Erythrocytes in multiple sclerosis: forgotten contributors to the pathophysiology?

Multiple sclerosis (MS) is an autoimmune disease characterised by lymphocytic infiltration of the central nervous system and subsequent destruction of myelin and axons. On the background of a genetic predisposition to autoimmunity, environmental triggers are assumed to initiate the disease. The majority of MS research has focused on the pathological involvement of lymphocytes and other immune cells, yet a paucity of attention has been given to erythrocytes, which may play an important role in MS pathology. The following review briefly summarises how erythrocytes may contribute to MS pathology through impaired antioxidant capacity and altered haemorheological features. The effect of disease-modifying therapies on erythrocytes is also reviewed. It may be important to further investigate erythrocytes in MS, as this could broaden the understanding of the pathological mechanisms of the disease, as well as potentially lead to the discovery of novel and innovative targets for future therapies

The Australian multiple sclerosis (MS) immunotherapy study: A prospective, multicentre study of drug utilisation using the MSBase platform

To prospectively characterise treatment persistence and predictors of treatment discontinuation in an Australian relapsing-remitting multiple sclerosis (RRMS) population. Tertiary MS treatment centres participating in the MSBase registry prospectively assessed treatment utilisation, persistence, predictors of treatment discontinuation and switch rates. Multivariable survival analyses were used to compare treatment persistence between drugs and to identify predictors of treatment discontinuation. 1113 RRMS patients were studied. Patients persisted on their first disease-modifying therapy (DMT) for a median of 2.5 years. Treatment persistence on GA was shorter than on all IFNβ products (p<0.03). Younger age at treatment initiation and higher EDSS were predictive of DMT discontinuation. Patients persisted on subsequent DMTs, for 2.3 years. Patients receiving natalizumab (NAT) as a subsequent DMT persisted longer on treatment than those on IFNβ or GA (p<0.000). The primary reason for treatment discontinuation for any drug class was poor tolerability. Annualised switch or cessation rates were 9.5–12.5% for individual IFNβ products, 11.6% for GA and 4.4% for NAT. This multicentre MS cohort study is the first to directly compare treatment persistence on IFNβ and GA to NAT. We report that treatment persistence in our Australian RRMS population is short, although patients receiving IFNβ as a first DMT persisted longer on treatment than those on GA. Additionally, patients receiving NAT as a subsequent DMT were more likely to persist on treatment than those switched to IFNβ or GA. EDSS and age at DMT initiation were predictive of DMT discontinuation. Treatment intolerance was the principal reason for treatment cessation

Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season

Background

Modeling the Cumulative Genetic Risk for Multiple Sclerosis from Genome-Wide Association Data

Background: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. Methods: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. Results: In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years). Conclusions: The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics.Version of Recor

Food Security Monitoring and Evaluation in Rural Mali: Preliminary Findings

African Sky is a non-profit organization that has been continuously involved in community development efforts in the Sikasso, Koulikoro, and Segou regions of Mali since 2001. To inform these efforts, an assessment of survey and census data was conducted focusing on the rural village of Dissan, in the Sikasso region. During the evaluation period between 2001-2010 Dissan experienced highly variable rainfall. We hypothesized these conditions would negatively impact farming output, and as a result, nutritional status of the people living in Dissan. Our analysis shows that while land use did not change significantly, by household the variety of sorghum crops increased and non-sorghum food crops decreased. Farmers in Dissan are changing crop distribution due to an increased availability of new sorghum seed and in response to a variety of environmental factors

Evaluation of a synthetic single-crystal diamond detector for relative dosimetry on the Leksell Gamma Knife Perfexion radiosurgery system

Purpose: To evaluate the new commercial PTW-60019 synthetic single-crystal microDiamond detector (PTW, Freiburg, Germany) for relative dosimetry measurements on a clinical Leksell Gamma Knife Perfexion radiosurgery system. Methods: Detector output ratios (DORs) for 4 and 8 mm beams were measured using a micro- Diamond (PTW-60019), a stereotactic unshielded diode [IBA stereotactic field detector (SFD)], a shielded diode (IBA photon field detector), and GafChromic EBT3 films. Both parallel and transversal acquisition directions were considered for PTW-60019 measurements. Measured DORs were compared to the new output factor reference values for Gamma Knife Perfexion (0.814 and 0.900 for 4 and 8 mm, respectively). Profiles in the three directions were also measured for the 4 mm beam to evaluate full width at half maximum (FWHM) and penumbra and to compare them with the corresponding Leksell GammaPlan profiles. Results: FWHM and penumbra for PTW-60019 differed from the calculated values by less than 0.2 and 0.3 mm, for the parallel and transversal acquisitions, respectively. GafChromic films showed FWHM and penumbra within 0.1 mm. The output ratio obtained with the PTW-60019 for the 4 mm field was 1.6% greater in transverse direction compared to the nominal value. Comparable differences up to 0.8% and 1.0% for, respectively, GafChromic films and SFD were found. Conclusions: The microDiamond PTW-60019 is a suitable detector for commissioning and routine use of Gamma Knife with good agreement of both DORs and profiles in the three directions

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Comparative grading scales, statistical analyses, climber descriptors and ability grouping: International Rock Climbing Research Association position statement

The research base for rock climbing has expanded substantially in the past 3 decades as worldwide interest in the sport has grown. An important trigger for the increasing research attention has been the transition of the sport to a competitive as well as recreational activity and the potential inclusion of sport climbing in the Olympic schedule. The International Rock Climbing Research Association (IRCRA) was formed in 2011 to bring together climbers, coaches and researchers to share knowledge and promote collaboration. This position statement was developed during and after the 2nd IRCRA Congress which was held in Pontresina, in September 2014. The aim of the position statement is to bring greater uniformity to the descriptive and statistical methods used in reporting rock climbing research findings. To date there is a wide variation in the information provided by researchers regarding the climbers’ characteristics and also in the approaches employed to convert from climbing grading scales to a numeric scale suitable for statistical analysis. Our paper presents details of recommended standards of reporting that should be used for reporting climber characteristics and provides a universal scale for the conversion of climbing grades to a number system for statistical analysis