43 results on '"Monif, Mastura"'
Search Results
2. Memory function in autoimmune encephalitis: a cross-sectional prospective study utilising multiple memory paradigms.
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Griffith, Sarah P., Wesselingh, Robb, Seery, Nabil, Rushen, Tiffany, Kyndt, Chris, Long, Brian, Seneviratne, Udaya, Kalincik, Tomas, Buzzard, Katherine, Butzkueven, Helmut, O'Brien, Terence J., Alpitsis, Rubina, Malpas, Charles B., and Monif, Mastura
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VERBAL memory ,PROSPECTIVE memory ,MEMORY disorders ,ASSOCIATIVE learning ,PSYCHOMETRICS ,VERBAL learning - Abstract
Background and objective: Autoimmune encephalitis (AE) is often associated with clinically significant memory impairment. This study aimed to evaluate memory in a cross-sectional prospective AE cohort using multiple memory paradigms. Methods: 52 patients (50% seropositive) meeting Graus criteria for possible AE were prospectively recruited between October 2019 and August 202. A comprehensive examination of memory was performed, including tests of supraspan verbal memory (list learning), logicosemantic memory (story learning), figural memory (learning of geometric designs), and verbal associative learning (verbal paired associates). Memory scores were compared to demographically adjusted normative data. Pattern analysis was conducted to assist in the identification of patterns in memory performances. Results: Mean memory scores were not significantly below the normative mean. At an individual patient level, over 20% of the cohort exhibited impaired delayed figural memory, supraspan verbal memory learning and recall. Observed performances were significantly below expected performance for story learning (p = 0.017) and recall (p = 0.003), figural recall (p < 0.0001), initial acquisition (p < 0.001) and final acquisition of a list (p < 0.001) and all delayed recall measures of the list (p < 0.00001). 54.76% of patients exhibited intact psychometrics, and 16 distinct patterns of impairment emerged, indicating variability in memory outcomes. Discussion: While statistical evidence for memory impairment did not emerge at an aggregate level, a proportion of patients present with evidence of abnormal memory performance on psychometrics. Variability in impaired memory measures argues for an individualised patient-focused approach to clinical assessment in AE. Future research should validate these findings with a larger sample size and explore the relationships between memory profiles and other cognitive functions. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Language impairments in seropositive and seronegative autoimmune encephalitis.
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Griffith, Sarah P., Wesselingh, Robb, D'Aprano, Fiore, Seery, Nabil, Rushen, Tiffany, Kyndt, Chris, Long, Brian, Seneviratne, Udaya, Kalincik, Tomas, Buzzard, Katherine, Butzkueven, Helmut, O'Brien, Terence J., Alpitsis, Rubina, Malpas, Charles B., and Monif, Mastura
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CENTRAL nervous system diseases ,ENCEPHALITIS ,ELECTRONOGRAPHY ,CENTRAL nervous system viral diseases ,LANGUAGE ability testing ,REFERENCE values ,GOODNESS-of-fit tests - Abstract
Background and objective: Autoimmune encephalitis (AE) is a rare neuroinflammatory disease affecting the central nervous system. To examine language functions in patients with different subsets of AE consisting of seropositive and seronegative groups. Methods: Fifty-two patients were recruited from neurology departments in Melbourne, Australia, who met clinical criteria for possible AE. Language tests include the Naming Test from the Sydney Language Battery (SydBat), the semantic fluency trial from the Controlled Oral Word Association Test (COWAT), and the Vocabulary and Similarities subtests of the Weschler Abbreviated Scale of Intelligence–Second Edition. The results were standardised with normative data. Results: The mean age of our cohort was 52.5 years old, with the average time from hospital admission to recruitment being 38.41 months. At an aggregate level, none of the mean language test z-scores were below normative data. At the patient level, impairment rates were 18.37% for COWAT (animals), 28.57% for SydBat (naming), 4.65% for Similarities, and 4.55% for Vocabulary. Chi-squared goodness of fit tests indicated that observed performances were significantly below expected performances for the SydBat (naming) test (p < 0.0001) and COWAT (animals) (p = 0.004). Discussion: While, on average, language functions were within normal limits in patients with AE, but a subgroup exhibited lower performance in semantic fluency and visual confrontation naming, with impairment rates below expected norms. To advance understanding of language in chronic AE patients, exploring the impact of seizure burden, antiseizure medication use, and the relationship of language functions with other cognitive functions is crucial. [ABSTRACT FROM AUTHOR]
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- 2024
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4. The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease.
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Liyanage, Ganesha, Trewin, Benjamin P., Lopez, Joseph A., Andersen, Jane, Tea, Fiona, Merheb, Vera, Nguyen, Kristy, Lee, Fiona X. Z., Fabis-Pedrini, Marzena J., Zou, Alicia, Buckland, Ali, Fok, Anthony, Barnett, Michael H., Reddel, Stephen W., Marignier, Romain, El Hajj, Aseel, Monif, Mastura, van der Walt, Anneke, Lechner-Scott, Jeannette, and Kermode, Allan G.
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NEUROMYELITIS optica ,MYELIN oligodendrocyte glycoprotein ,IMMUNOGLOBULINS ,POSTVACCINAL encephalitis - Published
- 2024
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5. Clinical outcomes among initial survivors of cryptogenic new‐onset refractory status epilepsy (NORSE).
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Costello, Daniel J., Matthews, Elizabeth, Aurangzeb, Sidra, Doran, Elisabeth, Stack, Jessica, Wesselingh, Robb, Dugan, Patricia, Choi, Hyunmi, Depondt, Chantal, Devinsky, Orrin, Doherty, Colin, Kwan, Patrick, Monif, Mastura, O'Brien, Terence J., Sen, Arjune, and Gaspard, Nicolas
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EPILEPSY ,TREATMENT effectiveness ,HOSPITAL admission & discharge ,STATUS epilepticus ,CRITICAL care medicine ,CONSORTIA - Abstract
Objective: New‐onset refractory status epilepticus (NORSE) is a rare but severe clinical syndrome. Despite rigorous evaluation, the underlying cause is unknown in 30%–50% of patients and treatment strategies are largely empirical. The aim of this study was to describe clinical outcomes in a cohort of well‐phenotyped, thoroughly investigated patients who survived the initial phase of cryptogenic NORSE managed in specialist centers. Methods: Well‐characterized cases of cryptogenic NORSE were identified through the EPIGEN and Critical Care EEG Monitoring Research Consortia (CCEMRC) during the period 2005–2019. Treating epileptologists reported on post‐NORSE survival rates and sequelae in patients after discharge from hospital. Among survivors >6 months post‐discharge, we report the rates and severity of active epilepsy, global disability, vocational, and global cognitive and mental health outcomes. We attempt to identify determinants of outcome. Results: Among 48 patients who survived the acute phase of NORSE to the point of discharge from hospital, 9 had died at last follow‐up, of whom 7 died within 6 months of discharge from the tertiary care center. The remaining 39 patients had high rates of active epilepsy as well as vocational, cognitive, and psychiatric comorbidities. The epilepsy was usually multifocal and typically drug resistant. Only a minority of patients had a good functional outcome. Therapeutic interventions were heterogenous during the acute phase of the illness. There was no clear relationship between the nature of treatment and clinical outcomes. Significance: Among survivors of cryptogenic NORSE, longer‐term outcomes in most patients were life altering and often catastrophic. Treatment remains empirical and variable. There is a pressing need to understand the etiology of cryptogenic NORSE and to develop tailored treatment strategies. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Characterizing cognitive function in patients with autoimmune encephalitis: an Australian prospective study.
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Griffith, Sarah P., Wesselingh, Robb, Seery, Nabil, Rushen, Tiffany, Kyndt, Chris, Long, Brian, Seneviratne, Udaya, Buzzard, Katherine, Butzkueven, Helmut, O'Brien, Terence J., Alpitsis, Rubina, Malpas, Charles B., and Monif, Mastura
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WECHSLER Adult Intelligence Scale ,CLINICAL neuropsychology ,COGNITIVE ability ,COGNITIVE processing speed ,EXECUTIVE function ,ENCEPHALITIS ,COGNITION - Abstract
Objective: This study uses the Wechsler intelligence and memory scales to characterize the cognitive function of patients with autoimmune encephalitis (AE) in the chronic stage of the disease. AE is a group of neuroinflammatory disorders, and cognitive impairment is a significant source of chronic morbidity in these patients. Methods: Fifty patients with an average disease duration of 3.2 years after diagnosis were prospectively recruited from four hospitals. They underwent a comprehensive cognitive examination using the Wechsler Abbreviated Scale of Intelligence (WASI-II), Wechsler Adult Intelligence Scale (WAIS-IV) and Wechsler Memory Scale (WMS-IV). Summary statistics were computed, and single-sample and independent-samples t tests were used to compare the cohort to normative data. Results: The results revealed significantly reduced performances in perceptual reasoning, processing speed, and working memory among AE patients. Seropositive AE patients exhibited below-norm processing speed, while the seronegative group showed reduced working memory and processing speed. Delayed memory performance was significantly below expectations only in seronegative patients. Pattern analysis indicated that intact cognition was the most observed outcome after AE, but significant heterogeneity was observed among the impaired patients. Conclusions: The study identified deficits in perceptual reasoning, processing speed, and working memory among chronic AE patients. Pattern analysis highlighted positive long-term cognitive outcomes for many but varied outcomes for those with ongoing difficulties. Although severely cognitively impaired patients were not included, the findings apply to AE cohorts who attend outpatient clinical neuropsychology consultations emphasizing the need for thorough cognitive assessment. The results suggest a need for further research targeting other cognitive domains, including executive functions. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Development and validation of a peripheral cell ratio and lactate score for differentiating status epilepticus from prolonged psychogenic nonepileptic seizures.
