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Oxygen has a profound influence on the behavior of many cell types, including trophoblast. The effects are mediated in part through the generation of oxygen free radicals, which act as signaling molecules. Because of their high reactivity, free radicals are, however, potentially damaging to a wide range of biomolecules, and if concentrations exceed homeostatic levels then cellular oxidative stress results. Responses of tissues to changes in oxygen concentration may therefore range from physiological adaptations to pathological insults. Placental development is heavily modulated by the prevailing oxygen concentration, and understanding the mechanisms involved is clearly important. Equally, trophoblastic oxidative stress plays a key role in the pathogenesis of pregnancy complications such as miscarriage and preeclampsia. This chapter describes techniques by which the effects of oxygen and oxidative stress on placental tissues can be systematically investigated in vitro.
Methods Mol Med 2006
PMID:Working with oxygen and oxidative stress in vitro. 1651 98

Fluorescent in situ hybridization (FISH) has been extensively used for identification of individual microbial cells within their natural environment. The present work describes the identification of Fusobacterium necrophorum in formalin-fixed tissue samples from three sets of ovine twins aborted at late pregnancy by a technique that combines laser capture microdissection (LCM) and fluorescent in situ hybridization (LCM-FISH). Cultural bacteriological examination had failed to identify an infectious agent but by histological examination, large colonies of bacteria associated with tissue inflammation were seen. In situ hybridization visualized the bacteria in the tissue samples and micro-colonies closely associated with lesions were isolated by LCM. PCR-amplification and sequencing of 16S rRNA gene from the microdissected bacteria identified the organisms as Fusobacterium necrophorum. A rRNA-targeting oligonucleotide probe specific for F. necrophorum was used in a FISH assay. In situ hybridization showed a high density of F. necrophorum in all examined tissue sections. Simultaneous probing with a general bacterial probe EUB338 and the specific probe for F. necrophorum showed that no other bacteria could be detected in the tissue sections. We therefore conclude that F. necrophorum was the likely cause of abortion in these sheep.
Mol Cell Probes 2006 Dec
PMID:Fusobacterium necrophorum determined as abortifacient in sheep by laser capture microdissection and fluorescence in situ hybridization. 1673 96

Cell-free fetal DNA in maternal plasma or serum is at present widely investigated as a source of fetal genetic material, both in studies of pregnancy-related disorders and in planning strategies for non-invasive prenatal diagnosis. Despite the number of trials already performed on the quantitation of fetal DNA, data about the amount of DNA at the beginning of pregnancy, in particular in the first trimester, remain limited. A new probe mapping on the deleted in azoospermia (DAZ) repetitive region of the Yq chromosome was designed for an early assessment of fetal DNA concentration in maternal serum. Among 57 pregnant women prospectively studied in their first trimester, fetal DNA was detected already by the 5th gestational week, with the analysis becoming reliable by the 8th week of gestation when a 100% accuracy in fetal sex determination was achieved. Moreover, in the three cases of pregnancy ending in fetal loss, the amount of fetal DNA apparently decreased before the abortion was diagnosed, whereas it consistently showed an increasing trend in normal pregnancies. Real-time PCR with the use of DAZ multilocus probe can efficiently quantitate free fetal DNA in the maternal serum at the beginning of pregnancy.
Mol Hum Reprod 2006 Sep
PMID:Quantitation of fetal DNA in maternal serum during the first trimester of pregnancy by the use of a DAZ repetitive probe. 1682 Apr 4

It has been documented that mutations in the human desmin gene lead to a severe type of myofibrillar myopathy, termed more specifically desminopathy, which affects cardiac and skeletal as well as smooth muscle. We showed recently that 14 recombinant versions of these disease-causing desmin variants, all involving single amino acid substitutions in the alpha-helical rod domain, interfere with in vitro filament formation at distinct stages of the assembly process. We now provide mechanistic details of how these mutations affect the filament assembly process by employing analytical ultracentrifugation, time-lapse electron microscopy of negatively stained and glycerol-sprayed/low-angle rotary metal-shadowed samples, quantitative scanning transmission electron microscopy, and viscometric studies. In particular, the soluble assembly intermediates of two of the mutated proteins exhibit unusually high s-values, compatible with octamers and other higher-order complexes. Moreover, several of the six filament-forming mutant variants deviated considerably from wild-type desmin with respect to their filament diameters and mass-per-length values. In the heteropolymeric situation with wild-type desmin, four of the mutant variants caused a pronounced "hyper-assembly", when assayed by viscometry. This indicates that the various mutations may cause abortion of filament formation by the mutant protein at distinct stages, and that some of them interfere severely with the assembly of wild-type desmin. Taken together, our findings provide novel insights into the basic intermediate filament assembly mechanisms and offer clues as to how amino acid changes within the desmin rod domain may interfere with the normal structural organization of the muscle cytoskeleton, eventually leading to desminopathy.
J Mol Biol 2006 Jul 28
PMID:Impact of disease mutations on the desmin filament assembly process. 1682 98

