Publications by authors named "Tanya L Medley"

8 Publications

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Australian Clinical Consensus Guideline: The diagnosis and acute management of childhood stroke.

Int J Stroke 2019 01 4;14(1):94-106. Epub 2018 Oct 4.

1 Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia.

Stroke is among the top 10 causes of death in children and survivors carry resulting disabilities for decades, at substantial cost to themselves and their families. Children are not currently able to access reperfusion therapies, due to limited evidence supporting safety and efficacy and long diagnostic delays. The Australian Clinical Consensus Guideline for the Diagnosis and Acute Management of Childhood Stroke was developed to minimize unwarranted variations in care and document best evidence on the risk factors, etiologies, and conditions mimicking stroke that differ from adults. Clinical questions were formulated to inform systematic database searches from 2007 to 2017, limited to English and pediatric studies. SIGN methodology and the National Health and Medical Research Council system were used to screen and classify the evidence. The Grades of Recommendation, Assessment, Development, and Evaluation system (GRADE) was used to grade evidence as strong or weak. The Guideline provides more than 60 evidence-based recommendations to assist prehospital and acute care clinicians in the rapid identification of childhood stroke, choice of initial investigation, to confirm diagnosis, determine etiology, selection of the most appropriate interventions to salvage brain at risk, and prevent recurrence. Recommendations include advice regarding the management of intracranial pressure and congenital heart disease. Implementation of the Guideline will require reorganization of prehospital and emergency care systems, including the development of regional stroke networks, pediatric Code Stroke, rapid magnetic resonance imaging and accreditation of primary pediatric stroke centers with the capacity to offer reperfusion therapies. The Guideline will allow auditing to benchmark timelines of care, access to acute interventions, and outcomes. It will also facilitate the development of an Australian childhood stroke registry, with data linkage to international registries, to allow for accurate data collection on stroke incidence, treatment, and outcomes.
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http://dx.doi.org/10.1177/1747493018799958DOI Listing
January 2019

Guideline for the diagnosis and management of hypertension in adults - 2016.

Med J Aust 2016 Jul;205(2):85-9

Royal Adelaide Hospital, Adelaide, SA.

The National Heart Foundation of Australia has updated the Guide to management of hypertension 2008: assessing and managing raised blood pressure in adults (updated December 2010). Main recommendations For patients at low absolute cardiovascular disease risk with persistent blood pressure (BP) ≥ 160/100 mmHg, start antihypertensive therapy. The decision to treat at lower BP levels should consider absolute cardiovascular disease risk and/or evidence of end-organ damage, together with accurate BP assessment. For patients at moderate absolute cardiovascular disease risk with persistent systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg, start antihypertensive therapy. Treat patients with uncomplicated hypertension to a target BP of < 140/90 mmHg or lower if tolerated. Changes in management as a result of the guideline Ambulatory and/or home BP monitoring should be offered if clinic BP is ≥ 140/90 mmHg, as out-of-clinic BP is a stronger predictor of outcome. In selected high cardiovascular risk populations, aiming for a target of < 120 mmHg systolic can improve cardiovascular outcomes. If targeting < 120 mmHg, close follow-up is recommended to identify treatment-related adverse effects including hypotension, syncope, electrolyte abnormalities and acute kidney injury. Why the changes have been made A 2015 meta-analysis of patients with uncomplicated mild hypertension (systolic BP range, 140-169 mmHg) demonstrated that BP-lowering therapy is beneficial (reduced stroke, cardiovascular death and all-cause mortality). A 2015 trial comparing lower with higher blood pressure targets in selected high cardiovascular risk populations found improved cardiovascular outcomes and reduced mortality, with an increase in some treatment-related adverse events.
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http://dx.doi.org/10.5694/mja16.00526DOI Listing
July 2016

Effect of oxygen on cardiac differentiation in mouse iPS cells: role of hypoxia inducible factor-1 and Wnt/beta-catenin signaling.

