TSC-22D1 isoforms have opposing roles in mammary epithelial cell survival.

Transforming growth factor beta (TGFbeta)-stimulated clone-22 domain family member 1 (TSC-22D1) has previously been associated with enhanced apoptosis in several cell systems. In an attempt to identify novel factors that are involved in the control of cell death during mammary gland involution, we found that the mRNA for isoform 2 of TSC-22D1 was highly upregulated 24 h after forced weaning, when a dramatic increase in cell death occurred, closely following the expression of the known inducer of cell death during involution, TGFbeta3. This was paralleled by strongly increased TSC-22D1 isoform 2 protein levels in the luminal epithelium. In contrast, RNA and protein expression levels of the isoform 1 of TSC-22D1 did not change during development. Whereas isoform 2 induced cell death, isoform 1 suppressed TGFbeta-induced cell death and enhanced proliferation in mammary epithelial cell lines. Furthermore, four distinct forms of isoform 2 protein were detected in the mammary gland, of which only a 15-kDa form was associated with early involution. Our data describe novel opposing functions of the two mammalian TSC-22D1 isoforms in cell survival and proliferation, and establish the TSC-22D1 isoform 2 as a potential regulator of cell death during mammary gland involution.

Ethnicity and the need for correction of biochemical and ultrasound markers of chromosomal anomalies in the first trimester: a study of Oriental, Asian and Afro-Caribbean populations.

OBJECTIVES: To assess whether there is a need to correct first-trimester biochemical markers (free beta-hCG and pregnancy-associated plasma protein-A (PAPP-A)) or first-trimester fetal nuchal translucency thickness (NT) in different ethnic groups, when screening for Downs syndrome at 11-14 weeks of gestation. METHODS: Free beta-hCG, PAPP-A and fetal NT were measured at 11-14 weeks of gestation in a group of women presenting for first-trimester screening in two OSCAR centres. The group comprised 61 219 sets of data from Caucasian women (the reference group); 4835 sets of data from South Asian women; 3450 sets of data from Oriental women and 2727 sets of data from Afro-Caribbean women. The Oriental data set was supplemented with a further 480 cases collected in Hong Kong and the Afro-Caribbean data set was supplemented with 216 cases collected from Kings College. The difference in marker values between the reference group and the other ethnic groups was compared before and after weight correction for the biochemical markers using standard statistical techniques. A correction factor for ethnic origin was applied for all three markers and the screen-positive rate before and after correction was assessed for the various groups. RESULTS: After maternal weight correction, in Afro-Caribbean women, the median PAPP-A was increased by 55% and the free beta-hCG increased by 11%. In south Asian women, the PAPP-A was increased by 8% and the free beta-hCG decreased by 7.5%. In Oriental women, the PAPP-A was increased by 9% and the free beta-hCG by 6%. For delta NT in Afro-Caribbean women, the values were 0.064 mm lower on average than in Caucasian women and for south Asian women 0.045 mm lower. The difference of -0.012 for Oriental women was not significant. Before correcting for ethnic origin, these changes resulted in the screen-positive rates being lower in the Afro-Caribbean group (3.7% vs 5.6%), the south Asian group (4.3% vs 5.6%) and Oriental group (4.9% vs 5.6%). After correction, the screen-positive rates were largely similar in the four groups. CONCLUSION: Differences in median PAPP-A, free beta-hCG and, to a lesser extent, in NT exist in Afro-Caribbean, South Asian and Oriental women. In populations where the medians and delta NT reference ranges are established in predominantly Caucasian populations, some correction for ethnicity is appropriate and can redress differences in screen-positive rates between these different groups.

Transvaginal ultrasound in pregnancy: its acceptability to women and maternal psychological morbidity.

OBJECTIVES: To assess the acceptability to women of antenatal transvaginal ultrasound scans; to compare the characteristics of women who accept the offer of a transvaginal scan with those who decline; to establish the prevalence of any psychological morbidity associated with the scan. METHODS: The study was a cross-sectional questionnaire survey. Women were recruited from two hospitals in South London. The sample consisted of 755 pregnant women who had a transvaginal scan at 23 weeks' gestation to assess the risk of preterm delivery and 167 women who were offered the transvaginal scan but declined. Women completed a questionnaire at home. Those who reported finding the scan a difficult experience were sent a questionnaire 4 weeks post-scan to assess its longer term impact. The main outcomes were acceptability (assessed by individual questionnaire items); anxiety before and during the scan (Spielberger State-trait Anxiety Inventory); pain during the scan (Present Pain Intensity Scale of the McGill Pain Questionnaire); psychological trauma (Impact of Event Scale). RESULTS: Over half (55.2%) of women accepted the offer of a transvaginal scan, according to hospital records. The majority of study participants who had transvaginal ultrasound reported finding the experience acceptable. Women experienced some anxiety before and during the scan and over a third experienced some (usually mild) pain during the procedure. Twelve women (1.6%) reported clinically significant levels of psychological trauma in relation to the scan. CONCLUSIONS: Antenatal transvaginal ultrasound for assessing the risk of preterm delivery is an acceptable procedure for the majority of women. A significant minority decline the scan. The procedure has some psychological sequelae for some women.

