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Research Article| June 30 2011
Associations of Ionizing Radiation and Breast Cancer-Related Serum Hormone and Growth Factor Levels in Cancer-Free Female A-Bomb Survivors
Eric J. Grant;
Eric J. Grant 1
a Department of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minamiku, Hiroshima 732-0815, Japan
1 Address for correspondence: Department of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, Hiroshima 732-0815, Japan; e-mail: egrant@rerf.or.jp.
Kazuo Neriishi;
Kazuo Neriishi
b Department of Clinical Studies, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minamiku, Hiroshima 732-0815, Japan
John Cologne;
John Cologne
c Department of Statistics, and, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minamiku, Hiroshima 732-0815, Japan
Hidetaka Eguchi;
Hidetaka Eguchi
d Translational Research Center, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan
Tomonori Hayashi;
Tomonori Hayashi
e Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minamiku, Hiroshima 732-0815, Japan
Susan Geyer;
Susan Geyer
f Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210
Shizue Izumi;
Shizue Izumi
g Department of Computer Science and Intelligent Systems, Oita University, 700 Dannoharu, Oita, 870-1192 Japan
Nobuo Nishi;
Nobuo Nishi
h Center for Collaboration and Partnership, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan
Charles Land;
Charles Land
i Radiation Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20892-7335
Richard G. Stevens;
Richard G. Stevens
j Department of Community Medicine, University of Connecticut Health Center, Connecticut 06030
Gerald B. Sharp;
Gerald B. Sharp
k Epidemiology Branch, Basic Sciences Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
Kei Nakachi
Radiat Res (2011) 176 (5): 678–687.
https://doi.org/10.1667/RR2631.1
Eric J. Grant, Kazuo Neriishi, John Cologne, Hidetaka Eguchi, Tomonori Hayashi, Susan Geyer, Shizue Izumi, Nobuo Nishi, Charles Land, Richard G. Stevens, Gerald B. Sharp, Kei Nakachi; Associations of Ionizing Radiation and Breast Cancer-Related Serum Hormone and Growth Factor Levels in Cancer-Free Female A-Bomb Survivors. Radiat Res 1 November 2011; 176 (5): 678–687. doi: https://doi.org/10.1667/RR2631.1
Levels of exposure to ionizing radiation are increasing for women worldwide due to the widespread use of CT and other radiologic diagnostic modalities. Exposure to ionizing radiation as well as increased levels of estradiol and other sex hormones are acknowledged breast cancer risk factors, but the effects of whole-body radiation on serum hormone levels in cancer-free women are unknown. This study examined whether ionizing radiation exposure is associated with levels of serum hormones and other markers that may mediate radiation-associated breast cancer risk. Serum samples were measured from cancer-free women who attended biennial health examinations with a wide range of past radiation exposure levels (N = 412, ages 26–79). The women were selected as controls for separate case-control studies from a cohort of A-bomb survivors. Outcome measures included serum levels of total estradiol, bioavailable estradiol, testosterone, progesterone, prolactin, insulin-like growth factor-1 (IGF1), insulin-like growth factor-binding protein 3 (IGFBP-3), and ferritin. Relationships were assessed using repeated-measures regression models fitted with generalized estimating equations. Geometric mean serum levels of total estradiol and bioavailable estradiol increased with 1 Gy of radiation dose among samples collected from postmenopausal women (17%1Gy, 95% CI: 1%–36% and 21%1Gy, 95% CI: 4%–40%, respectively), while they decreased in samples collected from premenopausal women (−11%1Gy, 95% CI: −20%–1% and −12%1Gy, 95% CI: −20%– −2%, respectively). Interactions by menopausal status were significant (P = 0.003 and P < 0.001, respectively). Testosterone levels increased with radiation dose in postmenopausal samples (30.0%1Gy, 95% CI: 13%–49%) while they marginally decreased in premenopausal samples (−10%1Gy, 95% CI: −19%–0%) and the interaction by menopausal status was significant (P < 0.001). Serum levels of IGF1 increased linearly with radiation dose (11%1Gy, 95% CI: 2%–18%) and there was a significant interaction by menopausal status (P = 0.014). Radiation-associated changes in serum levels of estradiol, bioavailable estradiol, testosterone and IGF1 were modified by menopausal status at the time of collection. No associations with radiation were observed in serum levels of progesterone, prolactin, IGFBP-3 or ferritin.
Exposure to ionizing radiation via diagnostic imaging, particularly CT scans, continues to increase worldwide 1. Numerous studies have proven the association between exposure to ionizing radiation and breast cancer 2. Moreover, data from the A-bomb survivors indicate that the breast is particularly susceptible to ionizing radiation exposure, with an attributable fraction for breast cancer of 27% for all women exposed to more than 5 mGy 3 [a radiation dose roughly twice the yearly background dose 4]. Breast cancer has also been associated with levels of endogenous hormones, particularly estradiol (E2) 5–7. Estrogens stimulate cell proliferation 8 and possibly exert a direct genotoxic effect on breast epithelial cells 9.
Other circulating hormones and proteins, including non-sex hormone-binding globulin (SHBG)-bound estradiol, testosterone 7 and insulin-like growth factor 1 (IGF1), have been associated with breast cancer 10. Additional serum markers have been hypothesized to be associated with breast cancer, including IGFBP-3 11, progesterone 12, prolactin 13 and ferritin. Ferritin levels and ionizing radiation are associated with increased levels of free radicals, and high ferritin levels have been reported to result in cell transformation and immortalization in mammary glands 14.
The question of whether ionizing radiation exposure modifies the underlying levels of risk-related circulating markers has not been addressed, however, and could be important in mechanistic studies of breast cancer or other hormone-related cancers after ionizing radiation exposure. The primary purpose of this project is to examine whether serum levels of risk-related markers vary with past radiation exposure in a representative sample of cancer-free female A-bomb survivors.
Study subjects were selected from the Adult Health Study (AHS), a longitudinal cohort study of A-bomb survivors initiated in 1958 15. The AHS features biennial clinical examinations with serum collection and well-characterized radiation doses for numerous body organs 16. Serum samples were selected in the context of concurrent case-control studies wherein controls were selected by incidence density sampling from all subjects who met eligibility requirements and were at risk for a first primary cancer of any type at the time an index case was diagnosed. Eligibility was defined as women who were free from various medical conditions (oophorectomy, current exogenous hormone treatment, prior malignancies, pregnant), were cancer-free for at least 2 years after serum collection, and had estimated radiation organ doses. Hormone-related diseases/conditions were based on self-reports or, in the case of extreme measured values, a medical chart review. Samples were matched to an index case on age at collection (±2 years), sample collection year (same decade), city (Hiroshima or Nagasaki), and counter-matched using breast radiation dose strata (low, medium and high with cut-points at 5 mGy and 790 mGy) 17. Counter-matching assures a wide exposure range while still providing an appropriate sample for inference of the exposure effects within the underlying cancer-free cohort 18. Because it is not known which organ system might be responsible for changes to serum markers, we used doses to the colon for purposes of analyses. The colon is a centrally located organ, and colon doses have been used as representative doses in other studies (e.g. for overall solid cancer risk estimates), although the results should be relatively insensitive to the organ chosen since the doses to all organs are highly correlated. Radiation doses to the colon were adjusted to account for random errors in the individual radiation dose estimates 19. Menopausal status at the time of sample collection was assigned using a two-step process. First, we used a conservative age range to assign menopausal status. If a woman was less than 43 years of age at the time of sample collection, she was designated premenopausal (N = 218); if she was older than 55 years, she was designated postmenopausal (N = 139). For women in the intermediate age group (43–55 years old), FSH (follicular stimulating hormone) levels were measured and used to assign menopausal status primarily based upon the manufacturer's test guidelines (premenopausal cutoff: FSH < = 15 mIU/ml, postmenopausal cutoff: FSH > = 23 mIU/ml) 20. Of those in the intermediate age range and assigned by FSH values (N = 152), 75 were designated premenopausal, 60 were postmenopausal, and the others were in between the two cutoff values and were designated perimenopausal (N = 17). Due to the paucity of samples collected from perimenopausal women, they were excluded. The final data set included 492 samples collected from 412 women (293 premenopausal and 199 postmenopausal samples). Of the 80 subjects with two separate samples, 63 had samples that were both collected prior to menopause, 6 subjects had samples that were both collected after menopause, and 11 had one sample collected before and one after menopause.
All blood samples were obtained with informed consent, and the Human Investigation Committee of the Radiation Effects Research Foundation (RERF) approved the study protocol.
Sample Storage and Serum Assays
Sera were collected in the Hiroshima and Nagasaki laboratories between 1969 and 1992 and stored in vials at −80°C. Samples for this study were pulled from the freezers simultaneously and assayed for total E2, bioavailable E2, testosterone, progesterone, prolactin, IGF-1, IGFBP-3, ferritin, and total protein and protein fractions (albumin and globulin). All assays were performed blinded to age, city of collection and radiation exposure but were not performed in duplicate due to the limited serum amounts available. Commercial laboratories with internal quality assurance systems performed all assays. Supplementary Table 1 (http:dx.doi.org/10.1667/RR2631.1.S1) lists the assays and their precision as reported by the kits' manufacturers.
Characteristics of Study Cohort and Collected Samples by Menopausal Status
Serum levels of IGF-1, IGFBP-3, FSH, prolactin, testosterone, progesterone and ferritin were measured at a single laboratory (SRL Laboratory, Hachioji, Japan). Total protein concentration and protein fractions were measured by SRL using the Biuret method and cellulose acetate membrane electrophoresis, respectively. Serum levels of total E2 and percentage bioavailable E2 were measured at a single laboratory (Mitsubishi Kagaku Bio-clinical Laboratories, Tokyo, Japan). Percentage bioavailable E2 (the fraction of serum E2 that is free or loosely bound to albumin) was determined by ammonium sulfate precipitation of SHBG-bound E2 21. Total E2 was multiplied by this percentage to obtain the concentration of bioavailable E2. Serum ferritin was measured by the conventional chemiluminescence enzyme immunoassay (CLEIA). When the aliquots of samples were transported to outside laboratories for testing, they were packed in appropriate protective shipping boxes with sufficient amounts of dry ice and checked at the time of receipt by the measuring laboratories.