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Tan, Tracie H.L., Sanfilippo, Paul, Colman, Blake, Perucca, Piero, Kwan, Patrick, O'Brien, Terence J., and Monif, Mastura
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PSYCHOGENIC nonepileptic seizures ,STATUS epilepticus ,MONOCYTE lymphocyte ratio ,LACTATES ,PLATELET lymphocyte ratio ,LYMPHOCYTE count ,NEUTROPHILS ,PILOCARPINE - Abstract
Objective: Differentiating status epilepticus (SE) from prolonged psychogenic nonepileptic seizures (pPNES) can be difficult clinically. We aimed to define the utility of peripheral cell counts, cell ratios, and lactate levels in distinguishing SE from pPNES. Methods: Retrospective two‐center study investigating the sensitivity and specificity of acute (≤12 h of event offset) peripheral cell counts, cell ratios (neutrophil–lymphocyte ratio, neutrophil–monocyte ratio, monocyte–lymphocyte ratio, platelet–lymphocyte ratio, systemic immune‐inflammatory index [SII], systemic inflammatory response index [SIRI]), and lactate levels in differentiating SE from pPNES. Patients were identified from two tertiary hospitals, with one forming the development cohort and the other the validation cohort. Using generalized additive models to generate biomarker vs time curves, optimal blood collection times were defined for set parameters. Three diagnostic scores combining neutrophil count, SII, or SIRI with lactate levels were developed and validated in separate cohorts. Results: For the development cohort, 1262 seizure‐like events were reviewed and 79 SE and 44 pPNES events were included. For the validation cohort, 241 events were reviewed and 20 SE and 11 pPNES events were included. Individually, the biomarkers generally had low sensitivity and reasonable specificity for differentiating SE from pPNES, with the neutrophil count, SIRI, and SII performing best with sensitivities of 0.65–0.84, specificities of 0.64–0.89, and ROC AUCs of 0.78–0.79. Lactate levels peaked at 60 min, while cell counts and ratios peaked after 240 min. Combining early peaking lactate levels and later peaking neutrophil count, SIRI or SII resulted in three scores that improved predictive potential with sensitivities of between 0.75 and 0.79, specificities between 0.93 and 1.00, and ROC AUCs of 0.89–0.91. Significance: Lactate levels peak early post‐SE, whereas cell counts and ratios do so later. The differing post‐event time profiles of lactate levels vs neutrophil count, SIRI, and SII allow incorporation into three separate scores which can assist in differentiating SE from pPNES. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Movement disorders in cell surface antibody mediated autoimmune encephalitis: a meta-analysis.
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Siriratnam, Pakeeran, McArthur, Laura, Zhibin Chen, Kempster, Peter, and Monif, Mastura
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CELL motility ,MOVEMENT disorders ,ENCEPHALITIS ,PROGNOSIS ,RECEPTOR antibodies ,ANTI-NMDA receptor encephalitis ,IMMUNOGLOBULINS - Abstract
Background: Autoimmune encephalitis (AE) is an increasingly recognized neuroinflammatory disease entity in which early detection and treatment leads to the best clinical outcomes. Movement disorders occur in AE but their characteristics are not well defined. Objectives: To identify the frequency, classification, and prognostic significance of movement disorders in AE. Methods: We conducted a systematic review and random-effects meta-analysis of movement disorders in cell surface antibody mediated AE. The frequency of any movement disorder as well as the classification of movement disorders in AE serotypes was determined. We looked at adults 18 years and older and included publications that described at least 10 cases. We used the following four electronic databases: Medline (Ovid), EMBASE (Ovid), APA Psychinfo, and Cochrane library. Results: A total of 1,192 titles and abstracts were reviewed. Thirty-seven studies were included in the final meta-analysis. At least one kind of movement disorder was present in 40% of the entire AE cohort, 53% with anti-NMDA receptor antibodies, 33% with anti-CASPR2 antibodies, 30% with anti-LGI1 antibodies and 13% with anti-GABA receptor antibodies. Dyskinesia was the commonest movement disorder in anti-NMDA antibody mediated AE and faciobrachial dystonic seizures were most frequent in anti-LGI1 antibody mediated AE. Patients with amovement disorder tended to have a highermortality. The risk of bias in the included studies was mostly moderate or high. Conclusion: Movement disorders are common in AE and their identification, in conjunction with other clinical and paraclinical features, may facilitate earlier diagnosis. The prognostic implications of movement disorders in AE warrant further dedicated study. [ABSTRACT FROM AUTHOR]
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- 2023
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9. P2X7 receptor antagonism by AZ10606120 significantly reduced in vitro tumour growth in human glioblastoma.
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Kan, Liyen K., Drill, Matthew, Jayakrishnan, Padmakrishnan C., Sequeira, Richard P., Galea, Emily, Todaro, Marian, Sanfilippo, Paul G., Hunn, Martin, Williams, David A., O'Brien, Terence J., Drummond, Katharine J., and Monif, Mastura
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GLIOBLASTOMA multiforme ,HUMAN growth ,BRAIN tumors ,LACTATE dehydrogenase ,TUMORS ,PURINERGIC receptors ,CELL culture - Abstract
Glioblastomas are highly aggressive and deadly brain tumours, with a median survival time of 14–18 months post-diagnosis. Current treatment modalities are limited and only modestly increase survival time. Effective therapeutic alternatives are urgently needed. The purinergic P2X7 receptor (P2X7R) is activated within the glioblastoma microenvironment and evidence suggests it contributes to tumour growth. Studies have implicated P2X7R involvement in a range of neoplasms, including glioblastomas, although the roles of P2X7R in the tumour milieu remain unclear. Here, we report a trophic, tumour-promoting role of P2X7R activation in both patient-derived primary glioblastoma cultures and the U251 human glioblastoma cell line, and demonstrate its inhibition reduces tumour growth in vitro. Primary glioblastoma and U251 cell cultures were treated with the specific P2X7R antagonist, AZ10606120 (AZ), for 72 h. The effects of AZ treatment were also compared to cells treated with the current first-line chemotherapeutic drug, temozolomide (TMZ), and a combination of both AZ and TMZ. P2X7R antagonism by AZ significantly depleted glioblastoma cell numbers compared to untreated cells, in both primary glioblastoma and U251 cultures. Notably, AZ treatment was more effective at tumour cell killing than TMZ. No synergistic effect between AZ and TMZ was observed. AZ treatment also significantly increased lactate dehydrogenase release in primary glioblastoma cultures, suggesting AZ-induced cellular cytotoxicity. Our results reveal a trophic role of P2X7R in glioblastoma. Importantly, these data highlight the potential for P2X7R inhibition as a novel and effective alternative therapeutic approach for patients with lethal glioblastomas. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Neuroimaging characteristics may aid in diagnosis, subtyping, and prognosis in autoimmune encephalitis.
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Broadley, James, Wesselingh, Robb, Beech, Paul, Seneviratne, Udaya, Kyndt, Chris, Buzzard, Katherine, Nesbitt, Cassie, D'Souza, Wendyl, Brodtmann, Amy, Macdonell, Richard, Kalincik, Tomas, O'Brien, Terence J., Butzkueven, Helmut, Monif, Mastura, on behalf of the Australian Autoimmune Encephalitis Consortium, Griffiths, Sarah, Rushen, Tiffany, Tan, Tracie, Malpas, Charles, and Halliday, Amy
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POSITRON emission tomography ,ENCEPHALITIS ,MAGNETIC resonance imaging ,DISEASE relapse ,BRAIN imaging - Abstract
Objective: To examine the utility of neuroimaging characteristics as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). Methods: In this multi-center study, we retrospectively analyzed 66 cases of seropositive AE. The MRI and PET imaging was assessed by independent visual inspection. Whole brain and regional volumes were imputed by IcoMetrix, an automated volumetric assessment package. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability. Other outcomes were mortality, first line treatment failure, medial temporal lobe (MTL) atrophy, and clinical relapse. Univariate and multivariable regression analysis was performed. Results: Abnormalities on MRI were detected in 35.1% of patients, while PET was abnormal in 46.4%. Initial median whole brain and hippocampal volumes were below the 5th and 20th percentile respectively compared to an age-matched healthy database. After a median follow-up of 715 days, 85.2% had good functional outcome (mRS ≤ 2). Nine patients developed MTL atrophy during follow-up. On multivariable analysis, inflammatory MTL changes were associated with development of MTL atrophy (HR 19.6, p = 0.007) and initial hippocampal volume had an inverse relationship with mortality (HR 0.04, p = 0.011). Patients who developed MTL atrophy had a reduced chance of good final mRS (HR 0.16, p = 0.015). Conclusions: Neuroimaging on initial hospital admission may be provide important diagnostic and prognostic information. This study demonstrates that structural and inflammatory changes of the MTL may have importance in clinical and radiological prognosis in seropositive AE. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Nogo receptor-Fc delivered by haematopoietic cells enhances neurorepair in a multiple sclerosis model.