Delta-NT or NT MoM: which is the most appropriate method for calculating accurate patient-specific risks for trisomy 21 in the first trimester?

OBJECTIVE: To assess whether in screening for trisomy 21 by nuchal translucency (NT) the delta or the multiples of the median (MoM) approach is the most appropriate method for calculating accurate individual patient-specific risks. METHODS: Data on fetal NT and crown-rump length from 128,030 unaffected and 428 trisomy 21 pregnancies, measured by sonographers who had obtained The Fetal Medicine Foundation Certificate of Competence in the 11-14-Week Scan, were used. We examined first, if the distribution of NT MoM and log(10)(NT MoM) was Gaussian; second, if the standard deviation of the distributions did not change with gestation; and third, if the median MoM in the affected population was a constant proportion of the median for unaffected pregnancies. All of these features are required to underpin the MoM approach. NT distributions and those of delta-NT were also analyzed. A non-parametric kernel density method was then used to assess the validity of both methods. Errors in the estimation of individual patient-specific risks using the MoM approach were assessed. RESULTS: In the unaffected pregnancies, the distributions of NT MoM and log(10)(NT MoM) were not Gaussian and the standard deviation of log(10)(NT MoM) decreased with gestation. In the trisomy 21 pregnancies, the median NT MoM decreased significantly with gestation, whereas the median delta-NT did not change with gestation. The non-parametric density approach showed that contours of constant likelihood ratio were parallel to the gestational age-dependent median NT values, thus supporting the delta-NT approach. The NT MoM approach resulted in women being given an overestimate of risk for trisomy at 11 weeks and a considerable underestimate of risk at 13 weeks. CONCLUSION: In the calculation of risk for trisomy 21 by NT the NT MoM approach is inaccurate and inappropriate because the underlying assumptions are not valid. In contrast, the delta-NT approach gives accurate estimates of risks.

One-stop clinic for assessment of risk of chromosomal defects at 12 weeks of gestation.

Prenatal diagnosis of trisomy 21 requires an invasive test in women considered to be at high risk after screening. At present, there are four screening tests. For a 5% false-positive rate, the sensitivities are approximately 30% for maternal age alone, 60-70% for maternal age and second-trimester maternal serum biochemical testing, 75% for maternal age and first-trimester fetal nuchal translucency (NT) scanning, and 90% for maternal age with fetal NT and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks. This article examines the methodology of first-trimester screening and summarizes the results from all studies reporting on the implementation of this method.

One-stop clinic for assessment of risk for trisomy 21 at 11-14 weeks: a prospective study of 15 030 pregnancies.

OBJECTIVE: To evaluate the performance of a one-stop clinic for assessment of risk (OSCAR) for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks of gestation. METHOD: Screening for trisomy 21 was carried out by OSCAR in 15 030 singleton pregnancies with live fetuses at 11-14 weeks. The estimated risk for trisomy 21 was calculated, and the women were counseled regarding this risk and the option of invasive testing or expectant management. Follow-up of the outcome of all pregnancies was carried out. The detection and false-positive rates for different risk cut-offs were calculated. RESULTS: Fetal NT and maternal serum free beta-hCG and PAPP-A were successfully measured in all cases. Pregnancy outcome, including karyotype results or the birth of a phenotypically normal baby, was obtained from 14 383 cases. The median maternal age of these cases was 34 (range 15-49) years and in 6768 (47.1%) the age was 35 years or greater. The median gestation at screening was 12 (range 11-14) weeks and the median fetal crown-rump length was 64 (range 45-84) mm. The estimated risk for trisomy 21 based on maternal age, fetal NT and maternal serum free beta-hCG and PAPP-A was 1 in 300 or greater in 6.8% (967 of 14 240) normal pregnancies, in 91.5% (75 of 82) of those with trisomy 21 and in 88.5% (54 of 61) of those with other chromosomal defects. For a fixed false-positive rate of 5% the respective detection rates of screening for trisomy 21 by maternal age alone, maternal age and serum free beta-hCG and PAPP-A, maternal age and fetal NT, and by maternal age, fetal NT and maternal serum biochemistry were 30.5%, 59.8%, 79.3% and 90.2%, respectively. CONCLUSION: Screening for trisomy 21 by a combination of maternal age, fetal NT and maternal serum biochemistry at 11-14 weeks can be provided in an OSCAR setting and is associated with a detection rate of about 90% for a false-positive rate of 5%.