Methods of Analysis
Due to the skewed distributions of the markers, analyses were performed using log-transformed values for all of the markers except IGF1 and IGFBP-3, which did not require transformation. Effects of radiation exposure were estimated with adjustment only for other factors that were significantly related to marker level for statistical efficiency. Explanatory factors considered were: age at time of sample collection, year of birth, menopausal status (pre or post), total protein, body mass index [weight (kg)/height (m2)] and its square, history of exogenous hormone use (yes or no), age at time of radiation exposure (including dichotomy at 15 years as a surrogate for pre- or postmenarche at time of exposure), number of full-term pregnancies, age at first full-term delivery, and radiation dose. Decisions for inclusion of factors other than radiation dose were based on a backward selection process where the least significant explanatory factor was removed until all factors were significant at a level of P ≤ 0.05. The variable selection process was conducted separately for each marker. Analyses were performed using a regression method for correlated (repeated) measurements (generalized estimating equations; GEE) 22. P values and 95% confidence intervals were based on the Wald statistic.
Radiation effects were assessed using linear dose–response functions. Dose responses were estimated with and without regard to effect modification by menopausal status at the time of blood collection and ionizing radiation exposure before or after age 15. For markers that were transformed prior to analyses, the radiation effects were reported on the untransformed scale by exponentiating the regression coefficient obtained using the log-transformed data and represent the association between 1 Gy radiation dose and the percentage change in geometric mean of the marker level. IGF1 and IGFBP-3, which were not transformed, were also reported on a relative scale by dividing the dose coefficient by the regression constant. To test the strength of the observed radiation effects, we identified and removed the most influential observations using the size-adjusted criterion 2/sqrt(n) for the t-statistic-like standardized deletion diagnostic DFBETAS of Belsley et al. 23. To alleviate concerns about misclassification of menopausal status at the time of sample collection due to possible nonspecificity of the FSH results, we conducted a sub-analysis after restricting samples to those collected from women at ages less than 43 or greater than 55 (135 samples omitted) and compared results to the full analyses.
Statistical comparisons between samples collected pre- and postmenopause were performed using χ2 tests (for counts), t tests for equality (for means) and Wilcoxon rank-sum tests for independent samples (for medians). Interactions of radiation effects by menopausal status or exposure before or after age 15 were tested using the likelihood ratio. To compare fits of statistically significant non-nested interaction models, the quasi-likelihood/independence criterion (QIC) was used 24. All results were obtained using Stata 25.
Table 1 shows the demographics of the study cohort and marker values for samples separated by menopausal status at the time of collection. The distribution of the radiation dose is broader than what would be expected from a random sampling of all cancer-free women since they were counter-matched (low, medium, high) against the dose status of the case to ensure a broad representation of doses. The average year of sample collection is somewhat later for postmenopausal samples because the AHS study is a fixed cohort; more women were postmenopausal in later calendar years.
Table 2 shows the agreement of assays for the 63 pairs of samples collected from women who were premenopausal at each collection. Comparisons of multiple samples collected from the same women while postmenopausal were not reported (N = 6 pairs). The earlier sample was collected at average age 39.7 years and the average interval between sample collections was 2.8 years. Correlation coefficients ranged from 0.11 for progesterone to 0.75 for ferritin. A paired t test comparing the difference of the paired values with zero was not significant for any marker except for serum prolactin, where the earlier value proved to be significantly higher than the second value.
Comparison of Assay Values from Women Donating Multiple Samples
The first column of Table 3 shows the associations of radiation with marker levels with no allowance for effect modification but with adjustment for other significant factors. No significant radiation associations were observed in any of the markers when ignoring menopausal status. Columns two through five in Table 3 show the radiation associations separately by menopausal status at the time of sample collection or by age at time of bombing (≤15 or >15 years; ATB15). Because menopausal status at blood donation was highly correlated with ATB15 in this study sample (particularly for a woman's first/only serum sample), the latter two columns largely mirror the results displayed in the former two. Total and bioavailable E2, testosterone and IGF-1 demonstrated statistically significant associations with radiation dose in one or both periods.
Relative Radiation Associations with Adjusted Mean Marker Values and Effect Modification By Menopausal Status and Age at Radiation Dose
Total E2 (Fig. 1) decreased with radiation dose in the premenopausal period (relative change 0.89 at 1 Gy; 95% CI: 0.80, 0.99; P = 0.027), or in other words, the level of total E2 changed as k*0.89dose, where k is the level of total E2 when the dose was zero (results from other log-transformed variables are interpreted in the same way). The level of total E2 increased with dose in the postmenopausal period (relative change 1.17 at 1 Gy; 95% CI: 1.01, 1.36; P = 0.037). Effect modification by menopausal status was highly significant (P = 0.003) and remained significant after removing the most influential values (P = 0.038). The association of total E2 with radiation dose was similar when categorizing subjects based on ATB15 (rather than menopausal status at the time of collection); relative change for a 1-Gy dose at age less than 15 years was 0.86 (95% CI: 0.76, 0.96; P = 0.010) and relative change for exposure after age 15 was 1.12 (95% CI: 0.99, 1.26; P = 0.063). Models used to estimate the radiation effects on total E2 included menopausal status, age at sample collection, total protein, BMI and a BMI*postmenopause interaction. The QIC values for the two models were very similar, but the value for the ATB15 interaction model was slightly lower (i.e. better fit) than for the model with interaction by menopausal status.
Log total estradiol (E2) by menopausal status and radiation dose. The relative change is the percentage change at a dose of 1 Gy. The regression lines and P values are based on the final models obtained for the markers (Table 3). The slopes of the two regression lines by menopausal status are significantly different (P = 0.003).
Bioavailable E2 (Fig. 2) showed a significant decrease with radiation dose in the premenopausal period, with a relative change of 0.88 at 1 Gy (95% CI: 0.80, 0.98; P = 0.022) and a significant increase with radiation dose in the postmenopausal period with a relative change of 1.21 at 1 Gy (95% CI: 1.04, 1.40; P = 0.011). Effect modification by menopausal status was highly significant (P < 0.001) and remained so after exclusion of influential observations (P = 0.003). As with total E2, bioavailable E2 also demonstrated similar radiation effects according to whether exposure was before or after age 15 (0.87 at 1 Gy; 95% CI: 0.77, 0.98; P = 0.019 and a relative increase of 1.13 at 1 Gy; 95% CI: 1.00, 1.27; P = 0.045, respectively). The model used to estimate the radiation effects on bioavailable E2 included menopause status, age at sample collection and total protein. Again the QIC value was slightly lower for the model with ATB15 interaction.
Log bioavailable estradiol (E2) concentration by menopausal status and radiation dose. The relative change is the percentage change at a dose of 1 Gy. The regression lines and P values are based on the final models obtained for the markers (Table 3). The slopes of the two regression lines by menopausal status are significantly different (P < 0.001).
Testosterone (Fig. 3) exhibited an increase with radiation dose in the postmenopausal period (relative change 1.30 at 1 Gy; 95% CI: 1.13, 1.49; P < 0.001) and a marginally significant decrease with radiation dose in the premenopausal period (0.90 at 1 Gy; 95% CI: 0.81, 1.00; P = 0.049). Estimates of effect modification by menopausal status were highly significant when estimates were derived using all observations (P < 0.001) and after excluding outliers (P = 0.003), whereas no effect modification was evident with ATB15. The testosterone model included menopause status, age at sample collection, total protein and a total protein*postmenopause interaction, and BMI.
Log testosterone by menopausal status and radiation dose. The relative change is the percentage change at a dose of 1 Gy. The regression lines and P values are based on the final models obtained for the markers (Table 3). The slopes of the two regression lines by menopausal status are significantly different (P < 0.001).
IGF-1 (Fig. 4) displayed a significant increase with radiation dose in the premenopausal period (relative change 1.11 per Gy; 95% CI: 1.02, 1.18; P = 0.024). Since the values from this assay were not log-transformed, the results are interpreted as the percentage change in marker levels per gray. No significant change with dose was observed in the postmenopausal period (relative change 0.91 per Gy; 95% CI: 0.75, 1.04; P = 0.18). Similar effects were seen when categorizing the women by age at exposure. Effect modification by menopausal status was significant (P = 0.014) and remained so after removing the most influential observations (P = 0.017). Comparing QIC values indicated that the model with menopausal interaction model was preferable to the one with ATB15 interaction. Estimates of the radiation effects were adjusted for age at sample collection, year of birth, total protein*premenopause interaction, and number of full-term pregnancies.
IGF-1 by menopausal status and radiation dose. The relative change is the percentage change at a dose of 1 Gy. The regression lines and P values are based on the final models obtained for the markers (Table 3). The slopes of the two regression lines by menopausal status are significantly different (P = 0.014).
