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News Article | May 17, 2017

MIND CONTROL without the side effects. That’s the aim of a device that could help people control robotic limbs using thought alone – without the need for brain surgery. The device will be trialled in people with paralysis next year. Several groups are developing brain-machine interfaces that allow people who are paralysed to operate a bionic exoskeleton just by thinking about it. These devices decode electrical brain signals and translate them into movement of robotic limbs. Usually, brain signals are detected via electrodes attached to the scalp or implanted directly in the brain. Placing them on the scalp avoids surgery, but the signals are muffled by the skull. Direct implantation allows precise recordings but the electrodes can stop working because the brain treats them as foreign bodies and wraps them in scar tissue. Now, a research team led by Thomas Oxley at the University of Melbourne has developed a way of implanting electrodes in the brain without opening up the skull. Their electrodes are attached to a metallic mesh tube that is guided through a small incision in the jugular vein in the neck and up into a blood vessel in the brain. There, the electrode can measure signals from nearby brain cells on the other side of the vessel wall. The technique is borrowed from cardiologists, who slide similar tubes called stents into arteries to keep them open. The electrode-studded stent – or “stentrode” – was tested in the brains of live sheep in 2016 (Nature Biotechnology, Like a cardiac stent, it sat in the blood vessel without causing any adverse effects. Because the metallic mesh does not directly touch brain tissue, no inflammation or scarring occurred over the six-month trial. “The brain doesn’t even know it’s there,” says David Grayden at the University of Melbourne, who oversaw the engineering of the device. The matchstick-sized stentrode was able to clearly detect electrical brain signals. “The recordings are not quite as detailed as those from directly implanted electrodes, but they’re close,” says Grayden. The team is now planning a clinical trial at the Royal Melbourne Hospital that will start next year. Up to five patients with no use of their arms or legs due to spinal cord injury, stroke, motor neurone disease or muscular dystrophy will be involved. The stentrode will be inserted into a blood vessel that runs along the motor cortex, the part of the brain that controls movement. Fine wires will run from the electrodes down through the blood system into a recording device implanted in the chest. This device will then wirelessly transmit the information to an external computer. “The end goal is that the person will be able to think about moving and an exoskeleton will obey” By asking participants to think about a particular action, like “move right fist”, the computer will learn to recognise the exact pattern of brain signals corresponding to each thought. “The end goal is that the person will be able to think about moving and an exoskeleton will obey,” says Grayden. The research is exciting, but it’s still unclear whether the stentrode will be able to pick up meaningful signals in the brains of humans, says Nick Ramsey at University Medical Center Utrecht in the Netherlands. “The stentrode research is worth doing, but I would not dismiss the technologies that are already much further ahead.” This article appeared in print under the headline “Brain control via blood vessel stent”

Wheeler D.C.,University College London | Becker G.J.,Royal Melbourne Hospital
Kidney International | Year: 2013

The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for management of blood pressure (BP) in chronic kidney disease (CKD) supersedes the 2004 Kidney Disease Quality Outcomes Initiative document on this topic. The new guideline has been designed to assist clinical decision making in patients with CKD who are not receiving dialysis. The recommendations in the guideline acknowledge that no single BP target is optimal for all CKD patients and encourage individualization of treatment depending on age, the severity of albuminuria, and comorbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mm Hg systolic and ≤90 mm Hg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 h (i.e., those with both micro- and macroalbuminuria), a lower target of ≤130 mm Hg systolic and ≤80 mm Hg diastolic is suggested. In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged. Use of agents that block the renin-angiotensin-aldosterone system is recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 h. Recommendations are almost identical in CKD patients with and without diabetes. Special considerations relevant to children and those of older age and those who have received a kidney transplant are included. Ongoing controversies in BP management in the context of CKD are highlighted along with key areas for future research. © 2012 International Society of Nephrology.