1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.

1alpha,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone with beneficial effects on Th1 mediated autoimmune diseases. Although the inhibitory effects of vitD3 on macrophages and dendritic cells are well documented, any direct effects of vitD3 on Th cell development are not clearly defined. Using CD4(+)Mel14(+) T cells derived from mice on a BALB/c and a C57BL/6 genetic background we examined the effect of vitD3 on Th cell development. We demonstrated that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-gamma production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10 production). These effects were observed in cultures driven with splenic APC and Ag, as well as with anti-CD3 and anti-CD28 alone, indicating that CD4(+) cells can also be direct targets for vitD3. The enhanced Th2 development by vitD3 was found in both BALB/c and C57BL/6 mice. An increased expression of the Th2-specific transcription factors GATA-3 and c-maf correlated with the increased production of Th2 cytokines after vitD3 treatment. The vitD3-induced effects were largely mediated via IL-4, because neutralization of IL-4 almost completely abrogated the augmented Th2 cell development after vitD3 treatment. These findings suggest that vitD3 acts directly on Th cells and can, in the absence of APC, enhance the development of a Th2 phenotype and augment the expression of the transcription factors c-maf and GATA-3. Our findings suggest that the beneficial effects of vitD3 in autoimmune diseases and transplantation operate through prevention of strong Th1 responses via the action on the APC, while simultaneously directly acting on the T cell to enhance Th2 cell development.

Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester.

OBJECTIVES: To study the outcome of chromosomally normal pregnancies with increased nuchal translucency at the 10-14-week scan. DESIGN: Retrospective study of 1320 chromosomally normal singleton pregnancies with nuchal translucency of > or = 3.5 mm. In addition to fetal karyotyping these patients were managed with follow-up scans at 14-16 and 20-22 weeks, specialist fetal echocardiography and in selected cases by infection screening and further genetic testing. RESULTS: In the 1320 pregnancies there were 68 (5.15%) spontaneous abortions or intrauterine deaths, 18 (1.36%) neonatal and infant deaths and 154 (11.67%) terminations of pregnancy. In the 1080 (81.82%) survivors, 60 (5.56%) had abnormalities requiring medical or surgical treatment or leading to mental handicap. The chance of a livebirth with no defects in the group with nuchal translucency of 3.5-4.4 mm was 86%, for those with translucency of 4.5-5.4 mm it was 77%, for those with translucency of 5.5-6.4 mm it was 67%, and for those with translucency of > or = 6.5 mm it was 31%. CONCLUSIONS: Increased fetal nuchal translucency is associated with chromosomal abnormalities, many fetal defects and genetic syndromes. In the majority of cases a series of antenatal investigations, including fetal karyotyping, detailed scans, fetal echocardiography, as well as genetic testing and infection screening, that can be completed by 20 weeks of gestation would distinguish between the pregnancies destined to result in adverse outcome and those leading to the delivery of infants without major defects.

Accreditation of Prior (Experiential) Learning: making the difference.

This paper considers the use of Accreditation of Prior (Experiential) Learning (AP[E]L) in pre registration nurse education. AP(E)L has opened up many new prospects in post registration nurse education but opportunities for pre registration have, to date, been few. The time for change, however, is upon us all, most particularly for those institutions which have been selected to develop a new approach to nurse education referred to in Making a Difference, published by the Department of Health in 1999 and Fitness for Practice, published by the UKCC in 1999. As one of the selected sites the Institute of Health Studies at the University of Plymouth, in conjunction with the Cornwall and South Devon and Somerset and North Devon Education Purchasing Consortia, is in the process of implementing those required changes. One of the changes integral to the new curriculum is that of AP(E)L for entry to, and exit from, pre registration nurse education.

Relationships and diseases among drug users and nonusers.

Human immunodeficiency virus (HIV) and syphilis are relationship-based diseases that are typically transmitted by the cooperative activities (sex or drug injection) of two persons. A sample of 215 drug users and 52 sociodemographically matched nonusers was collected to examine the behaviors and relationships related to HIV and syphilis transmission. Results showed that, although drug users had more risk opportunities (more sex partners and, of course, more injection partners) than nonusers, actual sex risk behaviors (never using condoms) did not differ appreciably among drug users and nonusers or with opposite-sex partners and same-sex partners. The similarity of sexual risk was supported by the similar levels of syphilis between drug users and nonusers. The unique risk to drug users was drug injection, although drug users were found to engage in fewer risky injection behaviors (sharing of drug injection equipment) than the risky sexual behaviors in which all participants engaged. Although drug users interacted as frequently with partners as nonusers, nonuser relationships were longer lasting and emotionally closer.

