The Combined Prognostic Significance of Alkaline Phosphatase and Intracranial Arterial Calcifications in Hemodialysis Patients.

INTRODUCTION: The prevalence of intracranial arterial calcification (ICAC) in maintenance hemodialysis (MHD) patients is about 90%, and its severity is correlated with age, hemodialysis vintage, and mineral bone disease. Elevated concentrations of calcium and phosphorus are not sufficient for medial calcification because of inhibition by pyrophosphate. Alkaline phosphatase (ALP) promotes calcification by hydrolyzing extracellular pyrophosphate. Epigenetic mechanisms involving ALP inhibition by apabetalone were investigated as a potential target for preventing vascular calcifications (VCs). This study assessed the combined impact of VCs and elevated serum ALP on mortality among chronic HD patients. METHODS: VCs represented by ICAC were measured simultaneously with mineral bone disease parameters including serum ALP of MHD patients who underwent noncontrast brain computed tomography from 2015 to 2018 in our institution. RESULTS: This retrospective study included 150 MHD patients (mean age 71.3 ± 12.1 years, 60.1% male). Of the total cohort, 12 (7.8%) had no brain calcifications and 69 (45.1%) had multiple intracranial calcifications. Considering the patients with normal ALP and no calcification as the reference group yielded adjusted odds ratios for all-cause mortality of 4.6 (95% CI: 1.7-12.7) among patients with brain calcifications and normal ALP (p = 0.003) and odds ratios for all-cause mortality of 6.1 (95% CI: 2.1-17.7) among patients with brain calcifications and elevated ALP (p= 0.001). CONCLUSION: We found an independent association between ICAC and the risk of death among MHD patients. The combined effect of ICAC and elevated ALP was associated with a higher odds ratio for all-cause mortality in MHD patients and may contribute to the risk stratification of these patients.

Increased Plasma VEGF Levels in Patients with Cerebral Large Artery Disease Are Associated with Cerebral Microbleeds.

BACKGROUND/PURPOSE: Because atherosclerotic factors and antithrombotic agents sometimes induce cerebral microbleeds (CMBs), patients with cerebral large artery disease (CLAD) tend to have more CMBs than control subjects. On the other hand, VEGF contributes to the disruption of the blood-brain barrier, and it may induce parenchymal edema and bleeding. We conducted a study to evaluate the role of vascular endothelial growth factor (VEGF) in the occurrence of CMBs in patients with CLAD. METHODS: CLAD is defined as stenosis or occlusion of either the carotid artery or the middle cerebral artery of 50% or more. We prospectively registered patients with CLAD who were hospitalized in our neurocenter. Biological backgrounds, atherosclerotic risk factors, administration of antithrombotics before hospitalization, and levels of cytokines and chemokines were evaluated. Susceptibility-weighted imaging or T2*-weighted MR angiography was used to evaluate CMBs. The Brain Observer MicroBleed Scale (BOMBS) was used for CMB assessments. Images were analyzed with regard to the presence or absence of CMBs. We also examined plasma VEGF concentrations using a commercial ELISA kit. Because more than half showed plasma VEGF levels below assay detection limits (3.2 pg/mL), the patients were dichotomized by plasma VEGF levels into two groups (above and below the detection limit). After univariate analyses, logistic regression analysis was conducted to determine the factors associated with the CMBs after adjustment for age, sex, the presence of hypertension, and administration of antithrombotic agents. A similar analysis with CMBs separated by location (cortex, subcortex, or posterior circulation) was also conducted. RESULTS: Sixty-six patients (71.1 ± 8.9 years, 53 males and 13 females) were included in this study. Plasma VEGF levels were not correlated with age, sex, and atherosclerotic risk factors; however, patients with VEGF levels >3.2 pg/mL tended toward more frequent CMBs (60.0 vs. 32.6%, in the presence and absence of CMBs, p = 0.056). With regard to the location of CMBs, those in the cortex and/or at the gray-white junction were observed more frequently in the patients with VEGF levels >3.2 pg/mL after multivariable analyses (odds ratio: 3.80; 95% confidence interval: 1.07-13.5; p = 0.039). CONCLUSIONS: In patients with CLAD, elevated plasma VEGF might be associated with CMBs, especially those located in the cortex and/or at the gray-white junction.

