The cellular transcription factor Brn-3a and the smoking-related substance nicotine interact to regulate the activity of the HPV URR in the cervix.

The cellular transcription factor Brn-3a differentially regulates different human papilloma virus (HPV)-16 variants that are associated with different risks of progression to cervical carcinoma in infected humans. The upstream regulatory regions (URRs) of high- and intermediate-risk HPV-16 variants are activated by the cellular transcription factor Brn-3a, whereas the URR of a low-risk HPV-16 variant is not. In this study, we show in transfection assays that Brn-3a and the smoking-related substance nicotine produce stronger responsiveness of the URR of the low- and high-risk variants than with either factor alone, but not the intermediate-risk variant. We determined that this synergistic activity of Brn-3a/nicotine is due to two nucleotide differences in the URR, crucial for oncogenic E6/E7 transactivation. Mutant constructs in which the nucleotide residues were substituted alter Brn-3a/nicotine responsiveness. Importantly, women smokers with high levels of Brn-3a infected with low- or high-risk HPV-16 variants have augmented E6 levels, and were more frequently diagnosed with higher grades of cervical intraepithelial neoplasia (CIN) and cancer, as compared with non-smokers who were infected with similar variants and expressed similar levels of Brn-3a. Therefore, this study defines the specific interplay between the cellular transactivator Brn-3a, the environmental smoking-related substance nicotine and specific HPV variants in cervical carcinogenesis, and thus helps to explain why some women are susceptible to rapid CIN progression and cancer and others are not.

Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a.

The Brn-3a POU family transcription factor is overexpressed in human cervical carcinoma biopsies and is able to activate expression of the human papilloma virus type 16 (HPV-16) upstream regulatory region (URR), which drives the expression of the E6 and E7 oncoproteins. Inhibition of Brn-3a expression in human cervical cancer cells inhibits HPV gene expression and reduces cellular growth and anchorage independence in vitro as well as the ability to form tumours in vivo. Here, we show that Brn-3a differentially regulates different HPV-16 variants that have previously been shown to be associated with different risks of progression to cervical carcinoma. In human cervical material, Brn-3a levels correlate directly with HPV E6 levels in individuals infected with a high risk variant of HPV-16, whereas this is not the case for a low-risk variant. Moreover, the URRs of high- and intermediate-risk variants are activated by Brn-3a in transfection assays, whereas the URR of a low-risk variant is not. The change of one or two bases in a low-risk variant URR to their equivalent in a higher-risk URR can render the URR responsive to Brn-3a and vice versa. These results help explain why the specific interplay between viral and cellular factors necessary for the progression to cervical carcinoma only occurs in a minority of those infected with HPV-16.

Pregnancy outcome in women with pre-existing lupus nephritis.

The aim of the present study was to assess the fetal and maternal outcome in a cohort of patients with lupus nephritis. Twenty-four pregnancies in 22 women with lupus nephritis occurring between 1991 and 2000 were analysed retrospectively. Lupus nephritis was biopsy proven before pregnancy in all cases. Women were followed from the beginning of pregnancy up to 6 months postpartum. Close fetal-maternal monitoring and frequent laboratory investigations were applied routinely to all patients. All women were prescribed steroid therapy from the beginning of the pregnancy. There were 18 live births, four spontaneous abortions and two stillbirths. Of the 18 live births, 14 were premature and four were term deliveries, representing a 25% fetal loss rate and 58% prematurity rate. There were two fetuses with congenital heart block. We recorded hypertension in 42%, proteinuria in 50% and pre-eclampsia in 25% of our patients. Proteinuria was irreversible in four cases. No maternal deaths or postpartum exacerbation of the disease were recorded in the study period. All renal flares were reversed postpartum. Patients positive for antiphospholipid antibodies had a worse perinatal outcome. Hypertension, proteinuria and antiphospholipid antibodies appear to be associated with adverse perinatal outcome and pregnancy complications. Pregnancy is not contraindicated in women with lupus nephritis, but is associated with significant fetal and maternal risks.

