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The diversity of placental structures in Eutherian mammals is such that drawing generalizations from the definitive forms is problematic. There are always areas of reduced interhaemal distance whether the placenta is epitheliochorial, synepitheliochorial, endotheliochorial or haemochorial. However, the thinning may be achieved by different means. The presence of a haemophagous area as an iron transport facilitator is generally associated with endotheliochorial placentae but is also found in sheep and goats (synepitheliochorial) and in tenrecs and hyaenas (haemochorial). Although similar chorioallantoic placentae are found within families, structure begins to diverge at the ordinal level and there is little correlation at the supraordinal level of phylogeny. Differences in formation and function of the yolk sac provide additional variation. There would appear to be considerable adaptive pressure for development or retention of the haemochorial type of chorioallantoic placenta. This type of placenta has several possible drawbacks including more ready passage of fetal cells to the maternal organism and, should the haemochorial condition be achieved early, oxidative stress. At any rate no animal larger than the human and gorilla has this type of placenta. The endotheliochorial condition is found in animals as large as the bears, manatee and elephants. In addition to the ungulates, the epitheliochorial condition is present in the largest animals with the longest gestation periods, the whales. Considering the length of time since the early stages of mammalian evolution, it is probable that few unmodified structural features are present in any currently surviving mammal. Nevertheless, more complete studies of divergent types of mammalian placenta should help our understanding of mammalian interrelationships as well as placental function.

Until recently, tenrecs were classified with insectivores in the order Lipotyphla, but nucleotide sequence data suggest they have closer affinities with a group of African mammals called Afrotheria. The placenta of Echinops has not been described and no studies involving electron microscopy of the placenta of any species of tenrec have been published. We used light and transmission electron microscopy to examine fixed placentae of embryos ranging from 25-66 mm in length. The placental disk is situated in the antimesometrial portion of the bicornuate uterus. The greater part of the disk consists of a labyrinth underlain by a spongy zone. The interhaemal barrier is unusual in that the trophoblastic component is a single layer of cytotrophoblast. These trophoblast cells have thick areas especially near the nuclei and extensive thin flanges but only occasionally have membrane-closed pore regions. The luminal surface has isolated patches of microvilli, and pinocytotic vesicles are numerous both apically and basally. In the centre of the placental disk is an elaborately folded haemophagous region. The primary folds have allantoic endoderm at one surface and columnar cytotrophoblast at the other. These trophoblast cells have numerous lipid droplets and vesicles, and often contain large yellow pigment crystalloids. The labyrinthine zone ends abruptly at the margins of the placental disk. However, the endoderm and connective tissue of the allantois and a layer of cytotrophoblast extend beyond the placental disk as a paraplacental region. Some of these distinctive features of Echinops placenta are shared with individual afrotherians, but no significant characteristic of definitive placentation is shared by all the Afrotheria.

P-selectin is a member of the selectin family of cell adhesion molecules which are important in the transient attachment of leukocytes to endothelial cells and platelets. A number of polymorphisms in the gene encoding P-selectin have been identified. Objectives were to investigate the relationship of soluble P (sP)-selectin with P-selectin gene polymorphisms and coronary artery disease (CAD). Two hundred and forty-nine patients, with extent of CAD characterized by >or=50% stenosis in one or more coronary arteries, and 252 healthy controls were studied. Soluble P-selectin was significantly higher in the patients than controls after adjustment for age, sex and smoking [patients 49.8 (47.5-52.1) ng mL-1; controls 46.7 (44.5-49.1) ng mL-1, P = 0.03). There was no association of sP-selectin with myocardial infarction (MI) or presence of >or=50% stenosis. The -1817 T/C, -1969 G/A and -2123 C/G (but not the Thr715Pro) polymorphisms were in strong linkage disequilibrium. The Thr715Pro polymorphism was significantly associated with sP-selectin even after adjustment for covariates [TT 48.9 (46.9-50.0) ng mL-1; TP + PP 40.7 (38.1-43.6) ng mL-1, P < 0.0001]. A significant interaction of Thr715Pro and smoking status was identified in the determination of sP-selectin levels. There was no significant association of genotype at any of the polymorphism in relation to MI or stenosis. The Thr715Pro polymorphisms is associated with plasma sP-selectin. This association is modulated by smoking, although the underlying mechanism remains unclear.

The functional correlates of structural remodelling of the preplacental arteries are not well known. We examined the responses of these vessels to vasoactive agents in guinea pigs at mid and late gestation, and attempted to relate them to changes in vessel structure. Segments were taken from the arcade artery, a mesometrial artery near its origin, and an artery near the placenta. They were mounted as rings in a myograph and concentration-response curves were obtained for U46619, endothelin-1 and arginine vasopressin. The vessel segments were then examined by histology and immunohistochemistry. Trophoblast was identified as immunopositive for cytokeratin, circular muscle stained positive for muscle actin and smooth muscle actin, and presumed myofibroblasts in the adventitial layer stained positive only for smooth muscle actin. At both gestational ages, arcade and mesometrial arteries had intact vessel walls. Midgestation placental arteries were characterized by partial or complete disruption of the internal elastic lamina and the presence of a large number of myofibroblasts and of periarterial trophoblast. In late pregnancy, the changes were more extensive, with almost complete dedifferentiation of the smooth muscle cells and trophoblast invasion of the adventitial layer. From midgestation to late gestation, the responses of placental arteries to U46619, endothelin-1 and arginine vasopressin, normalized to the response to K(+)depolarization, were significantly reduced. This suggests that the extensive changes in wall structure in late gestation, which accompany trophoblast invasion, modulate the responses of these vessels to vasoconstrictors. However, mesometrial arteries also demonstrated reduced responsiveness to U46619, suggesting the influence of factors other than trophoblast.

Background: The fibrinogen Aalpha Thr312Ala polymorphism occurs within the alphaC domain of fibrinogen, which is important for lateral aggregation and factor XIII-induced cross-linking of fibrin fibers. We have previously shown an association of Ala312 fibrinogen with poststroke mortality in subjects with atrial fibrillation and with pulmonary embolism in subjects with venous thrombosis., Methods and Results: We studied the properties of clots formed from purified Ala312 and Thr312 fibrinogen and found that Ala312 fibrinogen produces stiffer clots, associated with increased alpha chain cross-linking, as demonstrated by SDS-Page. On electron microscopy analysis, we found larger fiber diameters in the Ala312 clots and observed a lower number of fibers per square micrometer. The number of branch points per square micrometer was similar between genotypes., Conclusions: Our study shows that Ala312 influences clot structure and properties by increased factor XIII cross-linking and formation of thicker fibrin fibers. These findings may provide a mechanism by which Ala312 fibrinogen could predispose to clot embolization.