Hamilton J.A.,Royal Melbourne Hospital | Achuthan A.,Royal Melbourne Hospital
Trends in Immunology | Year: 2013

The colony stimulating factors (CSFs), granulocyte macrophage-CSF (GM-CSF), macrophage-CSF (M-CSF or CSF-1) and granulocyte-CSF (G-CSF) were first identified as in vitro hematopoietic growth factors. They have since been shown to regulate myeloid cell numbers and function at steady state and during inflammation. Preclinical data suggest that targeting CSFs might be beneficial in autoimmune and inflammatory disease, and manipulation of CSF biology is now being tested in clinical trials. Here, we examine recent insights into CSF function, at steady state and during pathology, as provided by CSF or CSF receptor neutralization/deletion studies or from CSF administration. We discuss controversies regarding the role of CSFs in controlling specific myeloid cell populations and highlight how the newly identified M-CSF receptor ligand, interleukin (IL)-34, is necessitating a reassessment of the field. © 2012 Elsevier Ltd.

Jacobs S.E.,Royal Melbourne Hospital
Cochrane database of systematic reviews (Online) | Year: 2013

Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects. To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects. We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012. We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI). We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia. There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.

Szer J.,Royal Melbourne Hospital
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

A majority of patients with acute myeloid leukemia (AML) will relapse after achieving complete remission. At relapse, patients should be risk stratified and a decision made about the appropriateness of intensive therapy and whether a potentially curative allogeneic stem cell transplantation (allo-SCT) is possible. Risk factors include duration of first complete remission and adverse cytogenetics, as well as age and FLT3 mutation status. Available therapies are steadily increasing, but for the most part should be regarded as either best palliation or as a bridge to allo-SCT. Simple symptomatic therapies for patients with extreme age or the worst prognosis should also be considered. Newer therapeutic options include novel cytotoxic chemotherapies including clofarabine, immunomodulatory agents, targeted therapies against FLT3 and mTOR, and immunoconjugates. All patients with relapsed AML should be considered for an appropriate clinical trial.

Manser R.,Royal Melbourne Hospital
The Cochrane database of systematic reviews | Year: 2013

This is an updated version of the original review published in The Cochrane Library in 1999 and updated in 2004 and 2010. Population-based screening for lung cancer has not been adopted in the majority of countries. However it is not clear whether sputum examinations, chest radiography or newer methods such as computed tomography (CT) are effective in reducing mortality from lung cancer. To determine whether screening for lung cancer, using regular sputum examinations, chest radiography or CT scanning of the chest, reduces lung cancer mortality. We searched electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5), MEDLINE (1966 to 2012), PREMEDLINE and EMBASE (to 2012) and bibliographies. We handsearched the journal Lung Cancer (to 2000) and contacted experts in the field to identify published and unpublished trials. Controlled trials of screening for lung cancer using sputum examinations, chest radiography or chest CT. We performed an intention-to-screen analysis. Where there was significant statistical heterogeneity, we reported risk ratios (RRs) using the random-effects model. For other outcomes we used the fixed-effect model. We included nine trials in the review (eight randomised controlled studies and one controlled trial) with a total of 453,965 subjects. In one large study that included both smokers and non-smokers comparing annual chest x-ray screening with usual care there was no reduction in lung cancer mortality (RR 0.99, 95% CI 0.91 to 1.07). In a meta-analysis of studies comparing different frequencies of chest x-ray screening, frequent screening with chest x-rays was associated with an 11% relative increase in mortality from lung cancer compared with less frequent screening (RR 1.11, 95% CI 1.00 to 1.23); however several of the trials included in this meta-analysis had potential methodological weaknesses. We observed a non-statistically significant trend to reduced mortality from lung cancer when screening with chest x-ray and sputum cytology was compared with chest x-ray alone (RR 0.88, 95% CI 0.74 to 1.03). There was one large methodologically rigorous trial in high-risk smokers and ex-smokers (those aged 55 to 74 years with ≥ 30 pack-years of smoking and who quit ≤ 15 years prior to entry if ex-smokers) comparing annual low-dose CT screening with annual chest x-ray screening; in this study the relative risk of death from lung cancer was significantly reduced in the low-dose CT group (RR 0.80, 95% CI 0.70 to 0.92). The current evidence does not support screening for lung cancer with chest radiography or sputum cytology. Annual low-dose CT screening is associated with a reduction in lung cancer mortality in high-risk smokers but further data are required on the cost effectiveness of screening and the relative harms and benefits of screening across a range of different risk groups and settings.

