Publications by authors named "Suzanne Hodgkinson"

72 Publications

Effects of Pulsed Electric Field Processing and Sous Vide Cooking on Muscle Structure and In Vitro Protein Digestibility of Beef Brisket.

Foods 2021 Mar 1;10(3). Epub 2021 Mar 1.

Riddet Institute, Massey University, 4442 Palmerston North, New Zealand.

Pulsed electric fields (PEF) in conjunction with sous vide (SV) cooking has been explored for meat tenderisation. The aim of this experiment was to study the effect of PEF-SV treatment on the muscle structure and in vitro protein digestibility of beef brisket. Pulsed electric field treatment (specific energy of 99 ± 5 kJ/kg) was applied to bovine and muscles in combination with sous vide (SV) cooking (60 °C for 24 h). A similar micro- and ultrastructure was detected between the control SV-cooked and PEF-treated SV-cooked muscles. The combined PEF-SV treatment increased the in vitro protein digestibility of the muscles by approximately 29%, in terms of ninhydrin-reactive free amino nitrogen released at the end of simulated digestion. An increment in proteolysis of the PEF-treated SV-cooked meat proteins (e.g., myosin heavy chains and C-protein) during simulated digestion was also observed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. More damaged muscle micro- and ultrastructure was detected in PEF-treated SV-cooked muscles at the end of in vitro digestion, showing its enhanced digestive proteolysis compared to the control cooked meat.
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http://dx.doi.org/10.3390/foods10030512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001486PMC
March 2021

Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS.

Neurol Clin Pract 2020 Dec;10(6):510-519

Department of Neurology (AC), Inselspital, Bern University Hospital, University of Bern, Switzerland; Division of Neuroimmunology and Neurovirology (JR), University of Utah, Salt Lake City, UT; Brain Institute (JR), University of Utah, Salt Lake City, UT; Department of Neurology (JR), University of Utah, Salt Lake City, UT; Rocky Mountain Multiple Sclerosis Center at the University of Colorado (EA), Aurora, CO; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (AB-O), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Children's Hospital of Philadelphia (AB-O), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Central Clinical School (HB), Monash University, VIC, Australia; Mellen Center for Multiple Sclerosis Treatment and Research (RJF), Cleveland Clinic, OH; Department of Neurology (RG), St. Josef-Hospital, Ruhr University Bochum, Germany; South Shore Neurologic Association PC (MG), Patchogue, NY; Eastern Health MS Service (JH), Box Hill, VIC, Australia; Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital (TS), University of Melbourne, Parkville, VIC, Australia; Department of Neurology and Neurotherapeutics (KW), University of Texas Southwestern Medical Center, Multiple Sclerosis and Neuroimmunology Imaging Program, Clinical Center for Multiple Sclerosis, Dallas, TX; Department of Neuroscience (DF, PS), Neurology Unit, Azienda Ospedaliera Universitaria, Modena, Italy; Liverpool Hospital (SH), NSW, Australia; Department of Medicine (TK), CORe Unit, University of Melbourne, VIC, Australia; Department of Neurology (TK), Royal Melbourne Hospital, VIC, Australia; School of Medicine and Public Health (JL-S), University Newcastle, NSW, Australia; Department of Neurology (JL-S), John Hunter Hospital, Hunter New England Health, Newcastle, NSW, Australia; Department of Neurology (C. McGuigan), St. Vincent's University Hospital and University College, Dublin, Ireland; Envision Pharma Group (KS), Fairfield, CT; and Biogen (CC, SF, FW, C. Miller), Cambridge, MA.

Background: Delayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF.

Methods: Data sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation.

Results: The majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC ≥0.8 × 10/L was 2-4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC ≥0.91 × 10/L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation; rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for ≥3 years, lymphocyte reconstitution to ≥0.91 × 10/L was 12-18 months vs 2-3 months in patients with lymphopenia persisting <6 months.

Conclusions: The majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2-4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.
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http://dx.doi.org/10.1212/CPJ.0000000000000800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837440PMC
December 2020

Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.

Neurology 2021 02 28;96(5):e783-e797. Epub 2020 Dec 28.