The other markers (IGFBP-3, progesterone, prolactin and ferritin) demonstrated no associations with radiation dose, either with or without effect modification. No effect modification of the radiation effects was observed in relation to the sample storage period, time since exposure, or the number of full-term pregnancies, although E2 levels did increase at a marginally significant level for each additional full-term pregnancy (results not shown). Model fits generally improved when including the number of full-term pregnancies (as either an effect modifier or a main effect), but the estimated coefficients for the number of pregnancies were never statistically significant and therefore the results were not reported. No improvements in model fit were detected by the addition of a quadratic dose term. Point estimates were generally unchanged by the removal of samples retrieved when women were aged 43 to 55.
The present study was designed to investigate the associations of ionizing radiation exposure with sex and growth hormones in cancer-free A-bomb survivors using stored sera. Increasing levels of ionizing radiation exposure led to disparate changes by menopausal status in a number of serum markers. Levels of E2 and bioavailable E2 increased in postmenopausal samples while they decreased in premenopausal samples. Caution must be used when interpreting the results in premenopausal samples, especially E2 levels, which are highly variable in premenopausal women due to the menstrual cycle. Table 2 illustrates the high variability of serum marker levels among premenopausal women. Controlling for the day of the menstrual cycle was not possible, because the clinical examination protocol did not attempt to record these values. It should be noted, however, that the point estimates for the radiation findings were largely unchanged after separately removing the most influential measurements (e.g., those associated with the E2 peak at ovulation) and excluding those in the perimenopausal age range 43–55. Also, it is unlikely that there is any association with the timing of blood sample collection and radiation dose, eliminating most concerns of confounding. Nevertheless, chance findings for the premenopausal hormone associations cannot be completely ruled out.
The magnitude of change in total E2 levels was about 10% at 1 Gy of radiation (negative in premenopausal women and positive in postmenopausal women). It is not clear that either of these are clinically significant changes, particularly among premenopausal women where there is so much variation. However, if E2 levels were assigned to quartiles in samples taken from postmenopausal women, a 10% change in any particular result would generally be sufficient to increase its quartile assignment by one category. Interpolating the results from Fig. 1 of the meta-analysis performed by Key et al. 7, this increase in total E2 would roughly correspond to a 25% increase in breast cancer risk.
The significance of IGF-1 and IGFBP-3 levels in pre- or postmenopausal breast cancer has been under debate. The most recent evidence indicates that high levels of IGF-1 confer an increased risk of breast cancer 10. In our study, radiation exposure appeared to increase the level of IGF-1 in premenopausal women but had no effect on levels of IGF-1 in postmenopausal women. Again, however, large variations were observed in the premenopausal IGF-1 levels. IGFBP-3 was not associated with radiation exposure.
If the results are correct, questions arise regarding the radiation-related biological pathways that may affect sex hormone levels, particularly the most potent hormone E2. In premenopausal women, E2 is produced primarily by the ovaries whereas after ovarian involution, estrogen is primarily produced in adipose tissue by converting androgen to estrogen via aromatase. A number of speculative mechanisms for an association between radiation and sex steroid alterations can be suggested, including damage to primordial ovarian follicles leading to decreased ovarian aromatase and depressed E2 production as observed in the samples taken from women who were exposed at less than 15 years of age 26, 27. Ataya et al. reported similar findings with decreased ovarian size and long-term decreased serum E2 levels in rhesus monkeys with ovarian exposure to ionizing radiation 28. Larsen et al. reported decreased ovarian volume in spontaneously ovulating women who had received chemotherapy and radiotherapy for cancers diagnosed at mean age 5.4 years; however, E2 levels were reported to be higher in those receiving (any type of) therapy compared to a control group of similar age 29.
For the results seen among older birth cohorts (i.e. postmenopausal samples), radiation-induced upregulation of inflammatory cytokines, specifically TNFα, can lead to increased estrogen biosynthesis 30–33; radiation can also alter lipid metabolism 34–36, possibly leading to hyperandrogenism through hypothalamus-pituitary-adrenal axis dysregulation 37. Either of these latter mechanisms would be consistent with the observed increased E2 and testosterone levels among the postmenopausal women.
No effect modification by the number of full-term pregnancies was evident in the radiation effects on any of the markers. The number of women reporting any history of exogenous hormone intake was less than 10%, and that variable was not a significant risk factor in any of the tested models. Therefore, we do not believe that hormone treatment had a meaningful impact on our findings. Interaction models categorizing exposures before or after age 15 more often had a better fit than models categorized by menopausal status at the time of serum collection. However, this may be due to misclassification of menopausal status as opposed to an important biological effect involving menarche status at the time of radiation exposure. McDougall et al. found no association of breast cancer risk and menarche status at the time of radiation exposure but did not consider serum marker levels 38.
Associations of radiation and markers modified by menopausal status were tested in the results of eight bioassays (the two parallel analyses of modification by either menopause status or ATB15 are effectively the same), which may raise concerns of finding associations due to multiple testing. Using the conservative Bonferroni correction for multiple testing (α = 0.05/8 = 0.00625), all of the tests for interaction remain significant with the exception of IGF-1 (P = 0.014).
The study boasts a number of strengths, including well-characterized radiation doses to a representative population of women, and data collected prospectively from cancer-free women as part of a long-term follow-up regimen, including medical history data on hormone-related conditions. However, there are also several weaknesses. The day of blood collection in relation to the menstrual cycle was not available, which is problematic for premenopausal estradiol measurements in particular. The use of FSH to assign menopausal status has been shown to be not fully specific 39. It is also likely that misclassification occurred when assigning menarche status by age. Due to the limited number of samples, duplicate assays for quality control were not attempted. A limited number of women did have multiple samples collected while premenopausal, for which the correlation between marker assays was generally poor, probably due to different times in the menstrual cycle. Despite these limitations, no major changes in the interactions between the measured radiation associations and menopausal status were detected after separately removing the most influential observations and those observations drawn from women in the perimenopausal age range, which helps confirm the robustness of the associations.
Previous studies have proven the potency of ionizing radiation as a carcinogen via direct damage effects to DNA while separate lines of research have established serum levels of E2, testosterone and IGF1 as risk factors for breast cancer. The results of this study suggest that ionizing radiation may lead to changes in serum levels of cancer-related hormones and proteins in cancer-free women and that these changes are dependent upon either the menopausal status at the time of collection or the menarche status at the time of exposure. Several mechanisms for these changes are suggested, but they are all speculative. Researchers of cancer etiology after whole-body ionizing radiation exposure should be aware of possible underlying changes in the levels of serum markers, which may confer independent carcinogenic risks.
We deeply thank the participating members of the AHS. The Radiation Effects Research Foundation (RERF), Hiroshima and Nagasaki, Japan is a private, non-profit foundation funded by the Japanese Ministry of Health, Labor and Welfare (MHLW) and the U.S. Department of Energy (DOE), the latter in part through the National Academy of Sciences. This publication was supported by RERF Research Protocol RP 06-02 and by US National Cancer Institute contract NO1-CP-31012 and the Japanese Ministry of Education, Culture, Sports, Science and Technology grants 14031227 and 15026220.
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Grant, E. J., Neriishi, K., Cologne, J., Eguchi, H., Hayashi, T., Geyer, S., Izumi, S., Nishi, N., Land, C., Stevens, R. G., Sharp, G. B. and Nakachi, K. Associations of Ionizing Radiation and Breast Cancer-Related Serum Hormone and Growth Factor Levels in Cancer-Free Female A-Bomb Survivors.
Note. The online version of this article (DOI: 10.1667/RR2631.1) contains supplementary information that is available to all authorized users.
by Radiation Research Society
10.1667_RR2631.1.S1.doc- doc file
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Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?
Pataje G. Prasanna, Gayle E. Woloschak, Andrea L. DiCarlo, Jeffrey C. Buchsbaum, Dörthe Schaue, Arnab Chakravarti, Francis A. Cucinotta, Silvia C. Formenti, Chandan Guha, Dale J. Hu, Mohammad K. Khan, David G. Kirsch, Sunil Krishnan, Wolfgang W. Leitner, Brian Marples, William McBride, Minesh P. Mehta, Shahin Rafii, Elad Sharon, Julie M. Sullivan, Ralph R. Weichselbaum, Mansoor M. Ahmed, Bhadrasain Vikram, C. Norman Coleman, Kathryn D. Held
Estimation of Dose-Rate Effectiveness Factor for Malignant Tumor Mortality: Joint Analysis of Mouse Data Exposed to Chronic and Acute Radiation
Kazutaka Doi, Michiaki Kai, Keiji Suzuki, Tatsuhiko Imaoka, Megumi Sasatani, Satoshi Tanaka, Yutaka Yamada, Shizuko Kakinuma
Differentiating Total- or Partial-Body Irradiation in Baboons Using mRNA Expression Patterns: A Proof of Concept
P. Ostheim, J. Haupt, S. Schüle, F. Herodin, M. Valente, M. Drouet, M. Majewski, M. Port, M. Abend
53BP1 Repair Kinetics for Prediction of In Vivo Radiation Susceptibility in 15 Mouse Strains
Eloise Pariset, Sébastien Penninckx, Charlotte Degorre Kerbaul, Elodie Guiet, Alejandra Lopez Macha, Egle Cekanaviciute, Antoine M. Snijders, Jian-Hua Mao, François Paris, Sylvain V. Costes
Germicidal Efficacy and Mammalian Skin Safety of 222-nm UV Light
Manuela Buonanno, Brian Ponnaiya, David Welch, Milda Stanislauskas, Gerhard Randers-Pehrson, Lubomir Smilenov, Franklin D. Lowy, David M. Owens, David J. Brenner


