Heme oxygenase-1 attenuates cadmium-induced mitochondrial-caspase 3- dependent apoptosis in human hepatoma cell line

Background: Cadmium (Cd) is a well known environmental and industrial toxicant causing damaging effects in numerous organs. In this study, we examined the role of heme oxygenase-1 (HO-1) in modulating the Cd-induced apoptosis in human hepatoma (HepG2) cells after 24 h exposure. Methods: HepG2 cells were exposed to 5 and 10 μM Cd as CdCl2 for 24 h while other sets of cells were pre-treated with either 10 μM Cobalt protoporphyrin (CoPPIX) or 10 μM Tin protoporphyrin (SnPPIX) for 24 h, or 50 μM Z-DEVD-FMK for 1 h before exposure to 5 and 10 μM CdCl2 for 24 h. Expressions of caspase 3, cytosolic cytochrome c, mitochondrial Bax and anti-apoptotic BCL-xl proteins were assessed by western blot. Intracellular reactive oxygen species (ROS) production was determined using the dihydrofluorescein diacetate (H2DFA) method. Cell viability was assessed by MTT assay, while a flow cytometry method was used to assess the level of apoptosis in the cell populations. Results: Our results show that there were a significant increase in the expression of cytosolic cytochrome c, mitochondrial Bax protein, and caspase 3 at 5 and 10 μM compared to the control, but these increases were attenuated by the presence of CoPPIX. The presence of SnPPIX significantly enhanced Cd-induced caspase 3 activities. CoPPIX significantly decreased the level of ROS production by 24.6 and 22.2 % in 5 and 10 μM CdCl2, respectively, but SnPPIX caused a significant increase in ROS production in the presence of CdCl2. HepG2 cell viability was also significantly impaired by 13.89 and 32.53 % in the presence of 5 and 10 μM CdCl2, respectively, but the presence of CoPPIX and Z-DEVD-FMK significantly enhanced cell survival, while SnPPIX enhanced Cd-impaired cell viability. The presence of CoPPIX and Z-DEVD-FMK also significantly decreased the population of apoptotic and necrotic cells compared with Cd. Conclusion: In summary, the present study showed that HO-1 attenuates the Cd-induced caspase 3 dependent pathway of apoptosis in HepG2 cells, probably by modulating Cd-induced oxidative stress

Subjective assessments of comorbidity correlate with quality of life health outcomes: Initial validation of a comorbidity assessment instrument

BACKGROUND: Interventions to improve care for persons with chronic medical conditions often use quality of life (QOL) outcomes. These outcomes may be affected by coexisting (comorbid) chronic conditions as well as the index condition of interest. A subjective measure of comorbidity that incorporates an assessment of disease severity may be particularly useful for assessing comorbidity for these investigations. METHODS: A survey including a list of 25 common chronic conditions was administered to a population of HMO members age 65 or older. Disease burden (comorbidity) was defined as the number of self-identified comorbid conditions weighted by the degree (from 1 to 5) to which each interfered with their daily activities. We calculated sensitivities and specificities relative to chart review for each condition. We correlated self-reported disease burden, relative to two other well-known comorbidity measures (the Charlson Comorbidity Index and the RxRisk score) and chart review, with our primary and secondary QOL outcomes of interest: general health status, physical functioning, depression screen and self-efficacy. RESULTS: 156 respondents reported an average of 5.9 chronic conditions. Median sensitivity and specificity relative to chart review were 75% and 92% respectively. QOL outcomes correlated most strongly with disease burden, followed by number of conditions by chart review, the Charlson Comorbidity Index and the RxRisk score. CONCLUSION: Self-report appears to provide a reasonable estimate of comorbidity. For certain QOL assessments, self-reported disease burden may provide a more accurate estimate of comorbidity than existing measures that use different methodologies, and that were originally validated against other outcomes. Investigators adjusting for comorbidity in studies using QOL outcomes may wish to consider using subjective comorbidity measures that incorporate disease severity

Competing risks of cancer mortality and cardiovascular events in individuals with multimorbidity

Background: Cancer patients with cardiovascular and other comorbidities are at concurrent risk of multiple adverse outcomes. However, most treatment decisions are guided by evidence from single-outcome models, which may be misleading for multimorbid patients. Objective: We assessed the interacting effects of cancer, cardiovascular, and other morbidity burdens on the competing outcomes of cancer mortality, serious cardiovascular events, and other-cause mortality. Design: We analyzed a cohort of 6,500 adults with initial cancer diagnosis between 2001 and 2008, SEER 5-year survival ≥26%, and a range of cardiovascular risk factors. We estimated the cumulative incidence of cancer mortality, a serious cardiovascular event (myocardial infarction, coronary revascularization, or cardiovascular mortality), and other-cause mortality over 5 years, and identified factors associated with the competing risks of each outcome using cause-specific Cox proportional hazard models. Results: Following cancer diagnosis, there were 996 (15.3%) cancer deaths, 328 (5.1%) serious cardiovascular events, and 542 (8.3%) deaths from other causes. In all, 4,634 (71.3%) cohort members had none of these outcomes. Although cancer prognosis had the greatest effect, cardiovascular and other morbidity also independently increased the hazard of each outcome. The effect of cancer prognosis on outcome was greatest in year 1, and the effect of other morbidity was greater in individuals with better cancer prognoses. Conclusion: In multimorbid oncology populations, comorbidities interact to affect the competing risk of different outcomes. Quantifying these risks may provide persons with cancer plus cardiovascular and other comorbidities more accurate information for shared decision-making than risks calculated from single-outcome models. Journal of Comorbidity 2014:4(1):29–3

APOE Genotype and Cardio-Respiratory Fitness Interact to Determine Adiposity in 8-Year-Old Children from the Tasmanian Infant Health Survey