Background: Polymorphisms in the fibrinogen and factor XIII genes are associated with atherothrombotic risk, but clinical studies have produced inconsistent results and laboratory studies have not explained these findings. We aimed to investigate interactions between polymorphisms in the factor XIII and fibrinogen genes, fibrinogen concentrations, and other cardiovascular risk factors in relation to fibrin structure and function., Methods: We used permeation analysis and electron microscopy to investigate interactions between fibrin structure, factor XIII Val34Leu, fibrinogen Aalpha Thr312Ala, fibrinogen Bbeta Arg448Lys, and fibrinogen concentrations in plasma and purified systems., Findings: Increased fibrinogen concentrations were associated with decreases in permeability, with tighter clot structures in the presence of factor XIII 34Val alleles compared with those in the presence of 34Leu alleles. Findings were confirmed by scanning electron microscopy of fibrin. Similar changes in permeability were noted for Aalpha fibrinogen 312Ala compared with that for 312Thr., Interpretation: Our results show interactions between coding polymorphisms in fibrinogen and factor XIII and fibrinogen concentrations that modify fibrin and explain the apparent paradox between epidemiological studies of factor XIII 34Leu and reported in-vitro effects on fibrin structure and function. We suggest a potential complexity of gene-gene and gene-environment interactions in determining cardiovascular risk.

Aims: To determine whether infection with Helicobacter pylori is a significant risk factor for stroke., Subjects: A total 467 in-patients with clinical evidence of acute ischaemic stroke and 388 healthy controls with no evidence of cerebrovascular disease., Methods: This was a case control study. The prevalence of Helicobacter pylori was measured by enzyme-linked immunosorbent assay in stroke patients and controls. A positive titre was defined as >15 U/ml and relationship with circulating plasma fibrinogen and social depravation was expressed using the Townsend Index., Results: There were significantly more Helicobacter pylori positive individuals (274/398 (69%)) in the cases compared to the controls (206/352 (58.5%)). Fibrinogen levels were also significantly higher in Helicobacter pylori positive (mean 4.14, standard deviation 1.33) than negative individuals (mean 3.78, standard deviation 1.28). The association between Helicobacter pylori and stroke was lost in a logistic model controlling for socio-economic status. Furthermore, fibrinogen levels were not associated with Helicobacter pylori status in a linear regression model controlling for socio-economic status., Conclusions: Infection with Helicobacter pylori is associated with an increased risk of stroke and increased fibrinogen levels but these findings can be attributed to a confounding effect of socio-economic status.

There is growing evidence for a role of factor XIII (FXIII) in vascular disease. FXIII measures were determined in (i) a nested case-control study from the Second Northwick Park Heart Study of 63 men with myocardial infarction (MI) and 124 age-matched controls and (ii) in a case-control study of 475 subjects with acute stroke and 461 controls followed up for 54 months for mortality. In both studies, measures of FXIII A- and B-subunit antigen, FXIII activity and prothrombin fragments (F1 + 2) were made. An in vitro model was used to investigate the effects of thrombin activity on FXIII A- and B-subunit antigen levels. In study 1, patients clinically free of coronary artery disease who later developed MI had lower adjusted FXIII A-subunit levels at recruitment (129.2%vs 113.3%, P = 0.007). In study 2, stroke patients with large vessel disease had lower A-subunit antigen levels (102.1%vs 127.2%, P < 0.001), but higher F1 + 2 levels (0.941%vs 0.753%, P < 0.05), than subjects with small vessel disease. Levels of FXIII A-subunit (100%vs 117%, P < 0.0001) were lower and F1 + 2 higher (1.020%vs 0.702%, P < 0.0001) in stroke patients who had died compared with those still alive at the end of the follow-up period. Low concentrations of FXIII A-subunit antigen predicted vascular outcome in otherwise healthy subjects and relate to both size of infarct and poor post-stroke survival in patients with acute ischaemic stroke. Low in vitro concentrations of FXIII A-subunit antigen wererelated to increased thrombin generation and, thus, increased risk of thrombotic events.

Determinants of fibrinogen level among South Asians are not established. In 1997-1999, plasma fibrinogen levels and prevalences of the fibrinogen polymorphisms A alpha Thr312Ala, beta-445G/A, and B beta Arg448Lys and correlates were compared among 100 apparently healthy United Kingdom South Asians and 100 age- and sex-matched Whites. Mean fibrinogen levels were higher in South Asians (3.33 g/liter, 95% confidence interval (CI): 3.16, 3.51) than in Whites (2.84 g/liter, 95% CI: 2.72, 2.96) (p < 0.0001), but genotype distributions were similar. B beta Arg448Lys was related to fibrinogen in South Asians (RR (n = 67): 3.22 g/liter, 95% CI: 3.03, 3.43; RK (n = 26): 3.72 g/liter, 95% CI: 3.65, 4.11; KK (n = 7): 3.07 g/liter, 95% CI: 2.53, 3.72) (p = 0.04) and Whites (p = 0.06). beta-455G/A was related to fibrinogen in Whites (GG (n = 56): 2.68 g/liter, 95% CI: 2.56, 2.86; GA (n = 37): 2.97 g/liter, 95% CI: 2.79, 3.17; AA (n = 5): 3.22 g/liter, 95% CI: 2.85, 3.65) (p = 0.02) and South Asians (p = 0.07). After adjustment for age, gender, body mass index, hypertension, cholesterol, triglycerides, smoking, A alpha Thr312Ala, and beta-455G/A, fibrinogen levels remained significantly higher in South Asians (3.56 g/liter, 95% CI: 3.35, 3.77) than in Whites (3.03 g/liter, 95% CI: 2.85, 3.22) (p < 0.0001). These findings suggest that increased fibrinogen levels among South Asians versus Whites are not due to differences in the prevalence of genetic polymorphisms that encode for fibrinogen.

Placentae of three hystricimorph rodents--capybara, agouti and paca--were examined by conventional histology, immunohistochemistry for cytokeratin and vimentin, and TUNEL staining. The placentae were divided into lobules of labyrinthine syncytium separated by interlobular and marginal trophoblast. The subplacenta comprised cytotrophoblasts, supported on lamellae of allantoic mesoderm, and syncytiotrophoblast. The central excavation was still apparent in the definitive placenta of capybara. In agouti and paca, the decidua of the junctional zone formed a mesoplacenta comprising a capsule and a pedicle. Towards term the pedicle formed a tenuous attachment between placenta and uterine wall comprising a few maternal vessels surrounded by degraded tissue. In paca placenta, it was shown by TUNEL staining that breakdown of this tissue occurred by apoptosis. The visceral yolk sac was highly villous and, in agouti, the yolk sac villi were extremely long. Lateral to its attachment to the placenta, the fetal surface was covered with non-vascular yolk sac endoderm. A layer of spongiotrophoblast cells was interposed between the endoderm and the marginal trophoblast., (Copyright 2002 Elsevier Science Ltd. All rights reserved.)