text:
Q: PHP how be sure to catch all exceptions Suppose I have some code that uses try{...} catch() { ... } blocks. Within the tried code, there are various non-trivial third party objects (or maybe other data).
Often these third party objects will throw their own third party exceptions; how can I be sure to catch these without knowing what these exceptions are actually named?
With various third party objects and methods in various parts of the code, is there a relatively quick way of catching all exceptions thrown for further investigation?
Detailed Usage Example (Stripe has numerous Exception cases)
$someObject = new \someNamespace\someClass();
try {
    $x = $someObject->someFunction($someData);
    $y = $stripeObject->StripeProcessing($x);
}
catch(\Stripe\Error\Card $ex) {
        // Since it's a decline, \Stripe\Error\Card will be caught
        error_log("Stripe Card Error: ".$ex->message);
        $message = "There was a card error: ".$err['message'];
    }
catch (\Stripe\Error\RateLimit   |
    \Stripe\Error\InvalidRequest |
    \Stripe\Error\Authentication |
    \Stripe\Error\ApiConnection  |
    \Stripe\Error\Base $ex) {
        $message = "There was a Stripe error: ".$ex->getMessage();
        error_log("Stripe Other Error: ".print_r($ex,true));
    }
catch( \someNamespace\GiggityException |
    \someNamespace\GiggityNewMexicoException){
    error_log("Family Guy! ".print_r($ex,true));
    }
catch (Exception $ex){
    error_log("Elvis has died! ".print_r($ex,true));
}