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Sining Ye, Theotokis, Paschalis, Jae Young Lee, Min Joung Kim, Nheu, Danica, Ellen, Olivia, Bedford, Thomas, Ramanujam, Padmanabhan, Wright, David K., McDonald, Stuart J., Alrehaili, Amani, Bakhuraysah, Maha, Jung Hee Kang, Siatskas, Christopher, Tremblay, Cedric S., Curtis, David J., Grigoriadis, Nikolaos, Monif, Mastura, Strittmatter, Stephen M., and Petratos, Steven
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- 2023
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12. Prediction of relapse activity when switching to cladribine for multiple sclerosis.
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Zhong, Michael, van der Walt, Anneke, Monif, Mastura, Hodgkinson, Suzanne, Eichau, Sara, Kalincik, Tomas, Lechner-Scott, Jeannette, Buzzard, Katherine, Skibina, Olga, Van Pesch, Vincent, Butler, Ernest, Prevost, Julie, Girard, Marc, Oh, Jiwon, Butzkueven, Helmut, and Jokubaitis, Vilija
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MULTIPLE sclerosis ,DIMETHYL fumarate ,NATALIZUMAB ,CONFIDENCE intervals - Abstract
Background: Patients with relapsing–remitting multiple sclerosis commonly switch between disease-modifying therapies (DMTs). Identifying predictors of relapse when switching could improve outcomes. Objective: To determine predictors of relapse hazard when switching to cladribine. Methods: Data of patients who switched to cladribine, grouped by prior disease-modifying therapy (pDMT; interferon-β/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab (NTZ)), were extracted from the MSBase Registry. Predictors of relapse hazard during the treatment gap and the first year of cladribine therapy were determined. Results: Of 513 patients, 22 relapsed during the treatment gap, and 38 within 1 year of starting cladribine. Relapse in the year before pDMT cessation predicted treatment gap relapse hazard (hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.03–5.71). After multivariable adjustment, relapse hazard on cladribine was predicted by relapse before pDMT cessation (HR = 2.00, 95% CI = 1.01–4.02), treatment gap relapse (HR = 6.18, 95% confidence interval (CI) = 2.65–14.41), switch from NTZ (HR compared to injectable therapies 4.08, 95% CI = 1.35–12.33) and age at cladribine start (HR = 0.96, 95% CI = 0.91–0.99). Conclusion: Relapse during or prior to the treatment gap, and younger age, are of prognostic relevance in the year after switching to cladribine. Switching from NTZ is also independently associated with greater relapse hazard. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Psychometric deficits in autoimmune encephalitis: A retrospective study from the Australian Autoimmune Encephalitis Consortium.
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Griffith, Sarah, Wesselingh, Robb, Broadley, James, O'Shea, Marie, Kyndt, Chris, Meade, Catherine, Long, Brian, Seneviratne, Udaya, Reidy, Natalie, Bourke, Robert, Buzzard, Katherine, D'Souza, Wendyl, Macdonell, Richard, Brodtmann, Amy, Butzkueven, Helmut, O'Brien, Terence J., Alpitsis, Rubina, Malpas, Charles B., and Monif, Mastura
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PSYCHOMETRICS ,COGNITIVE testing ,ENCEPHALITIS ,MAGNETIC resonance imaging ,URBAN hospitals ,CEREBROSPINAL fluid - Abstract
Background and purpose: Despite the rapid increase in research examining outcomes in autoimmune encephalitis (AE) patients, there are few cohort studies examining cognitive outcomes in this population. The current study aimed to characterise psychometric outcomes in this population, and explore variables that may predict psychometric outcomes. Methods: This retrospective observational study collected psychometric data from 59 patients across six secondary and tertiary referral centres in metropolitan hospitals in Victoria, Australia between January 2008 and July 2019. Frequency and pattern analysis were employed to define and characterize psychometric outcomes. Univariable logistic regression was performed to examine predictors of intact and pathological psychometric outcomes. Results: Deficits in psychometric markers of executive dysfunction were the most common finding in this cohort, followed by deficits on tasks sensitive to memory. A total of 54.2% of patients were classified as having psychometric impairments across at least two cognitive domains. Twenty‐nine patterns were observed, suggesting outcomes in AE are complex. None of the demographic data, clinical features or auxiliary examination variables were predictors of psychometric outcome. Conclusions: Cognitive outcomes in AE are complex. Further detailed and standardized cognitive testing, in combination with magnetic resonance imaging volumetrics and serum/cerebrospinal fluid biomarkers, is required to provide rigorous assessments of disease outcomes. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Flow cytometry identifies an early stage of platelet apoptosis produced by agonists of the P2X1 and P2X7 receptors.
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Wong, Joelyn, Gu, Ben J., Teoh, Harry, Krupa, Malgorzata, Monif, Mastura, Slee, Mark, and Wiley, James S.
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FLOW cytometry ,BLOOD platelets ,LIPID rafts ,CYTOSKELETON ,APOPTOSIS - Abstract
Platelets express P2X1 receptors and our data also show the expression of P2X7 receptors. We studied the role of both receptors in platelet apoptosis by incubation of PRP with P2X agonists, then centrifuged to remove viable platelets, and analyzed the supernatant by flow cytometry to identify a sparse platelet-derived population that stained with MitoTracker dyes and CD41. BzATP, a potent agonist of P2X receptors, and ABT737, an activator of intrinsic apoptosis, produced altered platelets that stained moderately for annexin V and corresponded to an early stage apoptotic platelet (ESAP). Over a range of BzATP concentrations, we observed a dose-dependent formation of ESAPs between 5 and 500 uM BzATP, together with a variable formation of ESAPs at nanomolar ATP or BzATP (50–200 nM). Production of ESAPs occurred with αβ-meATP, while responses with either BzATP or αβ-meATP showed desensitization at a higher agonist concentration. Formation of ESAPs by either 100 nM or 0.5 mM BzATP was inhibited by preincubation of platelets with latrunculin A, an inhibitor of the actin cytoskeleton that prevents apoptosis. ESAP production was totally inhibited by preincubation of platelets with methyl-beta-cyclodextrin, which removes cholesterol from lipid rafts. Our data show that both P2X1 and P2X7 receptors are localized in platelet lipid rafts where P2X-agonists act to produce early stage apoptotic platelets. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Effectiveness of Bioinks and the Clinical Value of 3D Bioprinted Glioblastoma Models: A Systematic Review.
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Leong, Shye Wei, Tan, Shing Cheng, Norhayati, Mohd Noor, Monif, Mastura, and Lee, Si-Yuen
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BIOLOGICAL models ,ONLINE information services ,CELL culture ,SYSTEMATIC reviews ,CARCINOGENESIS ,GLIOMAS ,BIOMEDICAL engineering ,BIOMEDICAL materials ,CELL survival ,ALGINATES ,PHARMACEUTICAL gels ,THREE-dimensional printing ,MEDLINE ,DRUG resistance in cancer cells - Abstract
Simple Summary: Glioblastoma is the most malignant cancer of the glioma series, and it is highly invasive. The progression and recurrence of glioblastoma remain common due to the development of drug resistance. Of the current disease models and strategies used in pre-clinical studies for drug testing, three-dimensional (3D) bioprinting is an emerging technology in constructing a glioblastoma model. In this paper, 19 out of 304 articles yielded from the database search were selected and analysed through a systematic process. The selected studies present the effectiveness of different bioinks, which were used to mimic the tumour microenvironment of glioblastoma in bioprinting. The clinical value of the 3D bioprinted glioblastoma models on the efficacy of treatments or drug response was evaluated. Many medical applications have arisen from the technological advancement of three-dimensional (3D) bioprinting, including the printing of cancer models for better therapeutic practice whilst imitating the human system more accurately than animal and conventional in vitro systems. The objective of this systematic review is to comprehensively summarise information from existing studies on the effectiveness of bioinks in mimicking the tumour microenvironment of glioblastoma and their clinical value. Based on predetermined eligibility criteria, relevant studies were identified from PubMed, Medline Ovid, Web of Science, Scopus, and ScienceDirect databases. Nineteen articles fulfilled the inclusion criteria and were included in this study. Alginate hydrogels were the most widely used bioinks in bioprinting. The majority of research found that alginate bioinks had excellent biocompatibility and maintained high cell viability. Advanced structural design, as well as the use of multicomponent bioinks, recapitulated the native in vivo morphology more closely and resulted in bioprinted glioblastoma models with higher drug resistance. In addition, 3D cell cultures were superior to monolayer or two-dimensional (2D) cell cultures for the simulation of an optimal tumour microenvironment. To more precisely mimic the heterogenous niche of tumours, future research should focus on bioprinting multicellular and multicomponent tumour models that are suitable for drug screening. [ABSTRACT FROM AUTHOR]
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- 2022
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16. Failure of alemtuzumab therapy in three patients with MOG antibody associated disease.