From CORe (T.K., I.D., S.S., C.M.), Department of Medicine, University of Melbourne; MS Centre (T.K., I.D., S.S., C.M.), Department of Neurology, Royal Melbourne Hospital, Australia; Karolinska Institute (T.S.), Stockholm, Sweden; Department of Neuroscience (T.S., V.J., A.v.d.W., O.S., H.B.), Central Clinical School, Monash University, Melbourne; Burnet Institute (T.S.), Melbourne, Australia; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), General University Hospital and Charles University in Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Hospital Universitario Virgen Macarena (G.I.), Sevilla, Spain; Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University "G. d'Annunzio," Chieti; Department of Biomedical and Neuromotor Sciences (A.L.), University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Hopital Notre Dame (A.P., M.G., P.D.), Montreal; CHUM and Universite de Montreal (A.P., M.G., P.D.); CISSS Chaudière-Appalache (P.G.), Levis, Canada; Department of Neurology (V.J., A.v.d.W., O.S., H.B.), Alfred Hospital, Melbourne, Australia; Neuro Rive-Sud (F. Grand'Maison), Quebec, Canada; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Isfahan University of Medical Sciences (V.S.), Isfahan, Iran; Amiri Hospital (R. Alroughani), Kuwait City, Kuwait; Zuyderland Ziekenhuis (R.H.), Sittard, the Netherlands; Medical Faculty (M. Terzi), 19 Mayis University, Samsun; KTU Medical Faculty Farabi Hospital (C.B.), Karadeniz Technical University, Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; UOC Neurologia (E.P.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Brussels, Belgium; University of Parma (F. Granella); C. Mondino National Neurological Institute (R.B.), Pavia; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.S.), Italy; Flinders University (M. Slee), Adelaide; Westmead Hospital (S.V.), Sydney, Australia; Nemocnice Jihlava (R. Ampapa), Czech Republic; University of Queensland (P.M.), Brisbane; Royal Brisbane and Women's Hospital (P.M.), Brisbane, Australia; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; CSSS Saint-Jérôme (J.P.), Canada; Hospital Universitario Donostia (J.O.), Paseo de Begiristain, San Sebastián, Spain; Hospital Italiano (E.C.), Buenos Aires, Argentina; Brain and Mind Centre (M.B.), University of Sydney, Australia; INEBA-Institute of Neuroscience Buenos Aires (M.L.S.), Argentina; Hospital de Galdakao-Usansolo (J.L.S.-M.), Galdakao, Spain; Liverpool Hospital (S. Hodgkinson), Sydney, Australia; Jahn Ferenc Teaching Hospital (C.R.), Budapest, Hungary; Craigavon Area Hospital (S. Hughes), UK; Jewish General Hospital (F.M.), Montreal, Canada; Deakin University (C.S.), Geelong; Monash Medical Centre (E.B.), Melbourne, Australia; South East Trust (O.G.), Belfast, UK; Perron Institute (A.K.), University of Western Australia, Nedlands; Institute of Immunology and Infectious Diseases (A.K.), Murdoch University; Sir Charles Gairdner Hospital (A.K.), Perth, Australia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences (B.S.), Mumbai, India; St Vincents Hospital (N.S.), Fitzroy, Melbourne, Australia; Veszprém Megyei Csolnoky Ferenc Kórház zrt (I.P.), Veszprem, Hungary; Royal Hobart Hospital (B.T.), Australia; Semmelweis University Budapest (M. Simo), Hungary; Central Military Emergency University Hospital (C.-A.S.), Bucharest; Titu Maiorescu University (C.-A.S.), Bucharest, Romania; BAZ County Hospital (A.S.), Miskolc, Hungary; and Box Hill Hospital (H.B.), Melbourne, Australia.

Objective: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients.

Methods: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity.

Results: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, = 0.0016), worsening of disability (0.56, 0.38-0.82, = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, = 10) and worsening of disability (0.81, 0.67-0.99, = 0.043).

Conclusion: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term.

Classification Of Evidence: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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http://dx.doi.org/10.1212/WNL.0000000000011242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884998PMC
February 2021

Shockwave processing of beef brisket in conjunction with sous vide cooking: Effects on protein structural characteristics and muscle microstructure.

Food Chem 2021 May 28;343:128500. Epub 2020 Oct 28.

Riddet Institute, Massey University, Palmerston North 4442, New Zealand. Electronic address:

We studied the effect of shockwave processing and subsequent sous vide cooking on meat proteins (molecular size and thermal stability) and muscle structures (molecular, micro- and ultrastructure). Beef briskets were subjected to shockwave (11 kJ/pulse) and were sous vide-cooked at 60 °C for 12 h. Shockwave processing alone decreased the enthalpy and thermal denaturation temperature of the connective tissue proteins (second peak in the DSC thermogram, p < 0.05) compared to the control raw samples, while the protein gel electrophoresis profile remained unaffected. It led to disorganisation of the sarcomere structure and also modified the protein secondary structure. More severe muscle fibre coagulation and denaturation were observed in the shockwave-treated cooked meat compared to the cooked control. The results show that shockwave processing, with and without sous vide cooking, promotes structural changes in meat, and thus may have the potential to improve the organoleptic quality of the tough meat cuts.
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http://dx.doi.org/10.1016/j.foodchem.2020.128500DOI Listing
May 2021

Determination of True Ileal Amino Acid Digestibility in the Growing Pig for Calculation of Digestible Indispensable Amino Acid Score (DIAAS).

J Nutr 2020 10;150(10):2621-2623

Riddet Institute, Massey University, Palmerston North, New Zealand.

Digestible indispensable amino acid score (DIAAS) has been recommended by the FAO for the evaluation of protein quality in human foods, but the application of DIAAS is currently limited because of a lack of published data on the true ileal amino acid (AA) digestibility of AAs in foods. The importance of DIAAS is highlighted. To calculate DIAAS, it is necessary to determine the true ileal AA digestibility of human foods using the growing pig as an animal model for the human based on previous FAO recommendations. A method is described in detail in Supplemental Methods to determine the true ileal AA digestibility of foods for humans using the pig as a model for the adult human. Adoption of the method will enable consistency in the development of databases on predicted true ileal AA digestibility in human foods for the calculation of DIAAS.
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http://dx.doi.org/10.1093/jn/nxaa210DOI Listing
October 2020

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Front Neurol 2020 16;11:537. Epub 2020 Jun 16.

Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Southport, QLD, Australia.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis ( < 0.001) and area postrema relapses ( = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS ( < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January ( = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.
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http://dx.doi.org/10.3389/fneur.2020.00537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308484PMC
June 2020

Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy.

Mult Scler 2021 03 12;27(3):465-474. Epub 2020 Jun 12.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background/objective: Observational clinical data from cladribine-treated patients with relapsing forms of multiple sclerosis (MS) were recorded in the Australian MS registry powered by the MSBase registry platform (5-year follow-up) and analysed to complement information from the pivotal cladribine clinical trials in MS.

Methods: A cohort of 90 cladribine-treated patients with follow-up data reported by treating physicians and recorded in the Australian MSBase registry (database lock February 2016) were examined. Clinical data included Expanded Disability Status Scale (EDSS) scores, relapses and other disease-modifying drugs (DMDs) administered before and after cladribine treatment.

Results: Mean age on starting cladribine was 47 years; mean age at MS onset was 34 years, and median baseline EDSS score was 5.25. Disability trajectories in patients with sufficient follow-up suggested an overall increasing trend prior to cladribine treatment which was reduced during the 2-year post-treatment. Approximately 80% of patients were EDSS progression-free, 65% remained relapse-free after 2 years and median time to next DMD was 1.7 years.

Conclusion: These observational data suggest a disease-modifying effect in this cohort of relapsing MS patients characterised by older and more disabled patients. Since these data represent a single-arm cohort, clinical trials and larger comparative post-marketing studies are needed to validate and extend these findings.
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http://dx.doi.org/10.1177/1352458520921087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897790PMC
March 2021

Autoantigen specific IL-2 activated CD4CD25T regulatory cells inhibit induction of experimental autoimmune neuritis.

J Neuroimmunol 2020 04 3;341:577186. Epub 2020 Feb 3.

Immune Tolerance Laboratory, Faculty of Medicine, UNSW Sydney, Ingham Institute, Liverpool, NSW, Australia; Department of Nephrology, Liverpool Health Service, Liverpool, NSW, Australia. Electronic address:

Experimental autoimmune neuritis (EAN) induced by peripheral nerve myelin (PNM) is self-limiting and re-immunization with PNM does not re-activate disease. This study showed inhibition of EAN by CD4CD25T cells both from sensitized hosts or from naïve hosts after ex-vivo activation by PNM and rIL-2. Transfer of naïve CD4CD25T cells has no effect on EAN, nor did naïve CD4CD25T cells activated with rIL-2 and renal tubular antigen. Culture of naive CD4CD25Treg with rIL-2 and PNM induced mRNA for the IFN-gamma receptor. We showed naïve CD4CD25T cells activated by specific auto-antigen and rIL-2 produced more potent antigen-specific Treg that may have therapeutic potential.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577186DOI Listing
April 2020

The clinical profile of NMOSD in Australia and New Zealand.

J Neurol 2020 May 31;267(5):1431-1443. Epub 2020 Jan 31.

Menzies Health Institute Queensland, School of Medicine, Griffith University, Gold Coast Campus, Gold Coast, QLD, 4222, Australia.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.
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http://dx.doi.org/10.1007/s00415-020-09716-4DOI Listing
May 2020

Protein Quality Assessment of Follow-up Formula for Young Children and Ready-to-Use Therapeutic Foods: Recommendations by the FAO Expert Working Group in 2017.

J Nutr 2020 02;150(2):195-201

UMR PNCA (Research Unit for Nutrition Physiology and Ingestive Behavior), AgroParisTech, INRA (National Institute for Agricultural Research), Université Paris-Saclay, Paris, France.

The FAO of the UN convened an Expert Working Group meeting to provide recommendations related to protein quality evaluation of Follow-up Formula for Young Children (FUF-YC) and Ready-to-Use Therapeutic Foods (RUTFs). The protein and amino acid (AA) scoring patterns for the target age groups were defined and recommendations provided on the use of currently available protein and indispensable AA digestibility data. For FUF-YC, an age category of 1-2.9 y was identified, and a matching protein requirement of 0.86 g · kg-1 · d-1 with corresponding AA requirements were recommended. For RUTF, the protein requirement recommended was 2.82 g · kg-1 · d-1, to achieve a catch-up weight gain of 10 g · kg-1 · d-1 in children recovering from severe acute malnutrition. The AA requirements were factorially derived based on the adult protein requirement for maintenance and tissue AA composition. A flowchart was proposed for the best available methods to estimate digestibility coefficients (of either protein or AAs), in the following order: human, growing pig, and rat true ileal AA digestibility values. Where this is not possible, fecal protein digestibility values should be used. The Expert Working Group recommends the use of the Protein Digestibility Corrected Amino Acid Score (PDCAAS), with existing protein digestibility values, or the Digestible Indispensable Amino Acid Score provided that individual AA digestibility values are available for protein quality evaluation using the latter score. The Group also recommends the use of ileal digestibility of protein or of AAs for plant-based protein sources, recognizing the possible effects of antinutritional factors and impaired gut function. A PDCAAS score of ≥90% can be considered adequate for these formulations, whereas with a score <90%, the quantity of protein should be increased to meet the requirements. Regardless of the protein quality score, the ability of formulations to support growth in the target population should be evaluated. Future research recommendations are also proposed based on the knowledge gaps identified.
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http://dx.doi.org/10.1093/jn/nxz250DOI Listing
February 2020

Alloactivation of Naïve CD4CD8CD25T Regulatory Cells: Expression of CD8α Identifies Potent Suppressor Cells That Can Promote Transplant Tolerance Induction.

