Outcome of surveillance and prophylactic salpingo-oophorectomy in asymptomatic women at high risk for ovarian cancer

OBJECTIVE: Women at high risk of ovarian cancer are currently offered two options: either surveillance or prophylactic bilateral salpingo-oophorectomy. The efficacy and outcome of surveillance remain unclear. METHODS: We performed a retrospective study. Between 1994 and 2000, we screened 383 high-risk women, of which 152 were BRCA1/2 mutation carriers. Surveillance consisted of annual gynecological examination, transvaginal ultrasound, and serum CA125 measurement. Exploratory or prophylactic surgery was performed in selected cases. RESULTS: There were no screen-detected primary ovarian cancers. Abnormal results at surveillance were observed in 74 (19.3%) of women; in 47 (63.5%), the abnormalities disappeared spontaneously. Exploratory surgery was performed in 20 (27.0%) women in whom one malignancy was found (metastatic breast cancer in the ovary). A rising CA125 value prompted further (non-surgical) evaluation in three women with a history of breast cancer: recurrent breast cancer was diagnosed in two women; in the third, a chondrosarcoma was found. 133 women opted for prophylactic bilateral salpingo-oophorectomy, whereby two unexpected malignancies were found (fallopian tube cancer and metastatic breast cancer). One interval primary ovarian cancer occurred, presenting as papillary serous carcinoma of the peritoneum 14 months after prophylactic bilateral salpingo-oophorectomy. Complications of prophylactic surgery were encountered in 15 (11.5%) women. CONCLUSIONS: Ovarian cancer surveillance has limited sensitivity, and a high number of false positive findings. This can lead to unnecessary surgical interventions, possibly resulting in surgery-related complications. It is important to inform high-risk women of these limitations. For now, prophylactic bilateral salpingo-oophorectomy remains the optimal risk-reducing strategy for women at high risk.     

Characterization of endotoxin and mouse allergen exposures in mouse facilities and research laboratories

OBJECTIVES: Researchers and technicians who use mice in research are exposed to complex mixtures containing mouse allergen, endotoxin and particulates from animals, bedding and feed. The particle characteristics of these different exposures, and whether they are encountered together or separately, are important to better understand their adjuvant and allergic effects. Endotoxin and mouse allergen are derived from the same animal source, but have different physicochemical attributes. It is not known if airborne exposures to these agents are correlated in the laboratory animal workplace. METHODS: Side-by-side personal and area samples for airborne endotoxin (52), mouse allergen (46) and total particulates (43) were obtained in the animal facility and laboratories of a medical research institution. Animal handlers and researchers reported time spent on work tasks with mice, symptoms upon exposure to mice and mouse sensitization was determined by skin test or RAST. RESULTS: Mean airborne endotoxin exposure was highest during mouse experiments in the animal facility at 960 pg m(-3), peaked at 3125 pg m(-3), and ranged from 46 to 678 pg m(-3) with work in mouse rooms and research labs. Mouse allergen concentrations were highest during direct mouse work and background in research labs (mean 63-68 ng m(-3), range 41-271 ng m(-3)), but were undetectable during mouse research performed under a hood. Endotoxin and mouse allergen concentrations were correlated during direct research with mice and mouse care activities. Particle counts were low, typically < 1 cm(-3), varied widely, and exhibited peaks and valleys during different work tasks. From 80-90% of particles were < 1 microm in aerodynamic diameter during background measurements. The contribution of respirable particles 1-5 microm in size increased to 25-30% during mouse care and mouse research activities, but we found no association between any particle size and endotoxin or mouse allergen concentrations. Animal handlers and researchers in the mouse facility were exposed to the highest daily endotoxin concentrations, whereas researchers working with mice in the mouse facility and in laboratories were exposed to the highest daily mouse allergen concentrations. CONCLUSIONS: These findings suggest that endotoxin and mouse allergen are co-exposures during mouse handling and research, and that control of exposure peaks may be necessary to limit allergic disease in the laboratory animal workplace.     

Identification and characterization of trypanocides by functional expression of an adenosine transporter from Trypanosoma brucei in yeast

The causative agents of sleeping sickness, Trypanosoma brucei rhodesiense and T. brucei gambiense, do not synthesize purines de novo but salvage purine bases and nucleosides from their hosts. We used yeast as an expression system for functional characterization of the trypanosomal adenosine transporter TbAT1. A selection of purine analogs and flavonoids were tested for their ability to interfere with adenosine transport, with the aims of identifying (a) trypanocidal TbAT1 substrates, and (b) inhibitors of trypanosomal purine transport. Cordycepin (3'-deoxyadenosine) was a TbAT1 substrate of high activity against T. brucei rhodesiense (IC50 0.2 nM). Inhibitors of mammalian nucleoside transport were not active, while the flavonol silibinin was a potent, noncompetitive inhibitor of TbAT1-mediated adenosine transport in yeast. Silibinin also inhibited melarsen-induced lysis of bloodstream form trypanosomes. IC50 values to T. brucei rhodesiense and to human carcinoma cells were 0.6 and 140 microM, respectively, indicating a good selectivity towards the parasites. Further studies are necessary to elucidate the effects of flavonoids on trypanosomal purine transport and their potential as trypanocides.     

