Abstract
STUDY QUESTION
Are JC polyomavirus (JCPyV) and BK polyomavirus (BKPyV) infections associated with spontaneous abortion (SA)?
SUMMARY ANSWER
There is no association of JCPyV or BKPyV with SA.
...WHAT IS KNOWN ALREADY
A large number of risk factors have been associated with SA. The role of polyomaviruses, including JCPyV and BKPyV, in SA remains to be clarified.
STUDY DESIGN, SIZE, DURATION
This is a case–control study including women affected by spontaneous abortion (SA, n = 100, the cases) and women who underwent voluntary interruption of pregnancy (VI, n = 100, the controls).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Viral DNAs were investigated by qualitative PCR and quantitative droplet-digital PCR (ddPCR) in matched chorionic villi tissues and peripheral blood mononuclear cells (PBMCs) from SA (n = 100) and VI (n = 100). Indirect ELISAs with mimotopes/synthetic peptides corresponding to JCPyV and BKPyV viral capsid protein 1 epitopes were then employed to investigate specific IgG antibodies against JCPyV and BKPyV in human sera from SA (n = 80) and VI (n = 80) cohorts.
MAIN RESULTS AND THE ROLE OF CHANCE
JCPyV DNA was detected in 51% and 61% of SA and VI samples, respectively, with a mean viral DNA load of 7.92 copy/104 cells in SA and 5.91 copy/104 cells in VI (P > 0.05); BKPyV DNA was detected in 11% and 12% of SA and VI specimens, respectively, with a mean viral DNA load of 2.7 copy/104 cells in SA and 3.08 copy/104 cells in VI (P > 0.05). JCPyV was more prevalent than BKPyV in both SA and VI specimens (P < 0.0001). In PBMCs from the SA and VI cohorts, JCPyV DNA was detected with a prevalence of 8% and 12%, respectively, with a mean viral DNA load of 2.29 copy/104 cells in SA and 1.88 copy/104 cells in VI (P > 0.05). The overall prevalence of serum IgG antibodies against JCPyV detected by indirect ELISAs was 52.5% and 48.7% in SA and VI groups, respectively, whereas BKPyV-positive sera were found in 80% SA and 78.7% VI samples.
LIMITATIONS, REASONS FOR CAUTION
This study did not investigate the presence of viral mRNA and/or proteins, which are indicative of an active viral infection, and these might be taken into consideration in future studies.
WIDER IMPLICATIONS OF THE FINDINGS
JCPyV and BKPyV DNA sequences were detected and quantitatively analyzed for the first time by PCR/ddPCR in chorionic villi tissues and PBMCs from SA and VI specimens. Moreover specific immunological approaches detected serum IgG against JCPyV/BKPyV. Statistical analyses, however, do not indicate an association between these polyomaviruses and SA.
STUDY FUNDING/COMPETING INTEREST(s)
This work was supported by the University of Ferrara, FAR research grants and the University Hospital of Ferrara/University of Ferrara joint grant. No potential conflicts of interest were disclosed.
Use of glucocorticoids in pregnancy Lunghi, L; Pavan, B; Biondi, C ...
Current pharmaceutical design,
01/2010, Letnik:
16, Številka:
32
Journal Article
Recenzirano
For many years glucocorticoids have been used world-wide in pregnant women for treatment of a variety of medical disorders, from bronchial asthma to systemic lupus erythematosous, to renal ...transplant. More recently their administration has been successfully addressed to the prevention of congenital fetal diseases. In some of these, such as for instance the 21-hydroxylase deficiency leading to congenital adrenal hyperplasia, the pathogenic mechanism is well known, while in others, such as the cystic adenomatoid malformation of the lung, it is not yet understood. Besides these types of diseases, there are acquired inflammatory conditions impairing the physiologic evolution of pregnancy that benefit from glucocorticoid administration. This is the case in recurrent miscarriage due to increased concentration of decidual Natural Killer cells, as well as in the Romero's syndrome, leading to premature parturition and related life threatening fetal complications. However, in spite of its prominent efficacy, the therapy is generally viewed with some suspicion because of possible fetal and maternal adverse effects. With the aim to contribute to a better knowledge of the basic mechanisms of glucocorticoid protection, we reviewed the regulation of their trans-placental passage, their biological effects on gestational environment, their possible 'programming' and teratogenic action, and their accepted use for prevention and cure of pregnancy complications. We believe that a more qualified and liberal use of these compounds will lead in many cases to a significant improvement of fetal and maternal prognosis.
