The radiosensitivity of the human oocyte Wallace, W.H.B.; Thomson, A.B.; Kelsey, T.W.
Human reproduction (Oxford),
01/2003, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Odprti dostop
BACKGROUND: We determined the best model available for natural follicle decline in healthy women and used this to calculate the radiosensitivity of the human oocyte. METHODS: Ovarian failure was ...diagnosed in six patients with a median age of 13.2 years (range 12.5–16.0) who were treated with total body irradiation (14.4 Gy) at 11.5 years of age (4.9–15.1). We previously estimated the dose of radiation required to destroy 50% of the oocytes (LD50) to be <4 Gy. This estimate is an oversimplification, because decay represents an instantaneous rate of temporal change based upon the remaining population pool, expressed as a differential equation: dy/dx = –y0.0595 + 3716/(11780 + y), with initial value y(0) = 701 200. RESULTS: Solving the differential equation, we have estimated the number of follicles left after irradiation given as sol(51 – s + r), where r equals age at treatment, s equals age at diagnosis of ovarian failure, and 51 years is the average age of menopause. The surviving fraction of oocytes as a percentage is 100 times this value divided by sol(r). The mean surviving fraction for the six cases is 0.66%. We obtain a function, g(z), which decreases in value from 100% at zero dosage to mean value at dosage z = 14.4 Gy. We have g(z) = 10mx+c, where c = log10100 = 2, and m = log10(0.66) – c/14.4. Solving g(z) = 50 gives an LD50 of 1.99. CONCLUSIONS: Based on new data and a revised mathematical model of natural oocyte decline, we have determined the surviving fraction of oocytes following irradiation and estimate the LD50 of the human oocyte to be <2 Gy.
STUDY QUESTION
Do the chemotherapeutic regimens of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) or OEPA-COPDAC (combined vincristine, etoposide, prednisone, doxorubicin (OEPA) and ...cyclophosphamide, vincristine, prednisone, dacarbazine (COPDAC)) used to treat Hodgkin lymphoma (HL), affect the density, morphology and in vitro developmental potential of human ovarian follicles?
SUMMARY ANSWER
Ovarian tissue from women treated with ABVD contained a higher density of non-growing follicles (NGFs) per cubic millimetre and increased numbers of multiovular follicles but showed reduced in vitro growth compared with patients with lymphoma who had not received chemotherapy, patients treated with OEPA-COPDAC, age-matched healthy women and age-related model-predicted values.
WHAT IS KNOWN ALREADY
Chemotherapy regimens can cause a loss of follicles within the ovary, which depends on the drugs given. Early stage HL is commonly treated by ABVD, a non-alkylating regimen that apparently has ovarian sparing qualities; thus it is important to investigate the histological appearance and distribution of follicles within ABVD-treated ovarian tissue.
STUDY DESIGN, SIZE, DURATION
Thirteen ovarian biopsies were obtained from HL patients (six adolescents and seven adults) and one biopsy from a non-HL patient. Two HL patients and the non-HL patient had received no treatment prior to biopsy collection. The remaining 11 HL patients received one of two regimens: ABVD or OEPA-COPDAC. Tissue was analysed histologically and compared to biopsies from healthy women, and in a subgroup of patients, tissue was cultured for 6 days in vitro.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Ovarian biopsies were obtained from patients undergoing ovarian cryopreservation for fertility preservation and from healthy women at the time of Caesarian section (‘obstetric tissue’). Follicle number and maturity were evaluated in sections of ovarian cortical tissue, and compared to an age-related model of mean follicle density and to age-matched contemporaneous biopsies. The developmental potential of follicles was investigated after 6 days of tissue culture.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 6877 follicles were analysed. ABVD-treated tissue contained a higher density of NGFs per cubic millimetre (230 ± 17) (mean ± SEM) than untreated (110 ± 54), OEPA-COPDAC–treated (50 ± 27) and obstetric (20 ± 4) tissue (P < 0.01), with follicle density 9–21 SD higher than predicted by an age-related model. Biovular and binucleated NGFs occurred frequently in ABVD-treated and in adolescent-untreated tissue but were not observed in OEPA-COPDAC–treated or obstetric tissue, although OEPA-COPDAC–treated tissue contained a high proportion of morphologically abnormal oocytes (52% versus 23% in untreated, 22% in ABVD-treated and 25% in obstetric tissue; P < 0.001). Activation of follicle growth in vitro occurred in all groups, but in ABVD-treated samples there was very limited development to the secondary stage, whereas in untreated samples from lymphoma patients growth was similar to that observed in obstetric tissue (untreated; P < 0.01 versus ABVD-treated, NS versus obstetric).
