Risk factors and seroprevalence of hepatitis E evaluated in frozen-serum samples (2002-2003) of pregnant women compared with female blood donors in a Southern region of Brazil.

Hepatitis E has always been related to morbidity in pregnant women. Its epidemiology is not well understood in Brazil. Therefore, we tested sera from 209 pregnant women and 199 female blood donors, collected at a single center in Curitiba, Brazil. The Wantai assay was used for testing the anti-hepatitis E virus (anti-HEV), immunoglobulin G (IgG), and an in-house polymerase chain reaction process for testing HEV RNA. Anti-HEV was detected in 22.5% of the total group, 19% in the pregnant women group, and 26% in the blood donor group (P = 0.11), a much higher prevalence when compared with other studies in Brazil. Demographical analysis showed that 92.4% were born in the South Region of Brazil, 4.9% in the Southeast, and 2.7% were distributed over other regions of the country. With respect to their origin, 99% were from the South, 0.7% from the Southeast, and 0.2% from the Central-West regions. Income, education, race, number of pregnancies, and abortion did differ significantly when comparing both the groups (P < 0.001). Age >30 (P = 0.012) and the number (>3) of pregnancies (P = 0.008) were related to anti-HEV positivity. All anti-HEV IgG-positive females were HEV RNA negative. In conclusion, HEV positivity was found in one out of five young women, which showed an urgent need for further epidemiological studies in Brazil.

Coping strategies and risk of cardiovascular disease incidence and mortality: the Japan Public Health Center-based prospective Study.

AIMS: Coping strategies may be significantly associated with health outcomes. This is the first study to investigate the association between baseline coping strategies and cardiovascular disease (CVD) incidence and mortality in a general population cohort. METHODS AND RESULTS: The Japan Public Health Center-based prospective Study asked questions on coping in its third follow-up survey (2000-04). Analyses on CVD incidence and mortality included 57 017 subjects aged 50-79 without a history of CVD and who provided complete answers on approach- and avoidance-oriented coping behaviours and strategies. Cox regression models, adjusted for confounders, were used to determine hazard ratios (HRs) according to coping style. Mean follow-up time was 7.9 years for incidence and 8.0 years for mortality.The premorbid use of an approach-oriented coping strategy was inversely associated with incidence of stroke (HR = 0.85; 95% CI, 0.73-1.00) and CVD mortality (HR = 0.74; 95% CI, 0.55-0.99). Stroke subtype analyses revealed an inverse association between the approach-oriented coping strategy and incidence of ischaemic stroke (HR = 0.79; 95% CI, 0.64-0.98) and a positive association between the combined coping strategy and incidence of intra-parenchymal haemorrhage (HR = 2.03; 95% CI, 1.01-4.10). Utilizing an avoidance coping strategy was associated with increased mortality from ischaemic heart disease (IHD) only in hypertensive individuals (HR = 3.46; 95% CI, 1.07-11.18). The coping behaviours fantasizing and positive reappraisal were associated with increased risk of CVD incidence (HR = 1.24; 95% CI, 1.03-1.50) and reduced risk of IHD mortality (HR = 0.63; 95% CI, 0.40-0.99), respectively. CONCLUSION: An approach-oriented coping strategy, i.e. proactively dealing with sources of stress, may be associated with significantly reduced stroke incidence and CVD mortality in a Japanese population-based cohort.

Review: role of cerebral vessels in ischaemic injury of the brain.

This review discusses the pathological changes in the heart and vessels underlying brain ischaemic injury, with a major focus on atherosclerotic disease of the brain induced by lesions of the extracranial cervical and major intracranial arteries and small-vessel disease of the brain. The carotid bifurcation is the primary site for atherosclerotic changes, for which extensive clinical trials and pathological analyses on carotid endarterectomy specimens have been performed. Plaque rupture and erosion give rise to thrombus formation, which leads to brain ischaemic injury. These changes have much in common with atherosclerotic lesions of the subepicardial coronary arteries. Emboli of various types of particles are characteristics of brain ischaemic injury. Thrombi rich in fibrin and red blood cells (red thrombi) that develop in the cardiac chambers are common sources of cerebral emboli. Small-vessel disease of the brain induces fibrinoid necrosis, microaneurysm, fibrohyalinosis, lipohyalinosis and microatheroma, changes commonly associated with hypertension. The acute hypertensive small-vessel changes organize to create segmental arterial disorganization and deep small infarcts when they escape from rupture. Some specific vascular diseases responsible for brain ischaemic injury are briefly reviewed also.

