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PubMed2006

From concept to practice: the recent history of preterm delivery prevention. Part II: Subclinical infection and hormonal effects.

Under the new cervical insufficiency postulate, the final common pathway theoretically may be influenced by multiple interventions including not only cerclage, but also antibiotics, anti-inflammatory drugs, or progesterone. Since the late 1970s, accumulating evidence has implicated intrauterine infection as a cause of preterm labor. The use of antimicrobial therapy for the prevention of preterm delivery (PTD), although plausible and appealing, has remained largely ineffective so far. A decade of antimicrobial intervention trials to prevent infection-mediated PTD has had disappointing results. Several randomized clinical trials have assessed the role of bacterial vaginosis (BV) treatment in prevention of PTD. The inconsistent results of these trials suggest that other processes, possibly immunomodulation, may be important. Additional factors, still unidentified, pertaining to infectious agent virulence or host immune response modulation, may be responsible for the increased risk of PTD in only a small subset of pregnant women with BV. Even a particular genetic susceptibility was proposed as an intervening factor in the correlation between BV and PTD. Autocrine, paracrine, and endocrine processes in the fetal-placental-uterine unit may contribute to the premature activation of parturitional mechanisms. Progesterone has been used in an attempt to prevent PTD since the 1970s, but the evidence accumulated until the 1990s was fraught by mixed results, and was based mostly on underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. Two recent randomized, controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone treatment may influence favorably the rate of preterm delivery, as well as perinatal mortality and morbidity. A major impediment in accepting progesterone as the magic bullet in the prevention of PTD is that its mechanism of action is less well understood than that of all the other prophylactic measures discussed in this review. The optimal formulation, route of administration, dose, and gestational age at initiation have yet to be established. Our ability to quantify prospectively the risk of PTD in a given patient is limited. Moreover, there are limited evidence-based strategies available for prevention of PTD, reflecting our incomplete understanding of the nature of preterm labor. Although an effective instrument in PTD prevention is still elusive, the studies conducted so far have led to a shift in our understanding of cervical insufficiency, infection-mediated PTD, and hormonal influences in human parturition.

Anti-Infective Agents↗

PubMed2004

Evidence for multiple cycles of strand invasion during repair of double-strand gaps in Drosophila.

DNA double-strand breaks (DSBs), a major source of genome instability, are often repaired through homologous recombination pathways. Models for these pathways have been proposed, but the precise mechanisms and the rules governing their use remain unclear. In Drosophila, the synthesis-dependent strand annealing (SDSA) model can explain most DSB repair. To investigate SDSA, we induced DSBs by excision of a P element from the male X chromosome, which produces a 14-kb gap relative to the sister chromatid. In wild-type males, repair synthesis tracts are usually long, resulting in frequent restoration of the P element. However, repair synthesis is often incomplete, resulting in internally deleted P elements. We examined the effects of mutations in spn-A, which encodes the Drosophila Rad51 ortholog. As expected, there is little or no repair synthesis in homozygous spn-A mutants after P excision. However, heterozygosity for spn-A mutations also resulted in dramatic reductions in the lengths of repair synthesis tracts. These findings support a model in which repair DNA synthesis is not highly processive. We discuss a model wherein repair of a double-strand gap requires multiple cycles of strand invasion, synthesis, and dissociation of the nascent strand. After dissociation, the nascent strand may anneal to a complementary single strand, reinvade a template to be extended by additional synthesis, or undergo end joining. This model can explain aborted SDSA repair events and the prevalence of internally deleted transposable elements in genomes.

Animals↗

PubMed1998

Prenatal sonographic diagnosis of skeletal dysplasias--a report of the diagnostic and prognostic accuracy in 35 cases.

Sonographic assessment of the skeleton is a routine part of fetal anomaly scanning. We report a series of 35 cases seen during a 7-year interval in which a skeletal dysplasia was suspected prenatally. In seven (20 per cent) of the 35 cases, a specific diagnosis could not be made either pre- or postnatally. Follow-up was incomplete in one case. In 32 (91 per cent) of the 35 cases, prenatal sonographic examination correctly predicted the prognosis, although in only 11 (31 per cent) of the 35 cases was the suggested prenatal diagnosis proven to be correct. The difficulty of making an accurate prenatal sonographic diagnosis in fetuses with suspected skeletal dysplasias throughout gestation, especially in the third trimester, and the importance of comprehensive multidisciplinary postnatal assessment in these cases are emphasized.

Abortion, Induced↗

PubMed2003

Umbilical cord lesions in early intrauterine fetal demise.

