Women with polycystic ovary syndrome (PCOS) exhibit an adverse cardiovascular risk profile, characteristic of the metabolic cardiovascular syndrome (MCS). The aim of this study was to determine the ...prevalence of coronary artery (CAC) and aortic (AC) calcification among middle-aged PCOS cases and controls and to explore the relationship among calcification, MCS, and other cardiovascular risk factors assessed 9 yr earlier. This was a prospective study of 61 PCOS cases and 85 similarly aged controls screened in 1993–1994 for risk factors and reevaluated in 2001–2002. The main outcome measures were CAC and AC, measured by electron beam tomography. Women with PCOS had a higher prevalence of CAC (45.9% vs. 30.6%) and AC (68.9% vs. 55.3%) than controls. After adjustment for age and body mass index, PCOS was a significant predictor of CAC (odds ratio = 2.31; P = 0.049). PCOS subjects were also 4.4 times more likely to meet the criteria for MCS than controls. High-density lipoprotein cholesterol and insulin appeared to mediate the PCOS influence on CAC. Interestingly, total testosterone was an independent risk factor for AC in all subjects after controlling for PCOS, age, and body mass index (P = 0.034). We conclude that women with PCOS are at increased risk of MCS and demonstrate increased CAC and AC compared with controls. Components of MCS mediate the association between PCOS and CAC, independently of obesity.
Dietary nitrate has been associated with health benefits as well as potential risks, thus presenting a paradox for consumers and health professionals. To address the issue, we applied the ...Benefit-Risk Analysis for Foods (BRAFO) framework to evaluate dietary exposure to nitrate by considering how the risks and benefits might vary under the reference scenario of the acceptable daily intake (ADI) set forth by JECFA (3.7 mg/kg-day), or under an alternative scenario of a higher ADI (independently developed herein). Results demonstrated that risk, as conservatively characterized by various toxicological benchmarks, was present at levels ranging from the current ADI value of 3.7 mg/kg-day (lowest end of the range) to >15 mg/kg-day. When these ADI values, both established by regulatory bodies as well as independently herein were compared to intakes associated with benefits (decreased blood pressure observed following repeated exposure to nitrates ∼4–18 mg/kg-day), along with considerations of current dietary exposures associated with healthy diets, the alternative scenario allowed for benefits without incurring additional risk. For consumers aged 12 weeks and older, ADI values ∼12–17 mg/kg-day—based on more reliable data than used to derive the current ADI—allow benefits to be realized while still protecting public health. The assessment serves as a case study in how benefits can be considered in a risk assessment paradigm for foods, thus providing useful information to decision makers.
•Dietary intake of nitrate presents a paradox: recognized cardiovascular benefits versus potential for health risks.•A Benefit-Risk Analysis for Foods (BRAFO) analysis was applied; this allows for the assessor to weigh the probability of an effect against the probability of benefit.•ADI values (independently derived and those from regulatory authorities) were used to evaluate the risk/benefit of exposure greater than the current ADI.•ADI values ∼12–17 mg/kg-day allow benefits to be realized while still protecting public health.
P-type point contact (PPC) HPGe detectors are a leading technology for rare event searches due to their excellent energy resolution, low thresholds, and multi-site event rejection capabilities. We ...have characterized a PPC detector’s response to
α
particles incident on the sensitive passivated and p
+
surfaces, a previously poorly-understood source of background. The detector studied is identical to those in the
Majorana
Demonstrator
experiment, a search for neutrinoless double-beta decay (
0
ν
β
β
) in
76
Ge.
α
decays on most of the passivated surface exhibit significant energy loss due to charge trapping, with waveforms exhibiting a delayed charge recovery (DCR) signature caused by the slow collection of a fraction of the trapped charge. The DCR is found to be complementary to existing methods of
α
identification, reliably identifying
α
background events on the passivated surface of the detector. We demonstrate effective rejection of all surface
α
events (to within statistical uncertainty) with a loss of only 0.2% of bulk events by combining the DCR discriminator with previously-used methods. The DCR discriminator has been used to reduce the background rate in the
0
ν
β
β
region of interest window by an order of magnitude in the
Majorana
Demonstrator
and will be used in the upcoming LEGEND-200 experiment.
Perfluorohexanoic acid (PFHxA) is a potential impurity and environmental degradation product of C6-based fluorotelomer products. Considering the potential endocrine activity of perfluoroalkyl acids, ...a hypothesis-driven weight-of-evidence (WoE) analysis was conducted to evaluate the potential endocrine disruptor activity of PFHxA, as defined by World Health Organization (WHO), across estrogen (E), androgen (A), thyroid (T), and steroidogenesis (S) pathways. A comprehensive literature search identified primary and secondary studies across species for review. The ToxCast/Tox21 database provided in vitro data. Studies identified were reviewed for reliability, and relevance, with endocrine endpoints ranked, and lines of evidence evaluated across pathways. Overall, PFHxA showed no endocrine effects in Japanese medaka, juvenile rainbow trout, chickens or reproductive parameters in northern bobwhite with no significant activity in rodent repeated-dose toxicity, lifetime cancer, or reproductive and developmental studies. In vitro, there was weak or negative activity for T transport protein or activation of E, A or T receptors. PFHxA was also negative in vitro and in vivo for disrupting steroidogenesis. Based on this WoE endocrine analysis, PFHxA exposure did not cause adverse effects associated with alterations in endocrine activity in these models, as such would not be characterized as an endocrine disruptor according to the WHO definition.
