Characteristics of Diffusional Kurtosis in Chronic Ischemia of Adult Moyamoya Disease: Comparing Diffusional Kurtosis and Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: Detecting microstructural changes due to chronic ischemia potentially enables early identification of patients at risk of cognitive impairment. In this study, diffusional kurtosis imaging and diffusion tensor imaging were used to investigate whether the former provides additional information regarding microstructural changes in the gray and white matter of adult patients with Moyamoya disease. MATERIALS AND METHODS: MR imaging (diffusional kurtosis imaging and DTI) was performed in 23 adult patients with Moyamoya disease and 23 age-matched controls. Three parameters were extracted from diffusional kurtosis imaging (mean kurtosis, axial kurtosis, and radial kurtosis), and 4, from DTI (fractional anisotropy, radial diffusivity, mean diffusivity, and axial diffusivity). Voxelwise analysis for these parameters was performed in the normal-appearing brain parenchyma. The association of these parameters with neuropsychological performance was also evaluated. RESULTS: Voxelwise analysis revealed the greatest differences in fractional anisotropy, followed, in order, by radial diffusivity, mean diffusivity, and mean kurtosis. In patients, diffusional kurtosis imaging parameters were decreased in the dorsal deep white matter such as the corona radiata and superior longitudinal fasciculus (P < .01), including areas without DTI abnormality. Superior longitudinal fasciculus fiber-crossing areas showed weak correlations between diffusional kurtosis imaging and DTI parameters compared with tissues with a single-fiber direction (eg, the corpus callosum). Diffusional kurtosis imaging parameters were associated with general intelligence and frontal lobe performance. CONCLUSIONS: Although DTI revealed extensive white matter changes, diffusional kurtosis imaging additionally demonstrated microstructural changes in ischemia-prone deep white matter with abundant fiber crossings. Thus, diffusional kurtosis imaging may be a useful adjunct for detecting subtle chronic ischemic injuries.

Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury.

The integrity of cerebral microvessels requires the close apposition of the endothelium to the astrocyte endfeet. Integrins alpha1beta1 and alpha6beta4 are cellular matrix receptors that may contribute to cerebral microvascular integrity. It has been hypothesized that focal ischemia alters integrin expression in a characteristic time-dependent manner consistent with neuron injury. The effects of middle cerebral artery occlusion (MCAO) and various periods of reperfusion on microvasclar integrin alpha1beta1 and alpha6beta4 expression were examined in the basal ganglia of 17 primates. Integrin subunits alpha1 and beta1 colocalized with the endothelial cell antigen CD31 in nonischemic microvessels and with glial fibrillary acidic protein on astrocyte fibers. Rapid, simultaneous, and significant disappearance of both integrin alpha1 and beta1 subunits and integrin alpha6beta4 occurred by 2 hours MCAO, which was greatest in the region of neuron injury (ischemic core, Ic), and progressively less in the peripheral (Ip) and nonischemic regions (N). Transcription of subunit beta1 mRNA on microvessels increased significantly in the Ic/Ip border and in multiple circular subregions within Ic. Microvascular integrin alpha1beta1 and integrin alpha6beta4 expression are rapidly and coordinately lost in Ic after MCAO. With loss of integrin alpha1beta1, multiple regions of microvascular beta1 mRNA up-regulation within Ic suggest that microvessel responses to focal ischemia are dynamic, and that multiple cores, not a single core, are generated. These changes imply that microvascular integrity is modified in a heterogeneous, but ordered pattern.

15-Deoxy-Delta(12,14)-prostaglandin J(2) induces G(1) arrest and differentiation marker expression in vascular smooth muscle cells.

