Antisense inhibition of BRCA1 expression and molecular analysis of hereditary tumors indicate that functional inactivation of the p53 DNA damage response pathway is required for BRCA-associated tumorigenesis

OBJECTIVE: The purpose of this investigation was to test the hypothesis that mutation of TP53 is a requirement for BRCA-associated cancer development. METHODS: A cell line experimentally deficient in BRCA1 protein was constructed using a regulatable antisense expression vector expressing 4000 bp from the BRCA1 cDNA. Changes in BRCA1, p53, and p21 protein levels were assayed by immunoblotting. Ovarian tumors with germline mutations in BRCA1 or BRCA2 were screened for mutations in TP53 by single-strand conformation polymorphism analysis. RESULTS: Antisense inhibition of BRCA1 protein caused p53 and p21 protein levels to rise, indicating that partial loss of BRCA1 function activates the p53 DNA damage response pathway. Somatic mutation of TP53 was observed in 7 of 14 BRCA-associated ovarian tumors. CONCLUSIONS: Our findings provide novel evidence that loss of BRCA1 function in human cells activates the p53 DNA damage response pathway and that loss of this pathway, by somatic mutation of TP53, is a likely requirement for BRCA-associated tumor development.     

Characterization of a TGFbeta-responsive human trophoblast-derived cell line

The placenta is formed by developing trophoblast cells to facilitate fluid, gas and nutrient exchange with the mother. Inappropriate trophoblast responsiveness can lead to life threatening complications during pregnancy including intrauterine growth retardation, pre-eclampsia, spontaneous abortion and malignancy that could lead to fetal loss. Transforming growth factor beta (TGFbeta) is a multifunctional cytokine required for embryonic development and is an important regulator of human trophoblast function. Although TGFbeta is critical for placental and embryonic development, there are currently no established TGFbeta-responsive human trophoblast-derived cell lines available to study the mechanisms by which TGFbeta regulates trophoblast function. Our studies have examined the transformed human trophoblast-derived cell line, ED27, to determine if it is responsive to TGFbeta. Our data indicate that TGFbeta dose responsively and reversibly inhibits cell growth in ED27 cells and induces classic TGFbeta response genes, fibronectin and plasminogen activator inhibitor 1 (PAI-1). TGFbeta also induces an inhibitor of trophoblast invasion, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in ED27 cells. Our studies have identified a human trophoblast-derived cell line that parallels isolated primary human trophoblasts in their responses to TGFbeta. This cell line may provide us with the opportunity to determine TGFbeta-mediated responses on human trophoblast functions not previously possible.     

Laparoscopic colposuspension

Laparoscopic urogynaecology started to develop following the first report of a laparoscopic colposuspension in 1991. The place of laparoscopic treatment of urinary incontinence has yet to be established and, as for all new techniques, case reports, case series and small randomized studies have been reported. Larger randomized studies with adequate power have yet to be reported. Current opinion is divided as to the success of these new operations. Assessment of outcome is further clouded by large variations in technique, such that like is not always compared with like. The present review assesses the recent literature and the place of the traditional colposuspension performed via the laparoscopic route.     

Predictors of Chlamydia trachomatis infection among women attending rural Midwest family planning clinics

OBJECTIVE: To determine predictors of Chlamydia trachomatis infection among women 14-24 years of age attending family planning clinics throughout a rural Midwestern state. METHODS: The study population included 16,756 women between the ages of 14 and 24 years attending family planning clinics for annual examinations throughout the state of Iowa in 1997. All women under 25 years of age having annual exams were tested for C. trachomatis during the visit. At the time of exam, both behavioral and demographic data were collected on all women participating in the study. RESULTS: The majority of women in the study (96%) reported no symptoms of chlamydia. Only 2.5% of all women had a positive test result. In the multivariate model, the odds ratios were significantly increased among the youngest age (14-17 years; OR = 2.2), those with mucopurulent cervicitis (OR = 3.4), cervical friability (OR = 2.2), symptomatic for infection (OR = 1.8), risk history (OR = 1.6), and black race (OR = 1.2) and predictive of a C. trachomatis infection. CONCLUSIONS: Risk factors predictive of C. trachomatis infection among younger aged women attending family planning clinics in a Midwest rural population are consistent with predictors of infection among women attending family planning clinics across the United States. The overall findings suggest the importance of developing screening guidelines as a means of lowering chlamydia rates. This may be a particularly difficult task in light of the low rate of symptoms that would lead a woman to seek medical care, even in younger age women who are at higher risk. In addition, screening guidelines would be more difficult to implement in a rural setting.     