An episode of hyperthermia is not uncommon during pregnancy. The consequences depend on the extent of temperature elevation, its duration, and the stage of development when it occurs. Mild exposures during the preimplantation period and more severe exposures during embryonic and fetal development often result in prenatal death and abortion. Hyperthermia also causes a wide range of structural and functional defects. The central nervous system (CNS) is most at risk probably because it cannot compensate for the loss of prospective neurons by additional divisions by the surviving neuroblasts and it remains at risk at stages throughout pre- and postnatal life. In experimental animals the most common defects are of the neural tube, microphthalmia, cataract, and micrencephaly, with associated functional and behavioral problems. Defects of craniofacial development including clefts, the axial and appendicular skeleton, the body wall, teeth, and heart are also commonly found. Nearly all these defects have been found in human epidemiological studies following maternal fever or hyperthermia during pregnancy. Suggested future human studies include problems of CNS function after exposure to influenza and fever, including mental retardation, schizophrenia, autism, and cerebral palsy.
Birth Defects Res A Clin Mol Teratol 2006 Jul
PMID:Review: Hyperthermia and fever during pregnancy. 1693 4

There are a limited number of human studies linking hot tub or spa use during early pregnancy to increased risks for neural tube defects (NTDs) or spontaneous abortion. However, these data can be considered in the context of human studies that have demonstrated an association between high maternal fever in early pregnancy and NTDs. In addition, there is a large volume of animal literature suggesting that, regardless of the heat source, an elevated core maternal temperature at or above the threshold of 2 degrees C over baseline, as well as timing and duration of exposure, are the critical factors in conferring risk. Therefore, the potential for hot tub or spa use to increase core maternal body temperature to risky levels and thus increase the risk for NTDs is likely. A woman who knows or who may not yet be aware that she is pregnant should be advised of the recommended limits of exposure. She should also be aware of the possible variability in hot tub or spa temperature readings and be able to accurately monitor maximum water temperature in the hot tub or spa so that her body temperature can be maintained below 38.9 degrees C.
Birth Defects Res A Clin Mol Teratol 2006 Aug
PMID:Risks of hyperthermia associated with hot tub or spa use by pregnant women. 1699 15

Increasing evidence supports a role for altered T helper 1 (Th1)-Th2 cytokine balance in idiopathic recurrent spontaneous abortion (RSA). The aim of this study was to investigate the association of the interleukin 10 (IL-10) promoter polymorphisms -592C/A, -819C/T and -1082A/G with RSA. Women (n = 350) with at least three consecutive spontaneous abortions (RSA cases) and 200 control women with at least two successful pregnancies were included. The frequency of the -819T allele [P = 0.05, odds ratio (OR) = 1.51], but not other single-nucleotide polymorphisms (SNPs), was higher among RSA patients. Complete linkage disequilibrium (LD) was seen between -592C and -819C and -1082G alleles, as well as between -592A and -819T and between -819C and -1082G alleles only among patients. Although the genotype frequencies (except for -819C/C) of the three polymorphisms were comparable between patients and controls, higher frequency of -592A/-819T/-1082A haplotype (OR = 4.01, 95% CI = 1.83-7.95) was seen in cases versus controls. Regression analysis indicated that, after adjusting for potential variables, -592C/A (OR = 3.32, 95% CI = 1.76-6.27) and -819C/T (OR = 5.06, 95% CI = 2.59-9.91) were associated with exclusively early but not exclusively late RSA, where negative association for both was noted. This supports the notion of involvement of IL-10-592C/A and -819C/T polymorphisms as inherited risk factors of idiopathic RSA.
Mol Hum Reprod 2006 Dec
PMID:Association of -592C/A, -819C/T and -1082A/G interleukin-10 promoter polymorphisms with idiopathic recurrent spontaneous abortion. 1704 Dec 36