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Seneviratne, Sinali O., Marriott, Mark, Ramanathan, Sudarshini, Yeh, Wei, Brilot-Turville, Fabienne, Butzkueven, Helmut, and Monif, Mastura
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ALEMTUZUMAB ,MYELIN oligodendrocyte glycoprotein ,MAGNETIC resonance imaging ,TRANSVERSE myelitis ,OPTIC neuritis - Abstract
Background: Myelin Oligodendrocyte Glycoprotein antibody-associated disease (MOGAD) is most classically associated in both children and adults with phenotypes including bilateral and recurrent optic neuritis (ON) and transverse myelitis (TM), with the absence of brain lesions characteristic of multiple sclerosis (MS). ADEM phenotype is the most common presentation of MOGAD in children. However, the presence of clinical phenotypes including unilateral ON and short TM in some patients with MOGAD may lead to their misdiagnosis as MS. Thus, clinically and radiologically, MOGAD can mimic MS and clinical vigilance is required for accurate diagnostic workup.Case Presentation: We present three cases initially diagnosed as MS and then treated with alemtuzumab. Unexpectedly, all three patients did quite poorly on this medication, with a decline in their clinical status with worsening of expanded disability status scale (EDSS) and an increasing lesion load on magnetic resonance imaging of the brain. Subsequently, all three cases were found to have anti-MOG antibody in their serum.Conclusions: These cases highlight that if a patient suspected to have MS does not respond to conventional treatments such as alemtuzumab, a search for alternative diagnoses such as MOG antibody disease may be warranted. [ABSTRACT FROM AUTHOR]- Published
- 2022
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17. Autoimmune Encephalitis in Long-Standing Schizophrenia: A Case Report.
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Vaux, Amy, Robinson, Karen, Saglam, Burcu, Cheuk, Nathan, Kilpatrick, Trevor, Evans, Andrew, and Monif, Mastura
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ENCEPHALITIS ,ANTI-NMDA receptor encephalitis ,DYSAUTONOMIA ,SYMPTOMS ,CENTRAL nervous system ,SCHIZOPHRENIA ,RECEPTOR antibodies - Abstract
Anti-N-methyl-D-aspartate (NMDA) receptor antibody (anti-NMDAR Ab)-mediated encephalitis is an autoimmune disorder involving the production of antibodies against NMDARs in the central nervous system that leads to neurological or psychiatric dysfunction. Initially described as a paraneoplastic syndrome in young women with teratomas, increased testing has found it to be a heterogeneous condition that affects both the sexes with varying clinical manifestations, severity, and aetiology. This case report describes a 67-year-old man with a 40-year history of relapsing, severe, treatment-refractory schizophrenia. Due to the worsening of his condition during a prolonged inpatient admission for presumed relapse of psychosis, a revisit of the original diagnosis was considered with extensive investigations performed including an autoimmune panel. This revealed anti-NMDAR Abs in both the serum and cerebrospinal fluid on two occasions. Following treatment with intravenous immunoglobulin and methylprednisolone, he demonstrated rapid symptom improvement. This is a rare case of a long-standing psychiatric presentation with a preexisting diagnosis of schizophrenia subsequently found to have anti-NMDAR Ab-mediated encephalitis. Whether the case is one of initial NMDAR encephalitis vs. overlap syndrome is unknown. Most importantly, this case highlights the need for vigilance and balanced consideration for treatment in cases of long-standing psychiatric presentation where the case remains treatment refractory to antipsychotics or when atypical features including seizures and autonomic dysfunction or focal neurology are observed. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Inflammatory complications of CGRP monoclonal antibodies: a case series.
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Ray, Jason C., Allen, Penelope, Bacsi, Ann, Bosco, Julian J., Chen, Luke, Eller, Michael, Kua, Hock, Lim, Lyndell L., Matharu, Manjit S., Monif, Mastura, Ruttledge, Martin, Stark, Richard J., and Hutton, Elspeth J.
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ANALGESICS ,CALCITONIN ,MONOCLONAL antibodies ,SYSTEMIC inflammatory response syndrome ,PEPTIDES - Abstract
Background: Calcitonin gene-related peptide (CGRP) is expressed throughout the body and is a known mediator of migraine, exerting this biological effect through activation of trigeminovascular, meningeal and associated neuronal pathways located in close proximity to the central nervous system. Monoclonal antibodies (mAb) targeting the CGRP pathway are an effective new preventive treatment for migraine, with a generally favourable adverse event profile. Pre-clinical evidence supports an anti-inflammatory/immunoregulatory role for CGRP in other organ systems, and therefore inhibition of the normal action of this peptide may promote a pro-inflammatory response. Cases: We present a case series of eight patients with new or significantly worsened inflammatory pathology in close temporal association with the commencement of CGRP mAb therapy. Conclusion: This case series provides novel insights on the potential molecular mechanisms and side-effects of CGRP antagonism in migraine and supports clinical vigilance in patient care going forward. [ABSTRACT FROM AUTHOR]
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- 2021
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19. Predicting Infection Risk in Multiple Sclerosis Patients Treated with Ocrelizumab: A Retrospective Cohort Study.
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Seery, Nabil, Sharmin, Sifat, Li, Vivien, Nguyen, Ai-Lan, Meaton, Claire, Atvars, Roberts, Taylor, Nicola, Tunnell, Kelsey, Carey, John, Marriott, Mark P., Buzzard, Katherine A., Roos, Izanne, Dwyer, Chris, Baker, Josephine, Taylor, Lisa, Spriggs, Kymble, Kilpatrick, Trevor J., Kalincik, Tomas, and Monif, Mastura
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MULTIPLE sclerosis ,COHORT analysis ,IMMUNOGLOBULIN G ,NATALIZUMAB ,INFECTION ,UNIVARIATE analysis - Abstract
Background: Ocrelizumab safety outcomes have been well evaluated in clinical trials and open-label extension (OLE) studies. However, risk factors for infection in patients with multiple sclerosis (MS) receiving ocrelizumab have not been extensively studied in the real-world setting. Objective: The aim of this study was to examine factors determining risk of self-reported infections and antimicrobial use in patients receiving ocrelizumab for MS. Methods: A retrospective, observational cohort study was conducted in patients receiving ocrelizumab at the Royal Melbourne Hospital. Infection type and number were reported by patients, and the associations of potential clinical and laboratory risk factors with self-reported infection and antimicrobial use were estimated using univariate and multivariable logistic regression models. Results: A total of 185 patients were included in the study; a total of 176 infections were reported in 89 patients (46.1%), and antimicrobial use was identified in 47 patients (25.3%). In univariate analyses, a higher serum IgA was associated with reduced odds of infection (OR 0.44, 95% CI 0.25–0.76). In multivariable analyses, older age (OR 0.94, 95% CI 0.88–0.99), higher serum IgA (OR 0.37, 95% CI 0.17–0.80) and higher serum IgG (OR 0.81, 95% CI 0.67–0.99) were associated with reduced odds of infection. Older age (OR 0.85, 95% CI 0.75–0.96) and higher serum IgA (OR 0.23, 95% CI 0.07–0.79) were associated with reduced odds of antimicrobial use, whilst longer MS disease duration (OR 1.22, 95% CI 1.06–1.41) and higher Expanded Disability Status Scale (EDSS) score (OR 1.99, 95% CI 1.02–3.86) were associated with increased odds of antimicrobial use. Conclusions: Higher serum IgA and IgG and older age were associated with reduced odds of infection. Our findings highlight that infection risk is not uniform in patients with MS receiving ocrelizumab and substantiate the need to monitor immunoglobulin levels pre-treatment and whilst on therapy. [ABSTRACT FROM AUTHOR]
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- 2021
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20. Cognition and psychopathology in autoimmune encephalitides: A focus on risk factors and patient outcomes.