Front Immunol 2019 14;10:2397. Epub 2019 Oct 14.

Immune Tolerance Laboratory, South Western Clinical School of Medicine, UNSW Sydney and Ingham Institute, Liverpool Hospital, Liverpool, NSW, Australia.

Therapy with alloantigen-specific CD4CD25 T regulatory cells (Treg) for induction of transplant tolerance is desirable, as naïve thymic Treg (tTreg) are not alloantigen-specific and are weak suppressor cells. Naïve tTreg from DA rats cultured with fully allogeneic PVG stimulator cells in the presence of rIL-2 express IFN-gamma receptor (IFNGR) and IL-12 receptor beta2 (IL-12Rβ2) and are more potent alloantigen-specific regulators that we call Ts1 cells. This study examined additional markers that could identify the activated alloantigen-specific Treg as a subpopulation within the CD4CD25Foxp3Treg. After culture of naïve DA CD4CD8CD25T cells with rIL-2 and PVG alloantigen, or rIL-2 without alloantigen, CD8α was expressed on 10-20% and CD8β on <5% of these cells. These cells expressed and . CD8α cells had increased that characterizes Ts1 cells as well was , a transcription factor induced by TCR activation. Proliferation induced by re-culture with rIL-12 and alloantigen was greater with CD4CD8αCD25Treg consistent with the CD8α cells expressing IL-12R. In MLC, the CD8α fraction suppressed responses against allogeneic stimulators more than the mixed Ts1 population, whereas the CD4CD8CD25T cells were less potent. In an adoptive transfer assay, rIL-2 and alloantigen activated Treg suppress rejection at a ratio of 1:10 with naïve effector cells, whereas alloantigen and rIL-2 activated tTreg depleted of the CD8α cells were much less effective. This study demonstrated that expression of CD8α by rIL-2 and alloantigen activation of CD4CD8CD25Foxp3T cells was a marker of activated and potent Treg that included alloantigen-specific Treg.
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http://dx.doi.org/10.3389/fimmu.2019.02397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802415PMC
October 2020

Risk of secondary progressive multiple sclerosis: A longitudinal study.

Mult Scler 2020 01 9;26(1):79-90. Epub 2019 Aug 9.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia/L4 Centre, Melbourne Brain Centre at Royal Melbourne Hospital, Parkville, VIC, Australia.

Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested.

Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis.

Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed.

Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02,  < 0.001), longer disease duration (HR = 1.01,  = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30,  < 0.001), more rapid disability trajectory (HR = 2.82,  < 0.001) and greater number of relapses in the previous year (HR = 1.07,  = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62,  = 0.039) and disease-modifying therapy exposure (HR = 0.71,  = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion.

Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.
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http://dx.doi.org/10.1177/1352458519868990DOI Listing
January 2020

Trends in acute stroke presentations to an emergency department: implications for specific communities in accessing acute stroke care services.

Postgrad Med J 2019 May 16;95(1123):258-264. Epub 2019 May 16.

Department of Neurology and Neurophysiology, Liverpool Hospital, Sydney, New South Wales, Australia.

Background And Purpose: South Western Sydney comprises of a culturally and linguistically diverse (CALD) and lower socioeconomic status population group within the state of New South Wales. Geographic location and sociodemographic factors play important roles in access to healthcare and may be crucial in the success of time-critical acute stroke intervention. The aim of this study was to examine the trends in the delayed presentation to emergency department (ED) and identify factors associated with prehospital delay for an acute stroke/transient ischaemic attack (TIA) at a comprehensive stroke centre.

Methods: Patient health-related data were extracted for stroke/TIA discharges for the period 2009-2017. Electronic medical record data were used to determine sociodemographic characteristics and prehospital factors, and their associations with delayed presentation≥4.5 hours from stroke onset were studied.

Results: During the 9-year period, population-adjusted stroke/TIA discharge rates increased from 540 to 676 per 100 000. A significant reduction in the proportion of patients presenting to ED<4.5 hours (56% in 2009 versus 46% in 2017, p<0.001) was observed. Younger patients aged 55-64 and 65-74 years, those belonging to Polynesia, South Asia and Mainland Southeast Asia, and those not using state ambulance as the mode of arrival to the hospital were at increased risk of prehospital delay.

Conclusions: Comprehensive reappraisal of educational programmes for early stroke recognition is required in our region due to delayed ED presentations of younger and specific CALD communities of stroke/TIA patients.
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http://dx.doi.org/10.1136/postgradmedj-2019-136413DOI Listing
May 2019

Clot Histopathology in Ischemic Stroke with Infective Endocarditis.