Platelet-Rich Emboli in Cerebral Large Vessel Occlusion Are Associated With a Large Artery Atherosclerosis Source.

Background and Purpose- Nearly 30% of large vessel occlusion acute ischemic stroke clots are from an unknown source. We assessed histological clot composition in a series of patients with large vessel occlusion and investigated correlations between clot composition and stroke pathogenesis. Methods- As part of the multi-institutional STRIP registry (Stroke Thromboembolism Registry of Imaging and Pathology), consecutive emboli retrieved during mechanical thrombectomy were stained using Martius Scarlett Blue and analyzed using machine learning software. We assessed proportions of red blood cells, fibrin, platelets, and white blood cells. Correlations between clot components and stroke pathogenesis (large artery atherosclerosis, cardioembolism, and stroke of undetermined pathogenesis) were assessed using SPSS22. Results- One hundred five patients were included. The proportion of platelet-rich clots (55.0% versus 21.2%; P=0.005) and percentage of platelet content (22.1±4.2% versus 13.9±14.2%; P=0.03) was significantly higher in the large artery atherosclerosis group compared with the cardioembolic group. The proportion of platelet-rich clots (50.0% versus 21.2%; P=0.024) was also significantly higher in the cryptogenic group compared with cardioembolic cases. Large artery atherosclerosis and cryptogenic cases had a similar proportion of platelet-rich clots (55.0% versus 50.0%; P=0.636). There was no significant difference between stroke pathogenesis and the other major clot components. Conclusions- High platelet content of emboli is associated with a large artery atherosclerosis etiology of large vessel occlusion.

Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke: Correlates of Stroke Cause and Recurrence.

BACKGROUND AND PURPOSE: Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS. METHODS: In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS. RESULTS: Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies. CONCLUSIONS: Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.

Urinary kallidinogenase for the treatment of cerebral arterial stenosis.

AIM: Urinary kallidinogenase (UK) has shown promise in improving cerebral perfusion. This study aimed to examine how UK affects cognitive status and serum levels of amyloid betas (Aßs) 1-40 and 1-42 in patients with cerebral arterial stenosis. METHODS: Ninety patients with cerebral arterial stenosis were enrolled, of whom 45 patients received UK + conventional treatment (UK group), and 45 patients received conventional treatment alone as control group. Cognitive status and Aß1-40 and Aß1-42 serum levels were determined before treatment and at 4 weeks and 8 weeks after treatment. RESULTS: At 4 weeks after treatment, cognitive status in patients treated with UK clearly improved accompanied by Aß1-40 serum levels decreasing while there was no change of Aß1-42. Cognitive status in patients receiving UK continued to improve, Aß1-40 serum levels declined further as well as Aß1-42 serum levels began to decrease dramatically at 8 weeks after treatment. CONCLUSION: UK could improve cognitive status and decrease both Aß1-40 and Aß1-42 serum levels to prevent ischemic cerebral injury, which represents a good option for patients with cerebral arterial stenosis.

Predictors of cholesterol and lipoprotein(a) testing in children with arterial ischemic stroke.

BACKGROUND: Professional societies recommend screening lipids in healthy children. Dyslipidemia and elevated lipoprotein(a) are risk factors for adult cardiovascular disease and stroke. Their role in childhood arterial ischemic stroke is unexplored. Inconsistencies in testing limit analysis of existing lipid data. The objective of this study is to identify predictors and modifiable barriers to lipid testing in pediatric stroke. METHODS: In this cross-sectional analysis, children (28 days-18 years) with arterial ischemic stroke were identified from the International Pediatric Stroke Study registry (January 2003-April 2012). Analyzed predictors of recorded lipid or lipoprotein a (Lp(a)) testing were age, sex, race, ethnicity, body mass index (BMI) category, other stroke risk factors, country, US region, and recurrent thrombosis. RESULTS: Among 1652 participants (median, 6 years [interquartile range, 1.7-12.7]; 59.0% male; 40.8% white; 7.0% black), at least 1 lipid parameter or Lp (a) was available for 461 (27.9%). Compared with infants, testing was incrementally higher for older age categories. Compared with whites, testing was lower in blacks (adjusted odds ratio [OR], .5; 95% confidence interval [CI], .4-.5; P < .0001). Hispanic ethnicity only predicted testing within the United States (OR, 2.2; 95% CI, 1.4-3.4; P = .001]. Testing was lower in the United States and Australia and higher in Chile. Any thrombotic recurrence and recurrent symptomatic arterial ischemic stroke were associated with testing, unlike male sex, BMI, other stroke risk factors, and region in the United States. CONCLUSIONS: Only a quarter of children with stroke had recorded lipid testing. Older age, white race, and recurrence predicted testing. In future study adjusting for these predictors may be necessary. Standardized lipid testing in children with arterial ischemic stroke may further our understanding of this potential risk factor.

