Citations

Background. Previous reports have shown a positive association between serum calcium level and prostate cancer mortality. However, there is no data regarding whether higher serum calcium levels are associated with increased risk of biochemical recurrence (BCR) following salvage radiation therapy (SRT) for prostate cancer. Herein, we evaluate the association between pretreatment serum calcium levels and BCR in a cohort of men who underwent SRT. Methods. We evaluated 165 patients who underwent SRT at our institution. Median dose was 65.0 Gy (range: 54.0–72.4 Gy). We considered serum calcium as both a continuous variable and a 3-level categorical variable (low [≤9.0 mg/dL], moderate [>9.0 mg/dL and ≤9.35 mg/dL], and high [>9.35 mg/dL]) based on sample tertiles. Results. We observed no evidence of a linear association between serum calcium and BCR (relative risk (RR): 0.96, P=0.76). Compared to men with low calcium, there was no significantly increased risk of BCR for men with moderate (RR: 0.94, P=0.79) or high (RR: 1.08, P=0.76) serum calcium levels. Adjustment for clinical, pathological, and SRT characteristics in multivariable analyses did not alter these findings. Conclusion. Our results provide evidence that pretreatment serum calcium is unlikely to be a useful tool in predicting BCR risk following SRT.

Controlling the overall cost of medical care requires controlling the number of physician visits. Nurse practitioners and physician assistants (NPs/PAs) may function as lower-cost substitutes for physicians or they may complement physician services. The association between NP/PA and physician visits when NPs/PAs are not working as primary care providers (PCPs) has not been thoroughly studied. A sample of 400 family medicine patients drawn from 1 large multisite practice was studied using multiple logistic regression analysis. NPs/PAs did not function as PCPs during the study period. Patients were defined as outliers if they visited physicians more than 5 times in a year. Patients who visited NPs/PAs in non-retail clinics were significantly more likely to be physician visit outliers. Visits to NPs/PAs in retail clinics were not related to physician visits. NP/PA visits in standard medical office settings complement physician visits when the NPs/PAs were not working as PCPs in this large multisite practice. Health care reform proposals relying on increased use of NPs/PAs may be more cost-efficient if NPs/PAs are located in retail settings or function as PCPs. ( Population Health Management 2013;16:242–245)

Inactivating mutations of the SOST (sclerostin) gene are associated with overgrowth and sclerosis of the skeleton. To determine mechanisms by which increased amounts of calcium and phosphorus are accreted to enable enhanced bone mineralization in the absence of sclerostin, we measured concentrations of calciotropic and phosphaturic hormones, and urine and serum calcium and inorganic phosphorus in mice in which the sclerostin ( sost ) gene was replaced by the β-D-galactosidase ( lacZ ) gene in the germ line. Knockout (KO) ( sost −/− ) mice had increased bone mineral density and content, increased cortical and trabecular bone thickness, and greater net bone formation as a result of increased osteoblast and decreased osteoclast surfaces compared with wild-type (WT) mice. β-Galactosidase activity was detected in osteocytes of sost KO mice but was undetectable in WT mice. Eight-week-old, male sost KO mice had increased serum 1α,25-dihydroxyvitamin D, decreased 24,25-dihydroxyvitamin D, decreased intact fibroblast growth factor 23, and elevated inorganic phosphorus concentrations compared with age-matched WT mice. 25-Hydroxyvitamin D 1α-hydroxylase cytochrome P450 ( cyp27B1 ) mRNA was increased in kidneys of sost KO mice compared with WT mice. Treatment of cultured proximal tubule cells with mouse recombinant sclerostin decreased cyp27B1 mRNA transcripts. Urinary calcium and renal fractional excretion of calcium were decreased in sost KO mice compared with WT mice. Sost KO and WT mice had similar serum calcium and parathyroid hormone concentrations. The data show that sclerostin not only alters bone mineralization, but also influences mineral metabolism by altering concentrations of hormones that regulate mineral accretion.