Can J Neurol Sci 2019 05 14;46(3):331-336. Epub 2019 Mar 14.

Department of Neurology & Neurophysiology,Liverpool Hospital,Sydney, NSW,Australia.

Background: Endovascular thrombectomy (EVT) has shown efficacy in acute ischemic stroke (AIS) patients with infective endocarditis (IE). The possibility to undertake advanced histopathological clot analysis following EVT offers a new avenue to establish the etiological basis of the stroke - which is often labelled "cryptogenic." In this paper, we present our findings from four consecutive patients with IE who underwent EVT following an AIS at our tertiary referral comprehensive stroke centre.

Methods: Comprehensive histopathological analysis of clot retrieved after EVT, including morphology, was undertaken.

Results: The consistent observation was the presence of dense paucicellular fibrinoid material mixed/interspersed with clusters of bacterial cocci. This clot morphology may be specific to septic embolus due to IE unlike incidental bacteraemia and could possibly explain the refractoriness of such clots to systemic thrombolysis.

Conclusion: Detailed morphological and histopathological analysis of EVT-retrieved clots including Gram staining can assist in etiological classification of the clot. Understanding the composition of the clot may be of clinical value in early diagnostics and mapping treatment planning in IE.
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http://dx.doi.org/10.1017/cjn.2019.8DOI Listing
May 2019

Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis.

J Neurol Neurosurg Psychiatry 2019 04 13;90(4):458-468. Epub 2019 Jan 13.

Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Objective: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.

Methods: We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).

Results: The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).

Conclusion: The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
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http://dx.doi.org/10.1136/jnnp-2018-319831DOI Listing
April 2019

Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study.

Mult Scler Relat Disord 2019 Feb 3;28:235-243. Epub 2019 Jan 3.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia; Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Australia. Electronic address:

Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing.

Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS.

Methods: We identified all women with RRMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed.

Results: Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births.

Conclusions: We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month.
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http://dx.doi.org/10.1016/j.msard.2019.01.003DOI Listing
February 2019

Cooking Conditions Affect the True Ileal Digestible Amino Acid Content and Digestible Indispensable Amino Acid Score (DIAAS) of Bovine Meat as Determined in Pigs.

J Nutr 2018 10;148(10):1564-1569

Riddet Institute, Massey University, Palmerston North, New Zealand.

Background: Cooking processes affect the physical, chemical, and structural properties of meat proteins. Cooking may also affect the protein quality of meat, as indicated by the true ileal digestibility of individual amino acids, the content of each truly digestible amino acid, and the digestible indispensable amino acid score (DIAAS).

Objective: The study aimed to determine the effect of the cooking process (raw, not cooked; boiled; grilled; pan-fried; roasted) of beef on true (standardized) ileal amino acid digestibility, true ileal digestible amino acid content, and DIAAS.

Methods: Beef topside steak was subjected to one of the following conditions: raw, boiled, grilled, pan-fried, or roasted, followed by mincing. The growing pig was used as an animal model for the adult human. Diets containing the raw or cooked meats (10% crude protein content) were fed to growing pigs (n = 6 per diet; mean ± SEM bodyweight, 23.6 ± 0.48 kg) and samples of terminal ileal digesta were collected under anesthesia. True ileal amino acid digestibility of the beef was determined and DIAAS values were calculated.

Results: There were only minor differences in true ileal amino acid digestibility across cooking conditions with all amino acids having true ileal amino acid digestibility in the range of 90-100%. In general, boiled meat had the highest true ileal digestible amino acid content (total of 724 g/kg dry matter), and roasted meat the lowest (total of 641 g/kg dry matter; P < 0.001). The DIAAS was greater (P < 0.001) for the raw, boiled, and pan-fried meat treatments (97-99%) than for roasted meat (91%) or grilled meat (80%). The high DIAAS (range 80-99%) across cooking conditions confirms that bovine meat is a high-quality protein source.

Conclusion: Cooking conditions affect the true ileal digestible amino acid content and DIAAS of beef, as determined with the use of the pig model.
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http://dx.doi.org/10.1093/jn/nxy153DOI Listing
October 2018

Predictors of relapse and disability progression in MS patients who discontinue disease-modifying therapy.

J Neurol Sci 2018 08 2;391:72-76. Epub 2018 Jun 2.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, VIC, Australia; Box Hill Hospital, Melbourne, VIC, Australia.

Background: Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of 'post-DMT' relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs.

Materials/methods: Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age ≥ 18 at index DMT start; ≥12 months on index DMT prior to discontinuation; ≥24 months of follow-up post-discontinuation; did not restart DMT for ≥6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for ≥1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation.

Results: 4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNβ preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) - fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP.

Conclusions: Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.
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http://dx.doi.org/10.1016/j.jns.2018.06.001DOI Listing
August 2018

Factors Associated with Stroke Misdiagnosis in the Emergency Department: A Retrospective Case-Control Study.

Neuroepidemiology 2018 9;51(3-4):123-127. Epub 2018 Aug 9.

Department of Neurology and Neurophysiology, Liverpool Hospital, Sydney, New South Wales,

Background: Failure to recognise acute stroke may result in worse outcomes due to missed opportunity for acute stroke therapies. Our study examines factors associated with stroke misdiagnosis in patients admitted to a large comprehensive stroke centre.