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Griffith, Sarah P., Malpas, Charles B., Kyndt, Chris, Alpitsis, Rubina, O'Brien, Terence J., and Monif, Mastura
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TREATMENT effectiveness ,ENCEPHALITIS ,SYMPTOMS ,DIAGNOSIS ,COGNITION ,CHRONIC diseases - Abstract
Neurocognitive compromise, neuropsychiatric symptoms and psychopathology are all evident in the acute stages of autoimmune encephalitides. These factors considerably affect functional independence after discharge. Drawing on psychometric assessments and qualitative descriptions, this review explores the nature, extent and diagnosis of cognitive disorder in autoimmune encephalitides. Potential pathophysiological and neuroanatomical architecture related to neurocognitive compromise in the acute and chronic stages of this illness is examined. In regard to outcomes, the review highlights clinicodemographic factors currently known to be associated with poorer cognitive outcome. Finally, the review delves into neuropsychiatric symptomology and psychological concerns that should be considered at diagnosis and during follow up of these patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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21. Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer.
- Author
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Drill, Matthew, Jones, Nigel C., Hunn, Martin, O'Brien, Terence J., and Monif, Mastura
- Abstract
The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on immune cells and is highly upregulated in a number of human cancers where it can play a trophic role in tumorigenesis. Activation of this receptor leads to the formation of a non-selective cation channel, which has been associated with several cellular functions mediated by the PI3K/Akt pathway and protein kinases. Due to its broad range of functions, the receptor represents a potential therapeutic target for a number of cancers. This review describes the range of mechanisms associated with P2X7R activation in cancer settings and highlights the potential of targeted inhibition of P2X7R as a therapy. It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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22. Elevated Serum Interleukin-1β Levels in Male, but not Female, Collision Sport Athletes with a Concussion History.
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O'Brien, William T., Symons, Georgia F., Bain, Jesse, Major, Brendan P., Costello, Daniel M., Sun, Mujun, Kimpton, Joshua S., Chen, Zhibin, Brady, Rhys D., Mychasiuk, Richelle, O'Brien, Terence J., Monif, Mastura, Shultz, Sandy R., and McDonald, Stuart J.
- Published
- 2021
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23. Patient Preferences for Time and Location of Infusible Therapies in Multiple Sclerosis and Neuroimmunologic Disorders.
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Rath, Louise, Campagna, Maria Pia, Stankovich, Jim, Ellis, Julian, Jokubaitis, Vilija, McCarthy, Denise, Nesbitt, Cassie, Wei Zhen Yeh, Zhong, Michael, Wesselingh, Robb, Monif, Mastura, Richards, Janene, Viet Bui Minh, Skibina, Olga, Butzkueven, Helmut, and van der Walt, Anneke
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DISEASE relapse ,MULTIPLE sclerosis treatment ,RITUXIMAB ,METHYLPREDNISOLONE ,DISEASE progression ,PILOT projects ,NEUROLOGICAL disorders ,INTRAVENOUS therapy ,STRATEGIC planning ,CONFIDENCE intervals ,TIME ,HOME care services ,CROSS-sectional method ,AGE distribution ,TRAVEL ,POPULATION geography ,MONOCLONAL antibodies ,PATIENT-centered care ,FISHER exact test ,PATIENTS' attitudes ,MATHEMATICAL variables ,SURVEYS ,EMPLOYMENT ,QUESTIONNAIRES ,PHYSICAL mobility ,IMMUNOLOGICAL adjuvants ,IMMUNOLOGIC diseases ,NATALIZUMAB ,LOGISTIC regression analysis ,ODDS ratio ,ANTIGENS ,LONGITUDINAL method - Abstract
Background: People with multiple sclerosis and neuroimmunologic disorders (herein referred to as patients) are increasingly treated with infusible monoclonal antibodies. This rise in demand has placed increased loads on current infusion services and mandates careful strategic planning. This study examined patient preferences for the timing and location of infusions and their association with demographic and disease variables to facilitate patient-focused strategic planning. Methods: Ninety-one patients receiving an infusible therapy at an infusion service during March 2019 were asked to complete a questionnaire exploring eight domains, including preferences for time of infusions and location of infusion centers. Potential access to home-based treatment was included as an option. Unstructured (free-text) feedback on current service was also obtained. Results: Eighty-three patients completed the survey (mean age, 42 years; 75% women). Infusions were predominantly natalizumab (66%) and ocrelizumab (25%). Of these patients, 71% were engaged in some form of work or study, and 83% of this group had to arrange time off from work or study to attend treatment. Seventy percent of patients would prefer their infusion before noon, and 60% would consider home-based infusions. Most used a car as their transport to the infusion service. Conclusions: These results suggest that patients are more likely to prefer infusible treatment in the morning and are open to home-based infusions. This study provides information for health services to target service delivery at peak preference times and consider alternate ways of delivering infusible treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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24. The prevalence of epileptic seizures in multiple sclerosis in a large tertiary hospital in Australia.
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Ooi, Suyi, Kalincik, Tomas, Perucca, Piero, and Monif, Mastura
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MULTIPLE sclerosis ,DIAGNOSIS ,THERAPEUTICS ,SEIZURES (Medicine) ,DISEASE relapse - Abstract
Rationale: To determine the prevalence of epileptic seizures in multiple sclerosis (MS) at an Australian tertiary hospital and to define their clinical features. Methods: We retrospectively analysed adult patients at the Royal Melbourne Hospital electronically identified to have ICD codes for MS and seizures and/or epilepsy between 1996 to 2019, utilising paper and electronic-based records. Results: Of the 2,125 MS patients identified, 16 (0.75%) experienced epileptic seizures during a mean follow-up period of 12.9 years. Median age of MS diagnosis (SD) was 38 (9.3) years. Four patients had relapsing remitting MS (25%), 10 secondary progressive MS (63.5%), and 2 primary progressive MS (12.5%). More than two-thirds of patients had seizure onset following the diagnosis of MS, and the majority of these had advanced disease (approximate EDSS >6) at the time of seizure onset. Focal onset-seizures occurred in 87.5% of patients with seizures. Conclusion: The estimated prevalence of seizures in our cohort was lower than in previous studies (0.75 vs 2–4%). In most cases, seizures occurred after the diagnosis of MS in the context of advanced disease. Further studies are required to determine if MS disease modifying treatments reduce the risk of seizures in this cohort. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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25. Inflammation, ictogenesis, and epileptogenesis: An exploration through human disease.
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Tan, Tracie Huey‐Lin, Perucca, Piero, O'Brien, Terence J., Kwan, Patrick, and Monif, Mastura
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ANTI-NMDA receptor encephalitis ,CYTOTOXIC T cells ,DIAGNOSIS ,NEUROLOGICAL disorders ,ENCEPHALITIS ,COMPLEMENT activation - Abstract
Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto‐antibodies and the subsequent growth in understanding of autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure‐associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long‐term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear‐cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection–related epilepsy syndrome (FIRES), and new‐onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision‐making are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. Peripheral Immune Cell Ratios and Clinical Outcomes in Seropositive Autoimmune Encephalitis: A Study by the Australian Autoimmune Encephalitis Consortium.
- Author
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Broadley, James, Wesselingh, Robb, Seneviratne, Udaya, Kyndt, Chris, Beech, Paul, Buzzard, Katherine, Nesbitt, Cassie, D'Souza, Wendyl, Brodtmann, Amy, Kalincik, Tomas, Butzkueven, Helmut, O'Brien, Terence J., and Monif, Mastura
- Subjects
ENCEPHALITIS ,NEUTROPHILS ,ROUTINE diagnostic tests ,DISEASE relapse ,HOSPITAL admission & discharge - Abstract
Objective: To examine the utility of the peripheral blood neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). Methods: In this multicenter study, we retrospectively analyzed 57 cases of seropositive AE with hospital admissions between January 2008 and June 2019. The initial full blood examination was used to determine each patients' NLR and MLR. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability at 12 months and then at final follow-up. Primary outcomes were mortality and mRS, while secondary outcomes were failure of first line treatment, ICU admission, and clinical relapse. Univariate and multivariable regression analysis was performed. Results: During initial hospital admission 44.7% of patients had unsuccessful first line treatment. After a median follow-up of 700 days, 82.7% had good functional outcome (mRS ≤2) while five patients had died. On multivariable analysis, high NLR was associated with higher odds of first line treatment failure (OR 1.32, 95% CI 1.03–1.69, p = 0.029). Increased MLR was not associated with any short or long-term outcome. Conclusions: NLR on initial hospital admission blood tests may be provide important prognostic information for cases of seropositive AE. This study demonstrates the potential use of NLR as a prognostic marker in the clinical evaluation of patients with seropositive AE. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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27. The prevalence of epileptic seizures in multiple sclerosis in a large tertiary hospital in Australia.
