Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
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The clinicopathological features of a 28-year-old woman with placental-site trophoblastic tumor (PSTT) are described. The patient presented with severe proteinuria and was found to have a cystic uterine tumor. The serum beta-human chorionic gonadotropin (hCG) level was only slightly elevated. The tumor extended to the serosa without gross metastasis, and was resected. The specimen was composed of active intermediate trophoblasts (IT) and degenerative or inactive ITs. The former component had round to oval and vesicular nuclei, and abundant amphophilic or lightly eosinophilic cytoplasm. The latter component had irregular-shaped pyknotic nuclei and deeply eosinophilic cytoplasm. However, the tumor lacked the bilaminar (cyto- and syncytiotrophoblastic) structure that is a characteristic feature of choriocarcinoma. Immunohistochemical evaluation with human placental lactogen (hPL) and hCG antisera revealed that most of the tumor cells contained abundant hPL, whereas only a small number of cells contained hCG. This method seemed to be most helpful for the differential diagnosis of PSTT from other trophoblastic tumors or non-trophoblastic uterine tumors, and also to be useful for determining the prognostic behavior of PSTT.
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PMID:Placental-site trophoblastic tumor of the uterus. Clinicopathological and immunohistochemical observations of a case. 283 63

Case reports are presented on 2 patients to show the importance of following up apparently false positive results of pregnancy tests. In case 1, a 25-year-old woman was admitted to the hospital with severe breathlessness in September 1987. After she had stopped using oral contraceptives (OCs) in 1985 her periods were irregular and on 4 occasions the results of pregnancy tests bought over the counter were positive. She was twice referred for ultrasound examinations, but the uterus was empty each time. In April 1987, dysfunctional uterine bleeding was diagnosed; she was treated with clomiphene. She then experienced intermittent pleuritic chest pain and breathlessness on exertion. In early September she was admitted with acute breathlessness and chest pain. A further pregnancy test was positive; results of laparoscopy of the pelvis were normal. A radioisotope ventilation-perfusion lung scan showed multiple filling defects in the left lung and no perfusion to the right. A presumptive diagnosis of choriocarcinoma was made with the syndrome of tumor growing in the pulmonary arteries. In case 2, a 32-year-old woman was admitted to the hospital in March 1988 with acute lower abdominal pain. A pregnancy test was positive, and she underwent laparoscopy for suspected ectopic pregnancy. A macroscopic tumor was found on the surface of the right ovary and a right salpingo-oophorectomy was performed. A subsequent histological examination showed choriocarcinoma. The 2 cases reported show the importance of seeking a definitive explanation for a false positive result of a pregnancy test. If the test has been performed correctly and proteinuria and drug interference, for instance, are ruled out, then a raised human chorionic gonadotropin concentration, particularly in young women, is virtually certain. In most cases this will be due to a pregnancy that ends in a 1st trimester abortion, but in a small minority it will be due to the hormone producing a tumor such as choriocarcinoma.
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PMID:Don't ignore a positive pregnancy test. 284 5

Blood and urinary tests which are necessary for pregnancy diagnosis and follow-up, for newborn and mother medical supervision, during the month following birthday, are today described in reglementary texts, laws, and recommendations such as advised medical references (RMO). These documents specify the nature of obligatory tests, the checking rhythm and the list of useless tests. hCG research remains necessary for pregnancy diagnosis, but hCG dosage is essential only in case of programmed medical assistance or pathological pregnancy (extrauterine pregnancy, hydatiform mole, choriocarcinoma). The obligatory follow-up of a pregnant woman includes determination of blood groups, research of infectious agents responsible for diseases (toxoplasmosis, rubeola, hepatitis B, syphilis), proteinuria and glycosuria research and blood count according to a given calendar. When the mother's condition is bad and reminiscent of a pathological pregnancy, when a genetic risk exists for the fetus or when fetal growth is abnormal as indicated by echographic control (intra-uterine growth retardation), laboratory tests are used to follow the maternal pathological course (arterial hypertension, diabetes mellitus, anemia, bacterial, viral or parasitic disease), to verify the existence of a genetic disease, to know about the fetal functional state (by amniocentesis or cordocentesis), to identify an erythrocyte fetomaternal incompatibility. Since last trimester pregnancy accidents are able to endanger mother's and fetus lives, the feto-maternal follow-up must be adjusted to pathological diagnosis types and requires a particular supervision of the delivery. Finally mother and child must undergo a post-natal follow-up during the four weeks after birthday (perinatality control).
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PMID:[Pregnancy and perinatality: biological follow-up]. 930 27