Reversal of multidrug resistance by synthetic isoprenoids in the KB human cancer cell line.

A colchicine resistant clone, Chr-24, derived from the human carcinoma KB cell line is extensively resistant to multiple drugs including vinblastine, vincristine, Adriamycin, actinomycin D, and daunomycin. In comparison with KB cells, very low accumulation of daunomycin or vincristine is observed in multidrug-resistant cells. Two isoprenoids with 9 to 10 isoprene chains (polyprenoids), N-(p-methylbenzyl)decaprenylamine and N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine overcame the multidrug resistance almost completely in cultured Chr-24, whereas they only slightly sensitized the parental KB cells to anticancer agents. Both isoprenoids enhance the accumulation of vincristine or daunomycin in Chr-24, possibly by inhibiting efflux and also by enhancing influx of anticancer agents. A verapamil-like structure of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine is discussed in relation to its ability to overcome drug resistance.

Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men : the Suita Study.

BACKGROUND: The Framingham Study recently revealed that the homozygous deletion polymorphism of the angiotensin-converting enzyme gene (ACE DD) is associated with increased risk for essential hypertension in a male-specific manner. However, this association has not been confirmed in races other than whites. METHODS AND RESULTS: Using a large number of Japanese subjects (n=5014) that were randomly selected from the general population (the Suita Study), we examined the association between ACE DD and hypertension. The frequency of DD (17.1%) in hypertensive men was significantly higher (P<0.0015) than that (11.8%) in other mildly hypertensive or normotensive men, and the estimated odds prevalence for hypertension (DD vs II) was 1.75 (95% CI 1.21 to 2.53). In contrast, no significant association was confirmed in women (OR 1.17, 95% CI 0.79 to 1.72). CONCLUSIONS: Despite the lower frequency of the DD genotype in Japanese than in whites, the ACE gene polymorphism was associated with increased risk for hypertension, suggesting that this polymorphism is a mild but certain genetic risk factor for essential hypertension in men.

Human prostacyclin synthase gene and hypertension : the Suita Study.

BACKGROUND: Prostacyclin (prostaglandin I(2)) is a strong vasodilator that inhibits the growth of vascular smooth muscle cells and is also the most potent endogenous inhibitor of platelet aggregation. Therefore, it has been considered to play an important roles in cardiovascular disease. On the basis of the hypothesis that variations of the prostacyclin synthase gene may also play an important role in human cardiovascular disease, we performed a screening for variations in the human prostacyclin synthase gene. METHODS AND RESULTS: We have detected a repeat polymorphism in the promoter region of the human prostacyclin synthase gene. The number of 9-bp (CCGCCAGCC) repeats in the promoter region, which encodes a tandem repeat of Sp1 transcriptional binding sites, varied between 3 and 7 in Japanese subjects. Luciferase reporter analysis indicated that the alleles of 3 and 4 repeats (R3 and R4, respectively) had less promoter activity in cultured human umbilical vein endothelial cells. We then investigated the possible association of this repeat polymorphism with blood pressure in a large population-based sample (the Suita Study), which consisted of 4971 Japanese participants. Multivariate models indicated that participants with the R3R3, R3R4, or R4R4 genotype (SS genotype, n=80) had significantly higher systolic pressure (P=0.0133) and pulse pressure (P=0.0005). The odds ratio of hypertension (140/90 mm Hg) for the SS genotype was 1.942 (95% confidence interval 3.20 to 1.19, P=0.0084). CONCLUSIONS: Repeat polymorphism of the human prostacyclin synthase gene seems to be a risk factor for higher pulse pressure and is consequently a risk factor for systolic hypertension in the Japanese population.