First-trimester screening for trisomy 21 in singleton pregnancies achieved by assisted reproduction.

BACKGROUND: The possible effect of assisted reproduction on first-trimester screening for trisomy 21 was examined by fetal nuchal translucency thickness (NT), maternal serum free beta-human chorionic gonadotrophin (HCG) and pregnancy-associated plasma protein-A (PAPP-A). METHODS: Parameters were measured at 11-14 weeks in 411 singleton pregnancies achieved by controlled ovarian stimulation, including 220 that had undergone IVF. Results were compared with 1233 singleton pregnancies conceived spontaneously. RESULTS: In the IVF pregnancies, the median fetal NT was not significantly different from that in controls, whilst the median free beta-HCG was significantly increased, and PAPP-A was significantly decreased. In the intracytoplasmic sperm injection group, fetal NT and free beta-HCG values were not significantly different from those in controls, but PAPP-A was significantly decreased. In those pregnancies achieved by ovarian stimulation, neither fetal NT, free beta-HCG nor PAPP-A were significantly different from the control group. CONCLUSIONS: In IVF pregnancies, screening for trisomy 21 by fetal NT, maternal serum free beta-HCG and PAPP-A levels may be associated with a 1.2% higher false-positive rate than in natural conception.

Cervicovaginal fibronectin and cervical length at 23 weeks of gestation: relative risk of early preterm delivery.

OBJECTIVES: To establish the prevalence of cervicovaginal fetal fibronectin positivity at 23 weeks of gestation in a routine population of singleton pregnancies and determine the relative risk of spontaneous delivery before 33 weeks in women with a fibronectin positive result. DESIGN: Prospective clinical study. SETTING: Inner city antenatal clinic. POPULATION: Singleton pregnancies attending for routine antenatal care. METHODS: Cervicovaginal fetal fibronectin and cervical length were measured at 23 weeks of gestation. The distribution of fibronectin positivity within subgroups according to maternal characteristics was calculated and the relative risk of spontaneous delivery before 33 weeks was estimated. MAIN OUTCOME MEASURES: Prevalence of a fibronectin positive result and its relation to cervical length measurement and spontaneous preterm delivery before 33 weeks. RESULTS: Of 5,146 women participating in the study, 182 (3.5%) had a fibronectin positive result and 76 (1.5%) had a cervical length of < 15 mm. Fibronectin positive women were more likely to be Afro-Caribbean in origin, to have had a previous second trimester miscarriage and to have a short cervix. In the 5,068 women who were managed expectantly, the significantly independent relative risk of spontaneous delivery at < 33 weeks was 46.2 (95% CI 18.8-113.6), for cervical length of < or = 15 mm, 8.1 (95% CI 3.8-17.5) for a fibronectin positive result, and 4.4 (95% CI 2.2-9.1) for cigarette smoking. CONCLUSION: Fibronectin positivity at 23 weeks of gestation provides useful prediction of pregnancies at risk of spontaneous preterm delivery before 33 weeks, with a relative risk that is twice as high as cigarette smoking, but is a sixth of that of cervical length.

The 11-14 week scan.

Fetal nuchal translucency thickness (NT) at the 11-14 week scan has been combined with maternal age to provide an effective method of screening for trisomy 21; for an invasive testing rate of 5%, about 75% of trisomic pregnancies can be identified. When maternal serum free-beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A at 11-14 weeks are also taken into account, the detection rate of chromosomal defects is about 90%. Increased NT can also identify a high proportion of other chromosomal abnormalities and is associated with major defects of the heart and great arteries, and a wide range of skeletal dysplasias and genetic syndromes. Other benefits of the 11-14 week scan include early diagnosis of major fetal defects and the detection of multiple pregnancies, as well as reliable identification of chorionicity. As with the introduction of any new technology into routine clinical practice, it is essential that those undertaking the 11-14 week scan are adequately trained and that their results are subjected to rigorous audit.

TGF-beta1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression.