Could result in:

PHP Fatal error:  Uncaught SomeDistributor\SomeClass\Exception: connection() failed. ...etc...etc...

So above has a bunch of Exceptions to catch, from two namespaces, as well as the general Exception at the end; While the code reactions to all of these are very similar; I still seem to need to know the name of each and every Exception class thrown and have these manually coded in;
So, is there a way of catching ALL possible exceptions in one place?
(Before then differentiating and branching how to handle specific ones, as needed)
I'm sure the solution to this is vey simple but I can't find liteature on this (d'oh; I have since found literature).

A: This website states:

The simplest way to catch exceptions is through the use of a generic try-catch block. Because exceptions are objects, they all extend a built-in Exception class (see Throwing Exceptions in PHP), which means that catching every exception thrown is as simple as type-hinting the global exception object, which is indicated by adding a backslash in front:
try {
  // ...
} catch ( \Exception $ex ) {
  // ...
}

redpajama_set_name: RedPajamaStackExchange


The first reason for making an equitable exception to a law was when the law suffered from "universality," that is, the law was stated too broadly by the legislators. Supposedly the legislators, had they given thought to the matter, would have created an exception to the general rule in certain cases. The defect is really one of inaccurate word-crafting on the part of the legislative drafters. Thus, in theory, the statute does not accurately reflect the true law.
Equity has also been justified in cases where common law judges refused, for whatever reason, to grant relief to a complainant. In such cases, the complainant would seek relief in another place (historically, in the Court of Chancery or a separate Court of Equity). In such cases, the law was viewed as not providing for a remedy that it ought to have.
A third justification for equity relates to so-called "hard cases," that is, where a strict application of the rule of law was clear and possible, but would have resulted in a hardship. In such cases, the harshness of the law was essentially viewed as contrary to justice.
Let's examine how these concepts of equity may be applied, if at all, to the law of God, and by analogy, to modern civil laws.
We have discovered that law is something permanent, uniform and universal. It would be helpful to determine the extent to which lonang supports the concept of equity as a necessary or desirable exception to the law. Accordingly, the present task is to discover instances where God's law is viewed as defective or erroneous, as contrary to justice, or subject to exceptions.
If God's law has any defect or error, it would be imperfect. An imperfect law would require that God Himself is imperfect, for a perfect God could not make an imperfect law. Similarly, a perfect law could not come from an imperfect God. Therefore, either God and His law are both perfect, or they are both imperfect.
1. Read Gen. 1:31, Deut. 32:3-4 and Matt. 5:48.
Does God have any defects or errors? What are the limitations of God's perfection, if any?
Does God make mistakes? To what extent was the creation of the world less than perfect? Were Adam and Eve created perfect?
The law of nature is God's will impressed upon the world from the time of its creation. Is the law of nature necessarily perfect? Why or why not?
2. Read Gen. 3:14-19 and Psalm 19:7. To what extent, if any, did the Fall of man and the resulting curse of the ground introduce any defects or errors into the law of nature? What was the Psalmist's view?
3. Read Matt. 5:17 and Heb. 8:1-13. We know that God's covenant law with Israel was to some extent modified or fulfilled (a matter which will be considered in greater detail in later studies).
Does this mean that God's covenant with Israel contained defects or errors?
Were the covenant modifications introduced by the church covenant equitable in nature?
If God's law could be shown to be unjust in any respect, it would require that God Himself is unjust, for a perfectly just God could not make an unjust law. Hence, the question is whether there is any injustice with God.
The concept of justice is linked both to impartiality and righteousness. That is, what is just is also right. The definition of "righteousness" is linked to the concept of law, for the law declares what is right (or righteous) and what is wrong (or unrighteous). The word "justice" itself is based on the latin word "jus," which means "law." Therefore, justice would seem to mean "carrying out of the law." And, if law is the will of God expressed as a "rule of action," then to do justice is to carry out the will of God when expressed as a legal rule.
It would seem to be a contradiction to carry out the law of God as it should, and have the result termed "unjust." Whenever God's law is followed, the result is always just. Conversely, whenever the law of God is not carried out, no matter what the result, injustice is the result. Consequently, "justice" is not a function of, or dependent upon, someone's opinion of the results of the administration of law. Rather, the question of justice is a matter of whether the administration of law was righteous and impartial.
Justice in civil judgment requires that judges not apply the law in a partial way. That is, justice imposes a duty on every judge not to be a "respecter of persons." God is not a respecter of persons, which means that His law applies uniformly to all people. This is also the standard for human laws. Accordingly, uniformity in the application of legal rules is a necessary element of justice. A law that is not uniform is not just.
1. Read Deut. 1:17, Deut. 16:18-20 and Lev. 19:15.
What is the link between justice and impartiality in civil judgment?
To what extent is granting exceptions to legal rules in a judicial setting a form of partiality prohibited by the law of God?
Is it ever appropriate to apply a rule of law to some people, but not others, or to people in some situations, but not others? Can the granting of legal exceptions be reconciled with the requirement that all laws must be uniform, that is, not relative as to person or situation?
Is justice a function of the result of the enforcement of law?
We know that God's law is uniform, not being relative as to person or situation, and that God is no respecter of persons. Yet, there are a number of situations recorded where Jesus acted in a manner the Pharisees regarded as unlawful. We now need to determine whether these actions can properly be considered either as unlawful or as exceptions to otherwise applicable rules of law. That is, did Jesus ever regard himself as being an exception to the rules of law applicable to everyone else?
1. Read Matt. 15:1-3,7-9. Here Jesus was accused of breaking the traditions of the Jewish elders.
Did Jesus justify His actions on the basis of an exception to the law?
Was the law Jesus was accused of breaking of human or divine origin? What difference would it make?
To what extent could Jesus be characterized as declaring that the "tradition of the elders" was not law at all? Was this an equitable judgment?
2. Read Matt. 12:1-3,5-6,8. Here, Jesus was accused of breaking the law of the Sabbath.
Is the principle of the sabbath rooted in creation and the law of nature? Was the specific offense Jesus was accused of based on the law of nature, or was it a human tradition?
Did Jesus set aside the law of the Sabbath? Did Jesus justify His actions on the basis of an equitable exception?
How did Jesus justify the actions of His disciples? Were they "privileged" not to obey the law because they were with Him? Were they living in an "exceptional" time or circumstance which excused obedience?
Would the justification of what the disciples did back then apply to us today as well? How does your answer impact the legal analysis of the disciples' actions?
3. Read John 8:3-11. Here, Jesus defends the woman caught in adultery.
Did Jesus make an exception to the law of adultery? Did He nullify that law? Did He justify the adulterous woman's actions?
To what extent did Jesus uphold the law of God and do justice? Was his defense equitable in nature, or was it procedural? What difference does it make?
4. Consider and discuss the merit of the following argument: The law of adultery in ancient Israel required both the man and the woman involved to be tried and punished. See, Deut. 22:22. The fact that only the woman was accused, and not the man, is a procedural error in the conduct of the "trial." Indeed, it is doubtful that the mob which accused the adulterous woman constituted a lawful civil tribunal at all. By directing his comments to "he who is without sin among you," was Jesus making a procedural argument, that is, that no one could convict the woman in those circumstances without sin?
It remains to be considered how the concepts of mercy and grace impact the nature of law and equity. It may be argued that mercy and grace permit (or even require) exceptions to be made to the law which are equitable in nature, since "mercy triumphs over judgment." See, James 2:13. That mercy and grace are repeatedly affirmed and commended in the Bible is not disputed. However, the question is not whether mercy and grace exist, but whether they create equitable exceptions to the law, and if so, to what extent.
It would seem that mercy and grace are by definition discretionary. That is, although the Bible repeatedly admonishes people to show mercy and grace, there is apparently no legal obligation to do so in any particular case. Whether a person shows mercy in a given case is entirely discretionary, or volitional, based on all the facts and circumstances.
Mercy and judgment, at least in the judicial context, would seem to be logically inconsistent with each other. As shown in an earlier study, judges are not supposed to exercise WILL, which is discretionary, but JUDGMENT, which is non-discretionary. Thus, if mercy is to be employed in a civil or legal context, it would seem to require employment in a non-judicial (i.e., executive or legislative) capacity.
In contrast to the discretionary mercy which executive officers may use, the biblical instruction to civil judges in pronouncing legal judgment is not to show mercy or to pardon. That is, judges were not to show pity because of the "harsh" result mandated by the law, nor allow a convict to avoid the legal penalty via payment of some form of ransom.
1. Read Rom. 9:15-16. When God shows mercy towards someone, is it discretionary or obligatory on His part? Is God ever unjust in showing mercy to some people but not to others?
2. Read Jer. 18:8 and Jonah 3:10. When God shows mercy towards someone, is He declaring that the law is not applicable to them, or is He merely staying execution? To what extent can the difference between these alternatives be explained on the basis of the distinction between judicial power and executive power?
3. Read Matt. 18:23-35. Jesus' parable concerning the unmerciful slave urges the reader to forgive his brother from the heart. Is the parable framed in terms of a judicial case? To what extent, if any, is the parable applicable to judicial officers acting in their civil capacities? To whom is the parable applicable?
4. Read Num. 35:31; Deut. 13:6,8-9; and Deut. 19:11,13.
To what extent, if any, are these scriptures applicable to judicial officers acting in their civil capacities?
How do you explain the difference between these texts and the New Testament admonition to forgive each other and show mercy? Do these scriptures describe two different Gods (one judgmental, one merciful), two different sets of laws (one for Israel, one for the Gentiles), or two different legal capacities (one for civil judges, one for private individuals)?
To what extent are the admonitions of Num. 35:31; Deut. 13:6,8-9; and Deut. 19:11,13 applicable to civil judges today?
The early history of equity jurisprudence in England and America clearly distinguished law from equity. However, the distinction between law and equity has become increasingly blurred over time.
The basis of equity is the administration of grace, or discretion, to do justice. For equitable purposes, though, "justice" does not mean carrying out the law in any strict sense, but to do what the judge thinks is fair or appropriate. Consequently, equity tends to be largely a matter of personal moral conscience.
The extraordinary, or discretionary, jurisdiction of equity (historically) was based on the idea that it was the English Chancellor's role to speak for the conscience of the king in order for justice to be served. Modern equity is based on this same idea, namely, that justice is a matter of personal conscience, not a legal prescription.
It is no accident that equity jurisprudence has its roots in executive power. Although the English common law courts exercised their powers under the general authority of the king, they were primarily judicial in nature and function, limiting themselves to a non-discretionary judgment of the laws. The Court of Chancery, however, was peculiarly executive in nature. The Chancellor purported to exercise the personal conscience of the king, that is, he wielded the power of executive discretion.
In some areas of equitable jurisprudence, rules of equity became formalized through repeated usage over time. Nonetheless, these rules of equity have never lost their character as a jurisprudence of discretionary justice. A continuing hallmark of equity is the case-by-case method of analysis. This form of individualized equity is characterized by a "facts and circumstances" analysis where every case (in some sense) is treated as exceptional.
1. To what extent is the exercise of the power to pardon an act of mercy? Is the pardon power executive or judicial in nature?
2. When, if ever, is it permissible for a judge to find that an "exception" must be made to a civil law to properly account for the applicability of divine law?
3. When, if ever, is it permissible for a judge to find that a civil law necessitates the creating of an exception to the law of nature?
4. When a court engages in a facts and circumstances analysis, is the rule of law applied by the court likely to be permanent, uniform and universal? Is a facts and circumstances analysis a legal analysis at all? That is, does it result in the application of a "rule of action" in the historic sense?
[T]he liberty of considering all cases in an equitable light must not be indulged too far, lest thereby we destroy all law, and leave the decision of every question entirely in the breast of the judge. And law, without equity, though hard and disagreeable, is much more desirable for the public good, than equity without law; which would make every judge a legislator, and introduce most infinite confusion; as there would then be almost as many different rules of action laid down in our courts, as there are differences of capacity and sentiment in the human mind.
To what extent has the danger Blackstone warned of already happened?


