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Rapamycin induces the expression of heme oxygenase-1 and peroxyredoxin-1 in normal hepatocytes but not in tumorigenic liver cells
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This author accepted manuscript is made available following 12 month embargo from date of publication (October 2018) in accordance with the publisher’s archiving policyRapamycin (sirolimus) is employed as an immunosuppressant following liver transplant, to inhibit the re-growth of cancer cells following liver resection for hepatocellular carcinoma (HCC), and for the treatment of advanced HCC. Rapamycin also induces the expression of antioxidant enzymes in the liver, suggesting that pretreatment with the drug could provide a potential strategy to reduce ischemia reperfusion injury following liver surgery. The aim of this study was to further investigate the actions of rapamycin in inducing expression of the antioxidant enzymes heme oxygenase-1 (HO-1) and peroxiredoxin-1 (Prx-1) in normal liver and in tumorigenic liver cells. A rat model of segmental hepatic ischemia and reperfusion, cultured freshly-isolated rat hepatocytes, and tumorigenic H4IIE rat liver cells in culture were employed. Expression of HO-1 and Prx-1 was measured using quantitative PCR and western blot. Rapamycin pre-treatment of normal liver in vivo or normal hepatocytes in vitro led to a substantial induction of mRNA encoding HO-1 and Prx-1. The dose-response curve for the action of rapamycin on mRNA expression was biphasic, showing an increase in expression at 0 - 0.1 μM rapamycin but a decrease from maximum at concentrations greater than 0.1 μM. By contrast, in H4IIE cells, rapamycin inhibited the expression of HO-1 and Prx-1 mRNA. Oltipraz, an established activator of transcription factor Nrf2, caused a large induction of HO-1 and Prx-1 mRNA. The dose response curve for the inhibition by rapamycin of HO-1 and Prx-4 mRNA expression, determined in the presence of oltipraz, was monophasic with half maximal inhibition at about 0.01 μM. It is concluded that, at concentrations comparable to those used clinically, pre-treatment of the liver with rapamycin induces the expression of HO-1 and Prx-1. However, the actions of rapamycin on the expression of these two antioxidant enzymes in normal hepatocytes are complex and, in tumorigenic liver cells, differ from those in normal hepatocytes. Further studies are warranted to evaluate preconditioning the livers of patients subject to liver resection or liver transplant with rapamycin as a viable strategy to reduce IR injury following liver surgery.This work was supported by the Cancer Council S.A.s Beat Cancer Project (on behalf of its donors and the State Government of South Australia through the Department of Health), the Flinders Foundation, and Flinders University of South Australia
Rural training pathways: the return rate of doctors to work in the same region as their basic medical training
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International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Limited evidence exists about the extent to which doctors are returning to rural region(s) where they had previously trained. This study aims to investigate the rate at which medical students who have trained for 12 months or more in a rural region return to practice in that same region in their early medical career. A secondary aim is to investigate whether there is an independent or additional association with the effect of longer duration of rural exposure in a region (18-24 months) and for those completing both schooling and training in the same rural region. Methods: The outcome was rural region of work, based on postcode of work location in 2017 for graduates spanning 1-9 years post-graduation, for one large medical program in Victoria, Australia. Region of rural training, combined with region of secondary schooling and duration of rural training, was explored for its association with region of practice. A multinomial logistic regression model, accounting for other covariates, measured the strength of association with practising in the same rural region as where they had trained. Results: Overall, 357/2451 (15%) graduates were working rurally, with 90/357 (25%) working in the same rural region as where they did rural training. Similarly, 41/170 (24%) were working in the same region as where they completed schooling. Longer duration (18-24 vs 12 months) of rural training (relative risk ratio, RRR, 3.37, 1.89–5.98) and completing both schooling and training in the same rural region (RRR: 4.47, 2.14-9.36) were associated with returning to practice in the same rural region after training. Conclusions: Medical graduates practising rurally in their early career (1-9 years post-graduation) are likely to have previous connections to the region, through either their basic medical training, their secondary schooling, or both. Social accountability of medical schools and rural medical workforce outcomes could be improved by policies that enable preferential selection and training of prospective medical students from rural regions that need more doctors, and further enhanced by longer duration of within-region training.University funds only
Could prenatal sound discrimination predict vocal complexity later in life?