Strong and significant relationships between aggregation of major coronary risk factors and the acceleration of carotid atherosclerosis in the general population of a Japanese city: the Suita Study.

BACKGROUND: Carotid arterial intimal-medial thickness (IMT) measured by high-resolution B-mode ultrasonography has come to be used as a noninvasive surrogate end point to measure progression of atherosclerosis. However, there are no detailed data on the relationship between aggregation of coronary risk factors and carotid atherogenesis. METHODS: Cross-sectional assessment of the relationship between carotid atherosclerosis detected by high-resolution ultrasonography and integration of major coronary risk factors by age and sex. Subjects aged 30 to 86 years were randomly selected from Suita, located in Osaka, the second largest urban area of Japan, including 1896 men and 2102 women. Carotid atherosclerosis was evaluated by using our atherosclerotic indexes of IMT, plaque number, plaque score, and percentage of stenosis of the carotid artery assessed using ultrasonography by sex and age group classified by number of major coronary risk factors (ie, hypertension [diastolic blood pressure > or =90 mm Hg and/or systolic blood pressure > or 140 mm Hg or receiving medication], smoking [current smoker], and hypercholesterolemia [serum total cholesterol level > or =5.68 mmol/L [220 mg/dL] or receiving medication]). RESULTS: The mean carotid atherosclerotic index value, especially the mean IMT value, of the subjects with 1 major coronary risk factor was on average 0.028 mm (3.2%) higher for men and 0.025 mm (2.9%) higher for women than that of the subjects without major coronary risk factors; for subjects with 2 risk factors, 0.054 mm (6.3%) higher for men and 0.053 mm (6.2%) higher for women; and for high-risk subjects with 3 major risk factors, 0.135 mm (15.8%) higher for men and 0.137 mm (15.4%) higher for women. The percentage of the subjects with severe stenosis of at least 50% increased stepwise with increases in the number of coronary risk factors and showed a significant difference (P<.05) between men and women, ie, 2.4% vs 0. 6% (P =.01) among the subjects with no risk factors; 6.7% vs 1.5% (P<.001), subjects with 1 risk factor; 10.7% vs 2.7% (P<.001), subjects with 2 risk factors; and 18.6% vs 5.0% (P =.01), high-risk subjects. CONCLUSIONS: Aggregation of established major coronary risk factors strongly influenced carotid atherogenesis in both sexes. There were significant differences between sexes in the acceleration or progression of carotid atherosclerosis.

Primary amyloidosis with familial vitreous opacities: an unusual case and family.

Peripheral neuropathy was not found even six to ten years after the onset of visual symptoms in a family with primary amyloidosis, except in the propositus at the terminal stage. The propositus had mainly ocular and CNS involvement. An ocular manifestation, the vitreous opacity, was the only involvement in the family members, in spite of the long clinical course. This family may have a different type of familial primary amyloidosis from that previously reported.

Abnormal expression of sphingomyelin acylase in atopic dermatitis: an etiologic factor for ceramide deficiency?

Previously, we demonstrated that there is a marked reduction in the amount of ceramide in the stratum corneum of both lesional and nonlesional forearms in atopic dermatitis (AD), suggesting that an insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry and barrier-disrupted skin. In this study, we investigated, as a possible mechanism involved in the ceramide deficiency, whether sphingomyelin (SM) metabolism is altered in AD as compared to normal controls. In stripped stratum corneum and biopsied whole epidermis of patients with AD, SM hydrolysis as measured at pH 4.7 using [choline-methyl-14C]sphingomyelin as a substrate were markedly increased by 27- and 7-fold, respectively. Radio-thin-layer chromatography of the reaction products revealed that, whereas the SM hydrolysis in age-matched normal controls were associated with sphingomyelinase (SMase) that degrades SM to yield ceramides and phosphorylcholine (PC), most of the SM hydrolysis detected in AD were attributable not to the SMase but to a hitherto undiscovered epidermal enzyme, SM acylase, which releases free fatty acid and sphingosyl-PC (Sph-PC) instead of ceramides. The potential of this acylase-like enzyme to generate Sph-PC through SM hydrolysis was corroborated by thin-layer chromatographic analysis of the reaction products obtained using porcine kidney acylase, followed by high-performance liquid chromatography-mass spectrometry. Furthermore, Sph-PC was also detected by high-performance liquid chromatography-mass spectrometry after incubation of SM with atopic stratum corneum samples. On the other hand, the stratum corneum of patients with contact dermatitis or chronic eczema exhibited neither increased SM hydrolysis nor the generation of Sph-PC upon radio-thin-layer chromatographic analysis. These findings suggest that SM metabolism is altered in AD, resulting in a decrease in levels of ceramides, which could be an etiologic factor in the continuous generation of atopic dry and barrier disrupted skin observed in AD.