text:
Protecting Healthcare Innovation
As we start to wrap-up 2015 with an eye towards the 2016 elections, our lawmakers will take up several issues that are important to the future of our nation's economy and healthcare innovation. Kentucky's innovators are carefully watching two pieces of legislation pending in Congress that stand to dramatically alter a U.S. patent system that has served our country well for over 200 years. The Kentucky Life Science Council and the life science companies that are growing the local economy would like to encourage Senator McConnell and the Kentucky delegation to support our universities and start-up community by voting against the Innovation Act (H.R. 9) and the PATENT Act (S. 1137).
For generations, the safeguards found in our patent system have incentivized innovation by shielding the valuable ideas and products of patent holders. In fact, the property rights patent holders enjoy are enshrined in the U.S. Constitution. These constitutional rights are the driving force behind the work of innovators – work that in many cases lasts several years or even a lifetime and would likely never occur if not for the defenses found in our country's defining document.
Our patent system also promotes economic growth and job creation not only in the communities where innovators live and work but across the entire country. In 2010, intellectual property-intensive industries accounted for approximately 35 percent of U.S. gross domestic product (GDP). During that same period, direct and indirect employment in these industries was responsible for roughly 40 million jobs, or 30 percent of all jobs in the U.S. In many cases these are high-quality, high-paying jobs that will be around for many years to come.
Maintaining a strong patent system also sends a clear message to countries like China that we deeply value the property of patent holders and will stop at nothing in defending it. This prevents counterfeit goods from flooding the domestic market and stops infringers in far-away places from illegally profiting off of American ingenuity.
Unfortunately, the U.S. House of Representative's Innovation Act is misguided in its approach and poses numerous problems for Kentucky's patent holders. Instead of tackling abusive patent activity head-on with targeted action it contains sweeping changes that will weaken our patent system. These proposals favor larger, well-established entities with unlimited resources and will undoubtedly put a squeeze on independent inventors, start-ups and small businesses that rely heavily on our patent system.
Under consideration in the U.S. Senate, the PATENT Act also contains several worrisome flaws. Of particular concern is language contained in this bill related to 'customer stay.' This broadly drafted provision will leave foreign manufacturers off the hook for the illegal use of patented technologies and would leave patent holders with no recourse for recovering losses related to such malicious activity.
We appreciate that abusive patent activity is a problem that we must continue to address, but these bills are not the solution. Instead of wiping the slate clean lawmakers should work together to ensure our patent system remains strong. Rushing to implement needless changes will have a host of unintended consequences and leave America at a severe disadvantage.
Kentucky's innovative community encourages Congress to vote down Innovation Act and the PATENT Act and protect a system that promotes economic growth.
-Kyle Keeney is Executive Director of the Kentucky Life Science Council.
Ben Keeton
Publisher at Medical News
Ben is the publisher of Medical News and focuses on the business of healthcare in Kentucky.
Latest posts by Ben Keeton (see all)
Nurses Must Set Example On Vaccines - June 7, 2021
Volunteers of America partners with Avesis to promote oral health among pregnant and parenting women - May 12, 2021
UK Markey Cancer Center and Mercy Health – Lourdes Hospital Announce Affiliation - January 16, 2020

redpajama_set_name: RedPajamaCommonCrawl


text:
Gazzosa alla menta (Diabolo menthe) è un film del 1977 diretto da Diane Kurys.

Trama
Il passaggio dall'infanzia all'adolescenza di due sorelle nella Francia degli anni sessanta.