Endothelial injury in childhood stroke with cerebral arteriopathy: a cross-sectional study.

OBJECTIVE: Circulating endothelial cells (CECs) and microparticles (MPs) have been reported to reflect endothelial injury, cellular activation, and MP-mediated thrombin generation. We tested the hypothesis that these indices differ between children with cerebral arteriopathy and arterial ischemic stroke (AIS) recurrence, and those with a single event. METHODS: This was a single-center cross-sectional study of 46 children with AIS and cerebral arteriopathy matched with pediatric controls. AIS recurrence was defined as new acute neurologic deficit with radiologic evidence of further cerebral infarction. CECs and MPs were identified with immunomagnetic bead extraction and flow cytometry, respectively. MP function as assessed by thrombin generation was determined using a fluorogenic assay. RESULTS: Ten children had AIS recurrence while 36 had a single AIS event. CECs were raised in children with recurrent AIS, compared to those with no recurrence (p = 0.0001), and in controls (p = 0.0001). Total circulating annexin V+ MPs were significantly greater in children with recurrence than in those with no recurrence (p = 0.0020). These MPs were of endothelial or platelet origin, and a subpopulation expressed tissue factor. Finally, MP-mediated thrombin generation was enhanced in children with recurrent AIS compared to those with no recurrence (p = 0.0001), providing a link between inflammation, endothelial injury, and increased thrombotic tendency. CONCLUSION: Despite the wide spectrum of clinical and radiologic presentation of childhood AIS, indices of endothelial injury and cellular activation are different in patients with single and recurrent events. This novel approach has potential for furthering understanding of AIS pathophysiology and prognosis.

[Serum levels of interferon-γ, interleukin-6 and tumor necrosis factor-α in patients with cerebral arterial stenosis].

OBJECTIVE: To investigate the relationship between interferon-γ(IFN-γ), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) and cerebral arterial stenosis and to compare serum levels of these inflammatory cytokines in different cerebral arteries stenosis groups. METHODS: According to the stenotic site, patients with cerebral arteries stenosis were divided into intracranial stenosis group (n=26), extracranial stenosis group (n=30), intracranial and extracranial stenosis group (n=27), and group of stenosis in middle cerebral artery (n=25). And there were 33 samples in the control group. Blood serum IFN-γ, IL-6 and TNF-α levels were analyzed using enzyme linked immunosorbent assays (ELISA). RESULTS: Serum IFN-γ and IL-6 levels were significantly increased in all the stenosis groups (P=0.000) as compared with the control group. But serum IFN-γ level had no significant difference between the two optional stenosis groups. And IL-6 level in intracranial stenosis group was lower than those in the other stenosis groups (P<0.05). In addition, we found that TNF-α of intracranial stenosis group (P=0.001) and MCA stenosis group (P=0.015) significantly increased as compared with the control group and the other two stenosis groups. CONCLUSION: The results suggest that IFN-γ, IL-6 and TNF-α are possible to participate in the formation of certain cerebral arterial stenosis.

The roles of anatomic factors, thrombophilia, and antithrombotic therapies in childhood-onset arterial ischemic stroke.

Childhood-onset arterial ischemic stroke (AIS) is a rare disorder with high risks of both recurrent stroke and life-long neurological morbidity. Anatomic risk factors for primary and/or recurrent AIS include a venous thrombotic source for paradoxical embolism via a patent foramen ovale, primary cardioembolism, extracranial dissection, and intracranial arteriopathies, among others. Genetic and acquired thrombophilias are common, some of which have been shown to have prognostic influence on risk of recurrent AIS. While knowledge of childhood AIS risk factors has grown considerably in recent years, an evidence-based understanding of optimal antithrombotic therapy strategies has not yet been attained. Consensus-based guidelines have been developed, but future research must emphasize identification of additional prognostic factors and the initiation of cooperative randomized controlled clinical trials.

