A murine model of hereditary hemorrhagic telangiectasia.
(57/1902)
Endoglin (CD105), an accessory protein of the TGF-beta receptor superfamily, is highly expressed on endothelial cells. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is associated with mutations in the Endoglin gene, leading to haploinsufficiency. To generate a disease model and ascertain the role of endoglin in development, we generated mice lacking 1 or both copies of the gene. Endoglin null embryos die at gestational day 10.0-10.5 due to defects in vessel and heart development. Vessel formation appears normal until hemorrhage occurs in yolk sacs and embryos. The primitive vascular plexus of the yolk sac fails to mature into defined vessels, and vascular channels dilate and rupture. Internal bleeding is seen in the peritoneal cavity, implying fragile vessels. Heart development is arrested at day 9.0, and the atrioventricular canal endocardium fails to undergo mesenchymal transformation and cushion-tissue formation. These data suggest that endoglin is critical for both angiogenesis and heart valve formation. Some heterozygotes, either with an inbred 129/Ola or mixed C57BL/6-129/Ola background, show signs of HHT, such as telangiectases or recurrent nosebleeds. In this murine model of HHT, it appears that epigenetic factors and modifier genes, some of which are present in 129/Ola, contribute to disease heterogeneity. (+info)
Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload.
(58/1902)
Erythroid 5-aminolevulinate synthase (ALAS-E) catalyzes the first step of heme biosynthesis in erythroid cells. Mutation of human ALAS-E causes the disorder X-linked sideroblastic anemia. To examine the roles of heme during hematopoiesis, we disrupted the mouse ALAS-E gene. ALAS-E-null embryos showed no hemoglobinized cells and died by embryonic day 11.5, indicating that ALAS-E is the principal isozyme contributing to erythroid heme biosynthesis. In the ALAS-E-null mutant embryos, erythroid differentiation was arrested, and an abnormal hematopoietic cell fraction emerged that accumulated a large amount of iron diffusely in the cytoplasm. In contrast, we found typical ring sideroblasts that accumulated iron mostly in mitochondria in adult mice chimeric for ALAS-E-null mutant cells, indicating that the mode of iron accumulation caused by the lack of ALAS-E is different in primitive and definitive erythroid cells. These results demonstrate that ALAS-E, and hence heme supply, is necessary for differentiation and iron metabolism of erythroid cells. (+info)
Hantavirus pulmonary syndrome in pregnancy.
(59/1902)
This comprehensive case review of hantavirus pulmonary syndrome (HPS) during pregnancy in 5 women characterizes the effect of Sin Nombre virus infection on maternal and fetal outcomes. Histopathologic, serological, and clinical information were evaluated for evidence of vertical transmission. Maternal ages ranged from 20 to 34 years and gestational ages from 13 to 29 weeks. Symptoms, physical findings, and laboratory values other than those related to pregnancy were not noticeably different from those of nonpregnant patients with HPS, although fevers were somewhat lower. One maternal death and 2 fetal losses occurred. Gross, microscopic, and immunohistochemical examination for hantavirus antigen were done on 2 fetal autopsies and 3 placentas showing no evidence of transplacental hantavirus transmission. There was no serological evidence of conversion in the 3 surviving children. Maternal and fetal outcomes of HPS appear similar to those of nonpregnant HPS patients and of pregnant patients with other causes of acute respiratory distress syndrome. No evidence of vertical transmission of Sin Nombre virus was found. (+info)
European stillbirth proportions before and after the Chernobyl accident.
(60/1902)
BACKGROUND: Numerous investigations have been carried out concerning the possible impact of the Chernobyl accident, in April 1986, on the prevalence of anomalies at birth and on perinatal mortality. The accident has contaminated Eastern Europe more heavily than Western Europe. If there was an effect of the radioactive contamination on perinatal mortality or stillbirth proportions one would expect to find it more pronounced in Eastern Europe as compared to Western Europe. We therefore studied long-term time trends in European stillbirth proportions. METHODS: Linear logistic regression was applied to model the time trends in stillbirth proportions. Dummy variables were used to account for effects that can be associated with certain years or locations. A synoptic logistic regression model is suggested for the western, central, and eastern parts of Europe. RESULTS: There is a marked differential effect in the long-term stillbirth time trends between Western Europe (Belgium, France, Great Britain, Iceland, Ireland, Luxembourg, Portugal, Spain), Central Europe (Austria, Denmark, Germany, Italy, Norway, Switzerland), and Eastern Europe represented by four countries (Greece, Hungary, Poland, Sweden). In contrast to the western and central European trends, the eastern European trend exhibits an absolute increase of the stillbirth proportion in 1986 as compared with 1985 and an apparent upward shift of the whole trend line from 1986 on. CONCLUSION: Our results are in contrast to those of many analyses of the health consequences of the Chernobyl accident and contradict the present radiobiological knowledge. As we are dealing with highly aggregated data, other causes or artefacts may explain the observed effects. Hence, the findings should be interpreted with caution and further independent evidence should be sought. (+info)
Oppositely imprinted genes p57(Kip2) and igf2 interact in a mouse model for Beckwith-Wiedemann syndrome.
