Medicine (RMH Academic Centre) - Research Publications
Now showing items 1-12 of 23
The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells
(IMPACT JOURNALS LLC, 2015-08-28)
Glioma cells release glutamate through expression of system xc-, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate.
Reversal of evoked gamma oscillation deficits is predictive of antipsychotic activity with a unique profile for clozapine
(NATURE PUBLISHING GROUP, 2016-04-19)
Recent heuristic models of schizophrenia propose that abnormalities in the gamma frequency cerebral oscillations may be closely tied to the pathophysiology of the disorder, with hypofunction of N-methyl-d-aspartate receptors (NMDAr) implicated as having a crucial role. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating that is disrupted in schizophrenia. We tested the ability for antipsychotic drugs with diverse pharmacological actions to (1) ameliorate NMDAr antagonist-induced disruptions to gamma oscillations and (2) attenuate NMDAr antagonist-induced disruptions to PPI. We hypothesized that antipsychotic-mediated improvement of PPI deficits would be accompanied by a normalization of gamma oscillatory activity. Wistar rats were implanted with extradural electrodes to facilitate recording of electroencephalogram during PPI behavioural testing. In each session, the rats were administered haloperidol (0.25 mg kg(-1)), clozapine (5 mg kg(-1)), olanzapine (5 mg kg(-1)), LY379268 (3 mg kg(-1)), NFPS (sarcosine, 1 mg kg(-1)), d-serine (1800 mg kg(-1)) or vehicle, followed by the NMDAr antagonists MK-801(0.16 mg kg(-1)), ketamine (5 mg kg(-1)) or vehicle. Outcome measures were auditory-evoked, as well as ongoing, gamma oscillations and PPI. Although treatment with all the clinically validated antipsychotic drugs reduced ongoing gamma oscillations, clozapine was the only compound that prevented the sensory-evoked gamma deficit produced by ketamine and MK-801. In addition, clozapine was also the only antipsychotic that attenuated the disruption to PPI produced by the NMDAr antagonists. We conclude that disruptions to evoked, but not ongoing, gamma oscillations caused by NMDAr antagonists are functionally relevant, and suggest that compounds, which restore sensory-evoked gamma oscillations may improve sensory processing in patients with schizophrenia.
Limited role for surveillance PET-CT scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission following primary therapy
(NATURE PUBLISHING GROUP, 2013-07-23)
BACKGROUND: The usefulness of positron emission tomography with computed tomography (PET-CT) in the surveillance of patients with diffuse large B-cell lymphoma (DLBCL) in complete metabolic remission after primary therapy is not well studied. METHODS: We performed a retrospective review of our database between 2002 and 2009 for patients with de novo DLBCL who underwent surveillance PET-CT after achieving complete metabolic response (CMR) following primary therapy. RESULTS: Four-hundred and fifty scans were performed in 116 patients, with a median follow-up of 53 (range 8-133) months from completion of therapy. Thirteen patients (11%) relapsed: seven were suspected clinically and six were subclinical (all within first 18 months). The positive predictive value in patients with international prognostic index (IPI) <3 was 56% compared with 80% in patients with IPI ≥3. Including indeterminate scans, PET-CT retained high sensitivity 95% and specificity 97% for relapse. CONCLUSION: Positron emission tomography with computed tomography is not useful in patients for the majority of patients with diffuse large B-cell lymphoma in CMR after primary therapy, with the possible exception of patients with baseline IPI ≥3 in the 18 months following completion of primary therapy. This issue could be addressed by a prospective clinical trial.
A blood-based biomarker panel indicates IL-10 and IL-12/23p40 are jointly associated as predictors of beta-amyloid load in an AD cohort
(NATURE PUBLISHING GROUP, 2017-10-25)
Alzheimer's Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose individuals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify individuals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer's participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk individuals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ε4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ε4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of individuals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial.
Placement Instability Among Young People Removed from Their Original Family and the Likely Mental Health Implications.