Vitamin C plays an important role in embryogenesis and fetal growth as well as in the progression of pregnancy and delivery. Therefore, it is important to understand the mechanism that mediates its ...transport to the fetus as well as the possible influences by endogenous and exogenous substances on its placental uptake. The aim of this study was to investigate placental sodium-dependent vitamin C transporters (SVCT) 1 and 2. By means of RT–PCR, we found that SVCT2, but not SVCT1, mRNA is expressed in human trophoblast cell line HTR-8/SVneo. Our method was able to confirm SVCT2 mRNA expression in human first-trimester chorionic villi but not in term placental tissue. Cell line kinetic studies of 14C ascorbic acid (AA) uptake indicated a one-site model and a saturable process. Fetal bovine serum (FBS) and epidermal growth factor (EGF) do not influence the transport properties, although they significantly increase the expression of SVCT2. Steroid hormones (17β-estradiol, progesterone and cortisol), flavonoids (genistein and quercetin) and non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin and diclofenac) inhibit 14CAA uptake in a dose-dependent and non-competitive manner. On the contrary, the process is not influenced by aspirin. Our study suggests the use of HTR-8/SVneo cells as a suitable model for trophoblast vitamin C transport investigation.
To study the behaviour of the peripheral lymphocyte subsets in foetuses affected by growth restriction.
Thirty consecutive pregnant women with an ultrasound diagnosis of foetal growth restriction ...were included in this study (group A) while 30 women with a physiologic pregnancy were recruited as control group (group B). The diagnosis was performed during the ultrasound of the third trimester and confirmed at birth. Blood samples were drawn after the ultrasound of the third trimester for all patients. The analyzed populations were: WBC, total lymphocytes, CD2+, CD3+, CD4+, CD5+, CD8+, CD19+, CD56+, HLA-DR+, CD45+, CD3+HLA-DR+, CD4+CD3+, CD3+CD8+, CD2+CD56+, CD19+CD5+, ratio (CD4+CD3+)/(CD3+CD8+).
The percentage and absolute value of the NK cells was higher in the group A (20.90 vs. 15.09)%, p = 0.0005; (419.55 vs. 341.40) UI/μl, p = 0.0005. This trend was confirmed by the CD2+CD56+ natural killer (NK) subset (18.84 vs. 13.42) UI/μl, p = 0.0005. Instead, the CD4+ percentage value was lower in the group A (41.15 vs. 44.84)%, p = 0.03 through the CD4+CD3+/CD3+CD8+ ratio was not significantly different.
Our findings reinforce the concept of pregnancy as a controlled systemic inflammatory state that if altered can have adverse consequences for the mother and the foetus.
To assess the eventual influence of low dose betamethasone throughout pregnancy on fetal growth.
320 patients - admitted to the Section of Obstetrics and Gynecology of Ferrara University from January ...2005 to December 2010 - were subdivided in two groups: 160 patients affected by recurrent spontaneous abortion (Group A), treated by low dose of betamethasone (0.5 mg/daily) throughout pregnancy for preventive purposes, 160 patients with physiological pregnancy as control group (Group B). Primary measured outcomes were neonatal biometric parameters such as birth weight, head circumference and neonatal length. Unpaired t-test was used to compare the neonatal biometric parameters.
Birth weight, length and circumference head resulted significantly lower in groups treated by GCs. However, excluding bias as pregnancy complicated by diseases, which could affect fetal growth, biometric neonatal parameters were not different between two groups. Furthermore, analyzing the distribution of the value of birth weight we observed that in the group A there were 44 newborns with a weight even higher than fiftieth percentile.
Betamethasone seems not to influence fetal growth. Our analysis demonstrates that fetal growth is influenced by several factors, therefore, homogeneous study population is essential to have convincing results.
Normal placentation requires a highly coordinated control of proliferation, migration and invasiveness of extravillous trophoblast cells. Since prostaglandin E2 is a major prostanoid synthesized by ...intrauterine tissues and highly involved in pregnancy homeostasis, we examined the possibility that it modulates extravillous trophoblast cell functions. Here, we report the presence of mRNAs for prostaglandin E2 EP2 and EP4 receptor isoforms and of proteins in both first-trimester human chorionic villi and in the human trophoblast-derived HTR-8/SVneo cells. Moreover we found that: (i) this cell line releases prostaglandin E2 and the output is enhanced by interleukin-1beta; (ii) the prostanoid consistently inhibits serum- or epidermal growth factor-induced cell proliferation and also migration. An involvement of cAMP in the prostaglandin E2 antiproliferative action is suggested by the observation that the prostanoid greatly enhances cAMP level in HTR-8/SVneo cells and that forskolin inhibits cell proliferation; moreover the administration of prostaglandin E2 plus forskolin, a condition which evokes a synergistic enhancement of cAMP, induces a major impairment of cell growth. Provided that our data are applicable to the trophoblast tissue in vivo, we suggest that prostaglandin E2 exerts an important control on extravillous trophoblast cell functions, preventing an excessive proliferation and migration.