In search of substances useful for the treatment of atherosclerotic vascular diseases, we studied the effects of 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), a natural ligand for peroxisome proliferator-activated receptor gamma, on the proliferation and differentiation of vascular smooth muscle cells (VSMCs). 15d-PGJ(2) but not WY14643, an agonist for peroxisome proliferator-activated receptor alpha, dose-dependently inhibited VSMC proliferation; the effect was maximal at 12 microM. This compound strongly suppressed the activities of cyclin-dependent kinases (Cdk) 4, 6, and 2, thereby preventing the phosphorylation of the retinoblastoma protein. These Cdks seemed to be inhibited through two mechanisms: the down-regulation of cyclin D1 and the up-regulation of Cdk inhibitor p21(Cip1/Waf1/Sdi1). 15d-PGJ(2) was found to inhibit the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which mediates cyclin D1 expression. Mitogenic stimulation of quiescent cells decreased the level of mRNA for the smooth muscle-specific myosin heavy-chain SM1, whereas this reduction was prevented by 15d-PGJ(2). A long-term treatment of exponentially growing VSMCs with 15d-PGJ(2) markedly elevated the mRNA level of SM1 and, moreover, induced SM2, another isoform expressed exclusively in mature VSMCs. 15d-PGJ(2) also increased the expression levels of calponin-h1 and smooth muscle alpha-actin. These results suggest that 15d-PGJ(2) induces G(1) arrest by two distinct mechanisms and promotes VSMC differentiation.

Does hypertension confer a hypercoagulable state in stroke-prone spontaneously hypertensive rats?

OBJECTIVE: To verify whether hypertension confers a hypercoagulable state in a hypertensive animal model. DESIGN: The parameters of blood coagulation were compared between stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. Each rat group consisted of a younger subgroup at 8-12 weeks old (n = 12) and an older subgroup at 16-20 weeks old (n = 12). METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT), fluorogenic PT, fibrinogen, fibrin/fibrinogen degradation products (FDP), thrombin-anti-thrombin III complex (TAT), factor Xa activity, anti-thrombin III (AT-III), tissue factor pathway inhibitor (TFPI), protein C and C1 inhibitor were measured in both rat groups. RESULTS: There was no significant difference in FDP and TAT levels between SHR-SP and WKY rats even at 16-20 weeks when SHR-SP developed severe hypertensive vascular lesions. Contrary to expectations, fluorogenic PT and factor Xa activity were significantly lower in SHR-SP than in WKY rats. While there was no significant difference in AT-III, TFPI and protein C activities between SHR-SP and WKY rats, C1 inhibitor activity was significantly higher in SHR-SP than in WKY rats. The elevated C1 inhibitor activity was inversely correlated with the reduced factor Xa activity. Gel-filtered fractionated plasma with C1 inhibitor activity had an inhibitory effect on the purified rat factor Xa, and immunodepletion of C1 inhibitor from the fractionated plasma attenuated the inhibitory effect CONCLUSION: These results suggest that SHR-SP get into a hypocoagulable state rather than a hypercoagulable state, and that the reduction of factor Xa activity in SHR-SP may be related to the elevation of C1 inhibitor activity.

Integrin alpha(IIb)beta(3) inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia.

BACKGROUND AND PURPOSE: Platelets become activated and accumulate in brain microvessels of the ischemic microvascular bed after experimental focal cerebral ischemia. The binding of glycoprotein IIb/IIIa (integrin alpha(IIb)beta(3)) on platelets to fibrinogen is the terminal step in platelet adhesion and aggregation. This study tests the hypothesis that inhibition of platelet-fibrin(ogen) interactions may prevent microvascular occlusion after experimental middle cerebral artery occlusion (MCA:O). METHODS: TP9201 is a novel Arg-Gly-Asp (RGD)-containing integrin alpha(IIb)beta(3) inhibitor. Microvascular patency after 3-hour MCA:O and 1-hour reperfusion within the ischemic and nonischemic basal ganglia was compared in adolescent male baboons who received high-dose TP9201 (group A: IC(80) in heparin, n=4), low-dose TP9201 (group B: IC(30) in heparin, n=4), or no treatment (group C: n=4) before MCA:O. RESULTS: After MCA:O, microvascular patency decreased significantly in group C. However, in the ischemic zones of groups A and B compared with group C, patencies were significantly greater in the 4.0- to 7. 5-microm-diameter (capillary) and 7.5- to 30.0-microm-diameter vessels (2P<0.05). A dose-dependent increase in hemorrhagic transformation was seen in group A (3 of 4 animals) compared with group B (1 of 4 animals), and no hemorrhage was visible in group C (chi(2) analysis for trend, P<0.05). CONCLUSIONS: Platelet activation contributes significantly to ischemic microvascular occlusion. Occlusion formation may be prevented by this RGD-integrin alpha(IIb)beta(3) inhibitor at a dose that does not produce clinically significant parenchymal hemorrhage. The effect of microvascular patency on neuron recovery can now be tested.