Potential of carotid enlargement as a useful indicator affected by high blood pressure in a large general population of a Japanese city: the Suita study.

BACKGROUND AND PURPOSE: Few studies have examined whether there is a relationship between carotid arterial diameter and cardiovascular risk factors in a large general population. The aim of this study was to investigate cross-sectionally whether, in a randomly selected general large population of a Japanese city, there is a relationship between common carotid artery (CCA) diameter and conventional cardiovascular risk factors. METHODS: The subjects of the present study were randomly selected from the residents of the city of Suita, located in the second largest urban area of Japan, and consisted of 2284 men and 2568 women aged 30 to 89 years. The outer and inner CCA diameters and intima-media thickness (IMT) of CCA were detected and measured by a single physician with high-resolution ultrasonography. We assessed cross-sectionally by age/sex group the relationships between IMT or CCA diameters and cardiovascular risk factors, especially blood pressure levels divided into 3 groups: the normal group of subjects had a diastolic blood pressure (DBP) <85 mm Hg and systolic blood pressure (SBP) <130 mm Hg and were not taking antihypertensive medication; the high group of subjects had DBP >/=90 mm Hg and/or SBP >/=140 mm Hg and/or were taking antihypertensive medication; and the moderate group consisted of all other subjects. RESULTS: The outer and inner CCA diameters for the high group were significantly (P:<0.05) enlarged in comparison with those for the moderate and normal groups in all age/sex groups of both sexes after adjustment for body mass index, pack-years of smoking, alcohol consumption, and total serum cholesterol. Multiple regression analysis showed that age, body mass index, SBP, pack-years of smoking, alcohol consumption, and IMT were positively and significantly (P:<0.005) related to both outer and inner CCA diameters in both sexes except for between alcohol consumption and outer CCA diameter in women and showed that only serum total cholesterol level was negatively and significantly (P:<0.01) related to inner CCA diameter in both sexes. CONCLUSIONS: Our present study showed that the outer and inner CCA diameters correlated with conventional cardiovascular risk factors, including high blood pressure and IMT. These findings suggest that the outer and inner CCA diameters may be a useful indicator of carotid atherosclerosis, particularly in relation to high blood pressure.

Low potentiality of angiotensin-converting enzyme gene insertion/deletion polymorphism as a useful predictive marker for carotid atherogenesis in a large general population of a Japanese city: the Suita study.

