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Richards A.M.,Royal Prince Alfred Hospital
Oncogene | Year: 2017

CTCF is a haploinsufficient tumour suppressor gene with diverse normal functions in genome structure and gene regulation. However the mechanism by which CTCF haploinsufficiency contributes to cancer development is not well understood. CTCF is frequently mutated in endometrial cancer. Here we show that most CTCF mutations effectively result in CTCF haploinsufficiency through nonsense-mediated decay of mutant transcripts, or loss-of-function missense mutation. Conversely, we identified a recurrent CTCF mutation K365T, which alters a DNA binding residue, and acts as a gain-of-function mutation enhancing cell survival. CTCF genetic deletion occurs predominantly in poor prognosis serous subtype tumours, and this genetic deletion is associated with poor overall survival. In addition, we have shown that CTCF haploinsufficiency also occurs in poor prognosis endometrial clear cell carcinomas and has some association with endometrial cancer relapse and metastasis. Using shRNA targeting CTCF to recapitulate CTCF haploinsufficiency, we have identified a novel role for CTCF in the regulation of cellular polarity of endometrial glandular epithelium. Overall, we have identified two novel pro-tumorigenic roles (promoting cell survival and altering cell polarity) for genetic alterations of CTCF in endometrial cancer.Oncogene advance online publication, 20 March 2017; doi:10.1038/onc.2017.25. © 2017 The Author(s)


Maron B.J.,Minneapolis Heart Institute Foundation | Maron M.S.,Hypertrophic Cardiomyopathy Center | Semsarian C.,University of Sydney | Semsarian C.,Royal Prince Alfred Hospital
Journal of the American College of Cardiology | Year: 2012

Hypertrophic cardiomyopathy (HCM) is the most common familial heart disease with vast genetic heterogeneity, demonstrated over the past 20 years. Mutations in 11 or more genes encoding proteins of the cardiac sarcomere (>1,400 variants) are responsible for (or associated with) HCM. Explosive progress achieved in understanding the rapidly evolving science underlying HCM genomics has resulted in fee-for-service testing, making genetic information widely available. The power of HCM mutational analysis, albeit a more limited role than initially envisioned, lies most prominently in screening family members at risk for developing disease and excluding unaffected relatives, which is information not achievable otherwise. Genetic testing also allows expansion of the broad HCM disease spectrum and diagnosis of HCM phenocopies with different natural history and treatment options, but is not a reliable strategy for predicting prognosis. Interfacing a heterogeneous disease such as HCM with the vast genetic variability of the human genome, and high frequency of novel mutations, has created unforeseen difficulties in translating complex science (and language) into the clinical arena. Indeed, proband diagnostic testing is often expressed on a probabilistic scale, which is frequently incompatible with clinical decision making. Major challenges rest with making reliable distinctions between pathogenic mutations and benign variants, and those judged to be of uncertain significance. Genotyping in HCM can be a powerful tool for family screening and diagnosis. However, wider adoption and future success of genetic testing in the practicing cardiovascular community depends on a standardized approach to mutation interpretation, and bridging the communication gap between basic scientists and clinicians. © 2012 American College of Cardiology Foundation.


Dentice R.,Royal Prince Alfred Hospital
The Cochrane database of systematic reviews | Year: 2013

Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day). Relevant randomised and quasi-randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international CF conference proceedings.Date of the most recent search: 22 February 2013. Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. We identified 99 trial reports representing 48 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change FEV1. Similarly, FVC and quality of life were not significantly affected; FEF25 was significantly worse with dornase alfa inhalation after airway clearance, MD -0.17 litres (95% CI -0.28 to -0.05), based on the pooled data from two small studies in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial, morning versus evening inhalation had no impact on lung function or symptoms. The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted.


Ahmed R.M.,Royal Prince Alfred Hospital
The Medical journal of Australia | Year: 2012

To review patients with severe bilateral vestibular loss associated with gentamicin treatment in hospital. A retrospective case series of presentations to a balance disorders clinic between 1988 and 2010. Relationship between vestibulotoxicity and gentamicin dose or dosing profile; indications for prescribing gentamicin. 103 patients (age, 18-84 years; mean, 64 years) presented with imbalance, oscillopsia or both, but none had vertigo. Only three noted some hearing impairment after having gentamicin, but audiometric thresholds for all patients were consistent with their age. In all patients, the following tests gave positive results: a bilateral clinical head-impulse test, a vertical head-shaking test for vertical oscillopsia, and a foam Romberg test. In 21 patients, imbalance occurred during gentamicin treatment (ignored or dismissed by prescribers in 20) and in 66 after treatment; the remaining 16 could not recall when symptoms were first noticed, except that it was after gentamicin treatment in hospital. Total gentamicin dose range was 2-318 mg/kg (mean, 52 mg/kg), daily dose range was 1.5-5.6 mg/kg (mean, 3.5mg/kg), and duration was 1-80 days (mean, 17 days). Six patients had only a single dose; 26 had five or fewer doses. Serum gentamicin levels, measured in 82 patients, were in the recommended range in 59. Time to diagnosis ranged from 4 days to 15 years. Nephrotoxicity developed in 43 patients. Gentamicin dosage complied with contemporary or current Australian antibiotic guidelines in under half the patients. Gentamicin ototoxicity is vestibular, not cochlear, producing permanent loss of balance, but not of hearing. Gentamicin can be vestibulotoxic in any dose, in any regimen, at any serum level.