Hepatitis C virus among high and low risk pregnant women in Dundee: unlinked anonymous testing

Objective To determine the prevalence of the hepatitis C virus among pregnant women, to gauge the non-injecting, particularly sexual, risk of them being hepatitis C virus infected and to assess the potential impact of selective antenatal screening.
Population Antenatal clinic attenders and women undergoing termination of pregnancy in 1997.
Setting Ninewells Hospital, Dundee.
Design Unlinked anonymous hepatitis C virus antibody testing of residual sera from specimens sent to the virus laboratory for routine serological testing. The results were linked to non-identifying risk information.
Results Overall anti-hepatitis C virus prevalence was 0.6% (23/3548). Prevalences among injecting drug users, non-injectors who had a sexual partner who injected, and those with neither risk respectively were 41% (7/17), 15% (5/33) and 0.3% (11/3498). Relative risks for being an injector and a sexual partner of an injector respectively were 131 (95% CI 58-297) and 48 (95% CI 5-32). It is estimated that one of the 18 antenatal clinic attenders gave birth to an infected child.
Conclusion Findings suggest that non-injecting partners of injectors may be at considerable risk of acquiring hepatitis C virus sexually. Efforts to promote the use of condoms among injectors and their sexual partners should be increased. Selective anti-hepatitis C virus screening of women who reported high risk behaviour would have failed to detect half the cases. Research to gauge the views of women of childbearing age on anti-hepatitis C virus testing is required.     

Rate of rise in maternal plasma corticotrophin-releasing hormone and its relation to gestational length

Objective To assess the relationship between rate of increase in maternal plasma corticotrophin-releasing hormone and gestational length.
Design A prospective observational study.
Setting Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Hong Kong.
Methods Serial venous samples taken at four to six week intervals from 81 pregnant Chinese subjects were assayed for corticotrophin-releasing hormone concentrations. The investigators responsible for the laboratory assay were blinded to the obstetric outcome.
Results A total of 380 blood samples were taken. Each subject provided three to seven samples (  median =5  ). Seven of the 81 subjects had preterm delivery. Maternal corticotrophin-releasing hormone levels increased exponentially as gestation advanced. A negative correlation between the rate of rise of logarithmic equivalence of corticotrophin-releasing hormone concentrations (Ln-corticotrophin releasing hormone) per week and the gestational age at delivery was demonstrated (  r =−0.45, P <0.001  ). The rate of increase of Ln-corticotrophin releasing hormone concentrations per week was also significantly greater for those who delivered preterm before 37 weeks compared with those with uncomplicated term deliveries (  0.27 Vs 0.22, P = 0.018  ).
Conclusions The rate of increase in maternal plasma corticotrophin-releasing hormone is inversely proportional to gestational length. Results in a Chinese population confirm and extend results from previous caucasian populations. This study provides another piece of evidence on the close link between maternal plasma corticotrophin-releasing hormone and the timing of human parturition. As the hormone is synthesized by the placenta, it supports the suggestion that the human placenta has an important role in determining gestational length.     

Evaluation of word associations as a reliable postoperative indicator of implicit memory formation during the intraoperative period.

Patients expect to receive an anesthetic that prevents the formation of memories during the intraoperative period. Unfortunately, explicit memory formation occurs 40,000 times per year in the United States, while the incidence of implicit memory is thought to be greater. The purpose of the study was to evaluate the effectiveness of word associations as a reliable postoperative indicator of implicit memory formation during the intraoperative period. Forty-eight participants scheduled to undergo general anesthesia for an elective procedure were selected. During the administration of 0.77 +/- .18 microgram/kg per minute of remifentanyl and 0.31 +/- .04 end-tidal volume percent of sevoflurane in air/oxygen, word associations in the form of "Trivial Pursuit" (Hasbro, Inc, Pawtucket, RI) game statements were presented via headphones. Within 24 hours of surgery, each participant was given a postoperative word association test that included the experimental and control word associations. No reports of explicit memory were noted. The experimental word associations were correctly answered 19.3% of the time, while the control word associations were correctly answered 12.8% of the time (P = .014). The findings illustrated that the word association test in the form of Trivial Pursuit game statements/answers may serve as a reliable postoperative indicator of implicit memory formation during the intraoperative period.