The G20210A polymorphism has been shown to alter the efficiency of prothrombin mRNA processing. Here we show that the G20210A mutation also alters prothrombin mRNA stability. Three-fold more prothrombin protein and mRNA were produced in NIH-3T3 cells transfected with the prothrombin cDNAs containing the 20210A variant compared to cells expressing the 20210G variant. mRNA stability assays using chimeric globin transcripts harboring the G or A variant of the 97 nt prothrombin 3'-UTR indicated that the 20210G variant conferred greater instability to the globin reporter transcript than the A variant in transfected HepG2 cells. Both variants of the prothrombin 3'-UTR were shown to provide binding sites for a number of cellular proteins including HuR, an RNA binding protein associated with mRNA stability. Our results indicate that the G20210A is a bifunctional polymorphism, as it not only alters the efficiency of mRNA processing, but also the decay rate of prothrombin mRNA.

In the present study, it was hypothesized that the adrenocorticotrophin hormone receptor (ACTH-R) would be up-regulated in the adrenal gland of the sheep fetus following infusion of physiological amounts of ACTH, as shown for adrenal cortical cells in culture. In chronically catheterized sheep, an intravenous infusion of ACTH(1-24) was given to 6 fetuses for 24 h at a rate of 0.5 microg h(-1), starting on Day 126 or 127 of gestation (term approximately 147 days). Four control fetuses received an infusion of vehicle (saline). Total RNA was extracted from the fetal adrenal glands by the guanidinium thiocyanate method. Expression of specific mRNAs was determined by ribonuclease protection assay using cRNA probes directed against: ACTH-R; the steroid enzymes side-chain cleavage (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17apha-hydroxylase (P450c17) and 21beta-hydroxylase (P450c21); and beta-actin. Ratios of mRNA expression to beta-actin mRNA expression (arbitrary units) were calculated to correct for differences in RNA quality between samples. The concentration (mean +/- SEM) of immunoreactive cortisol in fetal plasma was greater after ACTH infusion than after vehicle infusion (47 +/- 3 v. 13 +/- 2 ng mL(-1) respectively; P<0.001). Adrenal expression of P450scc and P450c21 mRNA increased after ACTH infusion (P<0.05), whereas expression of P450c17 and 3beta-HSD mRNA was unchanged. There was no difference in ACTH-R mRNA expression between ACTH- and vehicle-infused fetuses (254 +/- 48 v. 305 +/- 76 arbitrary units respectively). It was concluded that ACTH is able to increase plasma cortisol concentrations in the sheep fetus by up-regulating cortisol synthesis in the adrenal gland, but that in vivo this does not require up-regulation of ACTH-R mRNA.

Classical gene targeting has identified many genes important for fetal and placental development. Null mutation of these genes may lead to fetal growth restriction, malformation or embryonic death. Growth restriction of epigenetic basis can predispose to adult-onset diseases. The mechanisms underlying this process, termed 'fetal programming', are beginning to be understood.

Recent analyses of nucleotide sequence data suggest that living placental mammals belong to one of four superorders. The early divergence of these groups was followed by long periods of geographical isolation, due to the break up of continental land masses, allowing for convergent evolution of similar traits in different superorders. As an example, the transition from epitheliochorial to haemochorial placentation occurred independently in bats, rodents, anthropoid primates, armadillos and others. A group of ancient African mammals is suggested by the molecular data, but is not fully supported by morphological evidence. The hypothesis is, however, consistent with some of the data on fetal membranes, suggesting that it would be worthwhile to study the early development of tenrecs, golden moles and elephant shrews. Analyses of fetal membrane traits that group the tarsiers with anthropoid primates, and separate them from the lemurs, are challenged by the molecular data. Other relatives of the primates seem to include tree shrews and flying lemurs, and little is known about the fetal membranes of the latter group. Comparative studies of placental function normally are confined to primates, rodents, lagomorphs and domestic animals: the biological diversity represented by mammals that evolved in ancient Africa and South America is not represented. Therefore, future comparative studies should strive to include species such as the rock hyrax and the armadillo., (Copyright 2001 Harcourt Publishers Ltd.)

The development of cardiovascular disease is influenced by complex interactions between environmental and genetic factors. Despite a flurry of activity in the past decade to identify common genetic variants that predispose to cardiovascular disease the results have, on the whole, been inconclusive. In the present review we summarise the available information regarding genetic variants of fibrinolytic factors and discuss the issues pertinent to understanding the inconsistencies in their reported relationship to cardiovascular disease. Finally, we suggest that work in this area should continue, but with the emphasis firmly directed towards the use of genetic markers as tools for investigating and understanding the complexities of cardiovascular disease.

To investigate gender differences in conventional, coagulation and fibrinolytic factors in South Asian ischaemic stroke patients, we compared these variables in 50 South Asian females (SAFP) with 90 South Asian males (SAMP) with ischaemic stroke and in 52 females (SAFC) and 38 males (SAMC) without stroke. Plasminogen activator inhibitor-1 (PAI-1) antigen levels were significantly higher in SAFP compared with SAMP (18.2 vs. 13.3 U/ml, P = 0.04) even after adjustment for known covariates, but there was no difference in PAI-1 antigen levels between males and females in the control group. South Asian females exhibited higher levels of factor VII antigen and FVII:C activity in both stroke patients (114 vs. 99% in males, P = 0.01; 116 versus 104% in males, P = 0.04) and controls (116 vs. 97% in males, P = 0.004; 115 vs. 93% in males, P = 0.01). There were no significant differences in the levels of fibrinogen (3.8 vs. 3.7 g/l), FXIIa (2.2 vs. 2.4 ng/ml), von Willebrand factor (1.8 vs. 1.9 IU/ml) and tissue plasminogen activator (11.4 vs. 12.0 ng/ml) in SAMP and SAFP respectively. These results suggest that South Asian females have increased FVII levels and that females with a history of ischaemic stroke have a decreased fibrinolytic potential in comparison with males.