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International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Greater complexity of the learned vocal repertoire has been shown to increase mating and territory defence success in songbirds. Vocal learning in some songbird species begins in the egg and these songbird embryos can discriminate the sounds of different birds. Here, we test if prenatal sound discrimination positively correlates with song complexity in the Superb Fairy-wren (Malurus cyaneus). We use a habituation/dishabituation approach in natural and cross-fostered nests to measure prenatal sound discrimination of female vocalisations and later quantify observed song repertoire in fledgling sons and daughters. Results: Superb Fairy-wren fledglings produced learned songs consisting of 6-11 different elements by 12 weeks of age. Using multiple regression analysis, both prenatal sound discrimination strength and parental song complexity (total number of vocal elements) positively correlated with a fledgling's song complexity. The number of parental vocal elements was unrelated to the embryos's sound discrimination score. Conclusions: Prenatal sound discrimination strength was positively related to vocal complexity later in life. From previous research, we know that individuals with greater learned vocal complexity may have higher fitness. Therefore, characterizing the causes of prenatal sound discrimination can inform our understanding of fitness trajectories when phenotypes are shaped by learned cross-generational experience. Future research should explore causes of variance in prenatal sound discrimination.We thank the Hermon Slade Foundation, the Australian Research Council, the Australian Geographical Society, the National Geographic Society, and the Australian Acoustical Society for financial support. MEH was supported by the National Science Foundation and the Harley Jones Van Cleave Professorship in Host-Parasite Interactions
Knowledge translation for public health in low- and middle- income countries: a critical interpretive synthesis
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International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Effective knowledge translation allows the optimisation of access to and utilisation of research knowledge in order to inform and enhance public health policy and practice. In low- and middle- income countries, there are substantial complexities that affect the way in which research can be utilised for public health action. This review attempts to draw out concepts in the literature that contribute to defining some of the complexities and contextual factors that influence knowledge translation for public health in low- and middle- income countries. Methods: A Critical Interpretive Synthesis was undertaken, a method of analysis which allows a critical review of a wide range of heterogeneous evidence, through incorporating systematic review methods with qualitative enquiry techniques. A search for peer-reviewed articles published between 2000 and 2016 on the topic of knowledge translation for public health in low- and middle-income countries was carried out, and 85 articles were reviewed and analysed using this method. Results: Four main concepts were identified: 1) tension between "global" and "local" health research, 2) complexities in creating and accessing evidence, 3) contextualising knowledge translation strategies for low- and middle- income countries, and 4) the unique role of non-government organisations in the knowledge translation process. Conclusion: This method of review has enabled the identification of key concepts that may inform practice or further research in the field of knowledge translation in low- and middle- income countries.CM received financial support through the Australian Government Research
Training Program Scholarship
Synthesis and characterization of a novel inulin hydrogel crosslinked with pyromellitic dianhydride
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available under the CC-BY-NC-ND 4.0 license:
http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This author accepted manuscript is made available following 24 month embargo from date of publication (November 2018) in accordance with the publisher’s archiving policy.Smart hydrogels with pH and enzyme triggered release suitable for colon specific drug delivery were prepared by crosslinking inulin with pyromellitic dianhydride (PMDA) in a simple one pot synthesis. Back titration, Fourier transform infrared spectroscopy (FTIR) and ultraviolet spectrophotometry (UV) demonstrated that the hydrogel crosslinking reaction resulted in ester linkages and carboxylic acid groups and that the amount of the crosslinker in the hydrogel increased with increasing PMDA concentration in the crosslinking reaction. Thermal analysis and scanning electron microscopy (SEM) confirmed the chemical change by illustrating the hydrogels changed thermal properties and appearance compared to inulin. This hydrogel showed excellent swelling in water and the degree of swelling was inversely proportional to the cross-linking density, as determined using Flory-Rehner theory. Due to the presence of the carboxylic acid groups in the structure, the swelling was pH dependent, with significantly reduced swelling as acidity decreased from pH 7.4 to pH 1.2.This research work was also supported by a grant from the Australian Research Council's Linkage Projects funding scheme (Project number LP140100142)