Collegamenti esterni

Film ambientati in Francia
Film commedia drammatica
Film diretti da Diane Kurys

redpajama_set_name: RedPajamaWikipedia


☏ +1-800-961-6588 How to Fix QuickBooks Installation Error?
RemoteAccounting247 » How to Fix QuickBooks Installation Error?
How to Fix QuickBooks Installation Error?
It is a difficult situation when your primary accounting software is giving you a hard time during installation. There could be multiple reasons for the software to fail from installation and not everyone is an IT professional to fix QuickBooks Installation Error.
These small faults can prompt you with an installation error. Fixing these errors is not a rocket science but anything which we are unaware about is difficult. Let us see how to mend these errors and have a safe installation.
Scan your desktop in and out – malware can kill your system. It can generate error while installing QuickBooks. Try and scan your system to have a safe installation process.
Clean up your system junk – surfing over the internet or the using the computer can lead to junk accumulation which in turn is directed to a slow QuickBooks installation process, hence failure. Clean up your junk regularly for a smooth process.
Drivers – all the drivers installed on the system become obsolete within a few months. Update your PC device drivers frequently and this could avoid the QuickBooks installation error.
Install all available windows update.
Uninstall and reinstall the QB Software.
Save the file on the system and close all the ongoing programs.
Restart the system and try reinstalling the QuickBooks Software.
If the system is well installed with the updated windows, drivers and tools also, it meets the specifications of the QuickBooks software then the installation process shouldn't trouble you. We cannot predict errors; they can prompt you anytime and at any stage. You can give a call on QuickBooks support number +1-800-961-6588 and we would assist you right till the end.
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Today the FT has an article covering the subject that we covered in a piece of research in October – the underperformance of "most loved" stocks versus "least loved".
The FT looked at the UK market across all sectors and showed exactly what we showed in the chemical space in the US – that the least loved group outperforms the most loved.
We have looked at the performance of the stocks that we identified back in October and what we showed at the time has continued.
The 5 most loved Chemical stocks at the time have underperformed the 5 least loved by 11% on average (in a little over 3 months).


What is the most important quality that you want in a spouse? Of all the qualities, there is one transcending idea that must be at the top of your list. If your spouse has it, your chances for a great marriage are high.
One of the questions I ask engaged couples is why do they want to be married. There have been all kinds of responses to my query. Here are a few of the more common ones that I've heard.
I love him/her. He loves me.
We're in love. We have a lot in common.
We're so different from each other. We are meant for each other.
He treats me nice. It feels right.
People have said we're the perfect match. The Lord put us together.
She's fun to be with. I like his personality.
All of these qualities or desires have merit, and each one is worth considering when thinking about the person you want to marry. With that said, to base your reasons for marriage on any of those things could be anywhere from insufficient to dangerous, depending on the couple.
It is fair to say that every person who ever divorced had several of those things on their lists. Then when things became complicated, their marriages were not able to survive. The growing list of stuff they do not like about each other overshadows the things they did like about each other.
This marriage conundrum happens because of the effect of sin on our lives and relationships. Though the Bible is clear that every person is a sinner (Romans 3:23), rarely do people have an adequate plan to fight the encroachments of sin (1 John 3:8), and the longer they stay together, the more their sinfulness will seek to defile each other.
Sin can overpower, alter, and even obliterate the good qualities you previously enjoyed about your spouse. That is why there must be a transcending quality in the person you're hoping to marry. A transcending quality is the only quality that will give you your best shot at persevering in a marriage covenant.
There is no way in the world for you to know what the person you want to marry will be like ten years from now, but there is one thing you can count on: the person you marry today will be different in a decade.
All of us will regress into more self-centeredness, or we will progress into greater Christlikeness. The problem is that when a new couple first meets, they do not know which direction the other person is heading.
Is he increasing in spiritual leadership?
Is he decreasing in spiritual leadership?
The couple typically meets when they don't have much history. It's like being introduced to a new stock on the Stock Market. You don't know how it will trend. There is no history. Will this stock trend upward, and you reap the benefits, or will it tank?
The new couple begins building a new history together; this is the dating season. Unfortunately, the dating season is, partially, an artificial period where the hope-filled couple tries hard to be nice to each other.
If the dating season lasts more than twelve months, they will begin to see authentic evidence of who they are. Of course, the problem here is that love can blind, and when it comes to love, we tend to want to be blind. A bird in the hand is better than two in the bush.
Life is like a box of chocolates; you never know what you're going to get.
Spousal assessment is an opportunity that needs your attention. Some of the most religiously minded people married each other only to end their relationship in a bitter divorce. Then others began their covenant from a less desirable circumstance, but experienced an incredible transformation by the grace of God.
Thousands of preachers have miserable marriages, and thousands of non-ministry people have God-exalting, grace-empowered, mutually satisfying marriages. You can never fully know what you're going to get.
The initial criteria for assessing a person is too often inadequate, which is mystifying in light of what the Bible teaches us about the one transcending quality that will give you all you need to know to be married well.
Key Idea: If the person you want to marry does not have as their primary mission in life the glory of God, you need to give a long and sober consideration to the wisdom of marrying that person.
If the desire to glorify God is a person's passion, there is a good chance you could be in a meaningful and satisfying relationship with that person for the rest of your lives. There is nothing that transcends this God-centered quality.
That means there is no sin, sinful desire, or sinful temptation that can overcome a person's dogged and unflinching determination to glorify God. Whenever sin makes its advances, the desire to glorify God will eventually win the war against sin's intent.
When Joseph was left alone in Potiphar's home, his master's wife began to put a move on the young slave. What she did not know was how the Lord had already captured the young man's affections. From his perspective, there was no way he could sin against God.
Joseph's main intention in life was to spread the fame of God. He possessed a sober awareness of God's glory. He revered the Lord. A desire to magnify God through his difficult slave life consumed him (Psalm 34:3).
If you are looking to make a covenant with a "Joseph-type person," that is your best play. It will not keep you from future heartbreak, but there is not a piece of information out there that is more affirming than a person's authentic and measurable desire to glorify God.
Paul said that no matter what you did, your primary goal must be to glorify God. This ambition releases any person to be free to live their life in any way they want to as long as their life exalts the majesty and greatness of God.
That firm parameter will keep you from transgressing the line of right and wrong, and it will keep evil from penetrating your desire-to-gorily-God force field.
When the guardian of your heart is the glory of the Lord, you're in a place to be a good friend, great lover, and beautiful spouse. This quality is the kind of person you want to marry.
There are some ways you can discern if you're looking at a "whatever you do, do all to the glory of God" kind of person. I want to share with you three of those qualities.
Passionate – We are all passionate about something. To be passionate about the Lord is not something just for old Christians to emulate. Anybody can have a passion for God. If you're thinking about marrying someone, they should have a passion for God.
Does he (or she) have a Godward orientation?
Is the Lord what defines him?
At least one thing defines all of us. Nobody lacks passion. If you look long enough, you will find the thing that makes your dating partner emote. If it is not the Lord, buyer beware.
A desire to have a great job or to purchase a home or to build a future together are good and necessary things. But when it comes to the Lord, a preeminent longing for His glory should make all other loves look like hate by comparison (Luke 14:26-27).
The truth is that your spouse will sin against both you and God. I speak from experience, as one who has sinned many times against my wife and my Lord.
Glorifying God does not imply perfection. Living a perfect life is contrary to the Bible—for all have sinned (Romans 3:23), and if any of us say we don't sin, we're liars (1 John 1:7-10). But do not fear.
A person whose primary goal is to glorify God has a great backup plan: he will be a repenting person. Though he will have lapses in judgment, as experienced by doing something unkind to you, he will respond quickly with a broken-hearted confession (Psalm 51:17), plus a request for forgiveness.
Why: Because his chief aim is to glorify God.
The Lord wired us with a herd mentality. It is not okay for us to be alone (Genesis 2:18), which is why we pursue community. If you're a loner, that community may be your video games or Internet surfing. You're no different from me in that you want to surround yourself with what you like (1 Corinthians 15:33).
You can take the measure of a person by assessing their associations—the things they fill their lives with so they can enjoy life the way they want to. Nobody surrounds themselves with things they do not like. Even if they work a job they hate, they create hobbies to offset their disdain for their jobs.
We long for a community because God made us in the image of the original community (Genesis 1:26-27). How can the thing made be different from the person who made him?
There is one way. It is sin. The effect of sin is the only way we can have distorted desires for the wrong kind of community.
These three qualities will give you an indication of a person's desire to make God's name great in your relationship. But you want to be careful by making a distinction between the presence of these ideas and the perfection of them.
Nobody will be able to glorify God perfectly. We are in a continuous sanctifying process. What you want to discern is the presence of these qualities, even if they are in early forms.
If you have found the evidence of these things in your dating partner, you're at a great beginning. It is wise to ask other individuals who are familiar with both of you for their assessments of you. If you are unsure of the evidence you perceive in the person you want to marry, I appeal to you to not go forward (Romans 14:23).
There should be nothing more important to you than a person's desire to glorify God. Do not let any other piece of information supplant that one, even if he assures you of his love for you. If you dismiss this advice, you will live to regret it.
What is your number one passion: the Lord's fame or something else?
When there is nothing else for you two to talk about, what do you talk about: the Lord or something else?
What does repentance look like in your relationship?
How long does it take you both to confess your sins and forgive each other?
Describe your community experience, the things that have a gravitational tug on your hearts.
When you get to pick and choose what you want to do, what do you choose? Who are the people and what are the things that have become your primary companions?