Methods: Retrospective review comparing 156 consecutive stroke patients misdiagnosed in emergency department (ED) with 156 randomly selected stroke controls matched for age, gender, language spoken and stroke subtype for the period 2014-2016.

Results: There were 141 ischemic and 15 hemorrhagic misdiagnosed strokes (median age: 77 years, male:female = 1.3: 1). Symptom resolution, altered mental status, nausea/vomiting, dizziness and vertigo favored misdiagnosis (p < 0.05). Hemiparesis and dysarthria favored an accurate diagnosis (p < 0.05). Misdiagnosed patients were more commonly triaged into a lower ED category (62 vs. 42%, p = 0.001), clinically assessed as Face, Arm, Speech and Time (FAST) - negative (78 vs. 22%, p < 0.001) and underwent delayed CT imaging (median 4.1 vs. 1.5 h, p < 0.001). Misdiagnosed patients were more likely to have posterior circulation stroke (PCS; 39 vs. 22%, p = 0.01) and be admitted under non-neurological services (35 vs. 11%, p < 0.001) with worse discharge outcomes including increased mortality.

Conclusions: Patients with stroke misdiagnosis were commonly FAST-negative with nonspecific symptoms including altered mental status, dizziness and nausea/vomiting often associated with PCS. Improved diagnostic accuracy may increase access to acute therapies.
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http://dx.doi.org/10.1159/000491635DOI Listing
September 2019

Interleukin-5 Mediates Parasite-Induced Protection against Experimental Autoimmune Encephalomyelitis: Association with Induction of Antigen-Specific CD4CD25 T Regulatory Cells.

Front Immunol 2017 1;8:1453. Epub 2017 Nov 1.

Immune Tolerance Laboratory, UNSW Australia, Department of Neurology, Liverpool Hospital, Sydney, NSW, Australia.

Objective: To examine if the protective effect of parasite infection on experimental autoimmune encephalomyelitis (EAE) was due to interleukin (IL)-5, a cytokine produced by a type-2 response that induces eosinophilia. We hypothesize that, in parasite infections, IL-5 also promotes expansion of antigen-specific T regulatory cells that control autoimmunity.

Methods: larvae were used to infect Lewis rats prior to induction of EAE by myelin basic protein. Animals were sham treated, or given blocking monoclonal antibodies to interleukin 4 or 5 or to deplete CD25 T cells. Reactivity of CD4CD25 T regulatory cells from these animals was examined.

Results: Parasite-infected hosts had reduced severity and length of EAE. The beneficial effect of parasitic infection was abolished with an anti-IL-5 or an anti-CD25 monoclonal antibody (mAb), but not anti-IL-4 mAb. Parasite-infected animals with EAE developed antigen-specific CD4CD25 T regulatory cells earlier than EAE controls and these expressed more than controls. Treatment with IL-5 also reduced the severity of EAE and induced expressing CD4CD25 T regulatory cells.

Interpretation: The results of this study suggested that IL-5 produced by the type-2 inflammatory response to parasite infection promoted induction of autoantigen-specific CD25 T regulatory cells that reduced the severity of autoimmunity. Such a mechanism may explain the protective effect of parasite infection in patients with multiple sclerosis where eosinophilia is induced by IL-5, produced by the immune response to parasites.
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http://dx.doi.org/10.3389/fimmu.2017.01453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671975PMC
November 2017

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Brain 2017 Sep;140(9):2426-2443

Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
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http://dx.doi.org/10.1093/brain/awx185DOI Listing
September 2017

Changes in Reactivity of CD4CD25 and CD4CD25 T Cell Subsets in Transplant Tolerance.

Front Immunol 2017 22;8:994. Epub 2017 Aug 22.

Immune Tolerance Laboratory, Department of Medicine, Ingham Institute, University of New South Wales, Liverpool Hospital, Liverpool, NSW, Australia.

Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4CD25 T cells, yet in many models, proliferation of CD4 T cells from hosts tolerant to specific-alloantigen is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4, CD4CD25, and CD4CD25 T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naïve DA rats were examined. Proliferation of CD4 T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells. In mixed lymphocyte culture to PVG, proliferation of naïve CD4CD25 T cells was greater than naïve CD4 T cells. In contrast, proliferation of CD4CD25 T cells from tolerant hosts to specific-donor PVG was not greater than CD4 T cells, whereas their response to Lewis and self-DA was greater than CD4 T cells. Paradoxically, CD4CD25 T cells from tolerant hosts did not proliferate to PVG, but did to Lewis, whereas naïve CD4CD25 T cells proliferate to both PVG and Lewis but not to self-DA. CD4CD25 T cells from tolerant, but not naïve hosts, expressed receptors for interferon (IFN)-γ and IL-5 and these cytokines promoted their proliferation to specific-alloantigen PVG but not to Lewis or self-DA. We identified several differences in the patterns of proliferation to specific-donor alloantigen between cells from tolerant and naïve hosts. Most relevant is that CD4CD25 T cells from tolerant hosts failed to proliferate or suppress to specific donor in the absence of either IFN-γ or IL-5. The proliferation to third-party and self of each cell population from tolerant and naïve hosts was similar and not affected by IFN-γ or IL-5. Our findings suggest CD4CD25 T cells that mediate transplant tolerance depend on IFN-γ or IL-5 from alloactivated Th1 and Th2 cells.
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http://dx.doi.org/10.3389/fimmu.2017.00994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572370PMC
August 2017

Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis.