CONTEXT: The cause for intrauterine fetal demise (IUFD) occurring in early gestation in a high percentage of spontaneous abortions is unknown. OBJECTIVE: To determine the association, if any, of umbilical cord abnormalities with early IUFD. DESIGN: All cases of IUFD occurring within 16 weeks of gestation that presented to our hospitals between August 1998 and July 2001 were prospectively studied. Once the fetal demise was diagnosed, pregnancy was terminated by medical induction, such that the products of conception were largely delivered intact. Cases with an intact umbilical cord connecting the fetus and placenta were considered in the study, whereas disrupted cord and curettage material was excluded from the study. RESULTS: A total of 153 early IUFD cases were seen during the period of study. The medical induction yielded intact products of conception in 122 cases, whereas 31 cases had to be completed by curettage, as the expulsion of the conceptus was incomplete. Thirteen of the 122 IUFD cases showed abnormalities of the umbilical cord. The cord lesions most frequently encountered were constriction and coiling abnormalities. Other lesions seen included hemorrhage, thrombosis, edema, and amniotic band. CONCLUSIONS: A significantly high number (10.7%) of IUFD in early gestation are associated with umbilical cord abnormalities. Routine assessment of umbilical cords in early pregnancy might help to detect pregnancies at risk.

Edema↗

PubMed2000

Changes in the 17 bp spacer in the P(R) promoter of bacteriophage lambda affect steps in open complex formation that precede DNA strand separation.

Tau plots and temperature-shift experiments were used to determine which step in the formation of transcriptionally-competent open complexes is affected by changing the length of the 17 bp spacer separating the -10 and -35 consensus regions of the P(R) promoter of bacteriophage lambda. Abortive initiation assays at 37 degrees C indicate that the primary effect of insertion of a base-pair, thereby increasing spacer length to 18 bp, is a decrease in k(f), the rate constant for conversion from closed (RP(c)) to open (RP(o)) complexes, by approximately a factor of 4. The mutation did not significantly affect K(B), the equilibrium constant for formation of closed complexes, and decreased K(B)k(f) by a factor of 3. Deletion of a bp to create a 16 bp spacer had a much greater effect, decreasing the measured value of k(f) by a factor of about 25 to 30, and K(B)k(f) by a factor of 7 to 8. When the values of the parameters for the deletion mutant were corrected for incomplete occupancy of RP(o) at equilibrium, the effects of the deletion were even greater. In particular, the corrected value of K(B)k(f) was about 15 times lower than the corresponding value for two promoters with wild-type spacing. Based on temperature shift experiments, the changes in spacer length did not affect the equilibrium at 20 degrees C between RP(i), a stable intermediate in which DNA strands are not separated, and RP(o). Although differential sensitivity of single-stranded bases to KMnO(4) indicated that in about 20% of the open complexes at 20 degrees C the DNA strands are not fully separated (RP(o1)), the distribution between these complexes and RP(o2) (DNA strands fully separated) was also not affected significantly by changes in spacer length. Thus, changes in spacer length primarily affect k(2), the rate constant for conversion of RP(c) to RP(i), which corresponds to a nucleation of DNA strand-separation. Application of published data and/or algorithms for determining effects of nucleotide sequence on twist angle or rise at individual bp steps does not provide a simple explanation of the difference in promoter strength between P(R) derivatives with 16 bp spacing and those with 18 bp spacing.

Algorithms↗

PubMed2002

Bacterial vaginosis in pregnancy.

Bacterial vaginosis is associated with adverse pregnancy outcomes across all gestational ages. It is linked to first and second trimester fetal loss, chorioamnionitis, preterm delivery, low-birthweight infants and maternal/neonatal infectious morbidity. Infants who survive preterm birth are at an increased risk of subsequent neurodevelopmental delays and handicap, more so if there was underlying choriomnionitis. The exact mechanisms and pathways through which bacterial vaginosis exerts these adverse effects are incompletely understood. Not surprisingly, intervention studies in bacterial vaginosis-positive pregnant women have shown conflicting results, both in women at high and low risk of preterm birth. A much better understanding of the pathobiology of bacterial vaginosis in pregnancy is required to focus the designs of intervention studies on the disturbed cellular and biochemical pathways. Such studies may address the benefits of the treatment of bacterial vaginosis before conception and during early pregnancy, to determine whether treatment in populations of pregnant women may be beneficial.

Abortion, Spontaneous↗

PubMed1996

Holoprosencephaly and chromosomal anomalies.