Fluid shear stress induces lipocalin-type prostaglandin D(2) synthase expression in vascular endothelial cells.

Ligands for peroxisome proliferator-activated receptor gamma, such as the thiazolidinedione class of antidiabetic drugs and 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), modulate various processes in atherogenesis. In search of cells that generate prostaglandin D(2) (PGD(2)), the metabolic precursor of 15d-PGJ(2), we identified PGD(2) from culture medium of endothelial cells. To study how PGD(2) production is regulated in endothelial cells, we investigated the role of fluid shear stress in the metabolism of PGD(2). Endothelial cells expressed the mRNA for the lipocalin-type PGD(2) synthase (L-PGDS) both in vitro and in vivo. Loading laminar shear stress using a parallel-plate flow chamber markedly enhanced the gene expression of L-PGDS, with the maximal effect being obtained at 15 to 30 dyne/cm(2). The expression began to increase within 6 hours after loading shear stress and reached the maximal level at 18 to 24 hours. In contrast, shear stress did not alter the expression levels of PGI(2) synthase and thromboxane A(2) synthase. In parallel with the increase in the expression level of L-PGDS, endothelial cells released PGD(2) and 15d-PGJ(2) into culture medium. These results demonstrate that shear stress promotes PGD(2) production by stimulating L-PGDS expression and suggest the possibility that a peroxisome proliferator-activated receptor gamma ligand is produced in vascular wall in response to blood flow.

Differentiation-inducing factor-1, a morphogen of dictyostelium, induces G(1) arrest and differentiation of vascular smooth muscle cells.

Differentiation-inducing factor-1 (DIF-1) is a morphogen that induces differentiation of DICTYOSTELIUM: Recently, DIF-1 has been shown to inhibit proliferation and induce differentiation in tumor cells, although the underlying mechanisms remain unknown. In this study, we examined the effects of DIF-1 on the proliferation and differentiation of vascular smooth muscle cells, to explore novel therapeutic strategies for atherosclerosis. DIF-1 nearly completely inhibited DNA synthesis and cell division in mitogen-stimulated cells. DIF-1 inhibited the phosphorylation of the retinoblastoma protein and the activities of cyclin-dependent kinase (Cdk) 4, Cdk6, and Cdk2, which phosphorylate the retinoblastoma protein. DIF-1 strongly suppressed the expression of cyclins D1, D2, and D3, as well as those of cyclins E and A, which normally began after that of the D-type cyclins. The mRNAs for the smooth muscle myosin heavy chains SM1 and SM2 were expressed in quiescent cells in primary culture, and these expression levels decreased after mitogenic stimulation. In the presence of DIF-1, the rate of the reduction was significantly decelerated. Moreover, the addition of DIF-1 to dedifferentiated cells induced the expressions of SM1 and SM2, accompanied by a reduction in the level of SMemb, a nonmuscle-type myosin heavy chain. Therefore, DIF-1 seemed to interrupt a very early stage of G(1) probably by suppressing the expressions of the D-type cyclins. Furthermore, this compound may prevent phenotypic modulation and induce differentiation of vascular smooth muscle cells.

Linkage between alpha(1) adrenergic receptor and the Jak/STAT signaling pathway in vascular smooth muscle cells.

The Jak/STAT pathway is activated following stimulation of the type I angiotensin II receptor. To examine whether this pathway is shared among other G-protein-coupled receptors, we studied the linkage between the alpha(1) adrenergic receptor and this pathway. The alpha(1) agonist phenylephrine induced tyrosine phosphorylation of Jak2, Tyk2, and STAT1 in vascular smooth muscle cells. The phosphorylation of Jak2 was prevented by the alpha(1) receptor antagonists prazosin and chloroethylclonidine, but not by WB4101, and that of STAT1 was inhibited by prazosin and the Jak2 inhibitor AG490. After stimulation with phenylephrine, Jak2 and STAT1 were found to associate with alpha(1B) receptor. Phenylephrine stimulated the DNA binding activity of STAT1. Protein synthesis promoted by phenylephrine was inhibited by prazosin, AG490, and the introduction of a decoy oligonucleotide for STAT1. These results suggested that alpha(1) receptor is linked to the Jak/STAT pathway and that this pathway mediates alpha(1) agonist-induced smooth muscle hypertrophy.

