Coexposure to benzo[a]pyrene plus ultraviolet A induces 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in human skin fibroblasts: preventive effects of anti-oxidant agents

The influence of environmental benzo[a]pyrene (BaP) contamination under ultraviolet A (UVA) on normal human skin fibroblasts was examined. Treatment of human skin fibroblasts with UVA in the presence of BaP induced cytotoxicity in a UVA- and BaP-dose-dependent manner, involving oxidative DNA damage (formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG)). Singlet oxygen quenchers significantly inhibited the formation of 8-oxo-dG, whereas hydroxyl radical and superoixide anion radical scavengers showed no effect. N-Acetyl-l-cysteine prevented the formation of 8-oxo-dG. These findings suggested the possibility of increased carcinogenesis in the skin via singlet oxygen produced by sunlight plus environmental BaP contamination and the efficiency of anti-oxidant agents for its prevention.     

Hysteroscopic assessment of menopausal breast-cancer patients taking tamoxifen; there is a bias from the mode of endometrial sampling in estimating endometrial morbidity?

The aim of this study is to evaluate the accuracy of hysteroscopy in detecting tamoxifen-associated endometrial morbidity. Ninety-eight menopausal breast cancer patients taking tamoxifen underwent hysteroscopy because of an endometrial thickness above 4 mm measured by Transvaginal Ultrasonography. Thirty-one women recorded uterine bleeding while 67 were asymptomatic. Hysteroscopies with operative facilities were performed, mainly in out-patient setting. Hysteroscopic findings were matched with histopathology derived from various modalities of tissue collection as suction-curettage, oriented-streak curettage, hysteroscopically-targeted biopsies or polypectomies and hysterectomies. Accuracy of hysteroscopy to estimate a normal or abnormal endometrium was calculated. Abnormal endometrium was detected in 35 patients (64.5% in symptomatic and 22.3% in asymptomatic women, P < 0.001). We found six carcinomas, 18 polyps and 11 hyperplasias. Hysteroscopy showed sensitivity and specificity of 89.2 and 98.4%, respectively. By blind sampling, tissue collection was too scant to give a diagnosis in 29.1% of patients and in 80.5% of patients in whom hysteroscopy showed cystic atrophy the pathologist failed to confirm this condition. Moreover, eight endometrial polyps (36.3%) detected by hysteroscopy were missed. Conversely, by tissue sampling under vision no inadequate specimen was sent to the pathologist and all hysteroscopies showing cystic atrophy and polyps were pathologically confirmed. From literature data, the detection-rate of endometrial pathology in tamoxifen users varies from the lowest to the highest prevalences whether blind or hysteroscopically-targeted modalities of tissue sampling were used, respectively. Hysteroscopy with targeted sampling appears to be the most effective method to assess the endometrial lining. In our experience it is safe, well tolerated and it should be considered the reference test to assess a thickened endometrium in women under tamoxifen.     

Carboplatin plus taxol is an effective third-line regimen in recurrent undifferentiated nasopharyngeal carcinoma

BACKGROUND: Recurrent undifferentiated nasopharyngeal carcinoma is a chemosensitive disease. Few third-line treatments have been reported. METHODS: Twelve patients (9 males, 3 females; median age 50 years, range, 20-62) with recurrent undifferentiated nasopharyngeal carcinoma were treated with carboplatin AUC 5.5 + paclitaxel (175 mg/m2, 3-hr infusion) on day 1 every 3 weeks. All patients had been previously treated for recurrent disease with a first-line cisplatin-based chemotherapy and a second-line therapy with low-dose continuous infusion 5-fluorouracil. RESULTS: Overall, 54 courses were given (median, 5; range, 2-6). Three patients (25%) obtained a partial response lasting 6, 10 and 26+ months, 1 (8.3%) a minimal response lasting 6 months, and 3 (25%) no change with a median duration of 5 months. The median survival time was 14 months for patients who had a partial or minimal response or no change, and 5 months for nonresponders. Median overall survival was 9.5 months (3-30+). The treatment was well tolerated, and toxicity was manageable. CONCLUSIONS: The combination has a good palliative role as third-line chemotherapy in recurrent undifferentiated nasopharyngeal cancer.     

Health-related quality of life among the least dependent institutional elderly compared with the non-institutional elderly population

The purpose of this study was to investigate health-related quality of life (HRQOL) and functional ability among the least dependent elderly in residential care, and to compare them with information on the general population. A stratified systematic sample (n=1,587) was drawn from a one-day census of patients in all public residential homes in Finland on December 2, 1991. Sixty-nine per cent of residents in 1992 were able to participate (n=1,097) and 86% of them returned the questionnaire (n=948), of which n=795 were acceptable, the response rate being 72%. A postal survey was used for data collection. The personnel of residential homes were allowed to help residents complete the questionnaire, and 90% of respondents received such help. HRQOL was measured by the Nottingham Health Profile (NHP) and functional ability by a 14-item questionnaire. Finnish studies among the general population were used for comparisions. According to the NHP, the HRQOL appeared lower in institutional care and this was associated with the dependency level. Similarly, for most ADL items the general population had less restrictions than the least dependent residential care patients. In general, women expressed more difficulties in physical mobility and lack of energy than men. The longest stay elderly expressed better HRQOL. In multivariate models adjusted for age and gender those with poor vision had worse HRQOL in almost every dimension of NHP. Difficulties in speech were connected with emotional reactions and social isolation. Chronic illness limiting normal daily life predicted more problems in energy, pain, physical mobility, and emotional reactions. The married or widowed experienced less social isolation than single elderly. Higher education was related to better HRQOL in all NHP dimensions. Poorer perceived health was associated with lack of energy, pain, and emotional reactions. We conclude from these results that there are only a few clients in residential care whose HRQOL or functional ability compare with the non-institutionalized population.     