Matrix metalloproteinase-3 and intracranial arterial dolichoectasia.

OBJECTIVE: Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is defined as an increase in length and diameter of intracranial arteries. Abdominal aortic aneurysm and ectasia of coronary arteries have been reported in association with IADE. In both conditions, a dysfunction of matrix metalloproteinases (MMP)-2, -3, and -9 have been found. Our aim was to investigate these MMP pathways in stroke patients with IADE. METHODS: Five hundred ten Caucasians patients with brain infarction were consecutively recruited at 12 centers. The diagnosis of IADE was made by consensus between 2 neurologists based on magnetic resonance imaging scans. Determination of MMP-2, -3, and -9 plasma levels was centralized in 1 laboratory. Because we found a threshold effect of MMP-3 plasma levels with the risk of IADE, determination of the MMP-3 5A/6A polymorphism was carried out. RESULTS: IADE was identified in 12% of stroke patients. There was no association of IADE with mean MMP-2, -3, and -9 plasma levels. After categorization of MMP plasma levels into tertiles, we found a higher risk of IADE with the lowest MMP-3 tertile (adjusted odds ratio [OR], 2.48; 95% confidence interval [CI], 1.17-5.23). In genotype analysis, there was a significant additive effect of the 5A allele on the risk of IADE, with an adjusted OR of 1.62 (95% CI, 1.03-2.55). INTERPRETATION: In this cohort of stroke patients of Caucasian ancestry, IADE was associated with low MMP-3 plasma levels and with the 5A/6A polymorphism of the promoter region of MMP-3. These results suggest that MMP-3 may play a role in IADE.

Prevalence and risk factors for aspirin and clopidogrel resistance in patients with coronary artery disease or ischemic cerebrovascular disease.

The objective of this study was to identify possible risk factors associated with a lack of response to aspirin and clopidogrel treatments in patients with coronary or cerebral ischemic artery disease. A point-of-care analyzer, VerifyNow (Accumetrics, San Diego, CA), was used to measure adenosine-5-diphosphate and platelet P2YI2 receptor blockage to investigate the responses of a group of 197 patients to aspirin and/ or clopidogrel therapies (aspirin therapy, 178; clopidogrel therapy, 139; both drugs, 144). Of these 197 patients, 135 (68.5%) had coronary artery disease and 72 (31.5%) had ischemic cerebrovascular disease. Aspirin resistance was defined as an ARU (aspirin reaction units) > or =550, and clopidogrel resistance was defined as platelet inhibition <20%. Twenty-five of 178 aspirin users (14.0%) were resistant to aspirin, and 54 of 139 (38.8%) clopidogrel users were resistant to clopidogrel. The data indicate that low hemoglobin (Hb) level in aspirin users and high systolic and diastolic blood pressures in clopidogrel users are significantly related to treatment resistance (p < 0.05). The latter finding is possibly due to the greater adhesiveness and increased aggregability of platelets in hypertensive patients.

Association of plasma homocysteine concentration with cerebral white matter hyperintensity on magnetic resonance images in stroke patients.

BACKGROUND: Homocysteine (Hcy) has been recognized as a risk factor for atherosclerosis. White matter hyperintensity (WMH) on MRI has been regarded as a hallmark for cerebral small vascular disease. The study is to investigate the relationship between plasma Hcy level and WMH on a hospital-based cohort of Taiwanese stroke patients. METHODS AND RESULTS: A total of 352 consecutive stroke patients (64.7+/-11.2 years) were included. Severity of WMH was semi-quantitatively evaluated with a scoring system. The top WMH score tertile was defined as severe white matter change (sv-WMH). Associations between Hcy tertile levels and sv-WMH were examined, adjusting for demographics and atherosclerosis risk factors. Subjects in the top Hcy tertile (>10.25 micromol/L) had higher WMH scores and prevalence of sv-WMH than those in the middle and in the bottom tertile. The adjusted odds ratio of having sv-WMH was 2.04 (95% confidence interval 1.20-3.47, p=0.008) for the top Hcy level tertile than for the lower two tertiles combined. CONCLUSION: Hcy is a risk factor for cerebral white matter lesion in stroke patients. Even mild hyperhomocysteinemia can significantly increase severity of cerebral microangiopathy.

White matter hyperintensities in mid-adult life.