Demetrios M.,Royal Melbourne Hospital
The Cochrane database of systematic reviews | Year: 2013

Spasticity may affect stroke survivors by contributing to activity limitations, caregiver burden, pain and reduced quality of life (QoL). Spasticity management guidelines recommend multidisciplinary (MD) rehabilitation programmes following botulinum toxin (BoNT) treatment for post-stroke spasticity. However, the evidence base for the effectiveness of MD rehabilitation is unclear. To assess the effectiveness of MD rehabilitation, following BoNT and other focal intramuscular treatments such as phenol, in improving activity limitations and other outcomes in adults and children with post-stroke spasticity. To explore what settings, types and intensities of rehabilitation programmes are effective. We searched the Cochrane Stroke Group Trials Register (February 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 12), MEDLINE (1948 to December 2011), EMBASE (1980 to January 2012), CINAHL (1982 to January 2012), AMED (1985 to January 2012), LILACS (1982 to September 2012), PEDro, REHABDATA and OpenGrey (September 2012). In an effort to identify further published, unpublished and ongoing trials we searched trials registries and reference lists, handsearched journals and contacted authors. We included randomised controlled trials (RCTs) that compared MD rehabilitation (delivered by two or more disciplines in conjunction with medical input) following BoNT and other focal intramuscular treatments for post-stroke spasticity with placebo, routinely available local services, or lower levels of intervention; or studies that compared MD rehabilitation in different settings, of different types, or at different levels of intensity. We excluded RCTs that assessed the effectiveness of unidisciplinary therapy (for example physiotherapy only) or a single modality (for example stretching, casting, electrical stimulation or splinting only). The primary outcomes were validated measures of activity level (active and passive function) according to the World Health Organization's International Classification of Functioning, Disability and Health. Secondary outcomes included measures of symptoms, impairments, participation, QoL, impact on caregivers and adverse events. We independently selected the trials, extracted data, and assessed methodological quality using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Due to the limited number of included studies, with clinical, methodological and statistical heterogeneity, quantitative meta-analysis was not possible. Therefore, GRADE provided qualitative synthesis of 'best evidence'. We included three RCTs involving 91 participants. All three studies scored 'low quality' on the methodological quality assessment, implying high risk of bias. All studies investigated various types and intensities of outpatient rehabilitation programmes following BoNT for upper limb spasticity in adults with chronic stroke. Rehabilitation programmes included: modified constraint-induced movement therapy (mCIMT) compared with a neurodevelopmental therapy programme; task practice therapy with cyclic functional electrical stimulation (FES) compared with task practice therapy only; and occupational, manual therapy with dynamic elbow extension splinting compared with occupational therapy only. There was 'low quality' evidence for mCIMT improving upper limb motor function and spasticity in chronic stroke survivors with residual voluntary upper limb activity, up to six months, and 'very low quality' evidence for dynamic elbow splinting and occupational therapy reducing elbow range of movement at 14 weeks. Task practice therapy with cyclic FES did not improve upper limb function more than task practice therapy alone, only at 12 weeks. No studies addressed interventions in children and those with lower limb spasticity, or after other focal intramuscular treatments for spasticity. At best there was 'low level' evidence for the effectiveness of outpatient MD rehabilitation in improving active function and impairments following BoNT for upper limb spasticity in adults with chronic stroke. No trials explored the effect of MD rehabilitation on 'passive function' (caring for the affected limb), caregiver burden, or the individual's priority goals for treatment. The optimal types (modalities, therapy approaches, settings) and intensities of therapy for improving activity (active and passive function) in adults and children with post-stroke spasticity, in the short and longer term, are unclear. Further research is required to build evidence in this area.