Tumor suppressor p53 but not cGMP mediates NO-induced expression of p21(Waf1/Cip1/Sdi1) in vascular smooth muscle cells.

Cyclin-dependent kinase inhibitor p21(Waf1/Cip1/Sdi1) has been suggested to be involved in the antiproliferative effect of nitric oxide (NO) in vascular smooth muscle cells (VSMCs). To elucidate the mechanism underlying NO-induced p21 expression, we investigated the roles of tumor suppressor p53 and the guanylate cyclase-cGMP pathway. The induction of p21 by the NO donor S-nitroso-N-acetylpenicillamine (SNAP) seemed to be due to transactivation because SNAP elevated the activity of p21 promoter but did not stabilize p21 mRNA and protein. Because SNAP did not stimulate the deletion mutant of p21 promoter that lacked p53 binding sites, we tested the involvement of p53. The expression level of p53 was down-regulated after mitogenic stimulation, whereas it was sustained in the presence of SNAP. SNAP markedly stimulated DNA binding activity of p53. Furthermore, SNAP failed to induce p21 in VSMCs obtained from p53-knock out mice and in A431 cells that contained mutated p53. The antiproliferative effect of SNAP also was attenuated in these cells. NO stimulates guanylate cyclase and its product cGMP has been shown to inhibit VSMC proliferation. However, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a guanylate cyclase inhibitor, did not prevent SNAP-induced p21 expression. 8-Bromo-cGMP, 3-isobutyl-1-methylxanthine, and their combination did not induce p21. Although 8-bromo-cGMP had a small antiproliferative effect, the elevation of cGMP concentration induced by SNAP was little throughout the G(1) phase. The antiproliferative effect of SNAP was not attenuated by Rp-8-bromoguanosine-3',5'-monophosphorothioate, an inhibitor of cGMP-dependent protein kinase. These results suggested that NO induces p21 through a p53-dependent but cGMP-independent pathway.

Activated microvessels express vascular endothelial growth factor and integrin alpha(v)beta3 during focal cerebral ischemia.

Both vascular endothelial growth factor (VEGF) and integrin alpha(v)beta3 play roles in angiogenesis. In noncerebral vascular systems, VEGF can induce endothelial integrin alpha(v)beta3 expression. However, it is unknown whether VEGF, like integrin alpha(v)beta3, appears in the initial response of microvessels to focal brain ischemia. Their coordinate expression in microvessels of the basal ganglia after middle cerebral artery occlusion (MCAO) in the nonhuman primate model was examined quantitatively. Cells incorporating deoxyuridine triphosphate (dUTP+) by the polymerase I reaction at 1 hour (n = 3), 2 hours (n = 3), and 7 days (n = 4) after MCAO defined the ischemic core (Ic) and peripheral regions. Both VEGF and integrin alpha(v)beta3 were expressed by activated noncapillary (7.5- to 30.0-microm diameter) microvessels in the Ic region at 1 and 2 hours after MCAO. At 7 days after MCAO, the number of VEGF+, integrin alpha(v)beta3+, or proliferating cell nuclear antigen-positive microvessels had decreased within the Ic region. The expressions of VEGF, integrin alpha(v)beta3, and proliferating cell nuclear antigen were highly correlated on the same microvessels using hierarchical log-linear statistical models. Also, VEGF and subunit alpha(v) messenger ribonucleic acids were coexpressed on selected microvessels. Here, noncapillary microvessels are activated specifically early during a focal cerebral ischemic insult and rapidly express VEGF and integrin alpha(v)beta3 together.

Matrix metalloproteinases increase very early during experimental focal cerebral ischemia.