PLoS One 2013 12;8(11):e80280. Epub 2013 Nov 12.

Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.

Background: Disturbances in oxygen levels have been found to impair cardiac organogenesis. It is known that stem cells and differentiating cells may respond variably to hypoxic conditions, whereby hypoxia may enhance stem cell pluripotency, while differentiation of multiple cell types can be restricted or enhanced under hypoxia. Here we examined whether HIF-1alpha modulated Wnt signaling affected differentiation of iPS cells into beating cardiomyocytes.

Objective: We investigated whether transient and sustained hypoxia affects differentiation of cardiomyocytes derived from murine induced pluripotent stem (iPS) cells, assessed the involvement of HIF-1alpha (hypoxia-inducible factor-1alpha) and the canonical Wnt pathway in this process.

Methods: Embryoid bodies (EBs) derived from iPS cells were differentiated into cardiomyocytes and were exposed either to 24 h normoxia or transient hypoxia followed by a further 13 days of normoxic culture.

Results: At 14 days of differentiation, 59 ± 2% of normoxic EBs were beating, whilst transient hypoxia abolished beating at 14 days and EBs appeared immature. Hypoxia induced a significant increase in Brachyury and islet-1 mRNA expression, together with reduced troponin C expression. Collectively, these data suggest that transient and sustained hypoxia inhibits maturation of differentiating cardiomyocytes. Compared to normoxia, hypoxia increased HIF-1alpha, Wnt target and ligand genes in EBs, as well as accumulation of HIF-1alpha and beta-catenin in nuclear protein extracts, suggesting involvement of the Wnt/beta-catenin pathway.

Conclusion: Hypoxia impairs cardiomyocyte differentiation and activates Wnt signaling in undifferentiated iPS cells. Taken together the study suggests that oxygenation levels play a critical role in cardiomyocyte differentiation and suggest that hypoxia may play a role in early cardiogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080280PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827186PMC
July 2014

Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and matrix metalloproteinase expression.

Hypertension 2005 Nov 17;46(5):1129-34. Epub 2005 Oct 17.

Baker Heart Research Institute, University of Melbourne, Victoria, Australia.

Large artery stiffening increases cardiovascular risk and promotes isolated systolic hypertension which is more prevalent in elderly women than men. Variation in sex steroid levels between males and females and throughout life may modulate arterial stiffness. We hypothesized that sex steroids directly influence expression of important structural proteins which determine arterial biomechanical properties. Human aortic smooth muscle cells were incubated with physiological concentrations of 17beta-estradiol, progesterone, 17beta-estradiol and progesterone, or testosterone for 4 weeks. Collagen, elastin, and fibrillin-1 deposition was examined (histochemistry/immunohistochemistry). Gene and protein expression of 2 important matrix metalloproteinases (MMPs), MMPs 2 and 3, regulating matrix turnover was assessed. All sex steroids reduced collagen deposition relative to control (100%). However, the reduction was greater with female sex steroids than testosterone (control, 100%; 17beta-estradiol plus progesterone, 20+/-2%; testosterone 74+/-12%, P<0.001). Female sex steroids increased elastin deposition compared with control (control, 100%; 17beta-estradiol, 540+/-60%; progesterone, 290+/-40%; 17beta-estradiol plus progesterone, 400+/-80%, all P<0.01). The elastin/collagen ratio was >11-fold higher in the presence of 17beta-estradiol and progesterone compared with testosterone. Fibrillin-1 deposition was doubled in the presence of female sex steroids (17beta-estradiol plus progesterone) compared with testosterone (P<0.01). MMP-2 gene and protein expression was unaffected by any sex steroid. Testosterone increased both gene and protein expression of MMP-3 relative to both control and female sex steroids (P<0.01). This may contribute to degradation of elastic matrix proteins. In conclusion, female sex steroids promote an elastic matrix profile, which likely contributes to variation in large artery stiffness observed between sexes and with changes in hormonal status across the lifespan.
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http://dx.doi.org/10.1161/01.HYP.0000187016.06549.96DOI Listing
November 2005

Matrix metalloproteinase-9 genotype influences large artery stiffness through effects on aortic gene and protein expression.