The Aalpha-fibrinogen Thr312Ala polymorphism, which occurs in a region involved in factor XIII (FXIII)-dependent cross-linking processes, is associated with poststroke mortality in subjects with atrial fibrillation, suggesting an influence either on intraatrial clot formation or embolization. We have determined the association of Thr312Ala with deep vein thrombosis (DVT) and pulmonary embolism (PE) and have assessed the interaction of Thr312Ala with the FXIII Val34Leu polymorphism in 122 patients with DVT, 99 patients with PE, and 254 healthy control subjects. The genotype distribution of patients with PE (TT = 49%, TA = 36%, AA = 15%), but not DVT (TT = 50%, TA = 42%, AA = 8%), differed significantly from healthy control subjects (TT = 60%, TA = 34%, AA = 6%, P =.02). A significant interaction of Thr312Ala and Val34Leu was also identified (P =.01), indicating an inverse association between Leu34 and Ala312. These results support the hypothesis that Thr312Ala alters FXIII-dependent cross-linking, making formed fibrin clot more susceptible to embolization.

Objectives: The aim of this study was to investigate the relationship between the apo E genotype with acute cerebral infarction and primary intracerebral haemorrhage and to examine the relationship of the apo E genotype with mortality following acute stroke., Materials and Methods: We studied 592 cases of acute stroke and 289 healthy control subjects clinically free of cerebrovascular disease. Pathological type of stroke was determined by cranial computed tomography and the subtype of cerebral infarction classified according to the Oxfordshire Community Stroke Project Classification (OCSP). Apo E genotype was determined using polymerase chain reaction., Results: There was no difference in apo E genotype frequency between cases and controls (chi2 = 3.58, 5 d.f., P = 0.60). Apo E genotypes were not related to the pathological type of stroke (cerebral infarction, CI, n = 532 and primary intracranial haemorrhage, PICH, n = 60, (chi2 =3.738, 4 d.f., P=0.44) nor with the Oxfordshire Community Stroke Project Classification subtypes of cerebral infarction, lacunar infarction, LACI (n = 169), total anterior circulation infarction, TACI (n = 117), partial anterior circulation infarction, PACI (n = 173), posterior circulation infarction, POCS (n = 54) and including those cerebral infarcts which could not be classified (n= 19), chi2 =31.1, 20 d.f., P=0.153). At the time of the analysis, 243 cases (41.0%) had died. The median follow-up (including death) was 851 days. There was no relationship between time to death and apo E genotype in cases of either CI or PICH., Conclusion: In this population, there was no relationship between the apolipoprotein E polymorphism and the pathogenesis of cerebral infarction or primary intracerebral haemorrhage. Apo E genotype was not related to all-cause mortality following stroke.

To better understand the role of the insulin-like growth factors (IGF-I and -II) and their binding proteins (IGFBPs 1-6) in placental development and function, it is important to review similarities and differences between species in expression of the respective mRNAs. In human placenta, IGF-II mRNA is expressed in chorionic mesoderm and first trimester villous cytotrophoblast, but not in syncytiotrophoblast. In contrast, in rhesus monkey placenta, IGF-II mRNA is expressed in syncytiotrophoblast but not in chorionic mesoderm. IGFBP-3 mRNA is present in the chorionic mesoderm of placental villi from both these species and may modulate IGF-II action through a paracrine mechanism. In rodent placentae, IGF-II mRNA is expressed both in fetal mesoderm and in the trophoblast of the placental labyrinth. In guinea pig, where IGFBP-5 mRNA is expressed in the marginal and interlobular syncytium and IGF-II mRNA in the labyrinth, interaction between IGF-II and IGFBP-5 mRNA may be involved in vascularization of the placenta by fetal vessels. In sheep placenta, IGF-II mRNA is expressed, not in the trophoblast layer, but in the fetal mesoderm immediately adjacent to it. In the basal plate of human, rhesus monkey and baboon placentae, extravillous trophoblasts express IGF-II mRNA and uterine decidual cells IGFBP 1-6 mRNAs. The inference is that there is interaction between IGF-II and IGFBPs at the maternal-fetal interface of the primate placenta during trophoblast invasion and decidualization. IGFBP-1 expressed by the decidua may also interact with alpha(5)beta(1)integrin expressed by the extravillous trophoblast. The placentae of rodents are also of the invasive type. Glycogen cells of the mouse placenta are analogous with human extravillous trophoblast and express IGF-II mRNA. However, expression of IGFBP mRNAs in the mouse, as in the guinea pig, is confined to non-decidualized endometrium and myometrium. IGF-II mRNA is strongly expressed by trophoblasts invading uterine vessels in human and guinea pig placentae. Interactions probably occur between IGF-II expressed by these trophoblasts and IGFBPs expressed in the vessel walls. However, it is possible that IGFBPs expressed by maternal vessels are associated with processes that are independent of trophoblast invasion. Thus, IGFBP-3 mRNA is highly expressed in the maternal blood vessels of the non-deciduate sheep placenta. Findings to date highlight the diversity in the expression of the IGF system among placentae of man and different laboratory animals, and even between closely related species. Comparative studies will continue to be required to understand the functional role of IGFs and IGFBPs in each species.

At term of pregnancy, oxygen consumption by the human or ovine placenta accounts for 40 per cent of total oxygen uptake by the gravid uterus. In the sheep, most oxygen is used for oxidative phosphorylation of glucose; the remainder is probably utilized for non-mitochondrial processes. The ATP yield is expended mainly in protein synthesis and cation transport. The fractional protein synthesis rate of ovine placenta is 60 per cent per day. Applying these data to man, protein synthesis is estimated to account for about 30 per cent of placental oxygen uptake. Probably this reflects the high rates of synthesis of peptide and steroid hormones. The Na+ gradient is the basis for secondary active transport of amino acids and other substances, and the Na(+)-K(+)-pump probably accounts for 20-30 per cent of oxygen uptake, with a smaller contribution from Ca(2+)-ATPase. Placental oxygen uptake remains constant during acute reductions in uterine oxygen supply and is maintained at the expense of the fetus. In the longer term, in experimental models of fetal growth restriction, placental oxygen consumption is reduced to a greater extent than fetal oxygen consumption. Placental oxygen consumption is greatly reduced under in vitro experimental conditions, due largely to an inadequate oxygen supply. This results in reduced protein synthesis and possibly inhibition of Na(+)-K(+)-ATPase. However, if the placenta is subjected to hyperoxia, by raising the PO2 of the medium, there is an increase in anaerobic glycolysis and structural damage may ensue. Premature exposure of trophoblast to high oxygen tensions in vivo may result in reduced villous branching, but this is likely to be a cause, rather than a consequence, of reduced fetal growth and oxygen consumption.