Microvascular integrity is lost during focal cerebral ischemia. The degradation of the basal lamina and extracellular matrix are, in part, responsible for the loss of vascular integrity. Matrix metalloproteinases (MMPs) may play a primary role in basal lamina degradation. By using a sensitive modification of gelatin zymography, the authors investigated the activity of MMP-2 and MMP-9 in frozen 10-microm sections of ischemic and nonischemic basal ganglia and plasma samples of 27 non-human primates after middle cerebral artery occlusion/reperfusion (MCAO/R) for various periods. The gelatinolytic activities were compared with parallel cell dUTP incorporation in the ischemic zones of adjacent sections. In the brain, the integrated density of MMP-2 increased significantly by 1 hour after MCAO and was persistently elevated thereafter. Matrix metalloproteinase-2 expression was highly correlated with the extent of neuron injury and the number of injured neurons (r = 0.9763, SE = 0.004, 2P < 0.0008). Matrix metalloproteinase-9 expression only was significantly increased in subjects with hemorrhagic transformation. In plasma, only MMP-9 increased transiently at 2 hours of MCAO. These findings highlight the early potential role of MMP-2 in the degradation of basal lamina leading to neuronal injury, and an association of MMP-9 with hemorrhagic transformation after focal cerebral ischemia.

Heterogeneity in the appearance and distribution of macrophage subsets and their possible involvement in hypertensive vascular lesions in rats.

In hypertensive vascular lesions, various pathologic changes are exhibited. To clarify the mechanisms responsible for this diversity of vascular lesions, we immunohistochemically examined hypertensive vascular lesions in stroke-prone spontaneously hypertensive rats with reference to the distribution of macrophage subsets. The brain, kidney, heart, and aorta were dissected from stroke-prone spontaneously hypertensive rats and Wistar-Kyoto rats at 8, 12, 16, and 20 weeks of age. Immunohistochemistry was performed with antibodies against the macrophage markers ED1, ED2, and OX42, the MHC class II antigen marker OX6, the T-lymphocyte markers CD4, CD5, and CD8, and other markers, such as alpha-smooth muscle actin, proliferating cell nuclear antigen, and von Willebrand factor. Fibrinoid necrosis was dominant in the brain, and fibrocellular proliferative lesions were dominant in the kidney. Immunohistochemically, the decreased intensity of alpha-smooth muscle actin immunostaining preceded the formation of vascular lesions. Although preexisting ED2-positive perivascular resident macrophages completely disappeared in fibrinoid necrosis, MHC class II-negative and ED1-positive macrophages were scattered around the lesion and showed phagocytosis in the brain, which indicates that macrophages in fibrinoid necrosis had extravasated and acted only as scavengers. In the kidney, there was extensive accumulation of MHC class II-positive and ED1-positive macrophages with T lymphocytes along the affected arteries. These inflammatory cells seemed to be supplied through the perivascular interstitial space, not through the endothelium, and the accumulation of these cells preceded the development of fibrocellular proliferative lesions. In the heart and aorta, macrophage accumulation was either absent or slight, and vascular lesions were rarely observed. These findings suggest that heterogeneity in the time course of macrophage infiltration and in the distribution of macrophage subsets among the vascular trees of various organs seems to be correlated with the diversity of hypertensive vascular lesions. Differences in the routes that supply macrophages and their functions may determine the pathologic changes in the vascular lesions.

Decreased plasma tissue factor pathway inhibitor activity in ischemic stroke patients.

Although tissue factor pathway inhibitor (TFPI) plays an essential role in the regulation of blood coagulation, the quantitative changes in its levels in thrombotic disease are still undefined. We compared TFPI activity in ischemic stroke patients and control subjects matched for age and cholesterol level to determine whether TFPI activity is changed in the disease. TFPI activity was significantly lower in the stroke patients (1.01 +/- 0.24 U/ml) than in the control subjects (1.10 +/- 0.16 U/ml). In relation to clinical subtypes of stroke, TFPI activity in atherothrombotic infarction (0.93 +/- 0.19 U/ml) and lacunar infarction (0.99 +/- 0.23 U/ml) was significantly lower than in the control subjects, whereas the level in cardioembolic infarction (1.16 +/- 0.31 U/ml) was not. No relationship could be established between TFPI activity and other haemostatic parameters reflecting the production of thrombin/fibrin and the activation of fibrinolysis. These results may suggest that the moderately lower TFPI activity in stroke patients could be due to atherosclerotic changes rather than to consumptive coagulopathy.

An anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody recognized the third Kunitz domain (K3) of free-form TFPI but not lipoprotein-associated forms in plasma.