BACKGROUND: Young people in out-of-home care are more likely to experience poorer mental and physical health outcomes related to their peers. Stable care environments are essential for ameliorating impacts of disruptive early childhood experiences, including exposure to psychological trauma, abuse and neglect. At present there are very few high quality data regarding the placement stability history of young people in out-of-home care in Australia or other countries. OBJECTIVES: To undertake the first systematic census of background, care type and placement stability characteristics of young people living in the out-of-home care sector in Australia. METHODS: Data was collected from four non-government child and adolescent community service organisations located across metropolitan Melbourne in 2014. The sample comprised 322 young people (females 52.8%), aged between 12 - 17 years (mean age=14.86 [SD=1.63] years). RESULTS: Most young people (64.3%) were in home-based care settings (i.e., foster care, therapeutic foster care, adolescent care program, kinship care, and lead tenant care), relative to residential care (35.7%). However, the proportion in residential care is very high in this age group when compared with all children in out-of-home care (5%). Mean age of first removal was 9 years (SD=4.54). No gender differences were observed for care type characteristics. Three quarters of the sample (76.9%) had a lifetime history of more than one placement in the out-of-home care system, with more than a third (36.5%) having experienced ≥5 lifetime placements. Relative to home-based care, young people in residential care experienced significantly greater placement instability (χ2=63.018, p<0.001). CONCLUSIONS: Placement instability is common in the out-of-home care sector. Given stable care environments are required to ameliorate psychological trauma and health impacts associated with childhood maltreatment, well-designed intervention-based research is required to enable greater placement stability, including strengthening the therapeutic capacities of out-of-home carers of young people.
Staging in bipolar disorder: from theoretical framework to clinical utility
Illness staging is widely utilized in several medical disciplines to help predict course or prognosis, and optimize treatment. Staging models in psychiatry in general, and bipolar disorder in particular, depend on the premise that psychopathology moves along a predictable path: an at-risk or latency stage, a prodrome progressing to a first clinical threshold episode, and one or more recurrences with the potential to revert or progress to late or end-stage manifestations. The utility and validity of a staging model for bipolar disorder depend on its linking to clinical outcome, treatment response and neurobiological measures. These include progressive biochemical, neuroimaging and cognitive changes, and potentially stage-specific differences in response to pharmacological and psychosocial treatments. Mechanistically, staging models imply the presence of an active disease process that, if not remediated, can lead to neuroprogression, a more malignant disease course and functional deterioration. Biological elements thought to be operative in bipolar disorder include a genetic diathesis, physical and psychic trauma, epigenetic changes, altered neurogenesis and apoptosis, mitochondrial dysfunction, inflammation, and oxidative stress. Many available agents, such as lithium, have effects on these targets. Staging models also suggest the utility of stage-specific treatment approaches that may not only target symptom reduction, but also impede illness neuroprogression. These treatment approaches range from prevention for at-risk individuals, to early intervention strategies for prodromal and newly diagnosed individuals, complex combination therapy for rapidly recurrent illness, and palliative-type approaches for those at chronic, late stages of illness. There is hope that prompt initiation of potentially disease modifying therapies may preclude or attenuate the cognitive and structural changes seen in the later stages of bipolar disorder. The aims of this paper are to: a) explore the current level of evidence supporting the descriptive staging of the syndromal pattern of bipolar disorder; b) describe preliminary attempts at validation; c) make recommendations for the direction of further studies; and d) provide a distillation of the potential clinical implications of staging in bipolar disorder within a broader transdiagnostic framework.
Perfusion Patterns of Ischemic Stroke on Computed Tomography Perfusion
(KOREAN STROKE SOC, 2013-09-01)
CT perfusion (CTP) has been applied increasingly in research of ischemic stroke. However, in clinical practice, it is still a relatively new technology. For neurologists and radiologists, the challenge is to interpret CTP results properly in the context of the clinical presentation. In this article, we will illustrate common CTP patterns in acute ischemic stroke using a case-based approach. The aim is to get clinicians more familiar with the information provided by CTP with a view towards inspiring them to incorporate CTP in their routine imaging workup of acute stroke patients.