Mult Scler 2018 10 31;24(12):1617-1626. Epub 2017 Aug 31.

Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia/Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia/Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia.

Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab.

Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and ⩾1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1 year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed.

Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon ( p = 0.05), similar to fingolimod ( p = 0.31) and higher than on natalizumab ( p = 0.042). The probability of disability accumulation on cladribine was similar to interferon ( p = 0.37) and fingolimod ( p = 0.089) but greater than natalizumab ( p = 0.021). The probability of disability improvement was higher on cladribine than interferon ( p = 0.00017), fingolimod ( p = 0.0025) or natalizumab ( p = 0.00099). Sensitivity analyses largely confirmed the above results.

Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon β and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab.
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http://dx.doi.org/10.1177/1352458517728812DOI Listing
October 2018

Tumefactive lesions in retinal vasculopathy with cerebral leucoencephalopathy and systemic manifestations (RVCL-S): a role for neuroinflammation?

J Neurol Neurosurg Psychiatry 2017 Aug 9. Epub 2017 Aug 9.

Department of Neurology, Liverpool Hospital, University of NSW, Liverpool, New South Wales, Australia.

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http://dx.doi.org/10.1136/jnnp-2017-316142DOI Listing
August 2017

A Brain-Derived Neurotrophic Factor-Based p75 Peptide Mimetic Ameliorates Experimental Autoimmune Neuritis Induced Axonal Pathology and Demyelination.

eNeuro 2017 May-Jun;4(3). Epub 2017 Jul 4.

Department of Anatomy and Neuroscience, The University of Melbourne, VIC 3010, Australia.

Axonal damage and demyelination are major determinants of disability in patients with peripheral demyelinating neuropathies. The neurotrophin family of growth factors are essential for the normal development and myelination of the peripheral nervous system (PNS), and as such are potential therapeutic candidates for ameliorating axonal and myelin damage. In particular, BDNF promotes peripheral nerve myelination via p75 neurotrophin receptor (p75) receptors. Here, we investigated the therapeutic efficacy of a small structural mimetic of the region of BDNF that binds to p75 (cyclo-dPAKKR) in experimental autoimmune neuritis (EAN), an established animal model of peripheral demyelinating neuropathy. Examination of rodents induced with EAN revealed that p75 is abundantly expressed in affected peripheral nerves. We found that systemic administration of cyclo-dPAKKR ameliorates EAN disease severity and accelerates recovery. Animals treated with cyclo-dPAKKR displayed significantly better motor performance compared to control animals. Histological assessment revealed that cyclo-dPAKKR administration limits the extent of inflammatory demyelination and axonal damage, and protects against the disruption of nodal architecture in affected peripheral nerves. In contrast, a structural control peptide of cyclo-dPAKKR exerted no influence. Moreover, all the beneficial effects of cyclo-dPAKKR in EAN are abrogated in p75 heterozygous mice, strongly suggesting a p75-dependent effect. Taken together, our data demonstrate that cyclo-dPAKKR ameliorates functional and pathological defects of EAN in a p75-dependant manner, suggesting that p75 is a therapeutic target to consider for future treatment of peripheral demyelinating diseases and targeting of p75 is a strategy worthy of further investigation.
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http://dx.doi.org/10.1523/ENEURO.0142-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496185PMC
September 2018

Cytokines affecting CD4T regulatory cells in transplant tolerance. III. Interleukin-5 (IL-5) promotes survival of alloantigen-specific CD4 T regulatory cells.

Transpl Immunol 2017 08 23;43-44:33-41. Epub 2017 Jun 23.

Immune Tolerance Group, Faculty of Medicine, University of New South Wales Australia, Sydney, NSW, Australia; Ingham Institute, Liverpool, NSW, Australia.

CD4T cells mediate antigen-specific allograft tolerance, but die in culture without activated lymphocyte derived cytokines. Supplementation of the media with cytokine rich supernatant, from ConA activated spleen cells, preserves the capacity of tolerant cells to transfer tolerance and suppress rejection. rIL-2 or rIL-4 alone are insufficient to maintain these cells, however. We observed that activation of naïve CD4CD25FOXP3Treg with alloantigen and the Th2 cytokine rIL-4 induces them to express interleukin-5 specific receptor alpha (IL-5Rα) suggesting that IL-5, a Th2 cytokine that is produced later in the immune response may promote tolerance mediating Treg. This study examined if recombinant IL-5(rIL-5) promoted survival of tolerant CD4, especially CD4CD25T cells. CD4T cells, from DA rats tolerant to fully allogeneic PVG heart allografts surviving over 100days without on-going immunosuppression, were cultured with PVG alloantigen and rIL-5. The ability of these cells to adoptively transfer tolerance to specific-donor allograft and suppress normal CD4T cell mediated rejection in adoptive DA hosts was examined. Tolerant CD4CD25T cells' response to rIL-5 and expression of IL-5Rα was also assessed. rIL-5 was sufficient to promote transplant tolerance mediating CD4T cells' survival in culture with specific-donor alloantigen. Tolerant CD4T cells cultured with rIL-5 retained the capacity to transfer alloantigen-specific tolerance and inhibited naïve CD4T cells' capacity to effect specific-donor graft rejection. rIL-5 promoted tolerant CD4CD25T cells' proliferation in vitro when stimulated with specific-donor but not third-party stimulator cells. Tolerant CD4CD25T cells expressed IL-5Rα. This study demonstrated that IL-5 promoted the survival of alloantigen-specific CD4CD25T cells that mediate transplant tolerance.
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http://dx.doi.org/10.1016/j.trim.2017.06.003DOI Listing
August 2017