TGF-beta plays an important role in immune regulation in vivo and affects T cell differentiation in vitro. Here we describe how TGF-beta modulates Th2 development in vitro and investigate its mechanisms of action. TGF-beta down-regulated Th2 development of naive CD4+ Mel-14high T cells derived from the DO11.10 ovalbumin-specific TCR-transgenic mouse, and this was observed both in cultures driven with anti-CD3 and anti-CD28 and with splenic APC and antigen. TGF-beta down-regulated GATA-3 expression in developing Th2 and these cells showed a diminished IL-4-induced STAT6 activation. We found, however, that naive cells driven in Th2 conditions with TGF-beta did not show a significantly decreased STAT6 activation, suggesting that TGF-beta inhibits Th2 development via a STAT6-independent mechanism.

First trimester maternal serum AFP and total hCG in aneuploidies other than trisomy 21.

Total human chorionic gonadotropin (hCG) and alpha-fetoprotein (AFP) were measured in maternal serum at 10-14 weeks of gestation from 53 pregnancies affected by trisomy 18, 42 cases with trisomy 13, 46 with Turner's syndrome and 13 with other sex aneuploides. The only significant association was the finding of reduced levels of total hCG in cases of trisomy 18 and 13. The association of increased levels of AFP in cases of trisomy 18 with ventral wall defects and the slight increase in AFP in cases of sex chromosomal anomalies other than Turner's syndrome was found. AFP and total hCG are not likely to replace the markers free beta-hCG and PAPP-A in first trimester screening for chromosomal anomalies.

Should tissue from pregnancy termination and uterine evacuation routinely be examined histologically?

OBJECTIVE: To assess the value of routine histological examination of tissue samples collected at termination of pregnancy in the first trimester and emergency surgical uterine evacuation. SETTING: The gynaecological department of a teaching hospital. DESIGN: Prospective study of women attending the gynaecological department in a 12-month period. PARTICIPANTS: All women undergoing a therapeutic first trimester medical or surgical abortion or an emergency surgical evacuation of a failed pregnancy, suspected incomplete spontaneous miscarriage or incomplete induced abortion. MAIN OUTCOME: Association of pre-operative clinical diagnosis and the post-operative histological result. RESULTS: Of 1,576 women studied, the histological report confirmed that products of conception were obtained in 1,465 (93%); in two women (0.13%) molar changes were reported confirming the preoperative diagnosis by ultrasound. Products of conception were not confirmed in the tissue specimens in 0.5% medical terminations, 5% surgical terminations, 10% evacuations following a previous evacuation, 12% evacuations for a failed pregnancy, and 19% evacuations for an incomplete miscarriage. In 87 women (6%), decidua was reported; two of these women had undergone an evacuation for an ultrasound diagnosis of spontaneous miscarriage, but in both a tubal ectopic pregnancy was subsequently diagnosed. CONCLUSION: There did not appear to be any obvious benefit from routine histological examination of tissue removed at termination of pregnancy or emergency uterine evacuation. The histological result was sometimes not consistent with the pre-operative diagnosis and may result in unnecessary further investigation and treatment unless due consideration is given to the clinical presentation.

The relationship between perceived dysfunctional family-of-origin rules and intimacy in young adult dating relationships.

This study examined the relationship between perceived dysfunctional family-of-origin rules and intimacy in single young adult dating relationships. A sample of 754 single, Caucasian-American young adults completed measures of perceived dysfunctional family-of-origin rules and emotional, intellectual, and sexual intimacy in dating relationships. When controlling for the effects of gender and age, results showed that perceived dysfunctional family-of-origin rules had a negative impact on the perceived expression and experience of these three kinds of intimacy in dating relationships. Implications for relationship therapy are discussed.

Cutting edge: ectopic expression of the IL-12 receptor-beta 2 in developing and committed Th2 cells does not affect the production of IL-4 or induce the production of IFN-gamma.

The IL-12 receptor-beta 2 (IL-12R beta 2) chain is expressed on Th1 cells and lost upon differentiation to the Th2 phenotype. This has been suggested as the basis for commitment of Th1 cells, because early differentiated Th2 cells do not reverse their phenotype and do not produce IFN-gamma on restimulation in the presence of IL-12. In this study, we ectopically expressed the IL-12 receptor-beta 2 (IL-12R beta 2) bicistronically with enhanced green fluorescent protein by retroviral infection in developing and committed Th2 cells. Restimulation of Th2 cells expressing this ectopic IL-12R beta 2 in the presence of IL-12 led to levels of IL-4 production similar to those in control Th2 cells. The expression of IL-12R beta 2 in Th2 cells did not lead to significant levels of IFN-gamma production, although IL-12-mediated STAT signaling and proliferation were restored. Thus, although the IL-12R beta 2 and IL-12-dependent STAT4 activation are required for Th1 responses, activation of this pathway is not sufficient to restore a Th1 phenotype in developing or committed Th2 cells.