Prognostic value of uPA,PAI-1 and PAI-2 mRNA expression in primary breast cancer

BACKGROUND: The prognostic value of uPA, PAI-1 and PAI-2 mRNA expression was studied in a retrospective series of 130 primary breast cancer patients (median follow-up 8.1 years). MATERIALS AND METHODS: UPA, PAI-1 and PAI-2 mRNA were quantified by means of real-time quantitative RT-PCR. Comparison with the corresponding protein levels determined by ELISA was performed in 21 cases. RESULTS: Higher uPA protein values were found in cases with high mRNA values, but the relationship was of borderline significance. PAI-1 and PAI-2 mRNA were positively correlated to protein values. The mRNA expression of uPA, PAI-1 and PAI-2 was significantly correlated with one another. Higher uPA and PAI-1 mRNA values were significantly associated with shorter disease-free survival (DFS) (p = 0.002; p = 0.03, respectively). Low and very high PAI-2 mRNA values tended to be associated with longer DFS. In Cox multivariate analyses, higher uPA and PAI-1 mRNA values were independently associated with shorter DFS. PAI-2 was not retained as a significant variable in the Cox model. CONCLUSION: These preliminary results indicate that, in breast cancer, uPA, PAI-1 and PAI-2 mRNA analysis by quantitative RT-PCR give results comparable to those obtained at the protein level.     

The anti-apoptotic property of NS-398 at high dose can be mediated in part through NF-kappaB activation,hsp70 induction and a decrease in caspase-3 activity in human osteosarcoma cells

Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to produce an anti-proliferative and pro-apoptotic effect on different types of cancer cell lines. Previously, we demonstrated that high dose of NS-398 (100 microM), a selective cyclooxygenase-2 inhibitor, induced a cell cycle slowing or arrest and, in contrast to low dose (10 microM), a marked decrease in apoptosis in human 1547 osteosarcoma cells. In this study, we investigated particularly the effect of 100 microM NS-398 on p53 and p21 expression, caspase activities and nuclear factor-kappaB (NF-kappaB). We found a correlation between p53, p21 mRNA expression and NF-kappaB activation and, we observed an induction of heat shock protein 70 expression with a large decrease in caspase-3 activity after 100 microM NS-398 treatment. Moreover, the inhibition of apoptosis was correlated with an increase in bcl-2/bax ratio. Our new findings confirm the novel anti-apoptotic property of NS-398 at 100 microM, as we previously found, which contrasts to the described NS-398 pro-apoptotic effect on other cancer cell lines.     

The Rural Dental Health Program: Long-term Impact of Two Dental Delivery Systems on Children''s Oral Health

This paper addresses the long-term effect of two dental delivery systems established during the Rural Dental Health Program (RDHP) in 1975. At that time 725 children in grades K-2 were assigned randomly to an enriched dental health education program or regular health education program and to a SCHOOL- or COMMUNITY-based dental delivery system. Seven years after funding for RDHP ended, children originally assigned to the COMMUNITY group utilized more professional services and showed a higher level of dental knowledge than children assigned to the SCHOOL group. In addition, COMMUNITY-based children had, on average, twice as many sealed teeth. While the follow-up study did not reveal any statistically significant difference in the clinical oral health indices (DMFS, gingival index, calculus index, plaque index, periodontal probing depth, and orthodontic treatment priority index) the COMMUNITY-based children's higher level of professional dental service utilization, greater number of sealed teeth, and increased dental knowledge should lead to a higher level of oral health in the long run.     

Shock-related injury of pancreatic islets of langerhans in newborn and young infants

Variable degrees of injury of the pancreatic islets of Langerhans, with sparing of the acinar pancreas, were observed in three infants (age range, 1 day to 3 months) who died of profound shock. The duration of shock varied from 19 to 48 hours. In two of the infants, the shock stemmed from hypovolemia; in the remaining infant, the shock followed blood loss, sepsis, and heart failure. The islet lesions were devoid of cellular infiltrates, hemorrhage, and fibrin thrombi. Tissue manifestations of shock included acute renal tubular necrosis, massive hepatic centrilobular necrosis, ischemic enteropathy, and "shock" lung. Study of pancreatic sections from 30 children (age range, 13 hours to 15 years) with clinical and/or morphologic evidence of shock showed no additional instances of islet injury. These findings suggest that pancreatic islets in the young may be vulnerable to shock-induced ischemia. Studies are in progress in an animal model to test this hypothesis.