During early pregnancy, placentation occurs in a relatively hypoxic environment which is essential for appropriate embryonic development. Intervillous blood flow increases at around 10-12 weeks of gestation and results in exposure of the trophoblast to increased oxygen tension (PO2). Prior to this time, low oxygen appears to prevent trophoblast differentiation towards an invasive phenotype. In other mammalian systems, oxygen tension effects are mediated by hypoxia inducible factor-1 (HIF-1). We found that the ontogeny of HIF-1alpha subunit expression during the first trimester of gestation parallels that of transforming growth factor-beta3 (TGFbeta3), an inhibitor of early trophoblast differentiation. Expression of both molecules is high in early pregnancy and falls at around 10 weeks of gestation when placental PO2 levels are believed to increase. Antisense-induced inhibition of HIF-1alpha inhibited the expression of TGFbeta3, and stimulated extravillous trophoblast (EVT) outgrowth and invasion. Of clinical significance we found that TGFbeta3 expression was increased in pre-eclamptic placentae when compared to age-matched controls. Significantly, inhibition of TGFbeta3 by antisense oligonucleotides or antibodies restored the invasive capability to the trophoblast cells in pre-eclamptic explants. We speculate that if oxygen tension fails to increase, or trophoblasts do not detect this increase, HIF-1alpha and TGFbeta3 expression remain high, resulting in shallow trophoblast invasion and predisposing the pregnancy to pre-eclampsia. Effective fetal-maternal interactions during early placentation are critical for a successful pregnancy. Optimal placental perfusion requires the controlled invasion of trophoblast cells deep into the decidua to the spiral arteries. Trophoblast stem cells, also referred to as cytotrophoblast cells, reside in chorionic villi of two types, floating and anchoring villi. Floating villi, which represent the vast majority of chorionic villi, are bathed in maternal blood and primarily perform gas and nutrient exchange for the developing embryo. During early placentation, cytotrophoblast cells in the floating villi proliferate and differentiate by fusing to form the multinucleate syncytiotrophoblast layer. Cytotrophoblast cells in anchoring villi either fuse to form the syncytiotrophoblast layer, or break through the syncytium at selected sites and form multilayered columns of non-polarized extravillous trophoblast cells, which physically connect the embryo to the uterine wall (Figure 1). The extravillous trophoblast cells invade into the uterine wall as far as the first third of the myometrium and its associated spiral arteries, where they disrupt the endothelium and the smooth muscle layer and replace the vascular wall. This results in the conversion of the narrow calibre arteries into distended uteroplacental arteries, thereby increasing blood flow to the placenta and allowing an adequate supply of oxygen and nutrients to the growing fetus. The invasive activity of the extravillous trophoblast cells is at a maximum during the first trimester of gestation, peaking at around 10-12 weeks and declining thereafter. Insufficient invasion contributes to the development of pre-eclampsia, which often results in fetal intrauterine growth restriction, maternal hypertension and proteinuria. In contrast, unrestricted invasion is associated with premalignant conditions, such as invasive mole, and with malignant choriocarcinoma. Invading trophoblast cells undergo striking and rapid changes in cellular functions that are temporally and spatially regulated along the invasive pathway (Figure 1) (Cross, Werb and Fisher, 1994. The formation of the anchoring villi is accompanied by changes in synthesis and degradation of extracellular matrix proteins and their receptors, and changes in the spatial distribution of extracellular matrix proteins, as well as changes in the expression of adhesion molecules (Damsky, Fitzgerald and
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PMID:Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. 1083 Nov 18

Preeclampsia is a common pregnancy complication in the latter half of gestation diagnosed by hypertension and proteinuria. A key feature of preeclampsia is an altered placentation with reduced trophoblast invasion. Normal placentation requires controlled invasion of trophoblasts into the maternal uterine wall, with secretion of specific proteolytic enzymes able to degrade basement membranes and extracellular matrix, such as the matrix metalloproteinases (MMPs). 8-Iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is a marker of oxidative stress in vivo and is biologically active. We have recently reported an elevated content of free 8-iso-PGF(2alpha) in preeclamptic gestational tissue at delivery. Assuming an elevated level of 8-iso-PGF(2alpha) during the invasion period of the pregnancy, we hypothesized that 8-iso-PGF(2alpha) could reduce invasion of JAR cells, a choriocarcinoma cell line. We investigated JAR cell invasion with 2 types of Transwell assays and demonstrated that 8-iso-PGF(2alpha) (10 micromol/L) resulted in reduced cell invasion in both the colorimetric and radioactivity Transwell assays (P<0.01). Zymograms revealed reduced MMP-2 and MMP-9 activity in conditioned media from JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) (P<0.02). 8-Iso-PGF(2alpha) (10 micromol/L) also reduced the collagenase type IV activity in the conditioned media of JAR cells (P=0.04). No effects on MMP-2 and MMP-9 mRNA levels were observed after incubation with 8-iso-PGF(2alpha) (10 micromol/L), whereas protein levels were significantly decreased (P<0.02), suggesting a posttranscriptional regulation. We hypothesize a potential role for 8-iso-PGF(2alpha) in the reduced trophoblast invasion in preeclampsia.
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PMID:8-Iso-prostaglandin f(2alpha) reduces trophoblast invasion and matrix metalloproteinase activity. 1085 82

