Congenital chloride diarrhea in pregnancy: A case report.
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Adult↗
Biomedical subjects
Motoi Sugimura
Publications and source records attributed to Motoi Sugimura.
Exogenous vascular endothelial growth factor can induce preeclampsia-like symptoms in pregnant mice.
It is reported that expression of vascular endothelial growth factor (VEGF) in trophoblasts increases in cases with preeclampsia. Recently, we demonstrated that the lack of cyclin-dependent kinase inhibitor, p57kip2, expression in the fetus and the placenta plays a role in the development of preeclampsia-like symptoms in pregnant mice. Furthermore, we observed that VEGF mRNA and protein levels, especially VEGF (164), were higher and its expression was stronger in placentas of p57kip2-null embryos than in placentas of wild-type embryos. In this study we investigated whether exogenous murine VEGF (164) induced preeclampsia-like symptoms in pregnant mice, and anti-VEGF neutralized antibody could suppress these symptoms. Administration of VEGF induced hypercoagulation in the placental circulation and a significant elevation of systolic blood pressure in pregnant mice. Furthermore, we demonstrated that treatment with anti-VEGF antibody could suppress the hypercoagulability in placenta and the elevation of systolic blood pressure. These data suggest that VEGF is related to the pathophysiology of preeclampsia.
Animals↗
Phosphatidylserine/phosphatidylcholine microvesicles can induce preeclampsia-like changes in pregnant mice.
We established a phosphatidylserine (PS)/phosphatidylcholine (PC) microvesicles-induced preeclampsia-like model in mice. PS/PC were prepared by mixing 80% PC and 20% PS, and suspended in 0.05 M Tris-HCl at a concentration of 10 mg/mL. One hundred microliters of PS/PC (n = 6) and saline as a control (n = 10) were injected in tail veins of Institute of Cancer Research (ICR) mice every day from days 5.5 to 16.5 of pregnancy. Systolic blood pressure (SBP) was measured by means of the tail-cuff method. On day 17.5, the mice were anesthetized by diethyl ether and euthanized with the collapse of the circulation by drawing blood from the heart. The animals were dissected and the fetuses and placentas removed. Fetal weight and placental weight were evaluated. Plasma antithrombin activity (AT), thrombin-antithrombin complex (TAT), platelet counts, and proteinuria were measured on day 17.5. Placentas were fixed in 4% paraformaldehyde for histologic studies. Statistical analysis was evaluated by analysis of variance and Welch's t-test. Mice injected with PS/PC showed a significant elevation in SBP (124 versus 101 mm Hg; p < 0.001), a significant increase in TAT levels (23 versus 6.6 mug/L; p < 0.05), a significant decrease in platelet counts (88 versus 102 x 10 (10)/L; p < 0.05), a decrease in AT, an increase in proteinuria, and a significant reduction in fetal weight (1.2 versus 1.3 g; p < 0.0001) and placental weight (0.13 versus 0.15 g; p < 0.001), compared with controls. Placentas of mice injected with PS/PC showed diffuse fibrin depositions in the labyrinth layer. We have demonstrated that the artificial PS/PC vesicles induce intrauterine growth restriction with elevations of SBP. The elevation of plasma TAT and the diffuse fibrin depositions in the placentas indicate enhanced thrombin formation, and the significant elevations of SBP indicate preeclampsia-like changes that can be induced by hypercoagulation in the placenta.
Animals↗
Sensitivity to activated protein C in patients with deep vein thrombosis during early puerperium period.
BACKGROUND: In this study, we used an endogenous thrombin potential (ETP)-based assay to examine the response to activated protein C (APC) during early puerperium of 6 Japanese patients of deep vein thrombosis (DVT) and pulmonary embolism (PE) without a history of familial thrombophilia or antiphospholipid syndrome. METHODS: The patient group comprised 6 Japanese women diagnosed for DVT or PE at Hamamatsu University School of Medicine, between July 1997 and April 2000. The control group comprised 30 healthy Japanese women in early puerperium. APC-sensitivity ratio (APC-sr), complete blood count (CBC), and other coagulant variables (thrombin-antithrombin-complex (TAT) and fibrin/fibrinogen-degration product (FDP)-D-dimer levels) were determined. RESULTS: Mean APC-sr was 2.0 +/- 0.3 in the control group and significantly higher (3.3 +/- 1.0) in the patient group (P < 0.05). The FDP-D-dimer level was significantly higher in the patient group than in the control group, but there was no significant difference in the TAT complex level. CONCLUSIONS: We conclude that sensitivity to APC is reduced in patients with DVT or PE during early puerperium. Although further clinical studies are needed to confirm, it appears that sensitivity to APC detected by ETP-based assay could become a useful marker to estimate the occurrence of DVT or PE.
Activated Protein C Resistance↗
Alteration of integrins under hypoxic stress in early placenta and choriocarcinoma cell line BeWo.