Rosengren S.M.,Royal Prince Alfred Hospital | Kingma H.,Maastricht University
Current Opinion in Neurology | Year: 2013

PURPOSE OF REVIEW: Although the vestibular evoked myogenic potential (VEMP) measured from the cervical muscles (cVEMP, cervical VEMP) is well described and has documented clinical utility, its analogue recorded from the extraocular muscles (oVEMP, ocular VEMP) has been described only recently and is currently emerging as an additional test of otolith function. This review will, therefore, summarize recent developments in VEMP research with a focus on the oVEMP. RECENT FINDINGS: Recent studies suggest that the oVEMP is produced by otolith afferents in the superior vestibular nerve division, whereas the cVEMP evoked by sound is thought to be an inferior vestibular nerve reflex. Correspondingly, the oVEMP correlates better with caloric and subjective visual vertical tests than sound-cVEMPs. cVEMPs are more complicated than often thought, as shown by the presence of crossed responses and conflicting results of recent vibration studies. Altered inner ear mechanics produced by the vestibular diseases superior semicircular canal dehiscence and MénièreÊs disease lead to changes in the preferred frequency of the oVEMP and cVEMP. SUMMARY: The oVEMP provides complementary diagnostic information to the cVEMP and is likely to be a useful addition to the diagnostic test battery in neuro-otology. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Richards B.L.,Royal Prince Alfred Hospital
Cochrane database of systematic reviews (Online) | Year: 2012

Pain management is a high priority for patients with rheumatoid arthritis (RA). Despite deficiencies in research data, neuromodulators have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. The aim of this review was to determine the efficacy and safety of neuromodulators in pain management in patients with RA. Neuromodulators included in this review were anticonvulsants (gabapentin, pregabalin, phenytoin, sodium valproate, lamotrigine, carbamazepine, levetiracetam, oxcarbazepine, tiagabine and topiramate), ketamine, bupropion, methylphenidate, nefopam, capsaicin and the cannabinoids. We performed a computer-assisted search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, 4th quarter), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44, 2010) and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 and 2009 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) conference abstracts and performed a handsearch of reference lists of articles. We included randomised controlled trials which compared any neuromodulator to another therapy (active or placebo, including non-pharmacological therapies) in adult patients with RA that had at least one clinically relevant outcome measure. Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of a neuromodulator on pain, depression and function as well as their safety. Four trials with high risk of bias were included in this review. Two trials evaluated oral nefopam (52 participants) and one trial each evaluated topical capsaicin (31 participants) and oromucosal cannabis (58 participants).The pooled analyses identified a significant reduction in pain levels favouring nefopam over placebo (weighted mean difference (WMD) -21.16, 95% CI -35.61 to -6.71; number needed to treat (NNT) 2, 95% CI 1.4 to 9.5) after two weeks. There were insufficient data to assess withdrawals due to adverse events. Nefopam was associated with significantly more adverse events (RR 4.11, 95% CI 1.58 to 10.69; NNTH 9, 95% CI 2 to 367), which were predominantly nausea and sweating.In a mixed population trial, qualitative analysis of patients with RA showed a significantly greater reduction in pain favouring topical capsaicin over placebo at one and two weeks (MD -23.80, 95% CI -44.81 to -2.79; NNT 3, 95% CI 2 to 47; MD -34.40, 95% CI -54.66 to -14.14; NNT 2, 95% CI 1.4 to 6 respectively). No separate safety data were available for patients with RA, however 44% of patients developed burning at the site of application and 2% withdrew because of this.One small, low quality trial assessed oromucosal cannabis against placebo and found a small, significant difference favouring cannabis in the verbal rating score 'pain at present' (MD -0.72, 95% CI -1.31 to -0.13) after five weeks. Patients receiving cannabis were significantly more likely to suffer an adverse event (risk ratio (RR) 1.82, 95% CI 1.10 to 3.00; NNTH 3, 95% CI 3 to 13). These were most commonly dizziness (26%), dry mouth (13%) and light headedness (10%). There is currently weak evidence that oral nefopam, topical capsaicin and oromucosal cannabis are all superior to placebo in reducing pain in patients with RA. However, each agent is associated with a significant side effect profile. The confidence in our estimates is not strong given the difficulties with blinding, the small numbers of participants evaluated and the lack of adverse event data. In some patients, however, even a small degree of pain relief may be considered worthwhile. Until further research is available, given the relatively mild nature of the adverse events, capsaicin could be considered as an add-on therapy for patients with persistent local pain and inadequate response or intolerance to other treatments. Oral nefopam and oromucosal cannabis have more significant side effect profiles however and the potential harms seem to outweigh any modest benefit achieved.