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor with three tandem inhibitory domains, which inhibits the initial reactions of the extrinsic blood coagulation pathway through the first and second Kunitz domains. We prepared a monoclonal antibody against recombinant human TFPI (rTFPI) and determined the epitope as the third Kunitz domain, using fragments derived from rTFPI (K1-K2 fragment and K3 fragment) and synthetic peptides. We then developed an enzyme immunoassay (EIA) method using a combination of the monoclonal antibody and a polyclonal antibody. Although TFPI activity is distributed among LDL/VLDL-associated, HDL-associated, and free forms of TFPI after gel-filtration of human plasma, only the free form was detected by the EIA method. After incubation with LDL, the antigenicity of rTFPI was reduced, but that of K3 fragment was not. Gel-filtration analysis of the mixture of radiolabeled rTFPI or K3 with LDL demonstrated that rTFPI, but not K3, bound LDL. From these results, we concluded that the monoclonal antibody against TFPI recognized only a free form of TFPI in plasma, since the epitope of lipoprotein-associated TFPI had been masked by the interaction with lipoproteins.

Tissue factor pathway inhibitor activity in human plasma. Measurement of lipoprotein-associated and free forms in hyperlipidemia.

Tissue factor pathway inhibitor (TFPI), a protease inhibitor that is present in free and lipoprotein-associated forms in plasma and that also occurs as an endothelial cell-associated form, can inhibit the initial reactions of the tissue factor-mediated coagulation pathway. Although a positive correlation between plasma TFPI activity and cholesterol concentration in human plasma has been demonstrated, levels of the various forms of TFPI, ie, the LDL/VLDL-associated form, the HDL-associated form, and the free form, have not yet been completely determined in hyperlipidemia. We therefore established a method for the measurement of each of these forms of TFPI in plasma by gel filtration of plasma in buffer containing 1 mol/L NaCl. The recovery of TFPI activity in the free form was markedly greater as assessed by the new method than the recovery reported when other methods have been used. We employed the new method to analyze TFPI activity in 19 hyperlipidemic patients and compared the results with those for normal control subjects. The level of LDL/VLDL-associated TFPI in hyperlipidemic patients was significantly increased compared with control subjects' levels (0.383 +/- 0.112 versus 0.237 +/- 0.077 U/mL), whereas the level of the free form of TFPI in hyperlipidemic patients was significantly decreased (0.381 +/- 0.132 versus 0.495 +/- 0.106 U/mL), the former being positively correlated with cholesterol level, while the latter was negatively correlated.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino acid sequence and inhibitory activity of rhesus monkey tissue factor pathway inhibitor (TFPI): comparison with human TFPI.

Rhesus monkey cDNA for tissue factor pathway inhibitor (TFPI) was cloned by means of the reverse transcriptase-polymerase chain reaction, using liver mRNA, and its nucleotide sequence was determined by sequencing five independent clones. Monkey TFPI was found to have a signal peptide of 28 amino acid residues and to be a mature protein of 276 amino acid residues, in which three and seventeen amino acid residue substitutions compared to human TFPI were found, respectively. All the cysteine residues, three putative carbohydrate-linked asparagine residues, and the P1 amino acid residues of each of the three Kunitz inhibitor domains were conserved in the two species. Recombinant monkey TFPI (rTFPI) was isolated from the culture medium of transformed Chinese hamster ovary cells. Amino acid sequence analysis and immunoblotting analysis, using polyclonal and monoclonal antibodies, showed that the carboxyl-terminal basic part of Rhesus monkey rTFPI had been truncated. The inhibitory activity of monkey rTFPI was compared with that of human rTFPI without the carboxyl-terminal basic part. The prothrombin time of human plasma was slightly more prolonged by the addition of monkey rTFPI than by that of human rTFPI. However, no significant differences were found between the potencies of human and monkey rTFPI as to the inhibition of factor Xa and tissue factor-factor VIIa complex.

Response of plasma tissue factor pathway inhibitor to diet-induced hypercholesterolemia in crab-eating monkeys.