Casillas-Espinosa P.M.,Royal Melbourne Hospital
Epilepsia | Year: 2012

Synaptic transmission is the communication between a presynaptic and a postsynaptic neuron, and the subsequent processing of the signal. These processes are complex and highly regulated, reflecting their importance in normal brain functioning and homeostasis. Sustaining synaptic transmission depends on the continuing cycle of synaptic vesicle formation, release, and endocytosis, which requires proteins such as dynamin, syndapin, synapsin, and synaptic vesicle protein 2A. Synaptic transmission is regulated by diverse mechanisms, including presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors and signaling, and modulators of neurotransmission. Neurotransmitters released presynaptically can bind to their postsynaptic receptors, the inhibitory γ-aminobutyric acid (GABA)ergic receptors or the excitatory glutamate receptors. Once released, glutamate activates a variety of postsynaptic receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), kainate, and metabotropic receptors. The activation of the receptors triggers downstream signaling cascades generating a vast array of effects, which can be modulated by a numerous auxiliary regulatory subunits. Moreover, different neuropeptides such as neuropeptide Y, brain-derived neurotrophic factor (BDNF), somatostatin, ghrelin, and galanin, act as regulators of diverse synaptic functions and along with the classic neurotransmitters. Abnormalities in the regulation of synaptic transmission play a critical role in the pathogenesis of numerous brain diseases, including epilepsy. This review focuses on the different mechanisms involved in the regulation of synaptic transmission, which may play a role in the pathogenesis of epilepsy: the presynaptic modulators of synaptic vesicle formation and release, postsynaptic receptors, and modulators of neurotransmission, including the mechanism by which drugs can modulate the frequency and severity of epileptic seizures. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Smith E.R.,Royal Melbourne Hospital
Clinical Journal of the American Society of Nephrology | Year: 2014

The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. This review discusses the analytical and clinical challenges faced in translating fibroblast growth factor 23 testing into routine practice. As for other bone mineral markers, agreement between commercial fibroblast growth factor 23 assays is poor, mainly because of differences in calibration, but also, these differences reflect the variable detection of hormone fragments. Direct comparison of readout from different assays is consequently limited and likely hampers setting uniform fibroblast growth factor 23-directed targets. Efforts are needed to standardize assay output to enhance clinical use. Fibroblast growth factor 23 is robustly associated with cardiovascular and renal outcomes in patients with CKD and adds value to risk assessments based on conventional risk factors. Compared with most other mineral markers, fibroblast growth factor 23 shows better intraindividual temporal stability, withminimal diurnal andweek-to-week variability, but substantial interindividual variation,maximizing discriminative power for risk stratification. Conventional therapeutic interventions for the CKD-mineral bone disorder, such as dietary phosphate restriction and use of oral phosphate binders or calcimimetics, are associated with variable efficacy at modulating circulating fibroblast growth factor 23 concentrations, like they are for other mineral metabolites. Dual therapy with dietary phosphate restriction and noncalcium-based binder use achieves themost consistent fibroblast growth factor 23-lowering effect and seems bestmonitored using an intact assay. Additional studies are needed to evaluate whether strategies aimed at reducing levels or antagonizing its action have beneficial effects on clinical outcomes in CKD patients. Moreover, a better understanding of the mechanisms driving fibroblast growth factor 23 elevations in CKD is needed to inform the use of therapeutic interventions targeting fibroblast growth factor 23 excess. This evidence must be forthcoming to support the use of fibroblast growth factor 23 measurement and fibroblast growth factor 23-directed therapy in the clinic. © 2014 by the American Society of Nephrology.

McNab A.A.,Royal Melbourne Hospital
Survey of Ophthalmology | Year: 2014

Nontraumatic orbital hemorrhage (NTOH) is uncommon. I summarize the published reports of NTOH and offer a classification based on anatomic and etiologic factors. Anatomic patterns of NTOH include diffuse intraorbital hemorrhage, "encysted" hemorrhage (hematic cyst), subperiosteal hemorrhage, hemorrhage in relation to extraocular muscles, and hemorrhage in relation to orbital floor implants. Etiologic factors include vascular malformations and lesions, increased venous pressure, bleeding disorders, infection and inflammation, and neoplastic and nonneoplastic orbital lesions. The majority of NTOH patients can be managed conservatively, but some will have visual compromise and may require operative intervention. Some will suffer permanent visual loss, but a large majority have a good visual outcome. © 2014 Elsevier Inc.

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