Background and Purpose: The role of polymorphisms of the platelet glycoprotein (GP) IIb/IIIa receptor in the development of cardiovascular disease has been the subject of intensive research. The aim of this study was to determine the association of the HPA-3 polymorphism of platelet GPIIb with ischemic stroke and subsequent survival and to identify possible interactions of HPA-3 with classic risk factors., Methods: HPA-3 genotype was determined by restriction fragment length polymorphism in 515 patients with ischemic stroke and 423 healthy, age-matched control subjects., Results: There was no significant difference in the genotype distribution of patients and controls, nor was there any difference when patients were subclassified into small- and large-vessel disease. The genotype distribution of the 231 patients subsequently dying during 2.8 years of follow-up (aa=45.0%, ab=46.8%, bb=8.2%) was significantly different from that of those still alive (aa=37.0%, ab=48.2%, bb=14. 8%) (P=0.03). In a Cox regression model, the relative risks for poststroke mortality in patients of aa and ab genotype compared with those of bb genotype were 2.42 (95% CI, 1.24 to 4.71) and 2.13 (95% CI, 1.09 to 4.17), respectively, after we accounted for confounding factors. In addition, significant interactions of HPA-3 with the Pl(A) polymorphism of GPIIIa (P=0.002) and with fibrinogen (P=0.01) were identified in relation to mortality., Conclusions: HPA-3 is related to poststroke mortality, and the significant interaction of HPA-3 with Pl(A) and fibrinogen suggests that it may in some way influence the interaction of GPIIb/IIIa with fibrinogen, particularly in the presence of high fibrinogen.

Background: The alpha-fibrinogen Thr312Ala polymorphism occurs in close proximity to several sites important for factor XIIIa-dependent cross-linking, which raises the possibility that it affects fibrin clot stability., Methods and Results: We determined the association of this polymorphism with ischemic stroke, stroke subtype, and poststroke mortality. There was no significant difference in the genotype distributions of patients with acute ischemic stroke (n=519) and healthy control subjects (n=423), nor was there any association of this polymorphism with stroke subtype. In a Cox regression model, a significant interaction between Thr312Ala and atrial fibrillation was identified in relation to poststroke mortality (P=0.002). In subjects in sinus rhythm (n=418), there was no difference according to genotype in the proportion of subjects who survived (approximately 60% in each group), whereas in subjects with atrial fibrillation (n=101), there was decreased survival in those possessing the A allele (TT=42.1%, TA=18%, AA=0%)., Conclusions: The Thr312Ala polymorphism may give rise to an increased susceptibility for embolization of intra-atrial clot, and these findings could have important implications for identifying subjects most at risk of developing thromboembolic complications.

To determine the temporal and spatial distribution of insulin-like growth factor (IGF) and its family of binding proteins (IGFBPs), guinea-pig yolk sac and chorioallantoic placentae were collected at 15, 20, 25, 29, 44-45, 55 and 65-66 days of gestation. Messenger RNAs for IGF I, IGF II and IGFBP 1-6 were identified in tissue sections by in situ hybridization, using 35S-cRNA probes. Epithelial and mesenchymal cell types were identified by immunohistochemistry for cytokeratin and vimentin, respectively. At 15 days of gestation, IGF-II mRNA was expressed in ectoplacental mesoderm, cytotrophoblasts and syncytiotrophoblast, and IGFBP-5 mRNA was detected in the syncytiotrophoblast. In the mid-gestation placenta, IGFBP-5 mRNA was expressed in the marginal and interlobular syncytium and IGF-II mRNA in the labyrinth. Near term, when expansion of the labyrinth was complete, IGFBP-5 mRNA was coexpressed with IGF-II mRNA in the marginal and interlobular syncytium. These observations suggest that interaction between IGF-II and IGFBP-5 plays a role in the vascularization of the placenta by fetal vessels. IGF-II mRNA was not expressed in the maternal tissues at any gestational age. IGFBP-2, -3 and -5 mRNAs were expressed in the endometrial stroma at 7-12 days of gestation but, following establishment of the placenta, IGFBP mRNAs were more abundant in the myometrium than in the decidua. IGF-II mRNA was detected in trophoblasts invading the walls of maternal vessels, and the endothelium of the preplacental vessels expressed IGFBP-4 mRNA, while IGFBP-2 and IGFBP-5 mRNAs were present in the tunica media of mesometrial arteries that had not been invaded by trophoblast. These findings suggest that IGF-II produced by the trophoblast acts in an autocrine and/or paracrine fashion to promote trophoblast invasion and that this process is modulated by interaction with IGFBPs present in maternal tissues.

The aim of this study was to investigate disturbances in fibrinolytic components in Type 2 diabetes patients with acute ischaemic stroke. Levels of plasminogen activator inhibitor-1 (PAI-1) activity and tissue PA (t-PA) antigen were measured in Type 2 diabetes subjects with (n=40) and without (r=80) acute stroke compared to non-diabetic subjects with (n=80) and without (n=80) acute ischaemic stroke. Diabetes was defined by WHO criteria and absence of diabetes by blood glucose <7.8 mmol(-1) and HbA(IC) <6% (reference range for assay 4.5-6.5%). Levels of t-PA antigen were lower in healthy controls (9.2 ng ml(-1) than in either stroke group (non-diabetic stroke patient: 12.6 ng ml(-1); diabetic patient with stroke: 13.5 ng ml(-1)(each at p<0.05)) and intermediate in diabetic patients without stroke (11.1 ng ml(-1), ns). In a regression model levels of t-PA were related to stroke, BMI and age but not to diabetes or sex. Diabetic subjects without stroke had higher PAI-1 activity levels than either non-diabetic group (17.7 U ml(-1) vs 12.1 U ml(-1) and 9.2 U ml(-1) (each at p<0.05)). Levels were intermediate in diabetic subjects with stroke (12.8 U ml(-1), ns). In a regression model levels of PAI-1 were related to Type 2 diabetes, female sex, and body mass index but not stroke or age. These data suggest that further suppression of fibrinolysis does not occur with ischaemic stroke in Type 2 diabetes. The findings contrast with the importance of impaired fibrinolysis in coronary artery disease previously reported in both Type 2 diabetic patients and non-diabetic subjects.

Objective: To examine whether the increase in adrenal cortical blood flow induced by adrenocorticotropic hormone (ACTH) is linked to steroidogenesis, or if these effects can be separated., Study Design: Adrenal cortical responses to ACTH were measured in ovine fetuses at 105-112 days gestation, when the adrenal is hyporesponsive. Fetuses were given an intravenous infusion of ACTH(1-24) or of vehicle. We measured regional adrenal blood flows by the microsphere technique and plasma ACTH and cortisol levels by radioimmunoassay., Results: After 3 and 24 h of ACTH infusion, plasma cortisol concentrations had risen from 2.8+/-0.8 ng/ml to 8.4+/-0.3 and 78.0+/-15.8 ng/ml (means+/-S.E.M.). Adrenal cortical blood flow increased from 108+/-25 ml/min/100 g to 319+/-33 and 518+/-51 ml/min/100 g. Plasma cortisol levels and adrenal blood flow did not change in control fetuses., Conclusion: Since there was a rapid blood flow response to ACTH, despite the expected delay in the rise of plasma cortisol, we suggest that vascular responses to ACTH are not tightly linked to adrenal metabolic activity in the ovine fetus at 0.7 gestation.