Tissue factor pathway inhibitor (TFPI), a protease inhibitor associated with lipoproteins in plasma and endothelial cells, can inhibit the initial reactions of the tissue factor-mediated coagulation pathway. A positive relationship between TFPI and cholesterol has been demonstrated in human plasma. To investigate this relation in more detail, in the present study we measured TFPI in the plasma of monkeys on a high-cholesterol diet. After diet treatment, cholesterol levels and TFPI activity were increased 3- and 1.5-fold, respectively. Three forms of TFPI, low-density lipoprotein (LDL)/very-low-density lipoprotein (VLDL)-associated TFPI, high-density lipoprotein (HDL)-associated TFPI, and free TFPI, were measured after gel filtration of plasma. In hypercholesterolemic monkeys, levels of TFPI activity and antigen in the LDL/VLDL fraction were increased to about three times those of normal monkeys. Changes in HDL-associated TFPI and free TFPI were not significant compared with the change in LDL/VLDL-associated TFPI. After the monkeys received heparin infusions TFPI was increased about fivefold, but there was no significant difference in these increases between normal and hypercholesterolemic monkeys. The increase in TFPI after heparin infusion is discussed in terms of the relationship between lipoprotein-associated TFPI in plasma and endothelial cell-associated TFPI.

Magnetic resonance findings in spontaneous dissection of the cervical internal carotid artery--case report.

The magnetic resonance (MR) appearance of a spontaneous dissection of the cervical internal carotid artery (ICA) in a 53-year-old male is described. Cerebral angiograms demonstrated a long-segment stenosis of the left cervical ICA beginning above the common carotid bifurcation and extending to the skull base ("string sign"). T1-, T2-, and proton density-weighted MR images of the upper neck revealed a high-intensity crescent mass expanding the arterial wall and narrowing the arterial lumen of the left ICA. This high-intensity mass was considered to represent the mural hematoma of the involved ICA. Gradual improvement of the dissection was confirmed by both angiography and MR imaging. Cerebral angiograms have shown pathognomonic findings such as double lumen and intimal flap in only some patients with ICA dissection. Our experience suggests that MR demonstration of the mural hematoma is specific and important for diagnosis and follow-up in cases of spontaneous dissection of the cervical ICA.

[A case of venous thrombosis associated with medullary venous malformation].

A 16 year-old girl was admitted to our hospital complaining of headache and vomiting. She was born with an orbital lymphangioma, which was resected partially at a younger age. On admission she had mild confusion and light neck stiffness as neurological positive findings. Enhanced CT scan showed an eight-figure enhancement at the straight sinus and a linear enhancement at the vermis. Angiography showed venous thrombosis spreading in the deep cerebral veins and the right superior ophthalmic vein. Furthermore a medullary venous malformation (MVM) was disclosed in the posterior fossa. Administration of urokinase and glycerol relieved her symptoms gradually. After that treatment, partial recanalization of the deep cerebral veins and the straight sinus and disappearance of the MVM were recognized in the second angiography. In the present case, the MVM played an important role as collateral channel. But, in general, when venous thrombosis occurs, collateral circulation is maintained by cork-screw vessels, not by MVM. In the light of the presence of the lymphangioma, the present case was thought to be a rare condition in the venous system. It appears that residual fetal vessels have existed in the posterior fossa from birth. It is considered that the residual fetal vessels opened and dilated temporally and were recognized as an MVM in angiography, when cerebral venous flow was disturbed by the venous thrombosis.

[A case of posttraumatic delayed cerebral arterial spasm; case report and review of the literature on the pathogenesis].

A case of posttraumatic delayed cerebral arterial spasm is presented. A 71-year-old man was admitted to our hospital with head injury. Neurological examination on admission only revealed consciousness disturbance (Japan Coma Scale 30). CT scan 19 hours after the injury demonstrated a contusional hematoma in the right frontal lobe, faint subarachnoid hemorrhage in the left sylvian fissure and subdural hematoma in the interhemispheric fissure. His consciousness was disturbed on the 14th day. CT scan demonstrated a left subdural effusion, which was surgically evacuated. However, from the next day the patient developed left hemiparesis. Right carotid angiogram on the 17th day after the injury revealed multiple segmental arterial narrowing in the right anterior cerebral artery (ACA) and middle cerebral artery (MCA). We diagnosed a posttraumatic delayed cerebral arterial spasm. CT scan revealed low density areas in the right ACA and MCA territory. The pathogenesis of posttraumatic delayed arterial spasm is not yet well known. Now, four theories have been suggested as follows: (1) Subarachnoid hemorrhage, (2) Direct mechanical injury to the arterial wall, (3) Hypothalamus dysfunction, and (4) Disturbed autoregulation. In our case, three important factors are suggested. The first is direct injury to the artery, the second is cerebral contusion, and the third is subdural effusion.