Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases1. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof of concept studies involving abnormally fertilized human zygotes2 were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. Following optimisation, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.

BackgroundFactors influencing specialty choice have been studied in an attempt to find incentives to enhance the workforce in certain specialties. The notion of “controllable lifestyle (CL) specialties,” defined by work hours and income, is gaining in popularity. As a result, many reports advocate providing a ‘lifestyle-friendly’ work environment to attract medical graduates. However, little has been documented about the priority in choosing specialties across the diverse career opportunities.This nationwide study was conducted in Japan with the aim of identifying factors that influence specialty choice. It looked for characteristic profiles among senior students and junior doctors who were choosing between different specialties.MethodsWe conducted a survey of 4th and 6th (final)-year medical students and foundation year doctors, using a questionnaire enquiring about their specialty preference and to what extent their decision was influenced by a set of given criteria. The results were subjected to a factor analysis. After identifying factors, we analysed a subset of responses from 6th year students and junior doctors who identified a single specialty as their future career, to calculate a z-score (standard score) of each factor and then we plotted the scores on a cobweb chart to visualise characteristic profiles.ResultsFactor analysis yielded 5 factors that influence career preference. Fifteen specialties were sorted into 4 groups based on the factor with the highest z-score: “fulfilling life with job security” (radiology, ophthalmology, anaesthesiology, dermatology and psychiatry), “bioscientific orientation” (internal medicine subspecialties, surgery, obstetrics and gynaecology, emergency medicine, urology, and neurosurgery), and “personal reasons” (paediatrics and orthopaedics). Two other factors were “advice from others” and “educational experience”. General medicine / family medicine and otolaryngology were categorized as “intermediate” group because of similar degree of influence from 5 factors.ConclusionWhat is valued in deciding a career varies between specialties. Emphasis on lifestyle issues, albeit important, might dissuade students and junior doctors who are more interested in bioscientific aspects of the specialty or have strong personal reasons to pursue the career choice. In order to secure balanced workforce across the specialties, enrolling students with varied background and beliefs should be considered in the student selection process.

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22-2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) I n Japan, breast cancer is the most frequent malignancy in women and estimates of new cases and deaths in 2002 were 32 245 and 9178, respectively.(1) The standardized incidence ratio of breast cancer in Japan was approximately one-third that of the US (32.7 vs 101.7 per 100 000 women).(1) The incidence of breast cancer in Japanese women shows a steady increase; however, it is still much lower than in Western countries. In breast cancer, family history is the strongest risk factor for cancer predisposition. Epidemiological studies showed that 12% of women with breast cancer have one affected family member and 1% have two or more affected relatives.(2) Women with one, two, and three or more first-degree affected relatives have an increased breast cancer risk when compared with women who do not have an affected relative (risk ratios 1.8, 2.9, and 3.9, respectively).(2) Recent advances in molecular genetics elucidated BRCA1 and BRCA2 (BRCA1/2) as two major susceptibility genes for breast cancer predisposition.(3,4) Gene testing of BRCA1/2 is available as a routine clinical test for diagnosing hereditary breast/ovarian cancer (HBOC) in the US and other Western countries, (5,6) while only a few reports have been published concerning the prevalence of BRCA1/2 mutations among Japanese people. (7)(8)(9)(10)(11)(12) The methods of genetic analysis employed in these studies varied, such as polymerase chain reaction (PCR)/ single strand conformational polymorphisms (SSCP), protein truncation test, and PCR/direct sequencing, but they were performed as preliminary in-house tests in the research setting. In the US, commercial BRCA1/2 gene testing was initiated by M...