BACKGROUND AND PURPOSE: Some previous studies, almost all western, have investigated whether there is a relationship between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and carotid atherosclerosis. The results, however, have not been consistently positive. Further, there have been few investigations based on a large, general population. Therefore, the present study aimed to clarify whether ACE gene deletion polymorphism was associated with carotid atherosclerosis in a large Japanese general population with a more homogeneous genetic background than Caucasian populations. METHODS: Subjects aged 30 to 86 years were randomly selected from Suita City, located in Osaka, the second largest urban area of Japan, and included 1894 men and 2137 women. With the aid of high-resolution ultrasonography, carotid atherosclerosis was evaluated using our atherosclerotic indexes of intimal-medial thickness (IMT), plaque number (PN), plaque score (PS), and percentage of stenosis of the carotid artery assessed using high-resolution B-mode ultrasonography. ACE gene I/D polymorphism was detected by polymerase chain reaction. RESULTS: There were no significant differences among the ACE genotypes for age and conventional cardiovascular risk factors, except for systolic blood pressure (SBP) and the percentage of hypertension in men. The values of IMT, PN, and PS as carotid atherosclerotic indexes were not significantly different among genotypes for either sex. After adjusting for age, body mass index, smoking habit, high-density lipoprotein cholesterol, triglycerides, presence of hypertension, presence of diabetes mellitus, and presence of hyperlipidemia, the estimated ORs for the presence of IMT >/=1.10 mm (defined as thickened IMT), according to ACE genotype (DD versus II, DD+ID versus II, and DD versus ID+II), for men were 0.80 (95% CI 0.60 to 1.23), 0.89 (0.62 to 1.29), and 0.89 (0.70 to 1.28), respectively. On the other hand, the ORs for women after the same adjustment were 0.92 (95% CI 0.58 to 1.35), 0.93 (0.59 to 1.45), and 0.91 (0.59 to 1.27), respectively. CONCLUSIONS: Our present data suggest that ACE I/D polymorphism is not potentially a useful predictive marker for carotid atherogenesis when investigated in a large and homogeneous general Japanese population of 4031 subjects, a finding similar to that in a Caucasian population study, the Perth Carotid Ultrasound Disease Assessment Study, an Australian study based on a general population using 1111 subjects.

Effects of angiotensin and atrial natriuretic peptide on the cerebral circulation.

The purpose of the present study was to determine effects of angiotensin (ANG) II on the cerebral circulation. We measured the pial artery pressure (PAP) and CBF in anesthetized rabbits. ANG II (5 micrograms/min) was infused into each carotid artery, and systemic arterial pressure was maintained constant. During infusion of ANG II, there was a significant increase in CBF and fall of PAP, with no change in the large artery resistance (LAR) and a significant decrease in the small vessel resistance (SVR). To investigate whether prostaglandin modulated the ANG II-induced increase in CBF, indomethacin was administered (10 mg/kg i.v.) in another group of animals. Indomethacin itself reduced PAP and increased LAR significantly without changing CBF or SVR. Indomethacin did not attenuate the effects of ANG II on the cerebral circulation. The CMRO2 was assessed during ANG II intracarotid infusion in another group of rabbits. CMRO2 did not change during infusion of ANG II. We also investigated effects of alpha-atrial natriuretic peptide (ANP) on the cerebral circulation. Infusion of ANP (1 microgram/min) decreased LAR by 28% (p less than 0.05) without altering SVR. Administration of ANG II after ANP tended to reduce LAR (p greater than 0.05), with a significant decrease in SVR. The results of the present study suggest that high doses of ANG II can produce cerebral vasodilatation, particularly of small vessels. Blood-borne ANP dilated the large arteries of the cerebral circulation selectively and neither interfered with nor reversed the ANG II-induced increase in CBF.

Schwann cells and regenerated peripheral myelin in multiple sclerosis: an ultrastructural study.

Tissue of a multiple sclerosis plaque in the brachium conjunctivum of the pons known to contain peripheral myelin by light microscopic studies were removed from the paraffin block and processed for electron microscopic studies. The cells related to the peripheral myelin possessed the ultrastructural characteristics of Schwann cells, with basement membranes and associated collagen fibers. No continuity was seen with the peripheral within the central nervous tissues by selective maturation of multipotential primitive reticular cells, a phenomenon consistent with the view that Schwann cells are mesenchymal in character.

Atheromatous embolism in the brain: a clinicopathologic analysis of 15 autopsy cases.