Arterioscler Thromb Vasc Biol 2004 Aug 10;24(8):1479-84. Epub 2004 Jun 10.

Alfred and Baker Medical Unit, Baker Medical Research Institute, University of Melbourne, Victoria, Australia.

Objective: Because large artery stiffening contributes to myocardial ischemia, its determinants are of relevance as potential risk markers. This study examined whether matrix metalloproteinase (MMP)-9 (gelatinase B) genotype is associated with large artery stiffening and aortic MMP-9 gene and protein expression.

Methods And Results: MMP-9 genotype (C-1562T promoter polymorphism) was determined in 84 patients (73 male) with angiographically defined coronary artery disease (CAD). Carotid applanation tonometry was used to assess central blood pressures and, with Doppler velocimetry, to assess aortic stiffness (input and characteristic impedance). Gene expression real-time polymerase chain reaction (RT-PCR) and protein levels (Western blotting) were assessed in relation to genotype in aortic samples from a separate population. T-allele carriers (C/T and T/T) had stiffer large arteries (higher input and characteristic impedance) and higher carotid pulse and systolic blood pressure (all P<0.05) than C/C homozygotes. In aortic samples, gene expression was 5-fold higher and active protein levels were >2-fold higher in T-allele carriers.

Conclusions: Because the T allele was associated with greater MMP-9 mRNA and protein levels, the greater large artery stiffness in T-allele carriers may be secondary to excessive degradation of the arterial elastic matrix. The consequent higher pulse pressure may increase susceptibility to myocardial ischemia.
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http://dx.doi.org/10.1161/01.ATV.0000135656.49158.95DOI Listing
August 2004

Matrix metalloproteinase-3 genotype contributes to age-related aortic stiffening through modulation of gene and protein expression.

Circ Res 2003 Jun 15;92(11):1254-61. Epub 2003 May 15.

Alfred and Baker Medical Unit, Baker Heart Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria, 8008, Australia.

Matrix metalloproteinases (MMPs) include most major constituents of the arterial wall as substrates. A common promotor polymorphism (5A/6A) is associated with differences in MMP-3 (stromelysin-1) activity, and associations with certain forms of vascular disease have been shown. This study investigated whether the MMP-3 5A/6A promoter polymorphism contributes to age-related large artery stiffening. MMP-3 5A/6A genotype was determined in 203 (135 male) low cardiovascular risk, unmedicated individuals who were divided prospectively into two groups (30 to 60 years, n=126; > or =61 years, n=77). Noninvasive large artery stiffness was measured as ascending aortic input impedance from brachial blood pressure, carotid tonometry, and Doppler ascending aortic blood flow. In the older group, homozygotes had higher aortic input (P<0.01) and characteristic (P<0.01) impedance, ie, higher stiffness, than heterozygotes after correction for the effects of age, gender, and mean arterial pressure. There was no such difference in the younger group. Gene expression was subsequently investigated in dermal biopsies in randomly selected older men from the same cohort with real-time PCR (n=40). In 5A homozygotes, gene expression was 4-fold higher (P<0.05), and in 6A homozygotes, 2-fold lower (P<0.05) compared with the heterozygotes. Differences in gene expression were associated with corresponding significant changes in MMP-3 protein levels. Concordance between dermal and aortic gene and protein expression was shown in a separate cohort of postmortem aortic samples (n=7). We conclude that MMP-3 genotype may be an important determinant of vascular remodeling and age-related arterial stiffening, with the heterozygote having the optimal balance between matrix accumulation and deposition.
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http://dx.doi.org/10.1161/01.RES.0000076891.24317.CADOI Listing
June 2003

Large artery stiffness predicts ischemic threshold in patients with coronary artery disease.