The aim of this study was to determine the association of tPA antigen levels with CAD and ischaemic stroke and whether associations are independent of levels of PAI-1 antigen. In subjects with CAD (n = 247) tPA was associated with the number of coronary arteries with > or = 50% stenosis, but this association was lost after adjustment for PAI-1, which was found to be the largest determinant of tPA levels in linear regression models and accounted for as much as 38% of the variation in levels. Levels of tPA were significantly higher in patients with a history of MI compared with those without, even after adjustment for covariates and PAI-1 (MI: 10.0 [9.4-10.6] ng/ml; no MI: 8.9 [8.5-9.4] ng/ml, p = 0.004). In a logistic regression model comparing patients with MI to patients without MI, the odds ratio for tPA levels in the upper quartile compared with the lowest quartile was 2.03 (1.33-3.10). Levels of tPA in subjects with ischaemic stroke (n = 338) were significantly higher than age matched healthy control subjects (n = 366) and again this difference remained after adjustment (patients: 10.4 [9.9-10.9] ng/ml; controls: 9.0 [8.7-9.3] ng/ml, p <0.0001). In a logistic regression model comparing patients with ischaemic stroke to healthy control subjects the odds ratio for tPA in the upper quartile compared with the lowest quartile was 4.23 (3.02-5.92). These data suggest that the associations of tPA with acute thrombosis are independent of levels of PAI-1 but the mechanisms whereby enhanced fibrinolysis may predispose to thrombosis remain unclear.

Objective: To calibrate a reflectance pulse oximeter developed at the Division of Perinatal Physiology, University Hospital of Zurich, for monitoring of oxygen saturations below 70%., Methods: Oxygen saturation measured noninvasively with the reflectance pulse oximeter in fetal sheep was compared with oxygen saturation of arterial blood samples measured by a conventional two-wavelength oximeter. Oxygen saturation was varied by stepwise reduction of the inspired oxygen concentration of the ewe., Results: A total of 58 data pairs was obtained from five fetuses, with a range of 10.9-73.5% for the reference method and 6.8-69.2% for the pulse oximetry oxygen saturation values. There was good correlation between the results obtained by the two methods (r2 = .89, P < .0001), with a 95% confidence interval of +/- 12.5%. The pulse oximeter showed a precision of 6.2% oxygen saturation., Conclusion: The Zurich reflectance pulse oximeter offers valid measurements of oxygen saturation levels down to 10% oxygen saturation, and is therefore suitable for monitoring the fetus during delivery.

To define the epithelial and mesenchymal cell types of the guinea-pig placenta, immunostaining patterns were determined for the intermediate filament proteins cytokeratin and vimentin. Chorionic and yolk sac placentae were studied at 15, 20, 25, 29-30, 44-45, 55 and 65 days of gestation. Immunohistochemistry was performed on 5-microm thick sections of paraffin embedded tissue using specific antibodies against cytokeratin, a marker for epithelial cells, including trophoblast, and vimentin, a marker for mesenchymal cells and stromal decidua. Immunostaining was identified by the avidin-biotin-peroxidase technique with diaminobenzidine as the chromogen. Most of the surface of the placenta is covered by the columnar epithelium of the parietal yolk sac, beneath which is found a layer of chorionic giant cells. In the guinea-pig, a sheet of mesenchymal cells interposed between these cell layers immunostained for vimentin, a protein that is expressed only intracellularly, and had nuclei orientated parallel to the surface of the placenta. This cell layer is quite different from Reichert's membrane in the rat or mouse, which is acellular. Within the main placenta, cytokeratin immunostaining demonstrated that the trophoblasts lining the large maternal blood sinuses are different in character from the surrounding syncytiotrophoblast, confirming earlier ultrastructural observations. In the subplacenta, some trophoblast did not immunostain for cytokeratin and there was non-specific staining of cellular debris, so that immunostaining for vimentin provided the clearest indication of the maternal-fetal interface. In later stages of gestation (30-55 days), trophoblasts invading the walls of maternal arteries immunostained for cytokeratin and were vimentin negative. In early gestation, however, trophoblast invasion of the maternal vessels was indicated by cells that were immunoreactive for both cytokeratin and vimentin.

A number of polymorphisms of the platelet glycoprotein (GP) Ib-V-IX and IIb/IIIa complexes have been described, and the PlA polymorphism of GP IIIa has been associated with coronary thrombosis. We determined the levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) and the genotype distributions of PlA and a variable number tandem repeat (VNTR) polymorphism of GP 1b in subjects with acute stroke (n=609) and healthy control subjects (n=435). Levels of beta-TG were higher in patients both initially (47.4 [44.7 to 50.2] ng/mL, P<0.0001) and after 3 months (42.9 [40.3 to 45.7] ng/mL, P=0.03) compared with control subjects (39.4 [37.7 to 41.2] ng/mL). Initial levels of beta-TG were significantly higher in those who subsequently died (58.7 [52.3 to 65.8] ng/mL) compared with those still alive (42.7 [40.1 to 45.5] ng/mL, P<0.0001). In a logistic regression model, beta-TG remained an independent predictor of poststroke mortality, with an odds ratio for an increase in 10 ng/mL of 1.12 (1.03 to 1.21, P=0.006). In subjects who had never smoked, there was a significant difference in the genotype distributions of patients with atherothrombotic stroke (A1/A1=147, A1/A2=70, and A2/A2=2) compared with controls (A1/A1=165, A1/A2=47, and A2/A2=5, P=0.03). The PlA distribution of subjects with atherothrombotic stroke before the age of 50 years (A1/A1=19 and A1/A2+A2/A2=18) was also significantly different from age- and sex-matched controls (A1/A1=54 and A1/A2+A2/A2=20, P=0.02). We found no association of VNTR with stroke or poststroke mortality. These data indicate that there is a persistent state of enhanced platelet activation in subjects with acute stroke, which is associated with poststroke mortality. The increased frequency of the PlA2 allele in young subjects with atherothrombotic stroke lends further support for a role of the PlA polymorphism in acute thrombosis.