The appropriateness of coronary investigation in myocardial injury and type 2 myocardial infarction (ACT-2): A randomized trial design
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available under the CC-BY-NC-ND 4.0 license:
http://creativecommons.org/licenses/by-nc-nd/4.0/ which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This author accepted manuscript is made available following 12 month embargo from date of publication (October 2018) in accordance with the publisher’s archiving policyBackground: Elevated troponin level findings among patients presenting with suspected acute coronary syndrome (ACS) or another intercurrent illness undeniably identifies patients at increased risk of mortality. Whilst enhancing our capacity to discriminate risk, the use of high-sensitivity troponin assays frequently identifies patients with myocardial injury (i.e. troponin rise without acute signs of myocardial ischemia) or type 2 myocardial infarction (T2MI; oxygen supply-demand imbalance). This leads to the clinically challenging task of distinguishing type 1 myocardial infarction (T1MI; coronary plaque rupture) from myocardial injury and T2MI in the context of concurrent acute illness. Diagnostic discernment in this context is crucial because MI classification has implications for further investigation and care. Early invasive management is of well-established benefit among patients with T1MI. However, the appropriateness of this investigation in the heterogeneous context of T2MI, where there is high competing mortality risk, remains unknown. Although coronary angiography in T2MI is advocated by some, there is insufficient evidence in existing literature to support this opinion as highlighted by current national guidelines.Support for this study was granted from National Health and Medical Research Council of Australia (APP1146512)
Sphingosine kinase 2 supports the development of BCR/ABL-independent acute lymphoblastic leukemia in mice
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International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedBackground
Sphingosine kinase (SphK) 2 has been implicated in the development of a range of cancers and inhibitors of this enzyme are currently in clinical trial. We have previously demonstrated a role for SphK2 in the development of acute lymphoblastic leukemia (ALL).
Methods
In this and our previous study we use mouse models: in the previous study the disease was driven by the proto-oncogene BCR/ABL1, while in this study cancer risk was elevated by deletion of the tumor suppressor ARF.
Results
Mice lacking ARF and SphK2 had a significantly reduced incidence of ALL compared mice with wild type SphK2.
Conclusions
These results show that the role of SphK2 in ALL development is not limited to BCR/ABL1 driven disease extending the potential use of inhibitors of this enzyme to ALL patients whose disease have driver mutations other than BCR/ABL1.
Psychotropic medications in older people in residential care facilities and associations with quality of life: a cross-sectional study
Get PDFThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background
Psychotropic medications have been associated with many adverse outcomes in older people living in residential care. Home-like models of residential care may be preferable to traditional models of care and we hypothesized that this model may impact on the prevalence of psychotropic medications. The objectives were to: 1) examine associations between psychotropic medications and quality of life in older adults living in residential care facilities with a high prevalence of cognitive impairment and dementia and 2) determine if there was a difference in prevalence of psychotropic medications in facilities which provide a small group home-like model of residential care compared to a ‘standard model’ of care.
Methods
Participants included 541 residents from 17 residential aged care facilities in the Investigating Services Provided in the Residential Environment for Dementia (INSPIRED) study. Cross-sectional analyses were completed to examine the above objectives. Quality of life was measured with the dementia quality of life questionnaire (DEMQOL) and the EQ-5D-5L completed by the resident or a proxy.
Results
Overall, 70.8% (n = 380) of the population had been prescribed/dispensed at least one psychotropic medication in the 100 days prior to recruitment. An increased number of psychotropic medications was associated with lower quality of life according to DEMQOL-Proxy-Utility scores (β (SE): − 0.012 (0.006), p = 0.04) and EQ-5D-5L scores (− 0.024 (0.011), p = 0.03) after adjustment for resident-level and facility-level characteristics. Analysis of the individual classes of psychotropic medications showed antipsychotics were associated with lower DEMQOL-Proxy-Utility scores (− 0.030 (0.014), p = 0.03) and benzodiazepines were associated with lower EQ-5D-5L scores (− 0.059 (0.024), p = 0.01). Participants residing in facilities which had a home-like model of residential care were less likely to be prescribed psychotropic medications (OR (95% CI): 0.24 (0.12, 0.46), p < 0.001).