Invasion of the trophoblast into the decidua and the myometrium is very important for the establishment of a normal pregnancy. This invasion is regulated by the expression of integrins in the trophoblast. Recently, it has been shown that invasion of the trophoblast is impaired in preeclampsia. We report the effect of hypoxia on the expression of integrins and extracellular matrices at the mRNA level in early placenta and BeWo cells. Tissue RNA levels of fibronectin and integrin alpha5 were significantly higher in the hypoxic condition than under normoxic conditions. In contrast, tissue RNA levels of integrin alpha1 were significantly lower for the hypoxic condition than those under normoxic conditions. Alteration of the integrin components and increases in fibronectin expression were observed in early placenta and BeWo cells under hypoxic conditions. These results suggest that hypoxic stress regulates the synthesis of integrin and fibronectin mRNAs in early placenta.
Cells, Cultured↗
Estrogen administration enhances thrombin generation in rats.
Venous thrombosis is a serious disorder that may be fatal if complicated by pulmonary embolism. Venous thrombosis is usually related to one of three factors: reduced blood flow, changes in vessel wall integrity, or changes in the blood composition. Factors leading to thrombosis are classified as either genetic or acquired. Puerperium and oral contraceptives are examples of the acquired factors. The risk of thrombosis during pregnancy is high compared to that in the overall population,. however, this increases by three to five times in puerperium. Deep vein thrombosis (DVT) complicated by pulmonary thromboembolism (PE) is considered the leading cause of maternal death in the United States and Europe [Am. J. Obstet. Gynecol. 164 (1991) 603; Obstet. Gynecol. 84 (1994) 240] and the third cause in Japan [M Ishikawa, Maternal mortality and pulmonary thromboembolism. Study on maternal mortality in Japan. Report from the Ministry of Health of Japan in Maternal and Child Health Research, 1996. p. 123-128]. Patients without history of familial thrombophilia have 14-fold higher risk of DVT during puerperium [Thromb. Haemost. 25 (1999) 610]. Little is known about the underlying mechanism of thrombotic disorders in puerperium. It is recognized that oral contraceptive estrogen enhances the risk of DVT [Am. J. Epidemiol. 133 (1991) 32]. However, there is little research regarding the relation between estrogen and blood coagulation, although it is known that plasma estrogen reaches extremely high levels near term. We assume that high-level plasma estrogen plays an important role in the blood coagulation activity that results in the occurrence of DVT. To assess this likely association, we studied the effects of high estrogen levels on coagulation in rat plasma.
Animals↗
Recombinant adenovirus vector bearing antisense macrophage migration inhibitory factor cDNA prevents acute lipopolysaccharide-induced liver failure in mice.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine involved in delayed hypersensitivity and cellular immunity. MIF also acts as a proinflammatory cytokine and counterregulates the anti-inflammatory effects of glucocorticoids. Exogenous gene transfer mediated by adenovirus is useful to study a particular molecular function as well as to develop gene therapy strategies. A recombinant adenovirus containing sense and antisense murine MIF (mMIF) cDNA inserts was constructed using a cosmid-terminal protein complex method. The sense mMIF adenovirus (AxCA-mMIFS) efficiently induced mMIF in COS-7 cells that endogenously lack mMIF in a dose-dependent manner. In contrast, the antisense mMIF adenovirus (AxCA-mMIFAS) inhibited the expression of mMIF in NIH3T3 cells in a dose-dependent manner. To assess the pathophysiologic role of MIF in acute liver failure, we induced acute onset of liver damage in mice (male Jcl:ICR) by a combined treatment of Bacille Calmette-Guerin (BCG) and lipopolysaccharide (LPS). mMIF level in the liver of mice infected with AxCA-mMIFAS showed a significant reduction in MIF production in response to BCG-LPS compared with mice treated without viral infection and with AxCA-mMIFS. In addition, the immunohistochemical staining demonstrated that F4/80 antigen on macrophage was enhanced in liver infected with AxCA-mMIFS but reduced in liver infected with AxCA-mMIFAS. The staining intensity is correlated with the mMIF antigen level in liver tissue. The survival rate of mice infected with AxCA-mMIFAS was significantly higher than that of mice treated with PBS and infected with AxCA-LacZ in BCG-LPS. These results suggest that inhibition of MIF production, using recombinant adenovirus bearing the antisense MIF gene, reduced the mortality rate in BCG-LPS-induced liver failure in mice. This finding might aid in the further development of gene therapy targeting MIF.
3T3 Cells↗
Anti-macrophage inhibitory factor antibody inhibits PMSG-hCG-induced follicular growth and ovulation in mice.
PURPOSE: To investigate the effect of an anti-MIF antibody on PMSG-hCG-induced murine follicular growth and ovulation and to determine whether MIF plays an essential role in this process. METHODS: Mice were primed with an intraperitoneal injection of pregnant mare serum gonadotropin (PMSG) and were treated with an anti-rat MIF antibody and human chorionic gonadotropin (hCG) to induce ovulation. After that, the ovulated ova were counted. The ovaries were studied using standard histological procedures. RESULTS: Ovaries treated with the anti-MIF antibody showed reduced numbers of growing follicles surrounded by granulosa cells and theca cells with a little proliferation compared with the control. The average numbers of ova collected from mice treated with the anti-MIF antibody were reduced compared with those collected from control mice. CONCLUSIONS: Anti-MIF antibody inhibits the follicular growth and ovulation in mice, and MIF may play an important role in the inflammatory reactions during follicle growth and ovulation.