PURPOSE OF REVIEW: White matter hyperintensities on T2-weighted magnetic resonance imaging are frequent incidental findings in the brains of elderly individuals. Recent studies have reported that they may also be common in middle-aged individuals, and their systematic evaluation in younger populations is necessary. RECENT FINDINGS: Incidental white matter hyperintensities are common in brains of healthy individuals in their 60s and may be seen as early as the 30s and 40s. They are associated with subtle functional impairment and higher prevalence of neuropsychiatric disorders. While cerebrovascular risk factors such as hypertension, diabetes, high homocysteine, and so forth, are known risk factors for white matter hyperintensities, a significant proportion of the variance is unexplained. Genetic factors, alone or in interaction with environmental factors, appear to be important. There is a slight excess of white matter hyperintensities in women, the basis for which is not understood. Longitudinal studies show that those with baseline lesions have a greater progression over time. SUMMARY: New imaging techniques present an opportunity to examine white matter pathology in great detail in younger populations. Standardized methods to examine such pathology and its determinants will help inform strategies for their prevention, which is an important component of a healthy ageing agenda.

Elevated plasma homocysteine in acute stroke was not associated with severity and outcome: stronger association with small artery disease.

Homocysteine increases in the acute phase of ischaemic stroke and from the acute to the convalescent phase, suggesting that hyper-homocysteinaemia may be a consequence rather than a causal factor. Therefore we measured homocysteine plasma levels in stroke patients in order to investigate possible correlations of homocysteine with stroke severity and clinical outcome. Further we looked for eventual differences in stroke subtypes. We prospectively studied plasma homocysteine levels in acute stroke patients admitted to the stroke unit of our department. Seven hundred and seventy-five ischaemic stroke patients, 39 cerebral haemorrhages and 421 healthy control subjects have been enrolled. Stroke severity and clinical outcome were measured with the Scandinavian Stroke Scale, the Rankin Scale and the Barthel Index. Stroke severity by linear stepwise regression analysis was not an independent determinant of plasma homocysteine levels. Homocysteine was not correlated with outcome measured by the Barthel Index. Mean plasma homocysteine of both ischaemic and haemorrhagic stroke was significantly higher than controls (p<0.05). Homocysteine had an adjusted odds ratios (OR) of 4.2 (95% CI 2.77-6.54) for ischaemic stroke and of 3.69 (95% CI 1.90-7.17) for haemorrhagic stroke. Compared with the lowest quartile, the upper quartile was associated with an adjusted OR of ischaemic stroke due to small artery disease of 17.4 (95% CI 6.8-44.3). Homocysteine in the acute phase of stroke was not associated with stroke severity or outcome. Elevated plasma homocysteine in the acute phase of stroke was associated with both ischaemic and haemorrhagic stroke. Higher levels are associated with higher risk of small artery disease subtype of stroke.

Intracranial arterial dolichoectasia is associated with enlarged descending thoracic aorta.

BACKGROUND: Intracranial arterial dolichoectasia (IADE) is defined as an increase in length and diameter of the intracranial arteries and is present in 12% of stroke patients. The pathophysiology is unknown; some data suggest that IADE is not merely a complication of atherosclerosis, but a distinct arteriopathy characterized by loss of elastic tissue in the media. OBJECTIVE: To investigate the relationship between IADE and transesophageal echocardiography (TEE) variables such as ascending and descending thoracic aorta diameters. METHODS: The sample included 154 patients with brain infarction (BI) and with measurement of the descending thoracic aorta on TEE. IADE was diagnosed by consensus between two neurologists. Information on demographic characteristics and risk factors was collected using a structured questionnaire, and a carotid ultrasound scan was performed. RESULTS: IADE was identified in 23 of the 154 stroke patients (15%). The mean diameter (+/-SD) of the descending thoracic aorta was significantly higher in the IADE(+) than in the 131 IADE(-) stroke patients (mean +/- SD 26.6 +/- 3.6 vs 24.8 +/- 2.7 mm). The proportion of IADE increased regularly with the quartiles of descending thoracic aorta diameter: 5%, 13%, 18%, and 24% (test of linear trend, p = 0.02). The adjusted OR (95% CI) of IADE associated with a 1 mm increase in descending thoracic aorta diameter was 1.22 (95% CI, 1.02 to 1.45). CONCLUSION: Patients with intracranial arterial dolichoectasia (IADE) have larger descending thoracic aorta diameters than non-IADE patients, suggesting that the underlying process causing IADE also affects the descending thoracic aorta.