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Who Owns Youtube 2022 : YouTube Acquisition by Google
November 17, 2022 by ItsKnows Team
YouTube has become the most popular video-sharing site in the world. But surprisingly, few people know "who owns YouTube." The company was started in 2005 by Chad Hurley, Steve Chen, and Jawed Kiyani to provide a place for one-time, casual uploads of home video clips. It is now the third most visited website on the internet regarding traffic, behind Google and Facebook.
YouTube quickly became famous for not only its ease of use but also its vast library of content. The site developed an audience by providing everything from viral videos to educational videos to footage from live events. With more than 6 billion hours of video watched per month on Youtube, it has managed to stay relevant even after the dot com bust.
Who owns YouTube?
It's surprising to discover that Google owns Youtube. The video-sharing site is owned by a non-profit corporation known as the YT Network. The previous owner was Google's venture capital arm, Google Ventures. YouTuber Hank Green recently noted, "Google's the corporation. Youtube is the people."
To learn more about YouTube and its history, read on.
History of YouTube
Jawed Karim, Steve Chen, and Chad Hurley met in 2002 at Stanford University. Their goal was to create an easy way to share home videos with friends and family. Hurley and Chen were members of the video club, and Karim was an engineering student who took online classes. They started developing a new video-sharing site called the Labs project.
Why Google bought YouTube
We just saw who owns YouTube. I hope you understand. If you were to ask anyone in 2005 what Google was, most would probably respond "Google" in a confused tone. The company had just started as a search engine based on a research project created by two Stanford graduates Larry Page and Sergey Brin, in 1995. The following year the company moved to Stanford, and in 1998 they officially launched Google as a search engine.
Despite its early start, Google struggled to find its place in the market. The company initially missed the chance to provide a free alternative to Microsoft's Internet Explorer web browser. By 2005 Google found its niche, providing users with a quick and easy way to find information. And now they finally found their mojo, winning an Emmy award for its YouTube video coverage of the 9/11 tragedy.
How has YouTube changed since Google acquired it?
Google went on to acquire YouTube for a cool $1.65 billion. Although Google had expected to make some money from the site and was willing to wait a while to become profitable, the company has become the world's largest video-sharing website with a website that makes money by selling ads. When Google paid for it, YouTube had a couple of million registered users. Today, over 1.8 billion people visit the site every month. YouTube also operates a network of music, television, movies, and comedy sites, with over $7 billion in annual ad revenue.
Viewers now rely on Youtube to help them discover movies and video clips, and celebrities are growing to rely on it as well. As a result, Google has become a significant force in the entertainment industry and the media business.
The history of YouTube
When YouTube was founded, it was very much a side project to the three young men. Chad Hurley, Steve Chen, and Jawed Kiyani had met as co-workers at WebTV Networks (WTVN), a video-on-demand service that began in 1999. They soon began seeking a way to make it easier for people to upload videos. By 2004, they decided to develop the site into a website that would be "a place where users can upload, share, and discover videos online, and where everyone can create, build, and share their own YouTube channel." At the time, YouTube was one of the top 50 websites in the world.
In 2005, Steve Chen and Jawed Kiyani completed their mission and launched Youtube in the United States. The site quickly began to gain traction and soon attracted millions of users.
Why is YouTube so popular?
YouTube has created a global platform for video sharing that has managed to grow at a rapid pace without losing its popularity. The ease of uploading content to YouTube ensures that users can post any content that they have captured. Since users are not worried about getting the video ready before posting it, they are more likely to be spontaneous and relaxed about posting videos that are meant to be interesting.
Since the entire video takes up less space than a whole webpage, it makes sense for users to upload their videos on the internet. Although at times, YouTube may have restricted the upload of content that is inappropriate for children, the vast amount of content available on YouTube does not tend to be inappropriate for viewers under the age of 17.
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The Twitter Fiction Festival – a guest post by Lucy Coats
Posted by Lucy, November 28, 2012
A guest post by Lucy Coats, author of the forthcoming picture book title Captain Beastlie's Birthday (published in March 2014).
A month or so ago I saw a little tweet on my feed. "Click here to enter the Twitter Fiction Festival" it said. I investigated immediately, being (like Nosy Crow) a big fan of all things Twitter, and found out that the social networking site were challenging writers worldwide to come up with stories – any genre, any form – which they could tell in 140 characters. They wanted a quick pitch – so I had a think and came up with an idea.
Since myths are what I love best, I told them I'd take on the challenge of writing 100 Greek myths in 100 tweets. Simple, I thought airily, as I pressed the send button. A month or so later, I got an email. "We like what we're hearing," said the Twitter people. "Tell us more." That was when it got a little trickier. How was I going to do this? How could I condense these amazing stories into 140 characters (including the #twitterfiction hashtag)? I wrote a longer, much more detailed pitch, and decided that the only way to do this was to turn the myths into tabloid headlines. Sacrilege? I don't think so. These ancient stories are full of just the kind of scandal the tabloids of today love. Zeus is always having torrid affairs (sometimes with his close relations), or turning into a seductive beast. There's murder, there's jealousy, there's war, there's abduction, there are amazing catfights between goddesses, and, in general, more godly (and human) shenanigans than The Sun can shake a stick at. It's material newspaper editors can only dream of in real life.
About a week ago, I received a Top Secret email telling me that I'd succeeded. I'd been chosen as one of the 29 global participants who would be the official Twitter Fiction Festival writers, and last night Twitter made the announcement. It was a slightly nerve-wracking moment – because now I was actually going to have to come up with the mythic goods. I put everything else on hold, and started scribbling. The intellectual challenge of condensing the stories surprised me, but in the end I found it came down to finding the essence of the tale and cutting out everything else. Luckily I had the book I'd already written – Atticus the Storyteller's 100 Greek Myths – to hand as a ready reference guide.
I really hope I've succeeded in shining a fresh light on these wonderful, timeless stories – and that some of the people reading my tweets will want to go and discover more about them. No doubt the #twitterfiction audience will let me know loud and clear whether I have! Anyway, the die is cast now. I've scheduled all my mythic tweets, and I'm proud to say that I'm kicking off the whole Festival with my very first tweet being read out at 1.40pm today on Radio Four's The World at One. If you'd like to follow the proceedings, I tweet as @lucycoats.
Hooray for Twitter, I say, for backing and promoting this brand-new way of telling stories. I can't wait for it all to begin, and I'd love to hear what all of you think too!
Nosy Crow publishes The Snowman's Journey: an "instant" book of the 2012 John Lewis Christmas advert