- Author
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Ooi, Suyi, Kalincik, Tomas, Perucca, Piero, and Monif, Mastura
- Subjects
MULTIPLE sclerosis ,EPILEPSY ,THERAPEUTICS ,SEIZURES (Medicine) ,DISEASE relapse ,HOSPITALS - Abstract
Rationale: To determine the prevalence of epileptic seizures in multiple sclerosis (MS) at an Australian tertiary hospital and to define their clinical features. Methods: We retrospectively analysed adult patients at the Royal Melbourne Hospital electronically identified to have ICD codes for MS and seizures and/or epilepsy between 1996 to 2019, utilising paper and electronic-based records. Results: Of the 2,125 MS patients identified, 16 (0.75%) experienced epileptic seizures during a mean follow-up period of 12.9 years. Median age of MS diagnosis (SD) was 38 (9.3) years. Four patients had relapsing remitting MS (25%), 10 secondary progressive MS (63.5%), and 2 primary progressive MS (12.5%). More than two-thirds of patients had seizure onset following the diagnosis of MS, and the majority of these had advanced disease (approximate EDSS >6) at the time of seizure onset. Focal onset-seizures occurred in 87.5% of patients with seizures. Conclusion: The estimated prevalence of seizures in our cohort was lower than in previous studies (0.75 vs 2-4%). In most cases, seizures occurred after the diagnosis of MS in the context of advanced disease. Further studies are required to determine if MS disease modifying treatments reduce the risk of seizures in this cohort. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
28. P2X7 receptor antagonism inhibits tumour growth in human high-grade gliomas.
- Author
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Kan, Liyen Katrina, Seneviratne, Sinali, Drummond, Kate J., Williams, David A., O'Brien, Terence J., and Monif, Mastura
- Abstract
Gliomas, the most common primary brain cancer, are highly infiltrative and extremely difficult to treat. Despite advancements, current treatment is limited, with patients surviving for a median of 14–15 months post-diagnosis. Previous research has demonstrated the upregulation of a purinergic receptor, P2X7R, in human gliomas. P2X7R is expressed on both glioma cells and microglia within the glioma microenvironment. It is hypothesized that P2X7R contributes to tumour growth and proliferation via immune-mediated mechanisms involving tumour cells and surrounding microglia. We sought to elucidate the role of P2X7R in a human glioblastoma cell line (U251) and on surgically resected human glioma samples. We treated U251 and human glioma cultures for 72 h with P2X7R antagonists, Brilliant Blue G (BBG), oxidized ATP (oATP) and AZ10606120. Cell counting via fluorescence confocal microscopy was conducted to assess tumour proliferation. We observed no significant reductions in tumour cell numbers following P2X7R antagonism with BBG (20 μM) and oATP (250 μM) in both U251 cells and human glioma samples. Interestingly, there was a significant reduction in tumour cell number in both U251 cells (p = 0.0156) and human glioma samples (p = 0.0476) treated with varying concentrations of AZ10606120. When compared with the conventional chemotherapeutic agent, temozolomide, AZ10606120 was also found to more effectively inhibit tumour proliferation in U251 cells (p < 0.0001). Our pilot results demonstrate a potential trophic role of P2X7R where its inhibition by AZ10606120, a potent antagonist, hinders glioma growth directly or through the inactivation of microglia. This sheds new light on P2X7R as a therapeutic target for human gliomas. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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29. Seizures in autoimmune encephalitis: Kindling the fire.
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Wesselingh, Robb, Butzkueven, Helmut, Buzzard, Katherine, Tarlinton, David, O'Brien, Terence J., and Monif, Mastura
- Subjects
SEIZURES (Medicine) ,ENCEPHALITIS ,NEUROLOGICAL disorders ,NEURAL transmission ,BLOOD-brain barrier - Abstract
Epilepsy is a common neurological disorder that increases the risk of morbidity and mortality. Autoimmune epilepsy is a subset of epilepsy that occurs in the setting of autoimmunity, such as in autoimmune encephalitis (AIE). AIE is an autoimmune disorder characterized by immune‐mediated neuroinflammation resulting in a variety of neurological symptoms, including psychiatric disturbance, cognitive dysfunction, and seizures. Seizures in AIE are thought to be a result of antibodies directed against neuronal cell‐surface proteins involved in synaptic transmission. The role of blood‐brain barrier dysfunction, myeloid cell infiltration, and the initiation of proinflammatory cascades in epileptogenesis has been shown to be important in animal models and human patients with epilepsy. Epileptogenesis in AIE is likely to arise from the synergistic effect of both innately driven neuroinflammation and antibody‐induced hyperexcitability. Together, these processes produce persistent drug‐resistant seizures that contribute to the morbidity seen in AIE. Understanding the proinflammatory pathways involved in this process may improve diagnostics and provide alternative treatment targets in AIE. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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30. The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target.
- Author
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O'Brien, William T., Pham, Louise, Symons, Georgia F., Monif, Mastura, Shultz, Sandy R., and McDonald, Stuart J.
- Subjects
BRAIN injuries ,PATHOLOGY ,SEX (Biology) ,INFLAMMATION ,CHRONIC traumatic encephalopathy - Abstract
There is a great clinical need to identify the underlying mechanisms, as well as related biomarkers, and treatment targets, for traumatic brain injury (TBI). Neuroinflammation is a central pathophysiological feature of TBI. NLRP3 inflammasome activity is a necessary component of the innate immune response to tissue damage, and dysregulated inflammasome activity has been implicated in a number of neurological conditions. This paper introduces the NLRP3 inflammasome and its implication in the pathogenesis of neuroinflammatory-related conditions, with a particular focus on TBI. Although its role in TBI has only recently been identified, findings suggest that priming and activation of the NLRP3 inflammasome are upregulated following TBI. Moreover, recent studies utilizing specific NLRP3 inhibitors have provided further evidence that this inflammasome is a major driver of neuroinflammation and neurobehavioral disturbances following TBI. In addition, there is emerging evidence that circulating inflammasome-associated proteins may have utility as diagnostic biomarkers of neuroinflammatory conditions, including TBI. Finally, novel and promising areas of research will be highlighted, including the potential involvement of the NLRP3 inflammasome in mild TBI, how factors such as biological sex may affect NLRP3 activity in TBI, and the use of emerging biomarker platforms. Taken together, this review highlights the exciting potential of the NLRP3 inflammasome as a target for treatments and biomarkers that may ultimately be used to improve TBI management. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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31. Vitamin D status in an Australian patient population: a large retrospective case series focusing on factors associated with variations in serum 25(OH)D.
- Author
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Fong Voo, Veronica Tsin, Stankovich, Jim, O’Brien, Terence J., Butzkueven, Helmut, and Monif, Mastura
- Abstract
Objectives To investigate whether sex, age, medical specialty and seasonal variations in serum concentration of 25-hydroxy vitamin D (25(OH)D) are evident among an Australian patient population. Design Retrospective study analysing the results of serum 25(OH)D lab tests and vitamin D supplementation from Royal Melbourne Hospital (RMH) between 2014 and 2017. Setting Tertiary healthcare centre in Victoria, Australia. Participants 30 023 patients (inpatient and outpatient) who had their serum 25(OH)D levels measured at RMH between 2014 and 2017. Main outcome measures Serum 25(OH)D levels stratified according to patients’ sex, age and medical specialty admitted to, as well as the season and year (2014 to 2017) 25(OH)D level was measured. Results Mean serum 25(OH)D level of study population was 69.9 nmol/L (95% CI 69.5 to 70.2). Only 40.2% patients in this cohort were sufficient in vitamin D (>75 nmol/L). On average, 25(OH)D levels in male patients were 6.1 units (95% CI 5.4 to 6.9) lower than in females. Linear regression analysis found that 25(OH)D levels increased by 0.16 unit (95% CI 0.14 to 0.18) for every year increase in age. One-way analysis of variance showed patients from neurology had the highest average 25(OH) D level, 76.8 nmol/L (95% CI 74.2 to 79.3) compared with other medical specialties. Mean 25(OH)D level during winter, 64.9 nmol/L (95% CI 64.2 to 65.6) was significantly lower compared with other seasons despite supplementation. Average 25(OH)D level measured in 2014, 71.5 nmol/L (95 CI% 70.8 to 72.2) was significantly higher than levels measured in 2016–2017. Conclusions There is a sex, age, medical specialty, seasonal and yearly variation in vitamin D status in an Australian patient population. The association between low vitamin D status and winter despite supplementation suggests other interventions are required to boost serum 25(OH)D levels. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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32. Cerebellar Ataxia Followed by Stiff Person Syndrome in a Patient with Anti-GAD Antibodies.