LARGE SCALE DATA
N/A
LIMITATIONS, REASONS FOR CAUTION
Although a large number of follicles were analysed, these data were derived from a small number of biopsies. The mechanisms underpinning these observations have yet to be determined and it is unclear how they relate to future fertility.
WIDER IMPLICATIONS OF THE FINDINGS
This study confirms that the number of NGFs is not depleted following ABVD treatment, consistent with clinical data that female fertility is preserved. Our findings demonstrate that immature follicle density can increase as well as decrease following at least one chemotherapy treatment. This is the first report of morphological and follicle developmental similarities between ABVD-treated tissue and the immature human ovary. Further experiments will investigate the basis for the marked increase in follicle density in ABVD-treated tissue.
STUDY FUNDING/COMPETING INTEREST(S)
Funded by UK Medical Research Council Grants G0901839 and MR/L00299X/1. The authors have no competing interests.
Background:
Adjacent segment disease (ASD) following anterior cervical discectomy and fusion with plating (ACDF-P) may yield a poor prognosis or reoperation. This review aimed to summarize risk ...factors for radiographic ASD (RASD) and clinical ASD (CASD) after ACDF-P.
Methods:
Six electronic databases were searched from inception to October 30, 2021. Four reviewers independently screened titles, abstracts, and full-text articles to identify relevant studies. Methodological quality of the included studies was evaluated. Meta-analyses for risk factors were conducted, if possible.
Results:
Sixteen cohort and 3 case-control studies (3,563 participants) were included. These studies showed low (n = 2), moderate (n = 9), and high (n = 8) risk of bias. One risk factor for RASD was pooled for 2 meta-analyses based on the follow-up period. Four different risk factors for CASD at ≥4 years were pooled for meta-analyses. Limited evidence showed that multi-level fusion, greater asymmetry in total or functional cross-sectional area of the cervical paraspinal muscle, and preoperative degeneration in a greater number of segments were associated with a higher RASD incidence <4 years after ACDF-P. In contrast, no significant risk factors were identified for CASD <4 years after ACDF-P. At ≥4 years after ACDF-P, limited evidence supported that both cephalad and caudal plate-to-disc distances of <5 mm were associated with a higher RASD incidence, and very limited evidence supported that developmental canal stenosis, preoperative RASD, unfused C5-C6 or C6-C7 adjacent segments, use of autogenous bone graft, and spondylosis-related ACDF-P were associated with a higher CASD incidence.
Conclusions:
Although several risk factors for RASD and CASD development after ACDF-P were identified, the supporting evidence was very limited to limited. Future prospective studies should extend the existing knowledge by more robustly identifying risk factors for RASD and CASD after ACDF-P to inform clinical practice.
Level of Evidence:
Prognostic
Level IV
. See Instructions for Authors for a complete description of levels of evidence.
Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish ...consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). We studied the association between these fetal exposures and early child development in the Seychelles Child Development Nutrition Study (SCDNS). Specifically, we examined
a priori models of Ω-3 and Ω-6 LCPUFA measures in maternal serum to test the hypothesis that these LCPUFA families before or after adjusting for prenatal MeHg exposure would reveal associations with child development assessed by the BSID-II at ages 9 and 30 months. There were 229 children with complete outcome and covariate data available for analysis. At 9 months, the PDI was positively associated with total Ω-3 LCPUFA and negatively associated with the ratio of Ω-6/Ω-3 LCPUFA. These associations were stronger in models adjusted for prenatal MeHg exposure. Secondary models suggested that the MeHg effect at 9 months varied by the ratio of Ω-6/Ω-3 LCPUFA. There were no significant associations between LCPUFA measures and the PDI at 30 months. There were significant adverse associations, however, between prenatal MeHg and the 30-month PDI when the LCPUFA measures were included in the regression analysis. The BSID-II mental developmental index (MDI) was not associated with any exposure variable. These data support the potential importance to child development of prenatal availability of Ω-3 LCPUFA present in fish and of LCPUFA in the overall diet. Furthermore, they indicate that the beneficial effects of LCPUFA can obscure the determination of adverse effects of prenatal MeHg exposure in longitudinal observational studies.
Human ovarian physiology is still poorly understood, with the factors and mechanisms that control initiation of follicular recruitment and loss remaining particularly unclear. Conventional ...hypothesis-led studies provide new data, results and insights, but datasets from individual studies are often small, allowing only limited interpretation. Great power is afforded by the aggregation of data from multiple studies into single datasets. In this paper, we describe how modern computational analysis of these datasets provides important new insights into ovarian function and has generated hypotheses that are testable in the laboratory. Specifically, we can hypothesize that age is the most important factor for variations in individual ovarian non-growing follicle (NGF) populations, that anti-Müllerian hormone (AMH) levels generally rise and fall in childhood years before peaking in the mid-twenties, and that there are strong correlations between AMH levels and both NGF populations and rates of recruitment towards maturation, for age ranges before and after peak AMH levels.
