Assessment of the mutagenicity of dichloroacetic acid in lacI transgenic B6C3F1 mouse liver

Dichloroacetic acid (DCA) is a chlorination byproduct found in finished drinking water. When administered in drinking water this chemical has been shown to produce hepatocellular adenomas and carcinomas in B6C3F1 mice over the animal's lifetime. In this study, we investigated whether mutant frequencies were increased in mouse liver using treatment protocols that yielded significant tumor induction. DCA was administered continuously at either 1.0 or 3.5 g/l in drinking water to male transgenic B6C3F1 mice harboring the bacterial lacI gene. Groups of five or six animals were killed at 4, 10 or 60 weeks and livers removed. At both 4 and 10 weeks of treatment, there was no significant difference in mutant frequency between the treated and control animals at either dose level. At 60 weeks, mice treated with 1.0 g/l DCA showed a 1.3-fold increase in mutant frequency over concurrent controls (P = 0.05). Mice treated with 3.5 g/l DCA for 60 weeks had a 2.3-fold increase in mutant frequency over the concurrent controls (P = 0.002). The mutation spectrum recovered from mice treated with 3.5 g/l DCA for 60 weeks contained G:C-->A:T transitions (32.79%) and G:C-->T:A transversions (21.31%). In contrast, G:C-->A:T transitions comprised 53.19% of the recovered mutants among control animals. Although only 19.15% of mutations among the controls were at T:A sites, 32.79% of the mutations from DCA-treated animals were at T:A sites. This is consistent with the previous observation that the proportion of mutations at T:A sites in codon 61 of the H-ras gene was increased in DCA-induced liver tumors in B6C3F1 mice. The present study demonstrates DCA-associated mutagenicity in the mouse liver under conditions in which DCA produces hepatic tumors.      

Risk-Adjusted Cancer Screening and Prevention (RiskAP): Complementing Screening for Early Disease Detection by a Learning Screening Based on Risk Factors

BackgroundRisk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action.SummaryTherefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept.     

Theatre of paediatric surgery

In the 50 years since the first edition of this journal, operative paediatric surgery has undergone radical change. Many of the most common instruments are unchanged, both as a testament to their utility and in recognition of past surgeons remembered eponymously. Surrounding that basic core of instruments, theatre has changed radically as new tools and techniques have arisen. Surgeons have come down from their pedestals, recognising surgery as a team sport rather than a solo performance. More than half of the current paediatric surgical trainees are women, a higher proportion than in any other craft group of the Royal Australasian College of Surgeons. The appearance, and rapid development, of laparoscopy is to many observers the most notable change in surgery over the last 50 years. Placed in its context though, it is simply the most prominent example of a frameshift in surgical thinking. The patient as a whole is now the focus, rather than just the disease. Recent developments are as much about minimising harm to normal tissues as they are about extirpating pathology. As a surgical maxim, ‘Primum non nocere’ is even more in evidence in 2015 than it was in 1965.     

Early onset vulvar Lichen Sclerosus in premenopausal women and oral contraceptives

OBJECTIVE: For vulvar Lichen sclerosus (LS) immunological factors, genetic predisposition, and decreased 5 alpha-reductase activity have been discussed as aetiological factors. During the last decade an increase of LS in young women has been suspected. Aim of this study was to evaluate data of premenopausal women with early onset LS to find potential risk factors focussing on the use of oral contraceptives. STUDY DESIGN: We retrospectively analyzed the data of 40 premenopausal patients with early onset LS regarding use of oral contraceptives (OCPs), and first occurrence of LS. To compare these data in a case-control study we analyzed a matched control group of 110 healthy women. RESULTS: All our LS patients were using OCPs compared to 73 women (66.4%) in the control group. OCPs with anti-androgenic activity (chlormadinone acetate, cyproterone acetate, dienogest, and drospirenone) were used by 28 (70%) of the LS patients and by 35 (47.9%) of the 73 women using OCPs in the control group. Thus, the odds ratio for early onset LS for women using anti-androgenic OCPs was 2.53 (95% CI: 1.12-5.75). CONCLUSION: Our data suggest that disturbance of the androgen dependent growth of the vulvar skin by OCPs and especially by OCPs with anti-androgenic properties might trigger the early onset of LS in a subgroup of susceptible young women.     

Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase

A human O6-alkylguanine-DNA-alkyltransferase (ATase) cDNA-containing retrovirus was used to infect murine long-term primary bone marrow cultures. High levels of ATase expression were obtained, and colony- forming cells of the granulocyte-macrophage lineage from the cultures transduced with the human ATase retrovirus were three times more resistant to the alkylating agent, N-methyl-N-nitrosourea (MNU), than control cultures. Furthermore, expression of the human ATase protected long-term hematopoiesis, measured as the output of progenitor cells to the nonadherent fraction of the culture, against the cytotoxic effects of repeated exposures to MNU. These results clearly show that a human ATase cDNA-containing retrovirus can be used to infect long-term primary bone marrow cultures and that this attenuates their sensitivity to nitrosoureas.     

输尿管硬镜在尿路疾病治疗中的应用

目的:探讨输尿管硬镜在尿路疾病治疗中的应用效果。方法:对1000例尿路结石、输尿管及尿道狭窄、输尿管息肉、梗阻、异物存留等患者,均以输尿管硬镜配合其他设备进行治疗。结果:肾内结石34例治愈率76.5%,输尿管结石、膀胱及尿道结石治愈率为94.5%～99.8%;泌尿道狭窄治愈率66.7%～75%;33例泌尿道异物取出率97%。结论:基层医院在尿路疾病治疗中,根据病变的不同部位,将输尿管硬镜灵活配合现有并不高档的设备,同样可以取得较好的微创手术效果。