Holoprosencephaly is a rare cerebral malformation resulting from failure or incomplete cleavage of the forebrain. The sonographic diagnosis consists of monoventricle, fused thalami and absent cavum septum pellucidi. Chromosomal anomalies, diabetes mellitus, alcohol, autosomal recessive inheritance and toxins have been implicated. We describe seven cases of holoprosencephaly diagnosed in the antenatal and postnatal periods. The chromosomal anomalies included trisomy 13, triploidy, trisomy 13 with an unbalanced 13; 14 translocation and isochromosome of the long arm of 18. The clinicopathological findings and chromosomal anomalies are correlated.

Abortion, Therapeutic↗

PubMed1991

Ultrastructure of human retinal cell transplants with long survival times in rats.

Human fetal retinas (6-12 weeks post-conception) were obtained from elective abortions, transplanted to rat retinas and examined by electron microscopy. The oldest transplants that form the basis of this report were obtained 40 and 41 total weeks post-conception. The host rats were immunosuppressed with cyclosporin A. The transplants developed according to their intrinsic, genetically determined timetable. The development was heterogeneous with some parts showing almost normal differentiation and others, little. Both rods and cones developed with inner and outer segments and synaptic terminals. In regions corresponding to the inner plexiform layer, bipolar cell processes were seen in the typical dyad arrangement. Likewise, amacrine cell processes formed typical conventional synapses. Serial synapses were seen, engaging amacrine cell synapses as well as a few reciprocal synapses at the bipolar cell dyads. Monad-type synaptic complexes, a sign of immaturity, were common in bipolar cell processes. Similarly, incompletely differentiated synapses of both the amacrine and bipolar cell types were often observed. Ganglion cell processes could not be identified with certainty. A structure with morphological characteristics similar to the inner limiting membrane was noted to form inside the transplant. Both epi-retinal and sub-retinal transplants were obtained. Transplant cells touched host photoreceptor cells or pigment epithelium without any obvious specializations. The host pigment epithelium microvilli were absent adjacent to the graft. However, graft cells did appear in the host retina, and nerve cell processes were observed to cross the membrane separating the transplant and host.

Animals↗

PubMed2004

Brugada syndrome--an under-recognized electrical disease in patients with sudden cardiac death.

In 1992, Brugada and Brugada described 8 patients with a history of aborted sudden death and a distinct ECG pattern of right bundle-branch block with ST segment elevation in leads V1-V3 and normal QT interval in the absence of any structural heart disease. It is called Brugada syndrome now and is believed to be responsible for 4-12% of all sudden deaths and around 20% of deaths in patients with structurally normal hearts. Although this syndrome is observed worldwide and the exact prevalence is unknown, it is more common in the Southeast Asian countries. Repeated syncope, ventricular fibrillation, and sudden cardiac death have been reported in patients with Brugada syndrome. The clinical presentation of Brugada syndrome is distinguished by a male predominance and the appearance of arrhythmic events at an average age of 40 years. The Brugada syndrome is inherited in an autosomal dominant manner with incomplete penetrance and an incidence ranging between 5 and 66 per 10,000. The surface ECG manifestations of the syndrome can transiently disappear, but can be unmasked by potent sodium channel blockers in some cases. Mutations of the cardiac sodium channel SCN5A have been detectable in <20% of patients with Brugada syndrome. Recent genetic studies have confirmed the genetic heterogeneity of the disorder. Antiarrhythmic drugs appear to be of little use in prolonging survival and in preventing recurrences of ventricular arrhythmias. To date, implantable cardioverter defibrillator remains the best therapy to prevent sudden death in these patients.

Action Potentials↗

PubMed1975

[Present situation of prenatal diagnosis of neural tube defects].

Anencephaly and spina bifida both are malformations of unknown etiology which are caused by an absent or incomplete closure of the neural tube. The risk of recurrence for the malformations is 5% in families with one child with a neural tube defect and 10%, if two such children have already been born. Neural tube defects can be diagnosed already before 20th week of gestation by ultrasonics and alpha-fetoprotein measurement in amniotic fluid, if an underdeveloped neurocranium or a free communication between amniotic and cerebrospinal fluid is present. By these diagnostic techniques and possibly following interruption the probability in risk families can be significantly lowered.

Abortion, Legal↗

PubMedDate not supplied

[Investigation of subalin effect on urogenital microflora of pregnant women].