Animals↗
Coagulation index to distinguish severe preeclampsia from normal pregnancy.
The purpose of this study was to establish a new coagulation index to distinguish severe preeclampsia from normal pregnancy using optimal coagulation parameters. The difference between platelet counts in early gestation and before delivery (DeltaPlt = [platelet counts before delivery] - [platelet counts in early gestation]) was calculated as an index of changes in platelet counts. Antithrombin (AT) activity, thrombin-antithrombin (TAT) complex, fibrin degradation products (FDP) D-dimer, and DeltaPlt were investigated in 72 cases of normal pregnant women in the third trimester of pregnancy and 56 cases of severe preeclampsia. The new coagulation index was calculated using multivariate logistic regression analysis. As a result, in a case using four parameters, the following formula was obtained: Y = (-0.019 x AT activity) + (0.067 x TAT) + (0.067 x D-dimer) + (-0.064 x DeltaPlt) + 0.706. According to this formula, coagulation indices in normal pregnant women and in patients with severe preeclampsia were -0.77 +/- 0.51 and 1.41 +/- 1.56, respectively (p < 0.0001). Among patients with severe preeclampsia, coagulation and fibrinolysis disorders before delivery were typical in patients terminated by cesarean section (coagulation index = 1.62 +/- 1.66) compared with those with successful vaginal delivery (coagulation index = 0.52 +/- 0.34) (p < 0.05). These facts suggest that an excessive hypercoagulable state is associated with the termination of pregnancy resulting from the aggravation of preeclampsia. From the viewpoint of coagulation and fibrinolysis disorders, the predictive value in order to decide the optimal time for the termination of pregnancy could be recommended when the coagulation index exceeded 1.20.
Antithrombins↗
Anticholinergics induce eclamptic seizures.
Severe preeclampsia is a pathophysiological disorder specific to pregnancy and characterized by vasoconstriction and hypercoagulability. Eclampsia (convulsion associated with preeclampsia) and hemolysis, elevated liver enzymes, and low platelet count associated with preeclampsia (HELLP syndrome) are serious complications in patients with severe preeclampsia. They are thought to be characterized by generalized vasoconstriction and reduction in blood flow to various organs that may be explained by increased sensitivity of the vascular smooth muscles and increased vasopressors. Liver involvement in eclampsia and preeclampsia is referred to as HELLP syndrome, and epigastric and right upper quadrant pain is often a symptom of severe preeclampsia and may be indicative of imminent convulsions. In addition, marked dilatation of the stomach and the colon is often demonstrated in these patients. These phenomena result from the hyperactivity of the sympathetic nervous system but are not caused by the hyperactivity of the parasympathetic nervous system. The authors experienced two cases of eclamptic seizures after the administration of an anticholinergic (scopolamine butylbromide) in patients with severe preeclampsia complicated by HELLP syndrome. Anticholinergics, blocking agents of the parasympathetic nervous system, can enhance the hyperactivity of the sympathetic nervous system; therefore, vasospasms of the vessels may be easily aggravated, and eclamptic seizures may be induced in patients with severe preeclampsia, especially in those complicated by HELLP syndrome. The administration of anticholinergics should be avoided in patients with severe preeclampsia, especially when there is epigastralgia.
Adult↗
Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice.
p57Kip2, a potent inhibitor of several cyclin/cyclin dependent kinase complexes (CDK ), is a paternally imprinted gene in both humans and mice, and here we show that pregnant mice which are heterozygous for p57Kip2 deficiency display symptoms similar to preeclampsia. p57-/+ (heterozygotes for p57Kip2 ) female mice that were mated with p57-/+ males showed hypertension, proteinuria, thrombocytopenia, decreased anti-thrombin III activity, and increased endothelin levels during late pregnancy. In their kidneys, endotheliosis of glomeruli were recognized along with fibrinoid or hyalinoid deposits. These characteristics were also observed in pregnant p57-/+ females that were mated with wild type males, but not in pregnant wild type females mated with p57-/+ males or wild type males. The pregnant p57-/+ mice had conceptuses both with and without p57Kip2 expression. The conceptuses without p57Kip2 expression showed trophoblastic hyperplasia, which mimics the hallmark proliferation of intermediate trophoblasts in clinical preeclampsia. It is suggested that the preeclampsia-like symptoms of the pregnant p57-/+ mice might have been induced by the conceptus(es) without p57Kip2 expression. In addition, pregnant p57-/+ mice might serve as a new animal model for preeclampsia characterized by trophoblastic hyperplasia.
Animals↗