Employing a monoclonal antibody (B152) specific for a carbohydrate epitope found on a choriocarcinoma derived hCG, it was discovered that a similar hCG isoform is expressed during early pregnancy. This form differs from later pregnancy hCG in carbohydrate moieties. Profiling of these two hCG isoforms throughout pregnancy utilized two IRMA's: B152-B207 ("hyperglycosylated hCG"-specific assay) and B109-B108 (an IRMA for standard intact hCG isoforms in the WHO hCG reference preparation). The WHO hCG standard was used in both assays. Values were presented as a ratio of hCG isoform concentrations (B152/B109 ratio). In early pregnancy urine concentrations of B152 hCG were significantly higher in normal pregnancy (NP) compared to early pregnancy loss (EPL). Matched serum-urine samples from the first and third trimesters revealed that the B152 hCG form is predominant in both serum and urine in the first trimester compared with the third trimester. The proportion of the B152 hCG (HhCG) form is higher in urine than in matched serum. There was a significant difference in the B152/B109 ratio between days 5 and 20 from time of embryo transfer in normally developing pregnancy versus EPL in the urine of IVF patients. In spontaneous abortion (SA) the level of B109 hCG remained higher in NP compared with SA. However, the B152/B109 ratio declined with gestational age faster in SA than in NP suggesting perhaps a different loss mechanism in SA versus EPL. The cellular origin of the different hCG glycoforms was identified by assay of cell media from cytotrophoblasts (CTBs) and syncytiotrophoblasts (STBs). Isolated CTBs expressed predominantly HhCG. The level of expression was the highest in the first trimester. STBs were the source of the less glycosylated B109 hCG isoform. Analysis of hCG glycoforms during early pregnancy can distinguish pregnancies that will fail from those that will proceed normally. Since the B152 assay does not effectively discriminate between intact HhCG and free beta HhCG (HhCGbeta), a new HhCGbeta assay was developed. This assay recognizes the HhCGbeta which is produced by CTBs. We hypothesize that the measurement of HhCGbeta may have a potential use in screening for Down syndrome and perhaps other pregnancy disorders and certain types of cancer.
Mol Cell Endocrinol 2007 Jan 02
PMID:Hyperglycosylated HCG expression in pregnancy: cellular origin and clinical applications. 1709 38

Meiotic dysfunction increasingly afflicts women as they age, resulting in infertility, miscarriage and handicapped offspring. How aging disrupts meiotic function in women remains unclear, but as women increasingly delay childbearing, this issue becomes urgent. Telomeres, which mediate aging in mitotic cells, may also mediate aging during meiosis. Telomeres shorten during DNA replication. In mammals, oocytes remain quiescent, but their precursors replicated during fetal oogenesis. Moreover, eggs ovulated from older women entered meiosis later during fetal oogenesis than eggs ovulated when younger, and therefore underwent more replications. Telomeres also shorten from reactive oxygen, which triggers a DNA repair response, so the prolonged interval between fetal oogenesis and ovulation in some women would further shorten telomeres. Mice normally do not exhibit age-related meiotic dysfunction (interestingly, their telomeres are manyfold longer than telomeres in women), but genetic or pharmacologic shortening of mouse telomeres recapitulates the reproductive aging phenotype of women. This has led to a telomere theory of age-related meiotic dysfunction in women, and underlined the importance to human health of a mechanistic understanding of telomeres and meiosis.
Cell Mol Life Sci 2007 Jan
PMID:Telomeres and aging-related meiotic dysfunction in women. 1721 22

Plutella xylostella strain resistant (PXR) to Bacillus thuringiensis Cry1Ac toxin was not killed at even more than 1000 microg Cry1Ac/g diet but killed by Cry1Ab at 0.5 microg/g diet. In contrast, susceptible strain (PXS) was killed by Cry1Ac at 1 microg/g diet. Cy3-labeld Cry1A(s) binding to brush border membrane vesicles (BBMV) prepared from both strains were analyzed with direct binding assay. The Kd value of Cry1Aa to both BBMV was almost identical: 213.2 and 205.8 nM, and 263.5 and 265.0 nM for Cry1Ac. The highest Kd values were in Cry1Ab which showed most effective insecticidal activity in PXS and PXR, 2126 and 2463 nM, respectively. These results clearly showed that the BBMV from PXR and PXS could equally bind to Cry1Ac. The binding between BBMV and Cy3-labeled Cry1Ac was inhibited only by anti-175 kDa cadherin-like protein (CadLP) and -252 kDa protein antisera, but not by anti-120 kDa aminopeptidase. This supports that resistance in PXR resulted from the abortion of pore formation after the binding of Cry1Ac to the BBMV. And furthermore, the importance of 175K CadLP and P252 proteins in those bindings was suggested. We briefly discuss possible mechanisms of the resistance.
Comp Biochem Physiol B Biochem Mol Biol 2007 Aug
PMID:Binding of Bacillus thuringiensis Cry1A toxins to brush border membrane vesicles of midgut from Cry1Ac susceptible and resistant Plutella xylostella. 1754 62


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