable candidates for bypass surgery. Alternative therapies that boost the endogenous collateralization are required. Two mechanisms are naturally activated after onset of ischemia: 1. angiogenesis, sprouting of capillaries, and 2. arteriogenesis, enlargement of small preexisting arterioles. In the first part of this review, we describe the sequence of events during the development of collateral vessels. The second part focuses on two types of cells which are crucial for the development of collateral circulation, and which migrate to the site of vessel growth via peripheral blood: monocytes/macrophages and endothelial progenitor cells. The role of these cells and the implications for their use in treating ischemic diseases of cardiac and sceletal muscle are discussed.

Usefulness of waveform analysis of popliteal artery in type II diabetic patients using gated magnetic resonance 2D-cine-PC imaging and 31P spectroscopy.

AIMS/HYPOTHESIS: We studied 76 patients with Type II (non-insulin-dependent) diabetes mellitus and 16 age-matched non-diabetic subjects (control group) to clarify qualitative and quantitative abnormalities of waveform and flow volume of the popliteal artery. METHODS: The 76 diabetic patients comprised 16 patients with occlusive arterial disease in the lower extremities [arteriosclerosis obliterans (ASO) group] and 60 patients free from this disease (non-ASO group). We flow analysed the popliteal artery and measured the phosphocreatine to inorganic phosphate ratio of resting plantar muscles to identify risk factors for foot lesions using gated magnetic resonance two-dimensional cine-mode phase-contrast imaging and 31P spectroscopy. RESULTS: The control and non-ASO groups had a triphasic waveform with systolic, early and late diastolic components. All ASO patients had an abnormal monophasic waveform and a lower ankle brachial index than that of the control and non-ASO groups. To clarify the mechanism of reduced flow volume of lower extremities, we assigned the 60 patients of the non-ASO group to the three subgroups based on their levels of total flow volume of the popliteal artery. The lowest group showed an abnormal triphasic waveform with lower amplitudes of systolic and late diastolic components and flow velocities in foot arteries than those of the highest group although ABI was similar. From stepwise multiple regression analysis, late diastolic flow volume was identified as an independent determinant for the phosphocreatine to inorganic phosphate ratio (r2 = 0.484, p < 0.001). CONCLUSION/INTERPRETATION: Waveform analysis of popliteal artery provides a powerful tool for identifying impaired peripheral circulation caused by either occlusive arterial disease or increased arterial resistance in diabetic patients.

Protective effect of ginkgo extract on rat brain with transient middle cerebral artery occlusion.

It has been empirically known that Ginkgo extract is useful for reducing many symptoms associated with cerebral blood flow (CBF) insufficiency, but its mechanisms have been uncertain. In the present study, therefore, we gave Ginkgo extract to rats with per os digestion, and investigated its effect on CBF and ischemic brain damage with middle cerebral artery occlusion (MCAO). The treatment with Ginkgo extract (10 mg 100 g-1 rat) increased CBF in the normal condition, but the degree of increase in CBF was lesser during and after MCAO. TTC staining showed that infarct volume was reduced with Ginkgo treatment. TUNEL and HSP72 immunostaining confirmed the protective effect of Ginkgo treatment reducing numbers of TUNEL and HSP72 positive cells. Immunohistochemical analysis showed that caspase-3 expression was less abundant in Ginkgo treated rats. The present results suggest that Ginkgo extract contains a substance which increases normal CBF and reduces ischemic brain damage.