APOE plays a well established role in lipid metabolism. Animal model evidence suggests APOE may also be associated with adiposity, but this has not been thoroughly investigated in humans. We measured adiposity (BMI, truncal fat mass, waist circumference), physical activity (PA), cardiorespiratory fitness and APOE genotype (E2, E3, E4) in 292 8-year-old children from the Tasmanian Infant Health Survey (TIHS), an Australian population-based prospective birth cohort. Our aims were to examine the association of APOE with child adiposity, and to examine the interplay between this association and other measured factors. We found that APOE was associated with child lipid profiles. APOE was also associated with child adiposity measures. The association was E4 allele-specific, with adiposity lower in the E4-containing group (BMI: Mean difference -0.90 kg/m2; 95% confidence intervals (CI) -1.51, -0.28; p = 0.004). The association of APOE4 with lower BMI differed by fitness status (difference in effect p = 0.002), and was more evident among the less fit (mean difference -1.78 kg/m2; 95% CI -2.74, -0.83; p<0.001). Additionally, associations between BMI and lipids were only apparent in those of lower fitness who did not carry APOE4. Similar overall findings were observed when truncal fat mass and waist circumference were used as alternative adiposity measures. APOE4 and cardiorespitatory fitness could interact to influence child adiposity. In studies addressing the genetic determinants of childhood obesity, the context of child fitness should also be taken into account

Aspects of hairy black holes in spontaneously-broken Einstein-Yang-Mills systems: Stability analysis and Entropy considerations

We analyze (3+1)-dimensional black-hole space-times in spontaneously broken Yang-Mills gauge theories that have been recently presented as candidates for an evasion of the scalar-no-hair theorem. Although we show that in principle the conditions for the no-hair theorem do not apply to this case, however we prove that the `spirit' of the theorem is not violated, in the sense that there exist instabilities, in both the sphaleron and gravitational sectors. The instability analysis of the sphaleron sector, which was expected to be unstable for topological reasons, is performed by means of a variational method. As shown, there exist modes in this sector that are unstable against linear perturbations. Instabilities exist also in the gravitational sector. A method for counting the gravitational unstable modes, which utilizes a catastrophe-theoretic approach is presented. The r\^ole of the catastrophe functional is played by the mass functional of the black hole. The Higgs vacuum expectation value (v.e.v.) is used as a control parameter, having a critical value beyond which instabilities are turned on. The (stable) Schwarzschild solution is then understood from this point of view. The catastrophe-theory appproach facilitates enormously a universal stability study of non-Abelian black holes, which goes beyond linearized perturbations. Some elementary entropy considerations are also presented...Comment: Latex file, 50 pages, 2 figures (included as PS files at the end: plot1.ps, plot2.ps

Searching for G3G^3 in t \tbar Production

The triple gluon field strength operator $G^3$ represents the only genuinely gluonic CP conserving term which can appear at dimension-6 within an effective strong interaction Lagrangian. Previous studies of this operator have revealed that its effect on gluon scattering is surprisingly difficult to detect. In this article, we analyze the impact of $G^3$ upon top quark pair production. We find that it will generate observable cross section deviations from QCD at the LHC for even relatively small values of its coefficient. Furthermore, $G^3$ affects the transverse momentum distribution of the produced top quarks more strongly at high energies than dimension-6 four-quark and chromomagnetic moment terms in the effective Lagrangian. Top-antitop production at the LHC will therefore provide a sensitive and clean probe for the elusive triple gluon field strength operator.Comment: 20 pages, 8 figures (3 updated figures not included but available upon request), CALT-68-1941, BUHEP-94-18. (Some previously overlooked graphs are now included. Our conclusions remain unchanged.

Hadamard renormalized scalar field theory on anti-de Sitter spacetime

We consider a real massive free quantum scalar field with arbitrary curvature coupling on n-dimensional anti–de Sitter spacetime. We use Hadamard renormalization to find the vacuum expectation values of the quadratic field fluctuations and the stress-energy tensor, presenting explicit results for n=2 to n=11 inclusive

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer\u27s disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs)

Resonant and Non-Resonant Effects in Photon-Technipion Production at Lepton Colliders

Lepton collider experiments can search for light technipions in final states made striking by the presence of an energetic photon: e+e- \to \photon\technipion. To date, searches have focused on either production through anomalous coupling of the technipions to electroweak gauge bosons or on production through a technivector meson (\technirho, \techniomega) resonance. This paper creates a combined framework in which both contributions are included. This will allow stronger and more accurate limits on technipion production to be set using existing data from LEP or future data from a higher-energy linear collider. We provide explicit formulas and sample calculations (analytic and Pythia) in the framework of the Technicolor Straw Man Model, a model that includes light technihadrons.Comment: 11 pages, including title page, 3 figures; version 2: references adde

'Against the World': Michael Field, female marriage and the aura of amateurism'

This article considers the case of Katherine Bradley and Edith Cooper, an aunt and niece who lived and wrote together as ‘Michael Field’ in the fin-de-siècle Aesthetic movement. Bradley’s bold statement that she and Cooper were ‘closer married’ than the Brownings forms the basis for a discussion of their partnership in terms of a ‘female marriage’, a union that is reflected, as I will argue, in the pages of their writings. However, Michael Field’s exclusively collaborative output, though extensive, was no guarantee for success. On the contrary, their case illustrates the notion, valid for most products of co-authorship, that the jointly written work is always surrounded by an aura of amateurism. Since collaboration defied the ingrained notion of the author as the solitary producer of his or her work, critics and readers have time and again attempted to ‘parse’ the collaboration by dissecting the co-authored work into its constituent halves, a treatment that the Fields too failed to escape