Conclusions
An increased number of psychotropic medications were associated with lower quality of life scores. These medications have many associated adverse effects and the use of these medications should be re-examined when investigating approaches to improve quality of life for older people in residential care. Home-like models of residential care may help to reduce the need for psychotropic medications, but further research is needed to validate these findings
Non-pumping reactive wells filled with mixing nano and micro zero-valent iron for nitrate removal from groundwater: Vertical, horizontal, and slanted wells
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http://creativecommons.org/licenses/by-nc-nd/4.0/
This author accepted manuscript is made available following 24 month embargo from date of publication (Feb 2018) in accordance with the publisher’s archiving policyNon-pumping reactive wells (NPRWs) filled by zero-valent iron (ZVI) can be utilized for the remediation of groundwater contamination of deep aquifers. The efficiency of NPRWs mainly depends on the hydraulic contact time (HCT) of the pollutant with the reactive materials, the extent of the well capture zone (Wcz), and the relative hydraulic conductivity of aquifer and reactive material (Kr). We investigated nitrate removal from groundwater using NPRWs filled by ZVI (in nano and micro scales) and examined the effect of NPRWs orientations (i.e. vertical, slanted, and horizontal) on HCT and Wcz. The dependence of HCT on Wcz for different Kr values was derived theoretically for a homogeneous and isotropic aquifer, and verified using particle tracking simulations performed using the semi-analytical particle tracking and pathlines model (PMPATH). Nine batch experiments were then performed to investigate the impact of mixed nano-ZVI, NZVI (0 to 2 g l−1) and micro-ZVI, MZVI (0 to 4 g l−1) on the nitrate removal rate (with initial =132 mg l−1). The NPRWs system was tested in a bench-scale sand medium (60 cm length × 40 cm width × 25 cm height) for three orientations of NPRWs (vertical, horizontal, and slanted with inclination angle of 45°). A mixture of nano/micro ZVI, was used, applying constant conditions of pore water velocity (0.024 mm s−1) and initial nitrate concentration (128 mg l−1) for five pore volumes. The results of the batch tests showed that mixing nano and micro Fe0 outperforms these individual materials in nitrate removal rates. The final products of nitrate degradation in both batch and bench-scale experiments were , , and N2(gas). The results of sand-box experiments indicated that the slanted NPRWs have a higher nitrate reduction rate (57%) in comparison with vertical (38%) and horizontal (41%) configurations. The results also demonstrated that three factors have pivotal roles in expected HCT and Wcz, namely the contrast between the hydraulic conductivity of aquifer and reactive materials within the wells, the mass of Fe0 in the NPRWs, and the orientation of NPRWs adopted. A trade-off between these factors should be considered to increase the efficiency of remediation using the NPRWs system
PAX6 molecular analysis and genotype–phenotype correlations in families with aniridia from Australasia and Southeast Asia
Get PDFCreative Commons Attribution-NonCommercial-NoDerivatives License 3.0, or CC BY-NC-ND 3.0 (see http://creativecommons.org/licenses/by-nc-nd/3.0/ for license terms)Purpose
Aniridia is a congenital disorder caused by variants in the PAX6 gene. In this study, we assessed the involvement of PAX6 in patients with aniridia from Australasia and Southeast Asia.
Methods
Twenty-nine individuals with aniridia from 18 families originating from Australia, New Caledonia, Cambodia, Sri Lanka, and Bhutan were included. The PAX6 gene was investigated for sequence variants and analyzed for deletions with multiplex ligation-dependent probe amplification.
Results
We identified 11 sequence variants and six chromosomal deletions, including one in mosaic. Four deleterious sequence variants were novel: p.(Pro81HisfsTer12), p.(Gln274Ter), p.(Ile29Thr), and p.(Met1?). Ocular complications were associated with a progressive loss of visual function as shown by a visual acuity ≤ 1.00 logMAR reported in 65% of eyes. The prevalence of keratopathy was statistically significantly higher in the Australasian cohort (78.6%) compared with the Southeast Asian cohort (9.1%, p=0.002). Variants resulting in protein truncating codons displayed limited genotype–phenotype correlations compared with other variants.
Conclusions
PAX6 variants and deletions were identified in 94% of patients with aniridia from Australasia and Southeast Asia. This study is the first report of aniridia and variations in PAX6 in individuals from Cambodia, Sri Lanka, Bhutan, and New Caledonia, and the largest cohort from Australia