Persistent minor smear abnormalities: is large loop excision of the transformation zone (LLETZ) the solution?

This prospective observational study was carried out to evaluate the efficacy of large loop excision of the transformation zone (LLETZ) as a management strategy for women with four or more smears showing borderline changes or mild dyskaryosis. A total of 102 women with four or more smears showing minor abnormalities and no colposcopic evidence of high-grade disease opted to undergo LLETZ in preference to continued cytological surveillance. Histology of the LLETZ specimens showed 11 cases of CIN2/3, one CGIN, 32 CIN1 and 10 HPV changes. In 97 of the 102 (95%) women, the follow-up cervical smear reverted to negative.

Detection of cervical neoplasia using measurement of Brn-3a in cervical smears with persistent minor abnormality.

Measurement of the Brn-3a cellular transcription factor in cervical smears from women referred for colposcopy may improve the detection of underlying cervical neoplasia. In those women referred with persisting borderline or mildly dyskaryotic smears, those who had histologically proven underlying CIN II/III, had statistically significant higher Brn-3a levels than those with a similar smear but histologically shown to have HPV, CIN I, or no cervical abnormality. These results indicate that Brn-3a could play an important role in the near future in improving cervical cancer screening.

How significant is a cervical smear showing glandular dyskaryosis?

OBJECTIVE: To evaluate the incidence, outcome and predictive value of cytology showing glandular dyskaryosis. PARTICIPANTS: Fifty-seven women with a smear diagnosis of glandular dyskaryosis registered between January 1997 and December 2001. SETTING: Colposcopy and cytopathology units in a large district general hospital. RESULTS: Sixty smears in 57 women showing glandular dyskaryosis were identified from a cohort of 135,120 smears, giving an incidence of 0.05%. Hospital records were available for 50 women. Final diagnosis included 13 cases of cervical glandular intraepithelial neoplasia (CGIN), 4 microinvasive cervical adenocarcinomas, 2 undifferentiated tumours, 1 microinvasive squamous carcinoma, 21 cases of CIN and 13 cases of endometrial pathology (8 endometrial cancers). Twelve women had coexistent squamous and glandular disease. Forty-five out of 50 women had significant pathology (positive predictive value 90%). Colposcopy was seen to be of limited value in assessment of smears showing glandular dyskaryosis. Only 1 out of 13 glandular lesions was diagnosed by colposcopy. CONCLUSION: Smears showing glandular dyskaryosis are associated with significant pathology in 90% of cases and malignancy in 32% of cases. Hence, women with a smear showing glandular dyskaryosis should be referred urgently to a colposcopy clinic and flagged up as suspected cancer. Glandular dyskaryosis should be included in the national referral criteria for suspected gynaecological cancer.

Vaginal intraepithelial neoplasia: report of 102 cases.

BACKGROUND: Vaginal intraepithelian neoplasia (VAIN) is a rare asymptomatic disorder. The aims of the current study were to profile patients with VAIN and to evaluate the response to treatment. MATERIAL AND METHODS: We reviewed the records of 102 patients with VAIN diagnosed from 1990 to 2000. RESULTS: Patients with VAIN, VAIN2 and VAIN3 had the following mean ages 44.5, 47.8 and 61.8 years, respectively (p < 0.001). All patients with VAIN were found to have abnormal Papanicolaou smears. Localization of the lesions to the upper third of the vagina was observed in 80% of the cases. Recurrences following laser ablation and partial vaginectomy reached 21%. Patients with minimal VAIN lesions from whom punch biopsies were obtained had the lowest recurrence rate. Multifocality significantly affected the risk of recurrence (p = 0.03). CONCLUSION: VAIN most often involves the upper third of the vagina and is often multifocal. Patient selection and operator skill have a significant influence on the treatment outcome.