Bovine seminal ribonuclease is cytotoxic for both malignant and normal telomerase-positive cells

Bovine seminal-ribonuclease (BS-RNase) is a member of the 'ribonucleases with special biological actions' family since it possesses specific anti-tumour, anti-spermatogenic and embryotoxic activities and exerts an immunosuppressive effect on T lymphocytes. In previous studies it was demonstrated that BS-RNase induced apoptosis in proliferating, malignant and normal cells and that telomerase activity loss also caused apoptotic death in neoplastic cells. Since an obvious relationship between cell proliferation and telomerase activity exists, the aim of this work was to study if the pro-apoptotic cytotoxic action exerted by BS-RNase on proliferating malignant cells (HT29) and proliferating normal cells (PHA-stimulated lymphocytes) could be linked to a possible BS-RNase effect on telomerase activity. In BS-RNase-treated HT29 cells (Na-butyrate-differentiated or not) and human lymphocytes (proliferating or not), we investigated cell vitality (MTT method) and morphology (SEM), BS-RNase localization (immunofluorescence), telomerase activity (TRAP-ELISA method), hTR mRNA expression (RT-PCR), and hTERT levels (western blot). While no BS-RNase effect was detectable on not proliferating cells, a clear relationship was noticed between the diminished number of vital elements of both proliferating cell populations after treatment (48 h and 72 h for HT29 and PHA-stimulated lymphocytes, respectively) with 50 microg/ml BS-RNase and the decrease of their telomerase activity. At the same time, we found that hTR levels, the RNA subunit of telomerase, in proliferation-inhibited BS-RNase-treated cells were diminished. Moreover, by immunofluorescence technique, we detected BS-RNase in the HT29 cell nucleolus after 3-h treatment. Therefore, as hTR has been recently proven to co-fractionate with nucleoli, we hypothesize that a BS-RNase direct action on the telomerase hTR subunit could be a possible mechanism of action by which BS-RNase exerts its pro-apoptotic effects only on proliferating cells.     

Cx26 gene mutations in idiopathic progressive hearing loss

OBJECTIVE: The present study evaluated the frequency and type of mutations throughout the entire GJB2 region in a population of 39 patients affected with sporadic progressive "idiopathic" hearing loss. MATERIAL: A large series of patients suffering from progressive hearing loss underwent a systematic screening program to identify the etiology of the hearing loss. Of these patients, 39 presented with sporadic idiopathic progressive hearing loss and were included in this study. METHOD: We performed molecular analysis of GJB2 in each patient sequencing the genomic deoxyribonucleic acid (DNA) in both directions for detection of GJB2 mutations. Furthermore, in all patients bearing a Cx26 mutation, a search was also conducted for mutations or deletions of GJB6 (Cx30 gene) and for the A1555G mutation of the mitochondrial DNA. A control group was also considered to evaluate the frequency of Cx26 mutations in the normal population. RESULTS: A Cx26 gene mutation was detected in nine cases. One subject was found to bear a homozygous genotype for the 35delG mutation, another subject was compound heterozygous for 35delG and E47X, and the remaining patients showed heterozygous genotypes (35delG, L90P, R127H, M34T, V153I, V37I). No mutation or delection of the Cx30 gene was observed in these nine patients, and none of them presented with the A1555G mutation in the mitochondrial DNA. In the control group (40 individuals), a Cx26 mutation was detected in two cases (5%). CONCLUSIONS: About 23% of our patients (nine subjects) presented with mutations in GJB2, and 18% (seven subjects) were heterozygous. However, most of the described mutations are recessive, so a monogenic model of inheritance cannot explain the deafness phenotype. On the basis of these findings, we can speculate that the heterozygote Cx26 genotype could be a cause of progressive hearing loss, probably in association with mutations in other alleles. Thus, we recommend carefully following all hearing-impaired subjects with GJB2 mutations, even if they present with only mild hearing loss, because the hearing deficit could worsen. Furthermore, molecular analysis of the Cx26 gene should also be performed in adult patients affected with idiopathic progressive hearing loss.     

Loss of PNA staining in mouse aortico-pulmonary septum is associated with mesenchymal cell apoptosis

Massive apoptosis of mesenchymal cells in the septum of the aortico-pulmonary trunk was found in mouse fetuses at stage 14.5 dpc. It was associated with the appearance of cavities in the mesenchymal tissue, presumably due to cell loss, a strong reduction in the extent of lectin PNA staining, and the induction of metallothioneins in specialized mesenchymal cells. Cell loss was spatially restricted to an inner area of the septum and was due to a distinct apoptotic pattern of cells, different from that in the heart wall. These events led to a rapid reduction of the aortico-pulmonary septum as occurs during the late stages of heart morphogenesis. It coincided with the migration of other cell types that invaded the cell-depleted septum, and contributed to the histiogenesis of the mature heart.