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Effect of NADPH oxidase 1 and 4 blockade in activated human retinal endothelial cells
Get PDF© 2018 Royal Australian and New Zealand College of Ophthalmologists. This author accepted manuscript is made available following 12 month embargo from date of publication (January 2018) in accordance with the publisher's archiving policy.Background
Over‐production of reactive oxygen species (ROS) and resulting oxidative stress contribute to retinal damage in vascular diseases that include diabetic retinopathy, retinopathy of prematurity and major retinal vessel occlusions. NADPH oxidase (Nox) proteins are professional ROS‐generating enzymes, and therapeutic targeting in these diseases has strong appeal. Pharmacological inhibition of Nox4 reduces the severity of experimental retinal vasculopathy. We investigated the potential application of this drug approach in humans.
Methods
Differential Nox enzyme expression was studied by real‐time‐quantitative polymerase chain reaction in primary human retinal endothelial cell isolates and a characterized human retinal endothelial cell line. Oxidative stress was triggered chemically in endothelial cells, by treatment with dimethyloxalylglycine (DMOG; 100 μM); Nox4 and vascular endothelial growth factor (VEGFA) transcript were measured; and production of ROS was detected by 2′,7′‐dichlorofluorescein. DMOG‐stimulated endothelial cells were treated with two Nox1/Nox4 inhibitors, GKT136901 and GKT137831; cell growth was monitored by DNA quantification, in addition to VEGFA transcript and ROS production.
Results
Nox4 (isoform Nox4A) was the predominant Nox enzyme expressed by human retinal endothelial cells. Treatment with DMOG significantly increased endothelial cell expression of Nox4 over 72 h, accompanied by ROS production and increased VEGFA expression. Treatment with GKT136901 or GKT137831 significantly reduced DMOG‐induced ROS production and VEGFA expression by endothelial cells, and the inhibitory effect of DMOG on cell growth.
Conclusions
Our findings in experiments on activated human retinal endothelial cells provide translational corroboration of studies in experimental models of retinal vasculopathy and support the therapeutic application of Nox4 inhibition by GKT136901 and GKT137831 in patients with retinal vascular diseases
Poor dietary patterns at 1-5 years of age are related to food neophobia and breastfeeding duration but not age of introduction to solids in a relatively advantaged sample
Get PDFPrevious studies have investigated associations between individual foods or food group intake, and breastfeeding duration, age of solid introduction and food neophobia. This study aimed to investigate associations between whole dietary patterns in young children, and breastfeeding duration, age of solid introduction and food neophobia. Parents of children (N = 234) aged 1–5 years completed an online questionnaire. Dietary risk scores were calculated using the Toddler (1–3 years) or Preschool (>3–<5 years) Dietary Questionnaires which evaluates the previous week's food-group intake (scored 0–100; higher score = higher risk of poor dietary quality). Neophobia was measured using the Child Food Neophobia scale (1.0–4.0; higher score = more neophobic). Associations were investigated using multivariable linear regression, adjusting for covariates. Children (54% female, 3.0 ± 1.4 years) were from advantaged families and were breastfed until 11.8 (5.0–16.0) months, started solids at 5.6 ± 1.4 months of age, moderately neophobic (2.1 ± 0.7) and at moderate dietary risk (29.2 ± 9.2). Shorter breastfeeding duration (β = −0.21; p = 0.001) and poorer child food neophobia scores (β = 0.36; p < 0.001) were associated with higher dietary risk scores. Age of introduction to solids showed no association with dietary risk (p = 0.744). These findings suggest that in addition to breastfeeding promotion, supporting parents to manage neophobic behaviour may be important in promoting healthy eating patterns in early childhood
Optogenetic induction of colonic motility in mice
Get PDFBackground & Aims: Strategies are needed to increase gastrointestinal transit without
systemic pharmacologic agents. We investigated whether optogenetics, focal application of
light to control enteric nervous system excitability, could be used to evoke propagating
contractions and increase colonic transit in mice.
Methods: We generated transgenic mice with Cre-mediated expression of light-sensitive
channelrhodopsin-2 (CHR2) in calretinin neurons (CAL-ChR2 Cre+ mice); Cre– littermates
served as controls. Colonic myenteric neurons were analyzed by immunohistochemistry,
patch clamp, and calcium imaging studies. Motility was assessed by mechanical,
electrophysiological, and video recording in vitro and by fecal output in vivo.
Results: In isolated colons, focal light stimulation of calretinin enteric neurons evoked classic
polarized motor reflexes (50/58 stimulations), followed by premature anterograde propagating
contractions (39/58 stimulations). Light stimulation could evoke motility from sites along the
entire colon. These effects were prevented by neural blockade with tetrodotoxin (n = 2), and
did not occur in control mice (n = 5). Light stimulation of proximal colon increased the
proportion of natural fecal pellets expelled over 15 minutes in vitro (75 ± 17% vs 32 ± 8% for
controls) (P <.05). In vivo, activation of wireless light-emitting diodes implanted onto the
colon wall significantly increased hourly fecal pellet output in conscious, freely moving mice
(4.17 ± 0.4 vs 1.3 ± 0.3 in controls) (P<.001).