Liaison psychiatry in a central nervous system tumor service
(OXFORD UNIV PRESS, 2015-06-01)
Background: Tumors of the central nervous system (CNS) have physical and psychological effects that commonly interact and change over time. Although well suited to addressing problems at the interface between physical and psychological medicine, the role of the consultation-liaison psychiatrist has not been previously described in the management of these patients. The purpose of this paper is to summarize the experience of psychiatry liaison attachment within a CNS tumor service and to reflect on its utility within a complex multidisciplinary environment. Methods: A retrospective file review was performed on all cases seen by a psychiatrist in a CNS tumor service over the previous 5 years. A simple thematic inductive analysis was conducted of the common problems experienced by patients and their management by the psychiatrist and within the team. Results: Five common themes were identified: (i) facilitating adaptation to diagnosis; (ii) supporting living with lower-grade tumors; (iii) managing mental disorders; (iv) neuropsychiatric symptoms of tumor progression; and (v) grief and uncertainty in the advanced stages of illness. The capacity of the psychiatrist to understand and integrate the clinical, pathological, radiological, and treatment information, in communication with colleagues, helped address these challenges. Conclusions: Psychological challenges in CNS tumor patients have both psychological and neurological underpinnings. In our experience, the addition of a liaison psychiatrist to a CNS tumor service was efficient and effective in improving patient management and led to enhanced communication and decision-making within the team.
Total arterial coronary revascularization.
(European Association of Cardiothoracic Surgery (EACTS Publishing Ltd), 2013)
Arterial coronary grafts can be used in the majority of patients and have better patencies than saphenous vein grafts (SVGs), resulting in excellent perioperative and superior long-term outcomes. Barriers to their extensive use include potential for trauma and spasm, extra-operating time, unfamiliarity, concerns over hypoperfusion and deep sternal wound infection in patients in whom bilateral internal thoracic arteries are used-especially diabetics. This presentation addresses these concerns with particular attention to the radial artery, and skeletonized right internal thoracic artery harvest and construction of the proximal anastomoses of these grafts to the ascending thoracic aorta. The facile handling of these grafts and techniques identical to SVG grafting are emphasized. Avoidance of competitive flow and the importance of spasm prophylaxis cannot be overstated. Arterial grafts have patencies >90% at 10 years (SVG 50-60% at 10 years) and once functioning normally, remain free of atheroma. Long-term results are excellent, especially freedom from recurrent cardiac events and reoperations, even in patients with significant preoperative comorbidities such as diabetes and renal dysfunction. Depending on age, long-term survival is between 85 and 90% at 10 years and 75 and 80% at 15 years, and is always better than for one arterial graft plus SVG in all long-term risk-adjusted or propensity-matched studies.
Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status
(PUBLIC LIBRARY SCIENCE, 2016-03-01)
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients.
Getting RID of the blues: Formulating a Risk Index for Depression (RID) using structural equation modeling
(SAGE PUBLICATIONS LTD, 2017-11-01)
OBJECTIVE: While risk factors for depression are increasingly known, there is no widely utilised depression risk index. Our objective was to develop a method for a flexible, modular, Risk Index for Depression using structural equation models of key determinants identified from previous published research that blended machine-learning with traditional statistical techniques. METHODS: Demographic, clinical and laboratory variables from the National Health and Nutrition Examination Study (2009-2010, N = 5546) were utilised. Data were split 50:50 into training:validation datasets. Generalised structural equation models, using logistic regression, were developed with a binary outcome depression measure (Patient Health Questionnaire-9 score ⩾ 10) and previously identified determinants of depression: demographics, lifestyle-environs, diet, biomarkers and somatic symptoms. Indicative goodness-of-fit statistics and Areas Under the Receiver Operator Characteristic Curves were calculated and probit regression checked model consistency. RESULTS: The generalised structural equation model was built from a systematic process. Relative importance of the depression determinants were diet (odds ratio: 4.09; 95% confidence interval: [2.01, 8.35]), lifestyle-environs (odds ratio: 2.15; 95% CI: [1.57, 2.94]), somatic symptoms (odds ratio: 2.10; 95% CI: [1.58, 2.80]), demographics (odds ratio:1.46; 95% CI: [0.72, 2.95]) and biomarkers (odds ratio:1.39; 95% CI: [1.00, 1.93]). The relationships between demographics and lifestyle-environs and depression indicated a potential indirect path via somatic symptoms and biomarkers. The path from diet was direct to depression. The Areas under the Receiver Operator Characteristic Curves were good (logistic:training = 0.850, validation = 0.813; probit:training = 0.849, validation = 0.809). CONCLUSION: The novel Risk Index for Depression modular methodology developed has the flexibility to add/remove direct/indirect risk determinants paths to depression using a structural equation model on datasets that take account of a wide range of known risks. Risk Index for Depression shows promise for future clinical use by providing indications of main determinant(s) associated with a patient's predisposition to depression and has the ability to be translated for the development of risk indices for other affective disorders.