Bacteriological examination of 30 women with incomplete pregnancy has been conducted. Representatives of 18 genera of aerobic and anaerobic bacteria as well as yeast-like fungi of Candida genus were found. It has been established that spore-forming bacteria of the Bacillus genus from subalin preparation have antagonistic activity in respect of the strains of pathogenic and opportunistic bacteria with characteristic zones of growth depression of 12-15 mm. This demonstrates that the agents of infectional urogenital process are effectively suppressed by subalin.

Abortion, Threatened↗

PubMed1994

Atelencephalic aprosencephaly.

Absence of the telencephalon and diencephalon characterizes the syndrome of aprosencephaly, while in atelencephaly, only the telencephalon is absent. Atelencephalic aprosencephaly is characterized by the presence of at least a rudimentary diencephalon. Embryologically, aprosencephaly is thought to occur after the optic vesicles form but before the cerebral vesicles appear. The syndrome is quite rare, with only 10 cases previously reported. We describe two fetuses with atelencephalic aprosencephaly. A 25-week estimated gestational age fetus was born to first-cousin parents and had a prenatal ultrasonographic diagnosis of anencephaly. The second, a 19-week estimated gestational age fetus, was thought to have semilobar holoprosencephaly by prenatal ultrasound. At autopsy, neuropathologic examination in both cases showed virtual absence of the cerebral hemispheres with an incomplete diencephalon. Microscopic examination in one case revealed disorganized neuropil with a proliferative vasculopathy. The optic globes were completely formed and attached to hypoplastic optic nerves, but retinal dysplasia was apparent histologically in both cases, and bilateral colobomata were present in one case. The findings in these cases demonstrate a spectrum of congenital variations that lie between the syndromes of atelencephaly and aprosencephaly, underscoring the complexity of the congenital anomalies.

Abnormalities, Multiple↗

PubMed1982

Differentiation of the mammary gland and susceptibility to carcinogenesis.

It has been demonstrated that in humans certain factors such as early menarche, late pregnancy, and nulliparity are associated with a higher risk of developing breast cancer, while early pregnancy acts as a protective factor. Induction of mammary cancer in rats by administration of the chemical carcinogen 7,12-dimethylbenz(a)anthracene reveals that the same factors influencing human breast cancer risk also affect the susceptibility of the rat mammary gland to the chemical carcinogen. Nulliparous rats and rats undergoing pregnancy interruption are more susceptible to developing carcinomas. This fact has been attributed to the incomplete differentiation of the gland at the time of carcinogen administration. Parous rats are resistant to the carcinogenic effect of DMBA, which is explained by the complete development of the gland attained during pregnancy and lactation. This development is manifested by the differentiation of terminal end buds into secretory units, which have a smaller proliferative compartment; the epithelial cells of these secretory units have a longer cell cycle, less avidity for binding DMBA, and possess a more efficient DNA excision repair capacity.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1996

Fertility with testicular sperm extraction and intracytoplasmic sperm injection in non-obstructive azoospermic men.

In non-obstructive azoospermia spermatozoa can usually only be isolated from the testicles, and thus the most promising treatment model is testicular sperm extraction (TESE). Hormone concentrations, testicular volume determinations and testicular biopsy results are not uniform enough to select potential candidates for successful TESE and intracytoplasmic sperm injection (ICSI) approaches in advance. The aim of this study was to assess the efficacy of using ICSI with testicular spermatozoa in cases of non-obstructive azoospermia and to compare the inclusion criteria and sperm existence in the testicles in sperm obtainable and non-obtainable groups. All men showed either complete or incomplete (n = 14) maturation arrest in spermatogenesis, severe hypospermatogenesis (n = 10) or Sertoli cell-only syndrome (n = 5) in their testicular biopsies. Only 14 out of a total of 29 men provided enough spermatozoa for the ICSI procedure, while no spermatozoa were found in the testicular samples of the remaining 15 men. Out of 123 oocytes obtained from 14 females, 101 were injected with the husbands' testicular sperm cells. Total fertilization failure was observed in three cases. Of 39 oocytes fertilized, 38 cleaved. The fertilization and cleavage rates were 38.6 and 97.4% respectively. The pregnancy rate was 20.7% per initiated cycle. In the group from whom spermatozoa were obtainable, the pregnancy rate was 42.9% per initiated cycle and 54.5% per embryo transfer. A total of six pregnancies were achieved, of which two were twins and four were singletons. One singleton pregnancy resulted in abortion in the first trimester. There was no statistical difference concerning the serum follicle stimulating hormone concentration, testicular volume and biopsy results in groups in which spermatozoa were obtainable or not. In conclusion, although the association of TESE with ICSI obtained pregnancies for some patients with non-obstructive azoospermia, further studies are needed to determine the inclusion criteria for successful TESE.