Conclusions: In studies of mice, we found that focal activation of a subset of enteric neurons
can increase motility of the entire colon in vitro, and fecal output in vivo. Optogenetic control
of enteric neurons might therefore be used to modify gut motility.This work was supported by grants from the National Institutes of Health (NIH),
R01GM101218, R01DK103901 (to HH), Washington University School of Medicine Digestive Disease
Research Core Center (NIDDK P30 DK052574), The Center for the Study of Itch of Department of
Anesthesiology at Washington University School of Medicine (to HH) and NIH SPARC Award (NIBIB
U18EB021793) and NIH Director’s Transformative Research Award (TR01 NS081707) to RWG. TJH was
supported by a grant (#1127140) from the NH&MRC of Australia to NJS. Urology Care Foundation Research
Scholars Program and Kailash Kedia Research Scholar Award to VKS
Understanding and appraising medical students’ learning through clinical experiences: Participatory practices at work
Get PDF© The contributors. This author accepted manuscript book chapter is made available after an embargo period of 18 months from date of publication (December 2018) in accordance with the publisher's archiving policy.This chapter explores the participatory practices of some medical students’ learning through their clinical experiences. Participatory practices are those that comprise a duality between what is afforded by the social institutions in which individuals participate (e.g. educational and healthcare settings), on the one hand, and how individuals elect to engage in and learn through those practices (i.e. their processes of experiencing), on the other. Privileged here is not only the contributions to learning from these social settings and what individuals already know, can do and value, but also the relations between them. Indeed, the explanatory account of these students’ learning is founded on the concept of relational interdependence. That is, the relational nature of the interdependence between the social norms, forms and practices that individuals are afforded in these settings, and their experiencing of, and learning from what is afforded them. These concepts offer an account of the learning process associated with medical education, in which judgements about the educational worth of these programs are founded on the kinds and qualities of experiences provided for students, their relationships with the kinds of learning that arise from them, and ultimately, how students come to engage within them. This engagement includes, but is not wholly dependent upon, how students perceive the invitational qualities of these experiences
Extinction of gambling cue-reactivity: A pilot study in a problem gambling treatment setting
Get PDFCopyright: © Riley BJ (2018). This Article is distributed under the terms of Creative Commons Attribution 4.0 International LicenseClinical interventions which focus on extinction learn-ing have been shown to reduce craving and relapse in substance related and behavioural addictions. This paper reports a small pilot study with 20 problem gamblers re-ferred for treatment by a local court diversion program. We investigated the use of portable heart rate monitors to measure the effectiveness of Cue Exposure Therapy (CET) in extinguishing gambling cue-reactivity. Cue-reactivity pro-cedures consisted of a relaxation period followed by in-vivo exposure with response prevention in a gambling environ-ment. Cue exposure therapy was manualised. Dependent measures comprised both self-report (gambling urge and problem gambling questionnaire) and physiologic measures (heart rate). Significant increases in heart rate were ob-served during in-vivo pre-CET but not post-CET (p < 0.001). Following CET, significant reductions across all dependent variables were observed (p ≤ 0.001) with within-group ef-fect sizes ranging between r = -.55 and -.61. Overall, the results of this small pilot study support the feasibility and acceptability of the use of portable heart rate monitors to observe the extinction of gambling cue-reactivity. Portable heart rate monitors may provide a novel and useful tool for therapists and their problem gambling patients to monitor gambling cue-reactivity during treatment. Further research is needed to evaluate whether extinction of cue-reactivity can reduce problem gambling relapse
A Generalized Semi-Analytical Solution for the Dispersive Henry Problem: Effect of Stratification and Anisotropy on Seawater Intrusion
Get PDF© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).The Henry problem (HP) continues to play a useful role in theoretical and practical studies related to seawater intrusion (SWI) into coastal aquifers. The popularity of this problem is attributed to its simplicity and precision to the existence of semi-analytical (SA) solutions. The first SA solution has been developed for a high uniform diffusion coefficient. Several further studies have contributed more realistic solutions with lower diffusion coefficients or velocity-dependent dispersion. All the existing SA solutions are limited to homogenous and isotropic domains. This work attempts to improve the realism of the SA solution of the dispersive HP by extending it to heterogeneous and anisotropic coastal aquifers. The solution is obtained using the Fourier series method. A special hydraulic conductivity–depth model describing stratified heterogeneity is used for mathematical convenience. An efficient technique is developed to solve the flow and transport equations in the spectral space. With this technique, we show that the HP can be solved in the spectral space with the salt concentration as primary unknown. Several examples are generated, and the SA solutions are compared against an in-house finite element code. The results provide high-quality data assessed by quantitative indicators that can be effectively used for code verification in realistic configurations of heterogeneity and anisotropy. The SA solution is used to explain contradictory results stated in the previous works about the effect of anisotropy on the saltwater wedge. It is also used to investigate the combined influence of stratification and anisotropy on relevant metrics characterizing SWI. At a constant gravity number, anisotropy leads to landward migration of the saltwater wedge, more intense saltwater flux, a wider mixing zone and shallower groundwater discharge zone to the sea. The influence of stratified heterogeneity is more pronounced in highly anisotropic aquifers. The stratification rate and anisotropy have complementary effects on all SWI metrics, except for the depth of the discharge zone. View Full-Tex