- Author
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Seneviratne, Sinali O., Buzzard, Katherine A., Cruse, Belinda, and Monif, Mastura
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CEREBELLAR ataxia ,GLUTAMATE decarboxylase ,IMMUNOGLOBULINS ,GABA ,ANTI-NMDA receptor encephalitis ,ANTIBODY formation - Abstract
Anti-GAD antibody syndrome is a result of the production of antibodies against glutamic acid decarboxylase (GAD), the main enzyme responsible for the production of gamma-aminobutyric acid (GABA). Several neurological manifestations including cerebellar ataxia and stiff person syndrome have been reported in association with anti-GAD antibodies. In this paper, we present a case of a young woman with anti-GAD antibodies who initially presented with cerebellar ataxia followed by stiff person syndrome three and a half years later. Having both cerebellar ataxia and stiff person syndrome is a rare occurrence in anti-GAD antibody syndrome. We emphasise the importance of long-term follow-up of patients with anti-GAD antibody syndrome, as delayed neurological manifestations can occur. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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33. Innate Immunity in the Central Nervous System: A Missing Piece of the Autoimmune Encephalitis Puzzle?
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Wesselingh, Robb, Butzkueven, Helmut, Buzzard, Katherine, Tarlinton, David, O'Brien, Terence J., and Monif, Mastura
- Subjects
CENTRAL nervous system ,NATURAL immunity ,ANTI-NMDA receptor encephalitis ,ENCEPHALITIS ,IMMUNE response ,BLOOD diseases - Abstract
The autoimmune encephalitides are a group of autoimmune conditions targeting the central nervous system and causing severe clinical symptoms including drug-resistant seizures, cognitive dysfunction and psychiatric disturbance. Although these disorders appear to be antibody mediated, the role of innate immune responses needs further clarification. Infiltrating monocytes and microglial proliferation at the site of pathology could contribute to the pathogenesis of the disease with resultant blood brain barrier dysfunction, and subsequent activation of adaptive immune response. Both innate and adaptive immune cells can produce pro-inflammatory molecules which can perpetuate ongoing neuroinflammation and drive ongoing seizure activity. Ultimately neurodegenerative changes can ensue with resultant long-term neurological sequelae that can impact on ongoing patient morbidity and quality of life, providing a potential target for future translational research. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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34. Editorial: Interactions of the Nervous System With Bacteria.
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Hill-Yardin, Elisa L., Grabrucker, Andreas M., Franks, Ashley E., Luna, Ruth Ann, and Monif, Mastura
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NERVOUS system ,EPILEPSY ,PSYCHONEUROIMMUNOLOGY ,THERAPEUTICS ,DISABILITIES ,NEUROLOGICAL disorders ,ENTERIC nervous system - Abstract
Microbes, gastrointestinal tract, enteric nervous system, brain, neurological disorders, neuroinflammation, diet, dysbiosis Alterations in the gut microbiota may affect gut-brain signaling via neuronal, endocrine and immunological mechanisms, thereby influencing a range of neuronal network activities and ultimately host behaviors. Overall, we propose that via leveraging our understanding of the gut-brain axis, the modulation of gut microbes leading to significant benefits for brain health can become a reality. Keywords: microbes; gastrointestinal tract; enteric nervous system; brain; neurological disorders; neuroinflammation; diet; dysbiosis EN microbes gastrointestinal tract enteric nervous system brain neurological disorders neuroinflammation diet dysbiosis N.PAG N.PAG 3 05/17/21 20210423 NES 210423 Recent evidence that microbes influence mood and behavior via the gut-brain axis has opened up new avenues for research into neurological disorders. [Extracted from the article]
- Published
- 2021
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35. MonoMac syndrome with associated neurological deficits and longitudinally extensive cord lesion.
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Monif, Mastura, Huq, Aamira, Chee, Lynette, and Kilpatrick, Trevor
- Abstract
We present a case of monocytopaenia and mycobacteria related infection (MonoMac) syndrome in a 30-year-old man of Indian origin. The clinical diagnosis of GATA2 haploinsufficiency was suspected after an unusual neurological presentation on a background of myelodysplastic syndrome and childhood pulmonary tuberculosis. The patient had a longitudinally extensive spinal cord lesion and a lesion in the medulla. No obvious infective cause for the spinal cord MrI abnormality was found, and the lesions were presumed to be inflammatory in nature. The family history consisted of autosomal dominant clinical features suggestive of GATA2 haploinsufficiency. Genetic testing in peripheral leucocytes revealed a pathogenic mutation in GATA2. this is the first-ever published case of possible MonoMac syndrome with a neurological presentation. The case highlights the rarity and complexity of the diagnosis and the clinical sequelae that ensued with the patient dying of gram-negative septicaemia while receiving intravenous steroid therapy for the spinal cord lesion. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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36. Interleukin-1β has trophic effects in microglia and its release is mediated by P2X7R pore.
- Author
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Monif, Mastura, Reid, Christopher A., Powell, Kim L., Drummond, Katherine J., O'Brien, Terrence J., and Williams, David A.
- Subjects
INTERLEUKIN-1 ,PURINERGIC receptors ,MICROGLIA ,ELECTRON microscopy ,IMMUNOHISTOCHEMISTRY ,NEURODEGENERATION ,NEOPLASTIC cell transformation ,CELL metabolism ,ANIMAL experimentation ,ANIMAL populations ,CELL culture ,CELL receptors ,CELLS ,HIPPOCAMPUS (Brain) ,NEURONS ,RATS - Abstract
Background: Enhanced expression of the purinergic P2X7 receptor (P2X7R) occurs in several neuroinflammatory conditions where increased microglial activation is a co-existing feature. P2X7 receptors can function either as a cation channel or, upon continued stimulation, a large pore. P2X7R-over-expression alone is sufficient to drive microglial activation and proliferation in a process that is P2X7R pore dependent, although the biological signaling pathway through which this occurs remains unclear. Once activated, microglia are known to release a number of bioactive substances that include the proinflammatory cytokine interleukin-1β (IL-1β). Previous studies have linked P2X7R stimulation to the processing and release of IL-1β, but whether the channel or pore state of P2X7R is predominant in driving IL-1β release is unknown and is a major aim of this study. In addition, we will determine whether IL-1β has trophic effects on surrounding microglia.Methods: Electron microscopy and immunohistochemistry were used to delineate the sub-cellular localization of P2X7R and IL-1β in primary hippocampal rat cultures. FM1-43 fluorescent dye and confocal microscopy were used to quantify vesicular exocytosis from microglia expressing the pore-forming P2X7R versus a non-pore-forming point mutant, P2X7RG345Y. IL-1β in culture was quantified with an enzyme-linked immunosorbent assay (ELISA). IL-1β intracellular processing was blocked with inhibition of caspase 1 (with a synthetic peptide antagonist), and its extracellular form was neutralized with an IL-1β neutralizing antibody. Microglial activation and proliferation was quantified immunohistochemically with confocal microscopy.Results: P2X7R and IL-1β were co-localized in lysosomes. Vesicular exocytosis was higher in microglia expressing the pore-forming P2X7R compared to those expressing the non-pore-forming mutant. There was increased IL-1β in cultures expressing the pore-forming P2X7R, and this proinflammatory cytokine was found to mediate the trophic effects of P2X7R pore in microglia. Inhibition of IL-1β production and function resulted in a significant decrease in P2X7R-mediated microglial activation and proliferation.Conclusions: IL-1β is a mediator of microglial activation and proliferation, and its release/production is P2X7R pore dependent. Blockade of P2X7R pore could serve as a therapeutic target in alleviating the degree of inflammation seen in neurodegenerative and neoplastic conditions. [ABSTRACT FROM AUTHOR]- Published
- 2016
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37. Compartmentalizing Genetically Encoded Calcium Sensors.
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Williams, David A., Monif, Mastura, and Richardson, Kate L.
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- 2013
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38. P2X7 receptors are a potential novel target for antiglioma therapies.
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Monif, Mastura, O'Brien, Terence J., Drummond, Kate J., Reid, Christopher A., Liubinas, Simon V., and Williams, David A.
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GLIOMA treatment ,CELL receptors ,IMMUNOHISTOCHEMISTRY ,PROTEIN expression ,MICROGLIA - Abstract
Background Human gliomas pose significant morbidity and mortality to those afflicted by them, and currently there are no curative treatment modalities available for these highly invasive tumours. Methods With the approval from the human ethics committee, patients diagnosed with brain tumour (glioma) were recruited for this study. At the time of surgical resection, freshly resected tumour as well as 'peri-tumour' tissue were taken directly from theatre to the laboratory and were successfully cultured. Confocal fluorescence microscopy techniques and immunohistochemistry were used for characterization of human glioma cultures. Dye uptake experiments and confocal microscopy were utilized for P2X7 receptor (P2X7R) pore activity. Results We reveal human glioma cultures to contain microglia in close association with glioma (tumour) cells. Both glioma cells and microglia were found to express the purinergic, ATP sensing, P2X7R. P2X7R protein expression was increased in microglia derived from tumour when compared to 'peri-tumour' tissue. The pore capacity of P2X7R in tumour-associated microglia was functional, as evidenced by dye uptake experiments. Importantly, inhibition of P2X7R with the synthetic antagonist, brilliant blue G (BBG) resulted in a significant decrease in the number of glioma cells in culture. Conclusions P2X7R was found to be over-expressed in grade IV human gliomas and its pore capacity was functional. Antagonism of P2X7R with BBG resulted in a decrease in tumour cell number. This identifies P2X7R as a promising therapeutic target to combat human glioma proliferation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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39. Mal de Meleda in Indonesia: Mutations in the SLURP1 gene appear to be ubiquitous.
