Association between diabetes, diabetes treatment and risk of developing endometrial cancer.

BackgroundA growing body of evidence suggests that diabetes is a risk factor for endometrial cancer incidence. However, most of these studies used case-control study designs and did not adjust for obesity, an established risk factor for endometrial cancer. In addition, few epidemiological studies have examined the association between diabetes treatment and endometrial cancer risk. The objective of this study was to assess the relationships among diabetes, diabetes treatment and endometrial cancer risk in postmenopausal women participating in the Women's Health Initiative (WHI).MethodsA total of 88 107 postmenopausal women aged 50-79 years who were free of cancer and had no hysterectomy at baseline were followed until date of endometrial cancer diagnosis, death, hysterectomy or loss to follow-up, whichever came first. Endometrial cancers were confirmed by central medical record and pathology report review. Multivariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) (95% confidence interval (CI)) for diagnosis of diabetes and metformin treatment as risk factors for endometrial cancer.ResultsOver a mean of 11 years of follow-up, 1241 endometrial cancers developed. In the primary analysis that focused on prevalent diabetes at enrolment, compared with women without diabetes, women with self-reported diabetes, and the subset of women with treated diabetes, had significantly higher risk of endometrial cancer without adjusting for BMI (HR=1.44, 95% CI: 1.13-1.85 for diabetes, HR=1.57, 95% CI: 1.19-2.07 for treated diabetes). However after adjusting for BMI, the associations between diabetes, diabetes treatment, diabetes duration and the risk of endometrial cancer became non-significant. Elevated risk was noted when considering combining diabetes diagnosed at baseline and during follow-up as time-dependent exposure (HR=1.31, 95% CI: 1.08-1.59) even after adjusting for BMI. No significant association was observed between metformin use and endometrial cancer risk.ConclusionsOur results suggest that the relationship observed in previous research between diabetes and endometrial cancer incidence may be largely confounded by body weight, although some modest independent elevated risk remains

Utilization of the Zebrafish Model for Investigating Nitrated Polycyclic Aromatic Hydrocarbon Developmental Toxicity

Polycyclic aromatic hydrocarbons (PAHs) are among the most widely known and studied environmental contaminants, originating from a range of natural and anthropogenic sources. PAHs are known to occur in the environment as complex mixtures, containing both unsubstituted PAHs, as well as a range of PAH derivatives. Among the less-studied of these derivative PAH classes are nitrated PAHs (NPAHs). NPAHs are known to form from atmospheric reactions with PAHs and can be found in the environment in a variety of matrices. Many NPAHs are known to be mutagenic, in some cases more so than the corresponding unsubstituted PAH. Less is known about the toxicity of NPAHs in whole-animal systems and for non-cancer endpoints, in particular with regard to the developmental toxicity and metabolism across a wide number of NPAH compounds, in a consistent model system. One of the major challenges in studying PAHs, and related compounds, is the high hydrophobicity and low water solubility of these compounds, which can result in losses due to partitioning of the analytes out of the aqueous phase and on to the walls of the container or exposure vessel. Numerous in vitro and in vivo models utilize plastic plates as exposure vessels, including the use of polystyrene 96-well plates for developmental toxicity testing in the developing zebrafish (Danio rerio) model. We directly measured the losses which occur due to sorption to the polystyrene plates during zebrafish testing for a set of PAHs and NPAHs. Sorptive losses in some instances were greater than fifty percent, in particular for the lower of the two exposure concentrations tested. These sorptive losses decrease the concentration of chemical available to the zebrafish embryos, and therefore impact the interpretation of dose-response toxicity data. In an attempt to create a predictive model for sorptive losses, the measured sorption was modeled against the log K[subscript ow], molecular weight, and subcooled liquid solubilities of the corresponding compounds. The correlations between subcooled liquid solubility and PAH sorption was statistically significant (p<0.05) for both concentrations tested, as well as molecular weight at the higher concentrations tested. However, none of the correlations were statistically significant for NPAH sorption, indicating a need for increased research in this area. We utilized the developing zebrafish model to investigate the developmental toxicity, and potential contributing mechanisms of action, of a suite of 27 NPAHs, as well as 10 heterocyclic PAHs (HPAHs) and 2 amino-PAHs (potential metabolites of NPAHs). Results from the toxicity screen indicate that NPAHs and HPAHs have a wide range of bioactivities in the developing zebrafish, from non-toxic at the concentrations tested to acutely toxic at sub-micromolar exposure concentrations. Activation of the aryl hydrocarbon receptor (AHR) pathway was investigated using a transgenic reporter zebrafish line and morpholino oligonucleotide knockdown to isolate specific isoforms of the AHR. The compounds investigated induced cyp1a expression in five distinct tissues (liver, vasculature, skin, yolk, and neuromast), which we determined to be due to different isoforms of the AHR. A subset of NPAHs was also selected for further mechanistic analysis via qPCR, and genes related to xenobiotic metabolism, cardiac stress, and oxidative stress were investigated. Each NPAH resulted in a unique profile of differentially regulated genes, indicating several potential contributing mechanisms of action. Combined, the results indicate that NPAHs and HPAHs are diverse in their bioactivities towards developing zebrafish. To further investigate metabolism as a contributing factor in the developmental toxicity of NPAHs, we explored the use of a transgenic nitroreductase-expressing zebrafish line for developmental toxicity testing of NPAHs, as well as the applicability of this transgenic line for high-throughput toxicity screening for hepatotoxicity. Humans, and other vertebrate model systems, have endogenous nitroreductase activity, which is responsible for the reduction of nitro functional groups to amino functional groups, while zebrafish do not. Published protocols utilized this transgenic line for tissue-specific cell ablation for a specific exposure scenario. We expanded upon the published protocols for the utilization of this transgenic line for tissue-specific cell ablation, as well as explored potential uses beyond cell ablation. Nitroreduction of a NPAH to the corresponding amino-PAH would have resulted in a shift in the toxicity profile. Unfortunately, no such changes were observed, despite validation of the nitroreductase functionality of the transgenic line, suggesting that the nitroreductase does not have a suitably high affinity for NPAHs to allow for this use. We also exposed the transgenic embryos to compounds known to undergo hepatic metabolism (benzo[a]pyrene and retene) or known hepatotoxins (flutamide, acetaminophen), with and without hepatic ablation, to demonstrate the utility of this transgenic line in isolating the role of the liver in observed toxicity. Overall, the uses for this transgenic line expand beyond the intended and published protocol, but would be further expanded with the development of a similar line with utilized a higher-affinity nitroreductase enzyme. Together, these studies show the overall utility and challenges of using the zebrafish model for the investigation of NPAHs and similar hydrophobic or nitro-containing compounds

Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One aspect of anticoagulation therapy that is particularly challenging is the use of antithrombin (AT) supplementation for heparin resistance. This is especially controversial in the neonatal and pediatric population due to the baseline higher risk of bleeding in this cohort. The indication for AT supplementation is further compounded by the potential inaccuracy of the diagnosis of heparin resistance based on the standard laboratory parameters used to assess heparin effect. With concerns regarding the adverse impact of bleeding and thrombosis, clinicians and institutions are faced with making difficult, real-time decisions aimed at optimizing anticoagulation in this setting. In this clinically focused review, the authors discuss the complexities of anticoagulation monitoring and therapeutic intervention for patients on ECMO and examine the challenges surrounding AT supplementation given both the historical and current perspectives summarized in the literature on these topics

Hard X-ray emission from Eta Carinae

Context : If relativistic particle acceleration takes place in colliding-wind binaries, hard X-rays and gamma-rays are expected through inverse Compton emission, but to date these have never been unambiguously detected. Aims : To detect this emission, observations of Eta Carinae were performed with INTEGRAL, leveraging its high spatial resolution. Methods : Deep hard X-ray images of the region of Eta Car were constructed in several energy bands. Results : The hard X-ray emission previously detected by BeppoSax around Eta Car originates from at least 3 different point sources. The emission of Eta Car itself can be isolated for the first time, and its spectrum unambiguously analyzed. The X-ray emission of Eta Car in the 22-100 keV energy range is very hard (photon index around 1) and its luminosity is 7E33 erg/s. Conclusions : The observed emission is in agreement with the predictions of inverse Compton models, and corresponds to about 0.1% of the energy available in the wind collision. Eta Car is expected to be detected in the GeV energy range.Comment: 5 pages with 2 figures. Accepted as a Letter in Astronomy & Astrophysic

Hormone replacement therapy after surgery for stage 1 or 2 cutaneous melanoma

A total of 206 women were followed for a minimum of 5 years after primary melanoma surgery to establish if hormone replacement therapy (HRT) adversely affected prognosis. In all, 123 had no HRT and 22 have died of melanoma; 83 had HRT for varying periods and one has died of melanoma. After controlling for known prognostic factors, we conclude that HRT after melanoma does not adversely affect prognosis

Low mass loss rates in O-type stars: Spectral signatures of dense clumps in the wind of two Galactic O4 stars

We have analyzed the far-UV spectrum of two Galactic O4 stars, the O4If+ supergiant HD190429A and the O4V((f)) dwarf HD96715, using archival FUSE and IUE data. We have conducted a quantitative analysis based on the two NLTE model atmosphere and wind codes, TLUSTY and CMFGEN. We have derived the stellar and wind parameters and the surface composition of the two stars. The surface of HD190429A has a composition typical of an evolved O supergiant (N-rich, C and O-poor), while HD96715 exhibits surface N enhancement similar to the enrichment found in SMC O dwarfs and attributed to rotationally-induced mixing. We find that homogeneous wind models could not match the observed profile of O V1371 and require very low phosphorus abundance to fit the P V1118-1128 resonance lines. However, we are able to match the O V and P V lines using clumped wind models. We find that N IV1718 is also sensitive to wind clumping. For both stars, we have calculated clumped wind models that match well all these lines from different species and that remain consistent with Halpha data. These fits therefore provide a coherent and thus much stronger evidence of wind clumping in O stars than earlier claims. We find that the wind of these two stars is highly clumped, as expressed by very small volume filling factors, namely f=0.04 for HD190429A and f=0.02 for HD96715. In agreement with our analysis of SMC stars, clumping starts deep in the wind, just above the sonic point. The most crucial consequence of our analysis is that the mass loss rates of O stars need to be revised downward significantly, by a factor of 3 and more. Accounting for wind clumping is essential when determining the wind properties of O stars. Our study therefore calls for a fundamental revision in our understanding of mass loss and of O-type star winds. (abridged)Comment: To appear in Astronomy & Astrophysics; 16 pages; accepted version after minor revisio

