Measurement of H₂O₂ within living drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix

Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) is central to mitochondrial oxidative damage and redox signaling, but its roles are poorly understood due to the difficulty of measuring mitochondrial H<sub>2</sub>O<sub>2</sub> in vivo. Here we report a ratiometric mass spectrometry probe approach to assess mitochondrial matrix H<sub>2</sub>O<sub>2</sub> levels in vivo. The probe, MitoB, comprises a triphenylphosphonium (TPP) cation driving its accumulation within mitochondria, conjugated to an arylboronic acid that reacts with H<sub>2</sub>O<sub>2</sub> to form a phenol, MitoP. Quantifying the MitoP/MitoB ratio by liquid chromatography-tandem mass spectrometry enabled measurement of a weighted average of mitochondrial H<sub>2</sub>O<sub>2</sub> that predominantly reports on thoracic muscle mitochondria within living flies. There was an increase in mitochondrial H<sub>2</sub>O<sub>2</sub> with age in flies, which was not coordinately altered by interventions that modulated life span. Our findings provide approaches to investigate mitochondrial ROS in vivo and suggest that while an increase in overall mitochondrial H<sub>2</sub>O<sub>2</sub> correlates with aging, it may not be causative

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

The impact of women's social position on fertility in developing countries

This paper examines ideas about possible ways in which the extent of women's autonomy, women's economic dependency, and other aspects of their position vis-à-vis men influence fertility in Third World populations. Women's position or “status” seems likely to be related to the supply of children because of its links with age at marriage. Women's position may also affect the demand for children and the costs of fertility regulation, though some connections suggested in the literature are implausible. The paper ends with suggestions for future research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45660/1/11206_2005_Article_BF01124382.pd

Visiting medical student elective and clerkship programs: a survey of US and Puerto Rico allopathic medical schools

Abstract Background No published reports of studies have provided aggregate data on visiting medical student (VMS) programs at allopathic medical schools. Methods During 2006, a paper survey was mailed to all 129 allopathic medical schools in the United States and Puerto Rico using a list obtained from the Association of American Medical Colleges. Contents of the survey items were based on existing literature and expert opinion and addressed various topics related to VMS programs, including organizational aspects, program objectives, and practical issues. Responses to the survey items were yes-or-no, multiple-choice, fill-in-the-blank, and free-text responses. Data related to the survey responses were summarized using descriptive statistics. Results Representatives of 76 schools (59%) responded to the survey. Of these, 73 (96%) reported their schools had VMS programs. The most common reason for having a VMS program was "recruitment for residency programs" (90%). "Desire to do a residency at our institution" was ranked as the leading reason visiting medical students choose to do electives or clerkships. In descending order, the most popular rotations were in internal medicine, orthopedic surgery, emergency medicine, and pediatrics. All VMS programs allowed fourth-year medical students, and approximately half (58%) allowed international medical students. The most common eligibility requirements were documentation of immunizations (92%), previous clinical experience (85%), and successful completion of United States Medical Licensing Examination Step 1 (51%). Of the programs that required clinical experience, 82% required 33 weeks or more. Most institutions (96%) gave priority for electives and clerkships to their own students over visiting students, and a majority (78%) reported that visiting students were evaluated no differently than their own students. During academic year 2006-2007, the number of new resident physicians who were former visiting medical students ranged widely among the responding institutions (range, 0-76). Conclusions Medical schools' leading reason for having VMS programs is recruitment into residency programs and the most commonly cited reason students participate in these programs is to secure residency positions. However, further research is needed regarding factors that determine the effectiveness of VMS programs in residency program recruitment and the development of more universal standards for VMS eligibility requirements and assessment.</p