We report 15 autopsy cases with cerebral atheromatous embolism (14 men and one woman, 57 to 76 years of age) and analyze their pathologic features. Cardiovascular surgery or catheterization triggered the atheromatous embolism in the brain in six cases (aortocoronary bypass, two; emergency aortocoronary bypass after percutaneous transluminal coronary angioplasty, one; graft implantation for thoracic aortic aneurysm, two; coronary angiography, one). The events that had triggered embolism were not clear in the remaining nine cases. Pathologic examination of the brains revealed that nine cases had single or multiple cortical hemorrhagic infarcts corresponding to the border zones between two main cerebral arterial territories. Many of the leptomeningeal arteries located in the subarachnoid spaces of cortical sulci and surfaces adjacent to the infarcts were occluded by atheromatous emboli composed mostly of cholesterol crystals. The internal diameters of the occluded arteries ranged from 50 to 300 microns. Arterial territorial infarcts were present in six cases, three of which had thromboemboli containing various amounts of cholesterol crystals occluding the major arteries or their large branches supplying the infarcted areas, which were pale in two cases and hemorrhagic in one. The other three cases had hemorrhagic infarcts in which atheromatous emboli were present only in the small leptomeningeal arteries and were composed mostly of cholesterol crystals. Atheromatous embolism in the brain frequently causes border-zone infarcts by occlusion of the terminal cortical branches, and sometimes causes arterial territorial infarcts if the emboli are associated with fibrin and sufficiently large to occlude the larger arteries.

Interferon-gamma suppresses PDGF production from THP-1 cells and blood monocyte-derived macrophages.

Involvement of the immunological mechanisms in atherogenesis has recently been suggested by immunohistological detection of macrophages and T lymphocytes in atherosclerotic lesions. In the present study, we have investigated the regulatory effect of interferon-gamma (IFN-gamma), a cytokine secreted by activated T cells, on the production and secretion of platelet-derived growth factor (PDGF) from macrophages in culture. The human monocytic leukemia cell line, THP-1, was treated with phorbol 12-myristate 13-acetate (PMA) for 24 h to induce macrophage differentiation and PDGF production, and then various doses of recombinant human IFN-gamma (0-1000 I.U./ml) were added to the culture. After 48 h, the conditioned medium and the cells were harvested and analyzed for PDGF production. PDGF-dependent mitogenic activity in the conditioned medium, estimated by neutralization of mitogenic activity with anti-PDGF antibody, was suppressed by IFN-gamma treatment. Radioimmunoassays for PDGF also revealed a decrease in both PDGF-AA and -BB in the conditioned medium with IFN-gamma treatment, whereas neither total cell DNA as an indication of cell number nor overall protein synthesis based on [3H]leucine incorporation were decreased. Northern analysis of total RNA extracted from the cells demonstrated that IFN-gamma suppressed the level of PDGF mRNA. Analysis of mRNA degradation in the presence of actinomycin D demonstrated that the decrease in PDGF mRNA was not due to enhanced degradation of mRNA. A similar inhibitory effect of IFN-gamma on PDGF mRNA levels was also found in monocyte-derived macrophages cultured in the presence of granulocyte-macrophage colony stimulating factor. These results suggest that IFN-gamma modulates production and secretion of PDGF from macrophages and that the functions of macrophages in atherogenesis may be regulated by the cellular interactions between T cells and macrophages through the action of cytokines such as IFN-gamma.

Differential expression of proteoglycans biglycan and decorin during neointima formation after stent implantation in normal and atherosclerotic rabbit aortas.

Proteoglycans decorin and biglycan, which bind to TGF-beta, are thought to participate in regulation of extracellular matrix accumulation in arterial intimal hyperplasia. To investigate the correlation of these proteoglycans with the cellular localization and phenotypic modulation of smooth muscle cells (SMCs), we analyzed the spatial and chronological distribution of these proteoglycans and two cytokines, TGF-beta and IL-1beta, in the process of neointima formation after stent implantation in the aortas of rabbits fed a high-cholesterol diet (atherosclerotic group) or a regular diet (control group). We implanted metallic stents in the rabbit aortas and harvested the aortas 4-56 days later for immunohistochemical and mRNA in situ hybridization analyses. In the control group, TGF-beta and biglycan expression was in correspondence with the chronology and localization of embryonic SMCs. In the atherosclerotic group, TGF-beta and biglycan expression was sustained throughout the experimental period, which was in accord with the prolonged expression of embryonic SMCs. Decorin, which did not occur in neointima in the control group, appeared in the atherosclerotic aortas in the confined area of vascular SMCs surrounding the macrophages around the stent wire. These results indicate that biglycan and decorin kinetics during neointima formation after arterial injury are distinct, despite their similar construction; biglycan synthesis correlates with embryonic SMCs.

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.

Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: The Suita Study.

OBJECTIVES: Endothelium-derived nitric oxide plays a key role in the regulation of vascular tone. Recently, endothelial nitric oxide synthase (eNOS) gene polymorphisms were reported to be associated with hypertension or coronary spasm. We investigated the association between the eNOS gene polymorphisms and hypertension in a large population-based sample of 4055 Japanese. DESIGN AND METHODS: We investigated two polymorphisms of the eNOS gene, Glu298Asp polymorphism of exon 7 and T(-786)C polymorphism of the promoter region. The genotype distribution in hypertensive subjects was compared to that in the other subjects. The influence of the genotype on blood pressure values was analyzed in the subjects not taking hypertensive medication. The promoter activities of the eNOS gene with the (-786)T or (-786)C allele were measured by a luciferase reporter gene assay. RESULTS: There was significant linkage disequilibrium between the two polymorphisms (P < 0.0001). The genotype distribution of the Glu298Asp or T(-786)C polymorphism did not differ between the hypertensive and the other subjects. No significant differences in the blood pressure of subjects not taking hypertensive medication were observed among the three genotypes of Glu298Asp or T(-786)C polymorphisms. No significant differences in the promoter activity were observed between bovine endothelial cells transfected with the (-786)T and (-786)C alleles. CONCLUSIONS: Our data suggested that these polymorphisms of the eNOS gene are unlikely to be major factors in the susceptibility to hypertension in the Japanese population studied.

Basal forebrain and cerebral cortical muscarinic receptors mediate increase in cortical blood flow provoked by periaqueductal gray matter.

The midbrain periaqueductal gray matter has been identified as a reflex centre located uppermost in the central organization of diverse defensive reactions. We recently found that when activated, the caudal third of the lateral periaqueductal gray was also capable of provoking a marked increase in cortical blood flow. The response may be the combined outcome of a flow increase of nitrergic origin and that coupled to a possible concomitant cortical activation. In the present study, we attempted to clarify the neural substrates for mediation of the increase in flow (observed by laser-Doppler flowmetry), in 49 anaesthetized, artificially ventilated, and cervically cordotomized rats. The flow increase provoked by stimulation of the particular subdivision of the periaqueductal gray with N-methyl-D-aspartate (1 mM, 100 nl) was unaffected by i.v. pentolinium tartrate (10 mg/kg), suggesting little contribution by the cerebrovasodilator parasympathetic nervous system to the response. The response was abolished by i.v. or topical cortical administration of scopolamine hydrobromide (3.16 mg/kg or 1.0 mM, respectively). Placement of bilateral lesions in the basal forebrain with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (15 mM) impaired the cortical choline acetyltransferase activity and attenuated the flow response. Overall, we suggest that the cholinergic corticopetal neurons of the nucleus basalis of Meynert and cortical muscarinic receptors may form a principal efferent arm of a central circuitry emanating from the subdivision of the periaqueductal gray, in the mediation of the increase in cortical blood flow and possible cortical activation.

Monocyte-derived macrophages prime peripheral T cells to undergo apoptosis by cell-cell contact via ICAM-1/LFA-1-dependent mechanism.

We designed the present study to clarify the mechanism of superantigen-induced apoptosis of human mature T cells and to elucidate the pivotal roles of monocyte-derived macrophages in induction of T cell apoptosis. Exposure of unfractionated human peripheral blood mononuclear cells to SEA, SEB or PHA elicited apoptosis in T cells after 5-day culture. In purified T cell preparations, SEB was unable to induce apoptosis, but was inductive when the purified T cells were cocultured with monocyte-derived macrophages adhering to plastic culture dishes. Placing the T cells in the insert wells which physically separated them from the adhering macrophages resulted in a complete loss of SEB-induced apoptosis. The addition of blocking antibodies against LFA-1, ICAM-1 and CD2 to the cocultures significantly inhibited the SEB-induced T cell apoptosis. We concluded therefore that direct contact of macrophages with T cells is critical in SEB-induced T cell apoptosis, and that adhesion molecules such as LFA-1/ICAM-1 and CD2 may be involved in the mechanism of this effect.