Hard X-ray identification of Eta Carinae and steadiness close to periastron

Context: The colliding-wind binary Eta Car exhibits soft X-ray thermal emission that varies strongly around periastron, and non-thermal emission seen in hard X-rays and gamma-rays. Aims: To definitively identify Eta Car as the source of the hard X-ray emission, to examine how changes in the 2-10 keV band influence changes in the hard X-ray band, and to understand more clearly the mechanisms producing the non-thermal emission using new INTEGRAL observations obtained close to periastron. Methods: A Chandra observation encompassing the ISGRI error circle was analysed, and all other soft X-ray sources (including the outer shell of Eta Car itself) were discarded as likely counter-parts. New hard X-ray images of Eta Car were studied close to periastron, and compared to previous observations far from periastron. Results: The INTEGRAL component, when represented by a power law (with a photon index of 1.8), would produce more emission in the Chandra band than observed from any point source in the ISGRI error circle apart from Eta Car, as long as the hydrogen column density to the ISGRI source is lower than 1E24 cm^{-2}. Such sources are rare, thus the ISGRI emission is very likely to be associated with Eta Car. The eventual contribution of the outer shell to the non-thermal component also remains fairly limited. Close to periastron, a 3-sigma detection is achieved for the hard X-ray emission of Eta Car, with a flux similar to the average value far from periastron. Conclusions: Assuming a single absorption component for both the thermal and non-thermal sources, this detection can be explained with a hydrogen column density that does not exceed 6E23 cm^{-2} without resorting to an intrinsic increase in the hard X-ray emission. The energy injected in hard X-rays (averaged over a month) appears rather constant as close as a few stellar radii, well within the acceleration region of the wind.Comment: 9 pages with 5 figures. Accepted for publication in Astronomy & Astrophysic

Post-diagnosis body mass index and mortality among women diagnosed with endometrial cancer: Results from the Women\u27s Health Initiative.

Higher body mass index (BMI) measured before endometrial cancer diagnosis has been associated with greater risk of developing endometrial cancer and higher mortality, but the association between BMI measured after diagnosis and mortality risk is unclear. We identified 467 women (91 deaths) in the Women\u27s Health Initiative (WHI) with information on BMI measured after diagnosis and used Cox proportional hazards regression to generate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality. Comparing BMI 35+ with/m2, we observed no association with all-cause mortality (HR = 1.02, 95% CI 0.55-1.91). Our study does not support the hypothesis that higher BMI after endometrial cancer diagnosis is associated with poorer survival

Whole Earth Telescope observations of the hot helium atmosphere pulsating white dwarf EC 20058-5234

We present the analysis of a total of 177h of high-quality optical time-series photometry of the helium atmosphere pulsating white dwarf (DBV) EC 20058-5234. The bulk of the observations (135h) were obtained during a WET campaign (XCOV15) in July 1997 that featured coordinated observing from 4 southern observatory sites over an 8-day period. The remaining data (42h) were obtained in June 2004 at Mt John Observatory in NZ over a one-week observing period. This work significantly extends the discovery observations of this low-amplitude (few percent) pulsator by increasing the number of detected frequencies from 8 to 18, and employs a simulation procedure to confirm the reality of these frequencies to a high level of significance (1 in 1000). The nature of the observed pulsation spectrum precludes identification of unique pulsation mode properties using any clearly discernable trends. However, we have used a global modelling procedure employing genetic algorithm techniques to identify the n, l values of 8 pulsation modes, and thereby obtain asteroseismic measurements of several model parameters, including the stellar mass (0.55 M_sun) and T_eff (~28200 K). These values are consistent with those derived from published spectral fitting: T_eff ~ 28400 K and log g ~ 7.86. We also present persuasive evidence from apparent rotational mode splitting for two of the modes that indicates this compact object is a relatively rapid rotator with a period of 2h. In direct analogy with the corresponding properties of the hydrogen (DAV) atmosphere pulsators, the stable low-amplitude pulsation behaviour of EC 20058 is entirely consistent with its inferred effective temperature, which indicates it is close to the blue edge of the DBV instability strip. (abridged)Comment: 19 pages, 8 figures, 5 tables, MNRAS accepte