Adult↗

PubMed2003

Nuclear reprogramming of cloned embryos produced in vitro.

Despite the fact that cloned animals derived from somatic cells have been successfully generated in a variety of mammalian species, there are still many unsolved problems with current cloning technology. Somatic cell nuclear transfer has shown several developmental aberrancies, including a high rate of abortion during early gestation and increased perinatal death. One cause of these developmental failures of cloned embryos may reside in the epigenetic reprogramming of somatic donor genome. In mammals, DNA methylation is an essential process in the regulation of transcription during embryonic development and is generally associated with gene silencing. A genome-wide demethylation may be a prerequisite for the formation of pluripotent stem cells that are important for later development. We analyzed methylation patterns in cloned bovine embryos to monitor the epigenetic reprogramming process of donor genomic DNA. Aberrant methylation profiles of cloned bovine embryos were observed in various genomic regions, except in single-copy gene sequences. The overall genomic methylation status of cloned embryos was quite different from that of normal embryos produced in vitro or in vivo. These results suggest that the developmental failures of cloned embryos may be due to incomplete epigenetic reprogramming of donor genomic DNA. We expect that advances in understanding the molecular events for reprogramming of donor genome will contribute to clarify the developmental defects of cloned embryos.

Animals↗

PubMed1994

Circulating levels of placental protein 14 in ectopic pregnancy.

OBJECTIVE: To determine circulating levels of placental protein 14 (PP14) in complications of early pregnancy. DESIGN: Biochemical monitoring of women presenting with vaginal bleeding and/or abdominal pain. SETTING: An emergency gynaecological ultrasound clinic in a London teaching hospital. SUBJECTS: Venous blood samples were obtained from 67 women with normal pregnancy (n = 9), ectopic pregnancy (n = 26) and failed intrauterine pregnancy (n = 32). This group included anembryonic pregnancy (n = 18), missed miscarriage (n = 2), spontaneous miscarriage of a previously demonstrated live fetus (n = 6), incomplete miscarriage (n = 4), complete miscarriage (n = 1) and molar pregnancy (n = 1). MAIN OUTCOME MEASURES: Serum PP14 levels in the group of women with a failed intrauterine pregnancy in relation to the normal range for PP14. RESULTS: Eighty-one percent of women who miscarried spontaneously had normal serum PP14 levels; 81% of women with ectopic pregnancy had depressed (< 5th centile) serum PP14 levels. CONCLUSION: Measurements of PP14 may be useful in distinguishing spontaneous miscarriage from ectopic pregnancy, but not in the management of threatened miscarriage.

Abdominal Pain↗

PubMed1996

Occupational hazards for the male reproductive system.

The etiology of male infertilities is largely undetermined, and our knowledge of exogenous factors affecting the male reproductive system is still limited. In particular, the role of specific environmental and occupational factors is incompletely elucidated. Various occupational (physical and chemical) agents have been shown to affect male reproductive functions in animals, but large differences in reproductive function and/or xenobiotic handling between species limit extrapolation to humans. When available, human data are often conflicting and, except in a few instances, usually refer to broad and heterogenous occupational categories or to groups of agents (e.g., solvents). It is often difficult to elucidate the role of a single agent because occupational exposure conditions are often complex and various confounding factors related to lifestyle (smoking, alcohol, and diet) or socioeconomic state may also affect sperm quality, fertility, or pregnancy outcomes. The objective of this work is to summarize the main epidemiological and, where relevant, experimental findings pertaining to agents (physical and chemical) encountered in the occupational environment that might affect the male reproductive system (sperm count, motility and morphology, libido, and fertility) and/or related pregnancy outcomes (spontaneous abortion, stillbirth, low birth weight, and birth defects and childhood malignancy in offspring). Some methodological issues related to research on the reproductive effects of toxicants are also discussed briefly.

Anesthetics↗

PubMed1979

Psychologic aspects of gynecology and obstetrics.

In the preceding pages, an attempt has been made to emphasize some of the more important psychologic aspects of gynecology and obstetrics. This review should be considered incomplete and the interested reader should refer to the many excellent papers and reviews on each of the topics mentioned and many more not mentioned. If there is any one guiding principle, it is that the obstetrician-gynecologist, more than most specialists, must be able to listen to and to hear the fears and anxieties of his or her patients. The need to include the patient as a partner with a controlling interest in her care is paramount. The gynecologist-obstetrician can truly become the patient's primary physician in the finest sense of the word.

Abortion, Induced↗