The underlying mechanism behind age-induced wastage of the human ovarian follicle reserve is unknown. In this study, we identify impaired ATM (ataxia-telengiectasia mutated)-mediated DNA double strand break (DSB) repair as a cause of aging in mouse and human oocytes. We show that DSBs accumulate in primordial follicles with age. In parallel, expression of key DNA DSB repair genes BRCA1, MRE11, Rad51, and ATM, but not BRCA2, decline in single mouse and human oocytes. In BRCA1-deficient mice, reproductive capacity was impaired, primordial follicle counts were lower, and DSBs were increased in remaining follicles with age relative to wild-type mice. Furthermore, oocyte-specific knockdown of BRCA1, MRE11, Rad51 and ATM expression increased DSBs and reduced survival while BRCA1 overexpression enhanced both parameters. Likewise, ovarian reserve was impaired in young women with germline BRCA1 mutations compared to controls as determined by serum concentrations of anti-mullerian hormone. These data implicate DNA DSB repair efficiency as an important determinant of oocyte aging in women.

Cisplatin is a first-line chemotherapeutic agent for ovarian cancer that acts by promoting DNA cross links and adduct. However drug resistance and considerable side effects including reproductive toxicity remain a significant challenge. PTEN is well known as a tumor suppressor function which plays a fundamental role in the regulation of the cell cycle, apoptosis and development of cancer. At the same time PTEN has been revealed to be critically important for the maintenance of the primordial follicle pool. In this study, we investigated the role of PTEN/Akt/FOXO3 pathway in cisplatin-induced primordial follicle depletion. Cisplatin induced ovarian failure mouse model was used to evaluate how this pathway involves. In vitro maturation was used for oocyte rescue after cisplatin damage. We found that cisplatin treatment decreased PTEN levels, leading to a subsequent increase in the phosphorylation of key molecules in the pathway. The activation of the PTEN/Akt/FOXO3 pathway cascade increased cytoplasmic translocation of FOXO3a in cisplatin-treated follicles, which in turn increased the pool size of growing follicles, and rapidly depleted the number of dormant follicles. Once activated, the follicles were more prone to apoptosis, and their cumulus cells showed a loss of luteinizing hormone (LH) receptor expression, which leads to failure during final maturation and ovulation. In vitro maturation to rescue oocytes in a cisplatin-treated mouse model resulted in successful maturation and fertilization. This study is the first to show the involvement of the PTEN/Akt/FOXO3 pathway in premature ovarian failure after cisplatin treatment and the possibility of rescue through in vitro maturation.

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Foveal thickness may be a more sensitive indicator of primary retinal pathology than retinal nerve fiber layer thickness since the fovea contains no or sparse retinal nerve fiber layer, which coalesces into axons of the optic nerve. To our knowledge, few quantitative in vivo studies have investigated foveal thickness. By using optical coherence tomography, we measured foveal thickness to evaluate intrinsic retinal pathology. Seventy-two neuromyelitis optica spectrum disorder patients (99 eyes with optic neuritis and 45 eyes without optic neuritis) and 34 age-matched controls were included. Foveal thinning was observed both in eyes with non-optic neuritis (185.1 µm, p < 0.001) and optic neuritis (185.0 µm, p < 0.001) relative to controls (205.0 µm). Compared to controls, eyes with non-optic neuritis did not have peripapillary retinal nerve fiber layer thinning, but showed foveal thinning (p < 0.001). In neuromyelitis optica spectrum disorder, foveal thickness correlated with 2.5 % low contrast visual acuity, while retinal nerve fiber layer thickness correlated with high or low contrast visual acuity, extended disability status scale, and disease duration. In this study, we observed foveal thinning irrespective of optic neuritis; thus, we believe that subclinical primary retinal pathology, prior to retinal nerve fiber layer thinning, may exist in neuromyelitis optica spectrum disorder.

A 58-year-old woman was referred to our hospital due to progressive skin darkening, which began 5 months previously. The patient had strikingly diffuse blue-gray discoloration of the skin, most prominent in sun-exposed areas, especially her face and hands. The oral mucosa, tongue, gums, eye conjunctiva, ears, nail beds, and trunk were also involved. Bluish-gray discoloration of all nails was aggravated by cold weather. She had ingested 1 L of colloidal silver solution daily for approximately 16 months as a traditional remedy. Her serum silver concentration was 381 ng/ml which was a very high (reference level: <15 ng/ml). Light microscopic examination of a punch biopsy specimen from her nose revealed fine, minute, round, and brown-black granules deposited in the basement membrane of hair follicular epithelium. Scanning electron microscopic examination showed electron-dense granules deposited in the intercellular space of sweat glands. Energy disperse X-ray spectrometry analysis demonstrated peaks for silver and sulfur in the dense black deposits. The ingestion of colloidal silver appears to be an increasing practice among patients using alternative health practices. All silver-containing products including colloidal silver should be labeled with a clear warning to prevent argyria, especially in alternative health practices.

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Higher urinary BPA levels are associated with obesity, insulin resistance and metabolic disruption in Korean reproductive-aged women. BPA could play an important role in the pathogenesis of metabolic abnormalities. Further studies are required to elucidate the relationship between EDCs and metabolic disturbances in various age and sex groups.

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