A 26-year-old woman presented at our hospital with pretibial edema, swelling, and vaginal bleeding. She had nephrotic-level proteinuria and was diagnosed with choriocarcinoma after a histologic examination of her uterine curetting was performed. The renal biopsy specimen was compatible with membranous glomerulonephritis. The renal pathology in this case was thought to be secondary to choriocarcinoma because the nephrotic syndrome regressed after hysterectomy. We briefly present this first case of choriocarcinoma causing membranous glomerulonephritis.
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PMID:Membranous glomerulonephritis in a patient with choriocarcinoma: case report. 1263 Jun 48

Preeclampsia is a common disease of pregnancy, characterized by high blood pressure and proteinuria appearing from the second trimester of gestation. Preeclampsia has been shown to have a strong genetic component. In 2005 a positional cloning project led to the discovery of the STOX1 transcription factor, and mutations of this gene were proposed as causal for preeclampsia in Dutch families. Despite the publication of three contradictory studies, we have shown by analyzing the functional effects of STOX1 that its overexpression in choriocarcinoma cells recapitulates several transcriptomic aspects of preeclampsia. In this review, the current literature is analyzed to evaluate the possible involvement of STOX1 in the pathogenesis of this disease. While preeclampsia obviously cannot be considered as a disease caused by mutation in a single gene, we argue that STOX1 may be at the center of common pathways leading to preeclampsia.
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PMID:Re-evaluation of the role of STOX1 transcription factor in placental development and preeclampsia. 1957 9

Preeclampsia (PE) is a common human-specific pregnancy disorder defined by hypertension and proteinuria during gestation and responsible for maternal and fetal morbimortality. STOX1, encoding a transcription factor, was the first gene associated with PE as identified by positional cloning approaches. Its overexpression in choriocarcinoma cells mimics the transcriptional consequences of PE in the human placenta. Here, we created transgenic mouse strains overexpressing human STOX1. Wild-type female mice crossed with transgenic male mice reproduce accurately the symptoms of severe PE: gestational hypertension, proteinuria, and elevated plasma levels of soluble fms-like tyrosine kinase 1 and soluble endoglin. Placental and kidney histology were altered. Symptoms were prevented or alleviated by aspirin treatment. STOX1-overexpressing mice constitute a unique model for studying PE, allow testing therapeutic approaches, and assessing the long-term effects of the preeclamptic syndrome.
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PMID:Preeclampsia-like symptoms induced in mice by fetoplacental expression of STOX1 are reversed by aspirin treatment. 2335 80

Preeclampsia (PE) is a pregnancy-specific disorder characterized by new-onset hypertension and proteinuria that occurs after 20 weeks of gestation. It involves several organs and continues to be a leading cause of maternal and perinatal morbidity and mortality worldwide. Shallow trophoblast invasion is a common pathological feature of PE. Transthyretin (TTR) is a 56-kDa homotetrameric protein that binds thyroid hormone and retinol binding protein. Dysregulated TTR expression has been found in cases of PE. The aim of the present study was to determine the functional role of TTR in the migration and invasion of JEG-3 choriocarcinoma cells. JEG-3 cells were transfected with a plasmid construct expressing TTR (pCMV-Myc-TTR) or an empty plasmid (pCMV-Myc). Cell migration and invasion capacities were assessed by Transwell migration and invasion assays, respectively. These experiments demonstrated that TTR overexpression significantly increased the migration and invasion potential of JEG-3 cells. Matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases capable of degrading a wide range of extracellular matrix components. Western blot analysis revealed that TTR overexpression resulted in significantly increased levels of MMP2 and MMP9 in JEG-3 cells. In conclusion, our findings suggest an important role for TTR in regulating trophoblast invasion and migration, representing a possible underlying pathological and molecular mechanisms of PE.
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PMID:Transthyretin regulates the migration and invasion of JEG-3 cells. 2845 41