Richards B.L.,Royal Prince Alfred Hospital
Cochrane database of systematic reviews (Online) | Year: 2012

Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11).  Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.


Novikova N.,Royal Prince Alfred Hospital
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: Postpartum haemorrhage (PPH) is a common and occasionally life-threatening complication of labour. Several options for preventing PPH are available, but further advances in this field are important, especially the identification of safe, easy to use, and cost-effective regimes. Tranexamic acid, which is an antifibrinolytic that is used widely to prevent and treat haemorrhage, merits evaluation to assess whether it meets these criteria. OBJECTIVES: To determine, from the best available evidence, whether tranexamic acid is effective for preventing PPH. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 September 2009). SELECTION CRITERIA: All published, unpublished and ongoing randomised controlled trials (RCTs) evaluating the use of tranexamic acid alone or in addition to uterotonics in the third stage of labour or during caesarean section to prevent PPH. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We entered the data into Review Manager software and checked for accuracy. MAIN RESULTS: We included two RCTs. One RCT of unclear quality of 273 women compared tranexamic acid in two doses (0.5 g intravenously and 1 g intravenously) with aminomethylbenzoic acid (0.5 g intravenously) and with no treatment in women who had vaginal birth. We excluded the aminomethylbenzoic acid arm of this trial (92 patients).Another RCT of 180 women who underwent caesarean section compared tranexamic acid (1 g intravenously given 10 minutes before incision) with placebo.Blood loss greater than 400 ml was less common in women who received tranexamic acid after vaginal birth or caesarean section in the dosage of 1 g or 0.5 g intravenously (two studies, 453 women, risk ratio (RR) 0.51, 95% confidence interval (CI) 0.36 to 0.72). Mean blood loss was lower in the group of women who received intravenous tranexamic acid postpartum (two studies, 361 women, mean difference (MD) -75.17 ml, 95% CI -108.23 ml to -42.12 ml).No serious side effects were reported in women who received tranexamic acid in these trials. AUTHORS' CONCLUSIONS: Tranexamic acid decreases postpartum blood loss after vaginal birth and after caesarean section based on two RCTs of unclear quality which reported on only a few outcomes. Further investigations are needed on efficacy and safety of this regimen for preventing PPH.


Allman K.C.,Royal Prince Alfred Hospital
Journal of Nuclear Cardiology | Year: 2013

Observations of reversibility of cardiac contractile dysfunction in patients with coronary artery disease and ischemia were first made more than 40 years ago. Since that time a wealth of basic science and clinical data has been gathered exploring the mechanisms of this phenomenon of myocardial viability and relevance to clinical care of patients. Advances in cardiac imaging techniques have contributed greatly to knowledge in the area, first with thallium-201 imaging, then later with Tc-99m-based tracers for SPECT imaging and metabolic tracers used in conjunction with positron emission tomography (PET), most commonly F-18 FDG in conjunction with blood flow imaging with N-13 ammonia or Rb-82 Cl. In parallel, stress echocardiography has made great progress also. Over time observational studies in patients using these techniques accumulated and were later summarized in several meta-analyses. More recently, cardiac magnetic resonance imaging (CMR) has contributed further information in combination with either late gadolinium enhancement imaging or dobutamine stress. This review discusses the tracer and CMR imaging techniques, the pooled observational data, the results of clinical trials, and ongoing investigation in the field. It also examines some of the current challenges and issues for researchers and explores the emerging potential of combined PET/CMR imaging for myocardial viability. © 2013 American Society of Nuclear Cardiology.


The two key pathophysiologic features of asthma are bronchial hyperresponsiveness (BHR) and airway inflammation. Symptoms and lung function are the most accessible clinical markers for the diagnosis of asthma as well as for assessing asthma control using the most effective treatment of asthma, inhaled corticosteroids (ICS). However, BHR and inflammation usually take longer to resolve using ICS compared with symptoms and lung function. BHR can be assessed using "direct" stimuli that act on the airway smooth muscle (eg, methacholine) or "indirect"stimuli that require the presence of airway inflammation (eg, exercise, osmotic stimuli). Although there are practical limitations in using BHR to assess asthma control, efforts have been made to make BHR more accessible and standardized. Some studies have demonstrated that treatment aimed to decrease BHR with direct stimuli can lead to improved asthma control;however, it often results in the use of higher doses of ICS. Furthermore, BHR to direct stimuli does not usually resolve using ICS because of a fixed component. By contrast, BHR with an indirect stimulus indicates a responsive smooth muscle that occurs only in the presence of inflammation sensitive to ICS (eg, mast cells, eosinophils). BHR to indirect stimuli does resolve using ICS. Because ICS target both key pathophysiologic features of asthma, assessing indirect BHR in the presence of ICS will identify resolution or persistence of BHR and airway inflammation. This may provide a more clinically relevant marker for asthma control that may also lead to improving the clinical usefulness of ICS. © 2010 American College of Chest Physicians.

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