•PFHxA showed no bioactivity in 29 HTS (ToxCast/Tox21) E, A or T assays.•PFHxA showed weak TTR binding in vitro..•Based on WoE analysis across LoE from in vivo studies, PFHxA did not show activity in the E, A, T, or S pathways.
TBBPA is a non-genotoxic flame retardant used to improve fire safety in a wide variety of consumer products. Estimated human exposures to TBBPA are very low (<0.000084 mg/kg-day), relative to the ...doses (500 and 1000 mg/kg-day of TBBPA) administered in a recent bioassay that resulted in uterine tumors in Wistar Han rats following chronic exposure. As part of an effort to characterize the relevance of the uterine tumors to humans, data and biological knowledge relevant to the progression of events associated with TBBPA-induced uterine tumors in female rats were organized in an adverse outcome pathway (AOP) framework. Based on a review of possible MOAs for chemically induced uterine tumors and available TBBPA data sets, a plausible molecular initiating event (MIE) was the ability of TBBPA to bind to and inhibit estrogen sulfotransferases, the enzymes responsible for sulfation of estradiol. Subsequent key events in the AOP, including increased bioavailability of unconjugated estrogens in uterine tissue, would occur as a result of decreased sulfation, leading to a disruption in estrogen homeostasis, increased expression of estrogen responsive genes, cell proliferation, and hyperplasia. Available data support subsequent key events, including generation of reactive quinones from the metabolism of estrogens, followed by DNA damage that could contribute to the development of uterine tumors. Uncertainties associated with human relevance are highlighted by potential strain/species sensitivities to development of uterine tumors, as well as the characterization of a dose-dependent MIE. For the latter, it was determined that the TBBPA metabolic profile is altered at high doses (such as those used in the cancer bioassay), and thus an MIE that is only operative under repeated high dose, administration. The MIE and subsequent key events for the development of TBBPA-induced uterine tumors are not feasible in humans given differences in the kinetic and dynamic factors associated with high dose exposures in rats relative to human exposure levels to TBBPA.
Display omitted
•TBBPA-induced uterine tumors in female rats were organized in an adverse outcome pathway (AOP) framework.•The MIE was determined to be binding inhibition of estrogen sulfotransferases.•Evidence demonstrates that the MIE that is only operative under repeated high dose, administration.•TBBPA-induced uterine tumors are not feasible in humans when considering current exposure levels.
Imperfections in analog-to-digital conversion (ADC) cannot be ignored when signal digitization requirements demand both wide dynamic range and high resolution, as is the case for the Majorana ...Demonstrator 76 Ge neutrinoless double-beta decay search. Enabling the experiment's high-resolution spectral analysis and efficient pulse shape discrimination required careful measurement and correction of ADC nonlinearities. A simple measurement protocol was developed that did not require sophisticated equipment or lengthy data-taking campaigns. A slope-dependent hysteresis was observed and characterized. A correction applied to digitized waveforms prior to signal processing reduced the differential and integral nonlinearities by an order of magnitude, eliminating these as dominant contributions to the systematic energy uncertainty at the double-beta decay <inline-formula> <tex-math notation="LaTeX">Q </tex-math></inline-formula> value.
The objectives of this study were to (1) characterize MDR-MDCK monolayers as an in vitro model to predict brain uptake potential; (2) examine the ability of MDR-MDCK monolayers to identify the brain ...uptake potential of compounds that interact with P-glycoprotein (P-gp). The study measured the bi-directional transport of 28 compounds across MDR-MDCK monolayers. The brain uptake of a subset of the compounds was determined in the rat brain perfusion model. Drug concentrations were analyzed by LC–MS–MS. CNS-positive drugs exhibited absorptive permeability coefficients (Papp, A–B) values ranging from 3.4
×
10
−6 to 20.2
×
10
−6
cm/s; whereas CNS-negative drugs showed Papp (A–B) ranging from 0.03
×
10
−6 to 0.83
×
10
−6
cm/s. Inhibition of P-gp by cyclosporin A (CsA) significantly reduced secretory flux of compounds known to be P-pg substrates, but only enhanced the absorptive flux of compounds with high efflux ratio (>100). In vitro results were confirmed by brain perfusion studies on selected compounds. MDR-MDCK monolayers can be used to classify compounds into CNS-positive or CNS-negative based on the permeability coefficients (Papp, A–B). Under our experimental conditions, compounds with Papp (A–B)
>3
×
10
−6
cm/s have high brain uptake potential; compounds with Papp (A–B)
<
1
×
10
−6
cm/s are unable to penetrate the blood–brain barrier (BBB); the brain uptake of compounds with Papp (A–B)
<
1
×
10
−6
cm/s and a P-gp-mediated efflux ratio of >100 may be enhanced by inhibiting P-gp.
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