Evaluation of Global Genomic DNA Methylation in Human Whole Blood by Capillary Electrophoresis UV Detection
Get PDFCopyright © 2017 Angelo Zinellu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Alterations in global DNA methylation are implicated in various pathophysiological processes. The development of simple and quick, yet robust, methods to assess DNA methylation is required to facilitate its measurement and interpretation in clinical practice. We describe a highly sensitive and reproducible capillary electrophoresis method with UV detection for the separation and detection of cytosine and methylcytosine, after formic acid hydrolysis of DNA extracted from human whole blood. Hydrolysed samples were dried and resuspended with water and directly injected into the capillary without sample derivatization procedures. The use of a run buffer containing 50 mmol/L BIS-TRIS propane (BTP) phosphate buffer at pH 3.25 and 60 mmol/L sodium acetate buffer at pH 3.60 (4 : 1, v/v) allowed full analyte identification within 11 min. Precision tests indicated an elevated reproducibility with an interassay CV of 1.98% when starting from 2 μg of the extracted DNA. The method was successfully tested by measuring the DNA methylation degree both in healthy volunteers and in reference calf thymus DNA
The Australian Corneal Graft Registry 2018 Report
Get PDFCopyright, All rights reserved.The Australian Corneal Graft Registry (ACGR) opened in May 1985 and has now been operating for 33 years. Over the years, we have collected information on more than 35,000 corneal grafts. At registration, we seek information on the donor, eye bank practices, the recipient, the surgeon, the graft type and the operative procedure. Follow-up then occurs at approximately yearly intervals for an indefinite period, and ceases upon graft failure, or the death or loss-to-follow-up of the patient. At each round of follow-up, we request information on the survival of the graft, the visual outcomes, and any relevant post-operative events and treatments. The data are entered into an Access database and checked for consistency. Descriptive, univariate and multivariate analyses are subsequently performed using SPSS and Stata software, and the report is eventually collated
Predictors of Mainland Chinese students’ well‐being
Get PDFThis article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving'.
Copyright © 2018 John Wiley & Sons, Inc. All rights reserved
This author accepted manuscript is made available following 12 month embargo from date of publication (April 2018) in accordance with the publisher’s archiving policyThere has been substantial research in the USA, Europe and Australia about factors influencing students’ wellbeing. However, such research has been relatively rare in mainland China. We administered four predictor scales (School Satisfaction, Self-concept, Relationships and Resilience) and three outcome scales (Flourishing, Mental Health and Children’s Wellbeing) to 2,756 primary and middle school students in mainland China. Confirmatory factor analysis indicated that the measured concepts were salient to the participants. Structural equation modelling using MPlus showed that Resilience was a strong predictor of all outcome measures, particularly for Mental Health and Positive Emotional State. Global Self-Concept was the most notable predictor for Positive Outlook, while School Satisfaction was the strongest predictor of Flourishing. The results indicate potential areas for school-based competency building initiatives to promote mainland Chinese students’ wellbeing
Influence of First-Time Mothers' Early Employment on Severe Early Childhood Caries in Their Child
Get PDFCopyright © 2012 Kamila Plutzer and Marc J. N. C. Keirse. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Aim. To examine whether mothers' early employment status is related to the development of severe early childhood caries in their child. Methods. Questionnaire survey of 429 first-time mothers in metropolitan Adelaide, South Australia, and dental examinations of their child at 20 months of age. Results. At months of age, 5.6% of children exhibited caries defined as one or more demineralized or cavitated lesions on the upper incisors. Of the mothers, 52.2% had no paid employment, 39.6% were part-time and 8.2% full-time employed. Overall, mothers' participation in the workforce had no influence on the frequency of severe early childhood caries in their child, but there was a significant interaction with family structure. For mothers without employment there was no difference between single, and two-parent families, but children with an employed single mother more frequently had caries than those with a working mother in a two-parent family (). However, there were no significant differences in children's reported general health. Conclusions. The data indicate a need to explore strategies that may assist single mothers and especially those in the workforce to prevent severe early childhood caries in their child