Cyclic adenosine 3′-5′-monophosphate (cAMP) is a second messenger, which exerts an important role in the control of human first-trimester trophoblast functions. In the present study we demonstrate ...the existence of a mechanism that is able to extrude cAMP from trophoblast-derived cell lines, and show evidence indicating the involvement of multidrug resistance protein (MRP) 1, a transporter belonging to the ATP-binding cassette family, in cAMP egress. MRP1 is expressed in trophoblast cell lines and cAMP efflux is highly reduced by the MRP1 inhibitor, MK-571. In addition, interleukin-1β and estrone are able to enhance MRP1 gene expression and influence extracellular cAMP concentration. The occurrence of a MRP1-dependent cAMP efflux is also shown in human first-trimester placenta explants. Extracellular cAMP could represent a source for adenosine formation, which in turn could regulate cAMP-dependent responses in placental tissue. Evidence is provided that adenosine receptor subtypes are present and functional in human trophoblast-derived cells. A role for cAMP egress mechanism in the fine modulation of the nucleotide homeostasis is therefore suggested.
Connexins (Cx) are membrane proteins able to influence cell trophoblast responses, such as proliferation, differentiation, migration and invasiveness. Likewise, glucocorticoids are also known to ...modulate many factors involved in implantation, including trophoblast gap-junction intercellular communication, although their influence on pregnancy is controversial. In order to investigate the effects of betamethasone, a synthetic glucocorticoid, on Cx and glucocorticoid receptor (GR) expression and localisation, as well as on cell proliferation, the extravillous trophoblast-derived HTR-8/SVneo cell line was used as a model. The results, confirmed by means of immunofluorescence, demonstrate that betamethasone selectively modifies GR and Cx expression, enhancing the GRα isoform without affecting GRβ, and inhibiting Cx40 expression whilst increasing that of Cx43 and Cx45. Furthermore, betamethasone was shown to exert an inhibitory action on cell proliferation. In this model the abortion drug RU-486 (mifepristone), reported to be a GR antagonist, did not counteract this effect of betamethasone. On the contrary, it induced responses similar to those of the hormone. Knowing that RU-486 is also a potent progesterone-receptor antagonist, the effect of progesterone alone and in combination with the drug on Cx expression and cell proliferation was then tested. Progesterone showed the same effect as betamethasone on Cx expression, but it did not affect proliferation. Based on these results, neither the abortion effects of RU-486 nor the protective action of betamethasone and progesterone are exerted by modulation of Cx. RU-486 did not antagonise the progesterone effect, suggesting that its abortive action does not involve alteration of trophoblast Cx expression.
Abstract We have tested the hypothesis that human early trophoblast is a target for somatostatin (SRIF) regulatory actions. We report for the first time that SSTR2A and 2B transcripts and proteins ...are present in first-trimester human chorionic villi and the trophoblast-derived HTR-8/SVneo and JAR cells. In both cell lines, SSTR are functional since SRIF inhibits cyclic AMP pathway, stimulates arachidonic acid release and enhances cell proliferation. Moreover, in HTR-8/SVneo cells, considered a good model of first-trimester EVT, SRIF also enhances migration. An involvement of the cyclic AMP pathway in mediating SRIF effects on proliferation and migration is suggested. Our data support the idea that SRIF regulates early trophoblast functions mainly through an interaction with SSTR2.
BACKGROUND: The aim of the present study is to investigate the levels of some of the cytokines which may be involved in the mechanisms leading to the impairment of placental perfusion and to the ...onset of uterine contractions in pregnancies with fetal genetic abnormalities compared with controls. METHODS: The amniotic fluid and maternal plasma levels of interleukin-6, interleukin-8 and tumour necrosis factor-β in patients with fetal chromosomal abnormalities were measured, as well as in euploid pregnancies in the seventh week of gestation. RESULTS: An increase of interleukin-6 (P = 0.034) and a decrease of interleukin-8 (P ≤ 0.0001) in amniotic fluid, and a decrease of interleukin-6 in the maternal plasma (P = 0.026) was shown in pregnancies with fetal chromosomal abnormalities. A positive correlation was observed between amniotic interleukin-8 and serum interleukin-6 in the presence of fetal aneuploidy (P < 0.006). CONCLUSION: Further investigations of cytokine imbalance in pregnancies with poor outcome as a consequence of genetic disorders rather that infection is warranted.
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