We set out to determine the genotype distributions of the PI(A) polymorphism of platelet glycoprotein IIIa, the HPA-3 polymorphism of platelet glycoprotein IIb, and the variable number tandem repeat (VNTR) polymorphism of platelet glycoprotein Ib in subjects with Type 2 diabetes mellitus (Type 2 DM) with (n = 125) and without (n = 90) a clinical history of macrovascular disease. In 215 white European subjects with Type 2 DM, presence of coronary artery disease was determined as a clinical history of angina, myocardial infarction (MI), coronary angioplasty or coronary artery by-pass grafting. Presence of peripheral vascular disease was defined as a clinical history of intermittent claudication with confirmatory vascular ultrasound or angiography, intermittent claudication with undetectable foot pulses and no history of arthralgia or surgery for leg ischaemia, confirmed by reference to medical case notes. Polymorphisms were detected by polymerase chain reaction amplification of DNA. There was no difference in the genotype distributions of subjects with and without macrovascular disease. In subjects with a first MI before the age of 60 years (n = 26), there was a 38% incidence of PI(A2) compared to 29% in subjects free from clinically evident macrovascular disease, but this difference did not reach statistical significance. This study does not support the hypothesis that polymorphisms of platelet glycoproteins, in particular the PI(A) polymorphism of platelet glycoprotein IIIa, play an important role in the pathogenesis of macrovascular disease in subjects with Type 2 DM.

Little data is available regarding the activated form of factor XIIa (FXIIa) in survivors of myocardial infarction. 292 Caucasian patients characterised for extent of coronary atheroma by angiography and for a past history of myocardial infarction and 77 healthy controls were included in the study. To investigate the relationship between coronary artery disease, activated factor XII and other circulating factors, we studied levels of FXIIa, cholesterol, triglycerides, fasting insulin, fibrinogen, FVII:C, t-PA antigen and PAI-1 antigen. Factor XIIa levels were higher in all patients [2.5 (2.3-2.6) ng/ml] and in patients with a history of MI [2.6 (2.4-2.9) ng/ml] than in controls [1.9 (1.7-2.1) ng/ml], p < 0.0001. In patients, FXIIa levels positively correlated with FVII:C, BMI, cholesterol, insulin, PAI-1 antigen, t-PA antigen and triglycerides. In controls FXIIa levels only correlated with PAI-1 antigen and triglycerides. FXIIa levels were strongly associated with extent of coronary stenosis: 2.8 (2.6-3.1) ng/ml and 2.6 (2.3-2.9 ng/ml) in those with 2 and 3 vessels stenosed compared to 2.1 (1.9-2.3) ng/ml in those with 0 vessel stenosed (p = 0.0004). Activated FXII relates to both extent of coronary atheroma and to a past history of myocardial infarction and clusters with features of insulin resistance.

Background: Platelets and fibrinogen play an integral role in the development of thrombosis and are implicated in the process of atherosclerosis. The fibrinogen Bbeta 448 polymorphism and the Pl(A) polymorphism of platelet glycoprotein IIIa are reported to be independently associated with coronary artery disease. The aim of this study was to determine the association of the fibrinogen Bbeta 448 and the platelet glycoprotein IIIa Pl(A) polymorphisms in relation to extent of coronary atheroma as characterized by angiography and a past history of myocardial infarction (MI) as assessed by World Health Organization criteria., Methods and Results: Caucasian patients (n=405) admitted for routine angiography for investigation of chest pain or suspected coronary artery disease were recruited. Caucasian control subjects (n=216) were recruited from local Family Health Services Authority general practice registers. Fibrinogen levels were higher (P=.04) in male patients (3.24 g/L; CI, 3.14 to 3.35) than male control subjects (3.06 g/L; CI, 2.91 to 3.21). There was a trend toward a difference (P=.06) in fibrinogen genotype distributions between female patients (1/1=93, 1/2=31, and 2/2=1) and female control subjects (1/1=67, 1/2=34, and 2/2=5). In logistic regression models the Pl(A2) genotype was associated with MI (odds ratio, 1.66; CI, 1.15 to 2.39; P=.007) and stenosis of more than one vessel (odds ratio, 1.5; CI, 1.01 to 2.26; P=.04). In men suffering an MI before the age of 47 years there was a 50% incidence of the Pl(A2) allele (P=.05), and in these subjects there was evidence of an interaction with cholesterol (P=.04)., Conclusions: We found evidence of an association of the Pl(A2) polymorphism in MI and multiple-vessel stenosis. The association with MI was strongest in young men, in whom there was also evidence of an interaction with cholesterol.

Bone marrow smears and blood samples were examined in guinea pig fetuses in which intrauterine growth retardation (IUGR) had been induced by uterine artery ligation and compared with those of control (well-grown) fetuses from uterine horns with intact circulation. Differential bone marrow cell counts were obtained from a count of 300 cells per smear and blood samples were assayed for hemoglobin concentration and 2,3-diphosphoglycerate (DPG). Results of blood assays showed no difference in hemoglobin concentration. DPG levels were reduced in the IUGR guinea pigs (P < .05), which could be a consequence of decreased glucose availability or represent an adaptation to reduced oxygen availability. Comparisons of bone marrow counts revealed an increase in total erythrocyte precursors (P < .05) and a decrease in total granulocytic precursors (P < .05) in IUGR fetuses. Within the erythroid lineage there was a significant increase in late (orthochromatic) erythroblasts (P < .005) in the IUGR animals compared with control animals. The granulocytic lineage of the IUGR fetuses showed a significant decrease in mature neutrophils (P < .05) and eosinophilic precursors (P < .05) compared with controls. These data suggest that the hypoxic stress of uterine artery ligation leads to an increase in medullary erythropoiesis. In concert with a previous study that showed a reduction in hepatic erythropoiesis, these data suggest a precocious shift of the anatomic site of erythropoiesis from the liver to the bone marrow under conditions of hypoxia.

Diabetes mellitus is characterized by fasting hyperglycaemia and the development of chronic vascular complications. While microvascular disease has been strongly related to glycaemic control, the major cause of mortality in diabetes is due to macrovascular disease affecting the cardiac and cerebrovascular circulations, which appear to have a more complex pathogenesis. Diabetes is associated with a 3-5-fold increase in death from myocardial infarction and similar figures pertain to stroke. The processes involved in atherothrombotic disease are complex and include variation in lipid metabolism, vascular responses, cell/cell interactions, and in the fluid and cellular phases of coagulation and fibrinolysis. The complex interactions between all of these processes are crucially altered by the metabolic milieu that characterizes diabetes mellitus, tipping the delicate balance towards atheroma formation, platelet aggregation and thrombus formation. This article will review these mechanisms and the effects of diabetes in the pathogenesis of vascular disease.