Fish contain nutrients that promote optimal brain growth and development but also contain methylmercury (MeHg) that can have toxic effects. The present study tested the hypothesis that the intake of ...selected nutrients in fish or measures of maternal nutritional status may represent important confounders when estimating the effects of prenatal methylmercury exposure on child development. The study took place in the Republic of Seychelles, an Indian Ocean archipelago where fish consumption is high. A longitudinal cohort study design was used. A total of 300 mothers were enrolled early in pregnancy. Nutrients considered to be important for brain development were measured during pregnancy along with prenatal MeHg exposure. The children were evaluated periodically to age 30 months. There were 229 children with complete outcome and covariate data for analysis. The primary endpoint was the Bayley Scales of Infant Development-II (BSID-II), administered at 9 and 30 months of age. Combinations of four secondary measures of infant cognition and memory were also given at 5, 9 and 25 months. Cohort mothers consumed an average of 537
g of fish (nine meals containing fish) per week. The average prenatal MeHg exposure was 5.9
ppm in maternal hair. The primary analysis examined the associations between MeHg, maternal nutritional measures and children's scores on the BSID-II and showed an adverse association between MeHg and the mean Psychomotor Developmental Index (PDI) score at 30 months. Secondary analyses of the association between the PDI and only MeHg alone or nutritional factors alone showed only a borderline significant association between MeHg and the PDI at 30 months and no associations with nutritional factors. One experimental measure at 5 months of age was positively associated with iodine status, but not prenatal MeHg exposure. These findings suggest a possible confounding role of maternal nutrition in studies examining associations between prenatal MeHg exposures and developmental outcomes in children.
Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate ...whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time.
The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant's 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time.
Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89-1.21).
Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.
Genetic mutations affecting chromatin modifiers are widespread in cancers. In malignant peripheral nerve sheath tumors (MPNSTs), Polycomb repressive complex 2 (PRC2), which plays a crucial role in ...gene silencing, is inactivated through recurrent mutations in core subunits embryonic ectoderm development (EED) and suppressor of zeste 12 homolog (SUZ12), but mutations in PRC2’s main catalytic subunit enhancer of zeste homolog 2 (EZH2) have never been found. This is in contrast to myeloid and lymphoid malignancies, which harbor frequent loss-of-function mutations in EZH2. Here, we investigated whether the absence of EZH2 mutations in MPNST is due to a PRC2-independent (i.e., noncanonical) function of the enzyme or to redundancy with EZH1. We show that, in the absence of SUZ12, EZH2 remains bound to EED but loses its interaction with all other core and accessory PRC2 subunits. Through genetic and pharmacological analyses, we unambiguously establish that EZH2 is functionally inert in this context, thereby excluding a PRC2-independent function. Instead, we show that EZH1 and EZH2 are functionally redundant in the slowly proliferating MPNST precursors. We provide evidence that the compensatory function of EZH1 is alleviated upon higher proliferation. This work reveals how context-dependent redundancies can shape tumor-type specific mutation patterns in chromatin regulators.
Introduction
Frost events lead to A$360 million of yield losses annually to the Australian wheat industry, making improvement of chilling and frost tolerance an important trait for breeding.
...Objectives
This study aimed to use metabolomics and lipidomics to explore genetic variation in acclimation potential to chilling and to identify metabolite markers for chilling tolerance in wheat.
Methods
We established a controlled environment screening assay that is able to reproduce field rankings of wheat germplasm for chilling and frost tolerance. This assay, together with targeted metabolomics and lipidomics approaches, were used to compare metabolite and lipid levels in flag leaves of two wheat varieties with contrasting chilling tolerance.
Results
The sensitive variety Wyalkatchem showed a strong reduction in amino acids after the first cold night, followed by accumulation of osmolytes such as fructose, glucose, putrescine and shikimate over a 4-day period. Accumulation of osmolytes is indicative of acclimation to water stress in Wyalkatchem. This response was not observed for tolerant variety Young. The two varieties also displayed significant differences in lipid accumulation. Variation in two lipid clusters, resulted in a higher unsaturated to saturated lipid ratio in Young after 4 days cold treatment and the lipids PC(34:0), PC(34:1), PC(35:1), PC(38:3), and PI(36:4) were the main contributors to the unsaturated to saturated ratio change. This indicates that Young may have superior ability to maintain membrane fluidity following cold exposure, thereby avoiding membrane damage and water stress observed for Wyalkatchem.
Conclusion
Our study suggests that metabolomics and lipidomics markers could be used as an alternative phenotyping method to discriminate wheat varieties with differences in cold acclimation.
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