Carcinogenicity of hexavalent chromium

Hexavalent chromium (Cr(VI)), a commonly used industrial metal, is a well known human lung carcinogen. Epidemiology and animal studies suggest that the particulate Cr(VI) compounds, specifically the water insoluble compounds, are the more potent carcinogens, however, the carcinogenic mechanism remains unknown. Here we summarize recent Cr(VI)-induced human tumour, in vivo, cell culture and in vitro studies and put the data into context with three major paradigms of carcinogenesis: multistage carcinogenesis, genomic instability, and epigenetic modifications. Based on these studies, we propose a mechanism for chromate carcinogenesis that is primarily driven by the genomic instability paradigm

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Disruptive chemicals, senescence and immortality

Cell death is a process of dying within biological cells that are ceasing to function. This process is essential in regulating organism development, tissue homeostasis, and to eliminate cells in the body that are irreparably damaged. In general, dysfunction in normal cellular death is tightly linked to cancer progression. Specifically, the up-regulation of prosurvival factors, including oncogenic factors and antiapoptotic signaling pathways, and the down-regulation of proapoptotic factors, including tumor suppressive factors, confers resistance to cell death in tumor cells, which supports the emergence of a fully immortalized cellular phenotype. This review considers the potential relevance of ubiquitous environmental chemical exposures that have been shown to disrupt key pathways and mechanisms associated with this sort of dysfunction. Specifically, bisphenol A, chlorothalonil, dibutyl phthalate, dichlorvos, lindane, linuron, methoxychlor and oxyfluorfen are discussed as prototypical chemical disruptors; as their effects relate to resistance to cell death, as constituents within environmental mixtures and as potential contributors to environmental carcinogenesis.The publisher and the author(s) have made this article open access. This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press. The published article can be found at: http://carcin.oxfordjournals.org

Autologous microsurgical breast reconstruction and coronary artery bypass grafting: an anatomical study and clinical implications

OBJECTIVE: To identify possible avenues of sparing the internal mammary artery (IMA) for coronary artery bypass grafting (CABG) in women undergoing autologous breast reconstruction with deep inferior epigastric artery perforator (DIEP) flaps. BACKGROUND: Optimal autologous reconstruction of the breast and coronary artery bypass grafting (CABG) are often mutually exclusive as they both require utilisation of the IMA as the preferred arterial conduit. Given the prevalence of both breast cancer and coronary artery disease, this is an important issue for women's health as women with DIEP flap reconstructions and women at increased risk of developing coronary artery disease are potentially restricted from receiving this reconstructive option should the other condition arise. METHODS: The largest clinical and cadaveric anatomical study (n=315) to date was performed, investigating four solutions to this predicament by correlating the precise requirements of breast reconstruction and CABG against the anatomical features of the in situ IMAs. This information was supplemented by a thorough literature review. RESULTS: Minimum lengths of the left and right IMA needed for grafting to the left-anterior descending artery are 160.08 and 177.80 mm, respectively. Based on anatomical findings, the suitable options for anastomosis to each intercostals space are offered. In addition, 87-91% of patients have IMA perforator vessels to which DIEP flaps can be anastomosed in the first- and second-intercostal spaces. CONCLUSION: We outline five methods of preserving the IMA for future CABG: (1) lowering the level of DIEP flaps to the fourth- and fifth-intercostals spaces, (2) using the DIEP pedicle as an intermediary for CABG, (3) using IMA perforators to spare the IMA proper, (4) using and end-to-side anastomosis between the DIEP pedicle and IMA and (5) anastomosis of DIEP flaps using retrograde flow from the distal IMA. With careful patient selection, we hypothesize using the IMA for autologous breast reconstruction need not be an absolute contraindication for future CABG

Northern Eurasia Future Initiative (NEFI): facing the challenges and pathways of global change in the 21st century

During the past several decades, the Earth system has changed significantly, especially across Northern Eurasia. Changes in the socio-economic conditions of the larger countries in the region have also resulted in a variety of regional environmental changes that can have global consequences. The Northern Eurasia Future Initiative (NEFI) has been designed as an essential continuation of the Northern Eurasia Earth Science Partnership Initiative (NEESPI), which was launched in 2004. NEESPI sought to elucidate all aspects of ongoing environmental change, to inform societies and, thus, to better prepare societies for future developments. A key principle of NEFI is that these developments must now be secured through science-based strategies co-designed with regional decision makers to lead their societies to prosperity in the face of environmental and institutional challenges. NEESPI scientific research, data, and models have created a solid knowledge base to support the NEFI program. This paper presents the NEFI research vision consensus based on that knowledge. It provides the reader with samples of recent accomplishments in regional studies and formulates new NEFI science questions. To address these questions, nine research foci are identified and their selections are briefly justified. These foci include: warming of the Arctic; changing frequency, pattern, and intensity of extreme and inclement environmental conditions; retreat of the cryosphere; changes in terrestrial water cycles; changes in the biosphere; pressures on land-use; changes in infrastructure; societal actions in response to environmental change; and quantification of Northern Eurasia's role in the global Earth system. Powerful feedbacks between the Earth and human systems in Northern Eurasia (e.g., mega-fires, droughts, depletion of the cryosphere essential for water supply, retreat of sea ice) result from past and current human activities (e.g., large scale water withdrawals, land use and governance change) and potentially restrict or provide new opportunities for future human activities. Therefore, we propose that Integrated Assessment Models are needed as the final stage of global change assessment. The overarching goal of this NEFI modeling effort will enable evaluation of economic decisions in response to changing environmental conditions and justification of mitigation and adaptation efforts

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/ mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Plasticity in human sound localization induced by compressed spatial vision.

Item does not contain fulltextAuditory and visual target locations are encoded differently in the brain, but must be co-calibrated to maintain cross-sensory concordance. Mechanisms that adjust spatial calibration across modalities have been described (for example, prism adaptation in owls), though rudimentarily in humans. We quantified the adaptation of human sound localization in response to spatially compressed vision (0.5x lenses for 2-3 days). This induced a corresponding compression of auditory localization that was most pronounced for azimuth (minimal for elevation) and was restricted to the visual field of the lenses. Sound localization was also affected outside the field of visual-auditory interaction (shifted centrally, not compressed). These results suggest that spatially modified vision induces adaptive changes in adult human sound localization, including novel mechanisms that account for spatial compression. Findings are consistent with a model in which the central processing of sound location is encoded by recruitment rather than by a place code