Background: Elevated von Willebrand factor (vWF) is a risk factor in the development of acute myocardial infarction. The importance of vWF and factor VII:C in the pathogenesis of cerebrovascular disease (CVD) is poorly defined., Methods and Results: We studied 208 cases of stroke whose pathological type was defined by cranial computed tomography. Cerebral infarcts were grouped according to the Oxfordshire Community Stroke Project (OCSP) clinical classification. The results in patients were compared with 184 healthy reference subjects. In patients, vWF and FVIII:C levels were determined initially and after three months. Patients were followed prospectively for six months or until death. Levels of vWF and FVIII:C were elevated initially (1.86 IU/ml and 2.20 U/ml respectively) and after 3 months (1.51 IU/ml and 1.90 U/ml) compared with a healthy reference population (1.26 IU/ml and 1.49 U/ml p = 0.0001). In the initial sample, vWF was associated with age (p = 0.01). FVIII:C was related to age (p = 0.04), gender (p = 0.007 higher for females) and a history of diabetes mellitus (2.56 U/ml vs. 2.16 U/ml in non-diabetics, p = 0.008). Initial vWF levels were higher in subjects with large vessel disease (TACI/PACI) group compared with the small vessel disease (LACI) group [2.12 IU/ml, (n = 112) vs. 1.48 IU/ml (n = 59) respectively, p = 0.0001] and similarly in initial FVIII:C levels (2.43 U/ml vs. 1.87 U/ml, p = 0.0001). Analysis of six-month case fatality, vWF levels were associated with risk of death [p = 0.01, OR 1.73 (1.12, 2.66) for an increase of I U/ml], even after allowing for stroke type., Conclusion: The relationship of vWF with stroke mortality has not previously been described. Although we have not demonstrated a causal role for vWF in the pathogenesis of CVD, elevated circulating levels of vWF may be associated with increased risk of death following stroke. A prospective study would be required to establish whether vWF is predictive for the development of CVD.

The exact role of the fibrinolytic system in the pathogenesis of stroke remains to be established. Elevated circulating levels of plasminogen activator inhibitor-1, the principle inactivator of the fibrinolytic system, have been related to the development of myocardial infarction. There is evidence that a polymorphism in the promoter region of the PAI-1 gene is associated with circulating PAI-1 levels. We studied a common single nucleotide insertion/deletion (4G/5G) polymorphism by PCR in 558 patients with stroke, the pathological type of which was established by cranial computed tomography, and in 172 controls. 4G/5G genotype and PAI-1 activity were investigated in relation to 1) stroke type and 2) mortality occurring within four weeks, three months and six months of the stroke. No difference in genotype frequency was observed when all cases of stroke were compared with controls nor between the clinically determined subtypes of cerebral infarction. PAI-1 activity was significantly higher in patients with stroke (n = 245) both at presentation (11.6 U/ml) and after three months (11.8 U/ml), in paired samples, than in control subjects (8.8 U/ml, p < 0.0001). Thirty-seven (6.2%), 86 (14.5%) and 122 (20.5%) patients had died within one, three and six months of admission, respectively. PAI-1 activity was independently associated with all-cause mortality at one and three months after stroke (p = 0.02 and p = 0.03 respectively), but not after six months. In this population the 4G/5G promoter polymorphism is not associated with an increased risk of stroke. PAI-1 levels were elevated at the time of acute stroke which persisted after three months. PAI-1 level but not genotype was associated with early mortality following stroke.

Background and Purpose: FVII:C has been shown to be an independent risk factor for myocardial infarction and is related to environmental and genetic factors. This study sought to investigate FVII:C levels and factor VII (FVII) gene polymorphisms in relation to stroke and disease outcome., Methods: To examine the association of FVII:C and the Msp I and promoter insertion polymorphisms of the FVII gene in acute stroke, 317 patients and 198 age-matched control subjects were studied., Results: FVII:C levels were significantly lower in patients at onset than 3 months later (119% versus 135%, respectively; P < .0005). Levels were significantly lower in patients at onset than in control subjects (124% [95% confidence interval, 120% to 129%] versus 141% [95% confidence interval, 135% to 148%], respectively; P < .0005) but were not significantly different at 3 months (135% [95% confidence interval, 128% to 141%] versus 141% [95% confidence interval, 135% to 148%], respectively). We found no difference in genotype distribution for either polymorphism between patients and control subjects, no difference in FVII:C level or genotype distribution between pathological types of stroke, and no relationship with poststroke mortality. Both polymorphisms were significantly associated with FVII:C levels in patients and control subjects. In a multiple regression model for patients, Msp I genotype, cholesterol, and smoking remained as independent predictors of FVII:C levels, accounting for 32% of interindividual variation., Conclusions: These results suggest that neither FVII:C levels nor FVII gene polymorphisms are associated with cerebrovascular disease. There were no genotype-specific correlations of environmental factors with FVII:C, but there was evidence of an acute-phase or consumptive fall in FVII:C levels at the time of stroke, whereas levels increased to those similar for healthy age-matched control subjects by 3 months, when the acute phase had presumably subsided.

Fibrinogen is an independent risk factor for the development of stroke. Factors influencing circulating levels of fibrinogen include age, smoking, gender, and genetic factors. The aim of this study was to determine the relationship between a polymorphism at position 448 of the B beta fibrinogen gene, fibrinogen levels, gender, and the risk of stroke. Fibrinogen levels were determined in 305 patients with stroke, taken within 10 days of the acute event and 3 months later, and in 197 control subjects. Initial fibrinogen levels in patients (4.49 g/L) were significantly higher than at 3 months (3.85 g/L, P < .0001), consistent with resolution of the acute-phase response. At 3 months, levels were only significantly higher than for control subjects in the male patients (3.86 g/L versus 3.31 g/L, P < .0001). Fibrinogen levels were associated with B beta 448 genotype in male patients at 3 months (1/1 = 3.62 g/L, 1/2 + 2/2 = 4.27 g/L, P = .01). There was a significant difference in the genotype distribution in female patients and control subjects (patients: 1/1 = 95, 1/2 = 34, 2/2 = 6; control subjects: 1/1 = 61, 1/2 = 50, 2/2 = 3, P = .008). These data suggest that the mechanisms linking fibrinogen and the development of cerebrovascular disease are different in males and females. In male patients, the increase in fibrinogen levels may be influenced by environmental factors, while in females there may be a functional difference in the fibrinogen molecule unrelated to fibrinogen levels.

A 2-year reduction of $5.25 million in inpatient costs, representing a decrease of 74%, resulted from implementation of a Psychiatric Management Initiative at Munson Army Community Hospital. Case management was a major component. Management in the military Civilian Health and Medical Program of the Uniformed Services (CHAMPUS) system has major differences from the civilian sector. The military case manager functions as a "guest" in the civilian psychiatric hospitals with no authority to direct care. The practice involves trend analysis, team work, innovative treatment alternatives, and active discharge planning with follow-up. This program was successful in the recapture of CHAMPUS costs despite constraints by CHAMPUS regulations. Costs went from $3,555,285 in fiscal year 1993 down to $600,743 in fiscal year 1995.