J Am Coll Cardiol 2002 Aug;40(4):773-9

Alfred and Baker Medical Unit, Baker Medical Research Institute, Prahran, Victoria, Australia.

Objectives: The goal of this study was to determine whether large artery stiffness contributes to exercise-induced myocardial ischemia in patients with coronary artery disease (CAD).

Background: Large artery stiffness is an independent predictor of cardiovascular mortality and a major determinant of pulse pressure and, thus, cardiac afterload and coronary perfusion. Clinical relevance of the hemodynamic consequences of large artery stiffening has not previously been demonstrated in relation to myocardial ischemia.

Methods: We hypothesized that stiffer large arteries would reduce myocardial ischemic threshold as assessed by time to ST-segment depression of 0.15 mV during a treadmill exercise test in patients with CAD. Ninety-six patients with CAD (78 men) age 62 +/- 9 years (mean +/- SD) were classified as having single (52 patients), double (31 patients), or triple (13 patients) coronary vessel disease, based on angiographically confirmed stenoses >50%. Systemic arterial compliance, distensibility index, aortic pulse wave velocity, and carotid augmentation index were measured using carotid applanation tonometry and Doppler velocimetry of the ascending aorta, at rest.

Results: In univariate analysis, all large artery stiffness/compliance indexes correlated with time to ischemia (p = 0.01 to 0.009). Both carotid (p = 0.007) and brachial (p = 0.001) pulse pressure also correlated inversely with time to ischemia. In multivariate analysis including other major risk factors plus severity of coronary stenosis, indexes of arterial stiffness were significant independent predictors of ischemic threshold.

Conclusions: Within a patient group with moderate CAD, large artery stiffness was a major determinant of myocardial ischemic threshold.
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http://dx.doi.org/10.1016/s0735-1097(02)02009-0DOI Listing
August 2002

Fibrillin-1 genotype is associated with aortic stiffness and disease severity in patients with coronary artery disease.

Circulation 2002 Feb;105(7):810-5

Alfred and Baker Medical Unit, Baker Medical Research Institute Prahran, Victoria, Australia.

Background: Elevated pulse pressure is associated strongly with adverse cardiovascular outcome; however, the genetic basis of this condition is unknown. This study examined whether genotypic variation in the extracellular matrix protein fibrillin-1, the Marfan gene, was associated with aortic stiffening and therefore could contribute to cardiovascular risk associated with pulse pressure elevation in coronary disease.

Methods And Results: Patients (n=145; 113 men), 62+/-9 years of age (mean+/-SD), with angiographically confirmed coronary disease, were studied. Carotid applanation tonometry was used to assess central blood pressures, and in conjunction with Doppler velocimetry, to assess aortic input and characteristic impedance. Fibrillin-1 genotype was characterized by a variable nucleotide tandem repeat and 2 single-nucleotide polymorphisms. The variable nucleotide tandem repeat was a good predictor of underlying haplotypes with 3 genotypes (2-2, 2-4, and 2-3) accounting for 86% of the population. The 2-3 genotype had higher input impedance (P=0.002), characteristic impedance (P=0.005), and carotid pulse pressure (P=0.002) compared with the 2-2 and 2-4 genotypes. Disease severity assessed by previous angioplasties and the number of patients with a stenosis >90% was also greater in the 2-3 genotype. Furthermore, in a multivariate analysis, fibrillin-1 genotype and central pulse pressure were independent of conventional risk factors in determining coronary disease severity. There was no difference in age, sex ratio, body mass index, smoking status, cholesterol level, or medication among the 3 genotypes.

Conclusions: Although a causative link has not been shown, these data are consistent with an important role for fibrillin-1 genotype in cardiovascular risk associated with large-artery stiffening and pulse pressure elevation in individuals with coronary disease.
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http://dx.doi.org/10.1161/hc0702.104129DOI Listing
February 2002