We previously demonstrated that cardiac myosin can use 2-deoxy-ATP (dATP) as an energy substrate, that it enhances contraction and relaxation with minimal effect on calcium-handling properties in vitro, and that contractile enhancement occurs with only minor elevation of cellular [dATP]. Here, we report the effect of chronically enhanced dATP concentration on cardiac function using a transgenic mouse that overexpresses the enzyme ribonucleotide reductase (TgRR), which catalyzes the rate-limiting step in de novo deoxyribonucleotide biosynthesis. Hearts from TgRR mice had elevated left ventricular systolic function compared with wild-type (WT) mice, both in vivo and in vitro, without signs of hypertrophy or altered diastolic function. Isolated cardiomyocytes from TgRR mice had enhanced contraction and relaxation, with no change in Ca 2+ transients, suggesting targeted improvement of myofilament function. TgRR hearts had normal ATP and only slightly decreased phosphocreatine levels by 31 P NMR spectroscopy, and they maintained rate responsiveness to dobutamine challenge. These data demonstrate long-term (at least 5-mo) elevation of cardiac [dATP] results in sustained elevation of basal left ventricular performance, with maintained β-adrenergic responsiveness and energetic reserves. Combined with results from previous studies, we conclude that this occurs primarily via enhanced myofilament activation and contraction, with similar or faster ability to relax. The data are sufficiently compelling to consider elevated cardiac [dATP] as a therapeutic option to treat systolic dysfunction.

Abstract Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.

Recently, several high-impact reviews suggest that regular aerobic exercise is beneficial for maintaining cognitive function in aging adults. Higher cerebral blood flow and/or cerebrovascular reactivity may explain the favorable effect of exercise on cognition. In addition, prostaglandin-mediated vasodilator responses may be influenced by regular exercise. Therefore, our purpose was to evaluate middle cerebral artery (MCA) vasodilator responses in healthy adults before and after cyclooxygenase inhibition. A total of 16 young (26 ± 6 yr; 8 males, 8 females) and 13 older (64 ± 6 yr; 7 males, 6 females) healthy adults participated in the study. Aerobic fitness was determined by maximal aerobic capacity (V̇o2max) on a cycle ergometer. MCA velocity (MCAv) was measured at baseline and during stepped hypercapnia (2%, 4%, and 6% FiCO2) before and after cyclooxygenase inhibition using indomethacin. To account for differences in blood pressure, cerebrovascular conductance index (CVCi) was calculated as MCAv/mean arterial pressure. Cerebrovascular reactivity slopes were calculated from the correlation between either MCAv or CVCi and end-tidal CO2. Young adults demonstrated greater MCAv reactivity (1.61 ± 0.17 vs. 1.06 ± 0.15 cm·s−1·mmHg−1; P < 0.05) and CVCi reactivity (0.015 ± 0.002 vs. 0.007 ± 0.002 cm·s−1·mmHg−1; P < 0.05) compared with the older adults. There was no association between cerebrovascular reactivity and V̇o2maxin the combined group of subjects; however, in older adults MCAv reactivity was correlated with maximal aerobic fitness ( r = 0.64; P < 0.05). Furthermore, the change in MCAv reactivity (between baseline and indomethacin trials) was also associated with V̇o2max( r = 0.59; P < 0.05) in older adults. Cerebral vasodilator responses to hypercapnia were associated with maximal aerobic capacity in healthy older adults. These results may explain the physiological link between regular aerobic exercise and improved cognitive function in aging adults.

Abstract Background: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. Methods: Data from 14 ovarian cancer case–control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic “risk score” was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. Results: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48–1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet &lt; 0.001), parity (Phet &lt; 0.01), and tubal ligation (Phet = 0.041). Conclusions: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. Cancer Epidemiol Biomarkers Prev; 22(5); 880–90. ©2013 AACR.