Association between carotid atherosclerosis and hemostatic markers in patients with cerebral small artery disease.

The purposes of this study were to investigate the association between carotid atherosclerosis and hemostatic markers, and to elucidate the difference in hemostatic markers between intima-media thickening and plaque formation in patients with cerebral small artery disease. We investigated carotid atherosclerosis by assessing diffuse intima-media thickness measurements and localized plaque using B-mode ultrasonography, and we measured the concentrations of plasma fibrinogen, beta-thromboglobulin and platelet factor 4 as markers for platelet activation, and the activity of plasma von Willebrand factor as a marker for endothelial damage. The intima-media thickness was significantly associated with age, male sex, the concentrations of plasma beta-thromboglobulin and platelet factor 4, and the activity of plasma von Willebrand factor. The plaque score showed a significant association with male sex, the concentration of fibrinogen, and the activity of plasma von Willebrand factor. These results may indicate that underlying mechanisms are not the same between the intima-media thickness and plaque formation. We suggest that hemostatic markers could reflect the severity of carotid atherosclerosis in patients with cerebral small artery disease, and that preventive antiplatelet therapies against brain infarction might be necessary for patients with severe carotid atherosclerosis.

[Phospholipid levels in exploration of cerebral atherosclerosis in African Senegalese population]. / Intérêt du dosage des phospholipides dans l'exploration de l'athérosclérose cérébrale en milieu africain Sénégalais.

In the investigation of atherosclerosis, cholesterol and its fractions, triglycerides and glucose are more tested than phospholipids. We were interested by this category of lipids in Senegalese suffering from cerebrovascular disease. We did not find differences between healthy and non healthy subjects for the total phospholipids; but the high density lipoprotein phospholipids were significantly lowered in non healthy subjects. This decrease might explain in part, the atherosclerosis strike. Practicians should pay more attention in this lipidic parameter, using the reference values established in Senegalese.

AT-877, a Ca2+ antagonist, fails to reduce infarct size following rat middle-cerebral artery occlusion.

We investigated the effects of AT-877, a Ca2+ antagonist, on rat middle-cerebral artery occlusion. All rats had 6-h ischemia, and treated animals received either 3 or 10 mg/kg AT-877 s.c. just after the occlusion. Control animals received an equal volume of the vehicle. Prior to sacrifice, significant changes in the decrease of blood pressure and the increase of plasma glucose were observed in the treated rats. Although the infarct size tended to decrease, this decrease was not significant. Only when the blood pressure- or plasma glucose-matched subgroups were compared, the infarct volume decreased significantly in the drug-treated animals. Thus, AT-877 failed to reduce ischemic brain damage unless the blood pressure or plasma glucose were controlled.

Simplification of a venous occlusion test.

Chronological changes in plasma or serum concentrations of various fibrinolytic parameters, such as tissue-type plasminogen activator, plasminogen activator inhibitor, fibrinopeptide B beta 15-42 and FDP, were examined in 31 healthy volunteers before and after venous occlusion to determine a suitable time of venous stasis and a good parameter for use in a simplified venous occlusion test. After venous stasis for 5 min, a significant increase in the serum concentration of FDP (from 38.3 +/- 21.1 to 100.9 +/- 87.2 ng/ml (n = 24)) was observed, and the increase was parallel with changes in the plasma concentrations of other fibrinolytic parameters. The serum FDP level after 10 min VO was not significantly higher than that after 5 min VO. A significant decrease in ADP-induced platelet aggregation was observed after venous occlusion when measured by the impedance method, but not by the turbidimetric method. Therefore, as a simplified test, the change in the serum concentration of FDP after VO for 5 min was measured. The clinical significance of this simplified test was evaluated in fourteen patients with stenosis of cerebral artery. The mean percentage change in serum FDP concentration after venous stasis in the patients, 34.5 +/- 54.8%, was significantly less than that in normal subjects, 156.5 +/- 90.9%. Similar results were obtained on changes in plasma responses of other fibrinolytic parameters. Measurement of increase in serum FDP concentration after venous occlusion for 5 min should be useful as a screening tests for the hypofibrinolytic or thrombotic state due to vascular dysfunction.