Incidence and prevalence of NMOSD in Australia and New Zealand.

J Neurol Neurosurg Psychiatry 2017 08 26;88(8):632-638. Epub 2017 May 26.

School of Medicine, Griffith University, Gold Coast, Australia.

Objectives: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry.

Background: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established.

Methods: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases.

Results: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD.

Conclusions: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.
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http://dx.doi.org/10.1136/jnnp-2016-314839DOI Listing
August 2017

Cytokines affecting CD4T regulatory cells in transplant tolerance. II. Interferon gamma (IFN-γ) promotes survival of alloantigen-specific CD4T regulatory cells.

Transpl Immunol 2017 06 6;42:24-33. Epub 2017 May 6.

Immune Tolerance Group, Faculty of Medicine, UNSW Australia, Sydney and Ingham Institute Liverpool Hospital, NSW, Australia. Electronic address:

CD4T cells that transfer alloantigen-specific transplant tolerance are short lived in culture unless stimulated with specific-donor alloantigen and lymphocyte derived cytokines. Here, we examined if IFN-γ maintained survival of tolerance transferring CD4T cells. Alloantigen-specific transplant tolerance was induced in DA rats with heterotopic adult PVG heart allografts by a short course of immunosuppression and these grafts functioned for >100days with no further immunosuppression. In previous studies, we found the CD4T cells from tolerant rats that transfer tolerance to an irradiated DA host grafted with a PVG heart, lose their tolerance transferring ability after 3days of culture, either with or without donor alloantigen, and effect rejection of specific-donor grafts. If cultures with specific-donor alloantigen are supplemented by supernatant from ConA activated lymphocytes the tolerance transferring cells survive, suggesting these cells depend on cytokines for their survival. In this study, we found addition of rIFN-γ to MLC with specific-donor alloantigen maintained the capacity of tolerant CD4T cells to transfer alloantigen-specific tolerance and their ability to suppress PVG allograft rejection mediated by co-administered naïve CD4T cells. IFN-γ suppressed the in vitro proliferation of tolerant CD4T cells. Tolerant CD4CD25T cells did not proliferate in MLC to PVG stimulator cells with no cytokine added, but did when IFN-γ was present. IFN-γ did not alter proliferation of tolerant CD4CD25T cells to third-party Lewis. Tolerant CD4CD25T cells' expression of IFN-γ receptor (IFNGR) was maintained in culture when IFN-γ was present. This study suggested that IFN-γ maintained tolerance mediating alloantigen-specific CD4CD25T cells.
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http://dx.doi.org/10.1016/j.trim.2017.05.002DOI Listing
June 2017

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study.

Lancet Neurol 2017 04 11;16(4):271-281. Epub 2017 Feb 11.

Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Background: Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years.

Methods: In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models.

Findings: Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006).

Interpretation: Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles.

Funding: National Health and Medical Research Council, and the University of Melbourne.
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http://dx.doi.org/10.1016/S1474-4422(17)30007-8DOI Listing
April 2017

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis.

J Neurol Neurosurg Psychiatry 2016 Dec 3;87(12):1343-1349. Epub 2016 Nov 3.

Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

Background: Age at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on the aetiology of this complex disease, and have applications in the diagnostic process.

Methods: The study cohort of 22 162 eligible patients from 21 countries was extracted from the MSBase registry. Only patients with MS aged ≥16 years were included. To reduce heterogeneity, only centres of largely European descent were included for analysis. AAO was defined as the year of the first symptom suggestive of inflammatory central nervous system demyelination. Predictors of AAO were evaluated by linear regression.

Results: Compared with those living in lower latitudes (19.0-39.9°), onset of symptoms was 1.9 years earlier for those at higher latitudes (50.0-56.0°) (p=3.83×10). A reciprocal relationship was seen for ambient ultraviolet radiation (UVR), with a significantly increasing AAO for patients with MS per each quartile increment of ambient UVR (p=1.56×10). We found that the AAO of female patients was ∼5 months earlier than male patients (p=0.002). AAO of progressive-onset patients with MS were ∼9 years later than relapsing-onset patients (p=1.40×10).

Conclusions: An earlier AAO in higher latitude regions was found in this worldwide European-descent cohort and correlated inversely with variation in latitudinal UVR. These results suggest that environmental factors which act at the population level may significantly influence disease severity characteristics in genetically susceptible populations.
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http://dx.doi.org/10.1136/jnnp-2016-314013DOI Listing
December 2016