(61/1902)
Beckwith-Wiedemann syndrome (BWS) is a clinically variable disorder characterized by somatic overgrowth, macroglossia, abdominal wall defects, visceromegaly, and an increased susceptibility to childhood tumors. The disease has been linked to a large cluster of imprinted genes at human chromosome 11p15.5. A subset of BWS patients has been identified with loss-of-function mutations in p57(KIP2), a maternally expressed gene encoding a G(1) cyclin-dependent kinase inhibitor. Some patients display loss of imprinting of IGF2, a fetal-specific growth factor that is paternally expressed. To understand how the same disease can result from misregulation of two linked, but unrelated, genes, we generated a mouse model for BWS that both harbors a null mutation in p57(Kip2) and displays loss of Igf2 imprinting. These mice display many of the characteristics of BWS, including placentomegaly and dysplasia, kidney dysplasia, macroglossia, cleft palate, omphalocele, and polydactyly. Some, but not all, of the phenotypes are shown to be Igf2 dependent. In two affected tissues, the two imprinted genes appear to act in an antagonistic manner, a finding that may help explain how BWS can arise from mutations in either gene. (+info)
Reduced male births in major Italian cities.
(62/1902)
The downward trend in the sex ratio at birth that has occurred in several countries over the last 30 years was postulated to signal a deterioration in environmental conditions, particularly unfavourable for male conception and fetus survival. In Italy, in contrast, an upward trend has been observed. Assuming that exposure to reproductive hazards occurs mainly in the major cities, we contrasted the 1970-1995 sex ratio trend for the metropolitan area (defined as the four provinces containing the largest Italian cities) with that for the non-metropolitan area (defined as the rest of the country). In the metropolitan area, the proportion of live-born males showed a negative trend significantly different from the positive trend observed in the rest of the country. Moreover, the stillbirth rate among males was constantly and significantly higher in the metropolitan area. Our results suggest that the decrease in the sex ratio at birth observed in the metropolitan area might be interpreted as a signal of increasing exposure to hazardous environmental conditions for male conceptions and neonates. (+info)
Role of rubella in congenital malformations in India.
(63/1902)
In the present study rubella HI antibodies were determined in cases of congenital malformation and bad obstetric history to determine the role of rubella in such cases in India, as it has been reported to be rare in Japan in contrast to Western countries. The incidence of antibodies was statistically significant in cases of congenital eye, C.N.S., visceral and miscellaneous malformations and cases of spontaneous abortion and still-birth compared with controls of matching age groups. This is further supported by the demonstration of IgM antibodies in seven cases of congenital malformations and ten cases of spontaneous abortion. Our findings show that congenital rubella is not rare in India. (+info)
Repeated pregnancies in BALB/c mice infected with Coxiella burnetii cause disseminated infection, resulting in stillbirth and endocarditis.
(64/1902)
Q fever is a widespread zoonosis caused by the obligate intracellular bacterium Coxiella burnetii. Although this highly virulent organism is most concentrated in mammals during parturition, there are few reports on the manifestations of perinatal Q fever in the human and animal host. The affinity of C. burnetii to pregnancy and its abortifacient potential were investigated in a murine animal model. Intraperitoneal infection of female BALB/c mice with C. burnetii, followed by repeated pregnancies over a 2-year period, resulted in persistent infection associated with abortion and perinatal death, with a statistically significant decrease in viable offspring. In addition, endocarditis occurred in 2 of the adult animals, and C. burnetii antigen and DNA were detected in their heart valves. Taken together, these results demonstrate the abortifacient potential of C. burnetii and the increased risk of persistent infection and endocarditis in pregnant mice, probably related to a decline in cellular immunity during pregnancy. (+info)