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Taylor, Jessica A, Bondavalli, Davide, Monif, Mastura, Yap, Lee Mei, and Winship, Ingrid
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PALMOPLANTAR keratoderma ,GENETIC counseling - Abstract
Mal de Meleda is a rare autosomal recessive genodermatosis caused by mutations in the ARS B ( SLURP1) gene, with possible founder effects in the Mediterranean and Adriatic regions. We report an affected individual from Indonesia without known consanguinity in the family, suggesting that SLURP1 gene mutations are ubiquitous. Recognition of the phenotype can be confirmed by genetic testing, thus facilitating genetic counselling. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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40. The P2X7 Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X7R Pore.
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Monif, Mastura, Reid, Christopher A., Powell, Kim L., Smart, Megan L., and Williams, David A.
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NERVOUS system ,NEURONS ,MICROGLIA ,CELL membranes ,CELL proliferation - Abstract
Microglial activation is an integral part of neuroinflammation associated with many neurodegenerative conditions. Interestingly, a number of neurodegenerative conditions exhibit enhanced P2X
7 receptor (P2X7 R) expression in the neuroinflammatory foci where activated microglia are a coexisting feature. Whether P2X7 R overexpression is driving microglial activation or, conversely, P2X7 R overexpression is a consequence of microglial activation is not known. We report that overexpression alone of a purinergic P2X7 R, in the absence of pathological insults, is sufficient to drive the activation and proliferation of microglia in rat primary hippocampal cultures. The trophic responses observed in microglia were found to be P2X7 R specific as the P2X7 R antagonist, oxidized ATP (oxATP), was effective in markedly attenuating microgliosis. oxATP treatment of primary hippocampal cultures expressing exogenous P2X7 Rs resulted in a significant decrease in the number of activated microglia. P2X7 R is unusual in exhibiting two conductance states, a cation channel and a plasma membrane pore, and there are no pharmacological agents capable of cleanly discriminating between these two states. We used a point mutant of P2X7 R (P2X7RG345Y) with intact channel function but ablated pore-forming capacity to establish that the trophic effects of increased P2X7 R expression are exclusively mediated by the pore conductance. Collectively, and contrary to previous reports describing P2X7 R as a "death receptor," we provide evidence for a novel trophic role for P2X7 R pore in microglia. [ABSTRACT FROM AUTHOR]- Published
- 2009
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41. Vaccinations in patients with multiple sclerosis: review and recommendations.
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Nesbitt, Cassie, Rath, Louise, Zhong, Michael, Cheng, Allen C, Butzkueven, Helmut, Wesselingh, Robb, Skibina, Olga, Monif, Mastura, Yeh, Wei, Brotherton, Julia ML, Reddel, Stephen, and Van Der Walt, Anneke
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RUBELLA ,HEPATITIS B ,VACCINATION ,MULTIPLE sclerosis ,CENTRAL nervous system infections ,HERPES zoster vaccines - Abstract
Given a single-dose vaccine is protective for life, yellow fever vaccination could be offered before DMT commencement, especially if DMT initiation is delayed for other vaccinations. A small study of patients not on highly effective DMTs observed a significant increase in relapse rate following exposure to the yellow fever vaccine,11 although this was not corroborated in a recent case series.32 When yellow fever vaccination is essential, DMT cessation with a washout period is required. Keywords: Multiple sclerosis; Demyelinating diseases; Central nervous system infections; Vaccination EN Multiple sclerosis Demyelinating diseases Central nervous system infections Vaccination 350 350 1 05/04/21 20210501 NES 210501 In a new MS diagnosis, immunisation status may be overlooked - careful planning from early in the treatment course is key Multiple sclerosis (MS) is an autoimmune disorder treated with immunomodulatory or immunosuppressive disease-modifying therapies (DMTs). General vaccination considerations in patients with MS The immunisation status of patients should be considered at the time of MS diagnosis. [Extracted from the article]
- Published
- 2021
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42. Inhibition of purinergic P2X receptor 7 (P2X7R) decreases granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in U251 glioblastoma cells.
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Drill, Matthew, Powell, Kim L., Kan, Liyen Katrina, Jones, Nigel C., O'Brien, Terence J., Hamilton, John A., and Monif, Mastura
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GLIOBLASTOMA multiforme ,BRAIN cancer ,CANCER cell proliferation ,GRANULOCYTE-macrophage colony stimulating factor receptors ,IMMUNOCYTOCHEMISTRY ,CELL imaging ,CANCER cells - Abstract
Glioblastoma is the most aggressive form of primary brain cancer, with a median survival of 12–15 months. The P2X receptor 7 (P2X7R) is upregulated in glioblastoma and is associated with increased tumor cell proliferation. The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is also upregulated in glioblastoma and has been shown to have both pro- and anti-tumor functions. This study investigates the potential mechanism linking P2X7R and GM-CSF in the U251 glioblastoma cell line and the therapeutic potential of P2X7R antagonism in this setting. P2X7R protein and mRNA was demonstrated to be expressed in the U251 cell line as assessed by immunocytochemistry and qPCR. Its channel function was intact as demonstrated by live cell confocal imaging using a calcium indicator Fluo-4 AM. Inhibition of P2X7R using antagonist AZ10606120, decreased both GM-CSF mRNA (P < 0.05) and protein (P < 0.01) measured by qPCR and ELISA respectively. Neutralization of GM-CSF with an anti-GM-CSF antibody did not alter U251 cell proliferation, however, P2X7R antagonism with AZ10606120 significantly reduced U251 glioblastoma cell numbers (P < 0.01). This study describes a novel link between P2X7R activity and GM-CSF expression in a human glioblastoma cell line and highlights the potential therapeutic benefit of P2X7R inhibition with AZ10606120 in glioblastoma. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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43. Characterization of the human myelin oligodendrocyte glycoprotein antibody response in demyelination.
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Tea, Fiona, Lopez, Joseph A., Ramanathan, Sudarshini, Merheb, Vera, Lee, Fiona X. Z., Zou, Alicia, Pilli, Deepti, Patrick, Ellis, van der Walt, Anneke, Monif, Mastura, Tantsis, Esther M., Yiu, Eppie M., Vucic, Steve, Henderson, Andrew P. D., Fok, Anthony, Fraser, Clare L., Lechner-Scott, Jeanette, Reddel, Stephen W., Broadley, Simon, and Barnett, Michael H.
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MYELIN oligodendrocyte glycoprotein ,OLIGODENDROGLIA ,ANTIBODY formation ,CENTRAL nervous system ,DEMYELINATION ,CEREBROSPINAL fluid - Abstract
Over recent years, human autoantibodies targeting myelin oligodendrocyte glycoprotein (MOG Ab) have been associated with monophasic and relapsing central nervous system demyelination involving the optic nerves, spinal cord, and brain. While the clinical relevance of MOG Ab detection is becoming increasingly clear as therapeutic and prognostic differences from multiple sclerosis are acknowledged, an in-depth characterization of human MOG Ab is required to answer key challenges in patient diagnosis, treatment, and prognosis. Herein, we investigated the epitope, binding sensitivity, and affinity of MOG Ab in a cohort of 139 and 148 MOG antibody-seropositive children and adults (n = 287 patients at baseline, 130 longitudinal samples, and 22 cerebrospinal fluid samples). MOG extracellular domain was also immobilized to determine the affinity of MOG Ab. MOG Ab response was of immunoglobulin G1 isotype, and was of peripheral rather than intrathecal origin. High affinity MOG Ab were detected in 15% paediatric and 18% adult sera. More than 75% of paediatric and adult MOG Ab targeted a dominant extracellular antigenic region around Proline42. MOG Ab titers fluctuated over the progression of disease, but affinity and reactivity to Proline42 remained stable. Adults with a relapsing course intrinsically presented with a reduced immunoreactivity to Proline42 and had a more diverse MOG Ab response, a feature that may be harnessed for predicting relapse. Higher titers of MOG Ab were observed in more severe phenotypes and during active disease, supporting the pathogenic role of MOG Ab. Loss of MOG Ab seropositivity was observed upon conformational changes to MOG, and this greatly impacted the sensitivity of the detection of relapsing disorders, largely considered as more severe. Careful consideration of the binding characteristics of autoantigens should be taken into account when detecting disease-relevant autoantibodies. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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