Effects of High Efficacy Multiple Sclerosis Disease Modifying Drugs on the Immune Synapse: A Systematic Review.

BACKGROUND: Co-signaling and adhesion molecules are important elements for creating immune synapses between T lymphocytes and antigen-presenting cells; they positively or negatively regulate the interaction between a T cell receptor with its cognate antigen, presented by the major histocompatibility complex. OBJECTIVES: We conducted a systematic review on the effects of High Efficacy Disease Modifying Drugs (HEDMDs) for Multiple Sclerosis (MS) on the co-signaling and adhesion molecules that form the immune synapse. METHODS: We searched EMBASE, MEDLINE, and other sources to identify clinical or preclinical reports on the effects of HEDMDs on co-signaling and adhesion molecules that participate in the formation of immune synapses in patients with MS or other autoimmune disorders. We included reports on cladribine tablets, anti- CD20 monoclonal antibodies, S1P modulators, inhibitors of Bruton's Tyrosine Kinase, and natalizumab. RESULTS: In 56 eligible reports among 7340 total publications, limited relevant evidence was uncovered. Not all co-signaling and adhesion molecules have been studied in relation to every HEDMD, with more data being available on the anti-CD20 monoclonal antibodies (that affect CD80, CD86, GITR and TIGIT), cladribine tablets (affecting CD28, CD40, ICAM-1, LFA-1) and the S1P modulators (affecting CD86, ICAM-1 and LFA-1) and less on Natalizumab (affecting CD80, CD86, CD40, LFA-1, VLA-4) and Alemtuzumab (affecting GITR and CTLA-4). CONCLUSION: The puzzle of HEDMD effects on the immune synapse is far from complete. The available evidence suggests that distinguishing differences exist between drugs and are worth pursuing further.

Implantable Subcutaneous Peripheral Nerve Stimulation Improves Degenerative Ataxia.

Degenerative cerebellar ataxias have no pharmacological or rehabilitation evidence-based treatment so far. Patients remain highly symptomatic and disabled despite receiving the best medical treatment available. This study investigates the clinical and neurophysiologic outcomes of the use of subcutaneous cortex stimulation (in keeping with the established protocol of peripheral nerve stimulation applied in chronic intractable pain) in degenerative ataxia. We report a case of a 37-year-old right-handed man who developed moderate degenerative cerebellar ataxia at the age of 18 years. His symptoms progressively worsened and impaired his daily activities. We observed clinical improvement for at least one month following an initial two-week trial of parietal transcranial direct current stimulation. Although preoperative non-invasive transcranial neuromodulation application does not predict invasive cortex stimulation outcome, we pursued a long-lasting effect by implanting parietal and occipital subcutaneous electrodes. At 12 months following permanent implantation, the patient exhibited amelioration of his symptoms and a change in neurophysiologic parameters. Central neuromodulation based on peripheral stimulation is considered part of neurosurgical clinical practice for the treatment of a variety of neurological disorders. The underpinning neurophysiological mechanism that explains the effectiveness of the method has not been fully elucidated. We believe that further studies are warranted to investigate these promising results in such devastating conditions.

Seasonal adherence to, and effectiveness of, subcutaneous interferon ß-1a administered by RebiSmart® in patients with relapsing multiple sclerosis: results of the 1-year, observational GEPAT-SMART study.

BACKGROUND: Little is known about whether tolerability and adherence to treatment can be influenced by weather and temperature conditions. The objective of this study was to assess monthly and seasonal adherence to and safety of sc IFN-ß1a (Rebif®, Merck) in relapsing-remitting multiple sclerosis (RRMS) patients using the RebiSmart® electronic autoinjector. METHODS: A multicentre, prospective observational study in Greece in adult RRMS patients with EDSS < 6, under Rebif®/RebiSmart® treatment for ≤6 weeks before enrollment. The primary endpoint was monthly, seasonal and annual adherence over 12 months (defined in text). Secondary endpoints included number of relapses, disability, adverse events. RESULTS: Sixty four patients enrolled and 47 completed all study visits (Per Protocol Set - PPS). Mean annual adherence was 97.93% ± 5.704 with no significant monthly or seasonal variations. Mean relapses in the pre- and post- treatment 12-months were 1.1 ± 0.47 and 0.2 ± 0.54 (p < 0.0001, PPS). 10 patients (22%) showed 3-month disability progression, 19 (40%) stabilization and 18 (38%) improvement. EDSS was not correlated to pre- (r = 0.024, p = 0.87) or post-treatment relapses (r = 0.022, p = 0.88). CONCLUSION: High adherence with no significant seasonal or weather variation was observed over 12 months. While the efficacy on relapses was consistent with published studies, we could not identify a relationship between relapses and disability. TRIAL REGISTRATION: Greek registry of non-interventional clinical trials ID: 200136 , date of registration: February 18th, 2013.

Abnormal central motor conduction at the upper but not lower limbs correlates with severe cervical spondylosis: discussion of an unexpected observation.

INTRODUCTION: A novel pattern of transcranial magnetic stimulation (TMS) abnormalities in cervical spondylotic myelopathy (CSM) comprising abnormal central motor conduction time (CMCT) to the upper limbs and normal CMCT to the lower limbs was observed. CSM was more severe radiologically and tended to be more severe clinically when this pattern was encountered. CASE PRESENTATION: To further characterize this observation, 414 consecutive TMS evaluations of cervical spondylosis were reviewed. Those cases in which (a) CMCT was abnormal at the upper and (b) normal at the lower limbs and (c) a cervical spine magnetic resonance imaging (MRI) was available (ULabnormal group) were included for further analysis. Cases where CMCT was abnormal at the lower limbs only (LLabnormal) were used for comparison. MRI-measured sagittal and parasagittal diameters of the spinal canal at all intervertebral levels and cervical spinal cord T2 hyperintensities were compared between these groups. Four patients fulfilled all inclusion criteria in each group. In ULabnormal, all patients had T2 hyperintensities, compared to none in LLabnormal (P=0.004). The C6-7 right (6 mm±1.05 vs 8.48 mm±4.01, P=0.05) and left (6.58 mm±1.39 vs 9.17 mm±5.03, P=0.06) parasagittal spinal canal diameters tended to be smaller in ULabnormal. The modified Japanese Orthopaedic Association scale tended to be lower in ULabnormal (11.5±2.65 vs 15.75±0.96, P=0.13). DISCUSSION: CMCT abnormalities isolated to the upper limbs constitute a less frequent pattern of involvement, which may correlate with more severe CSM.

Hypothyroidism is a Risk Factor for New-Onset Diabetes: A Cohort Study.

OBJECTIVE: To identify risk factors for the development of statin-associated diabetes mellitus (DM). RESEARCH DESIGN AND METHODS: The study was conducted in two phases. Phase one involved high-throughput in silico processing of a large amount of biomedical data to identify risk factors for the development of statin-associated DM. In phase two, the most prominent risk factor identified was confirmed in an observational cohort study at Clalit, the largest health care organization in Israel. Time-dependent Poisson regression multivariable models were performed to assess rate ratios (RRs) with 95% CIs for DM occurrence. RESULTS: A total of 39,263 statin nonusers were matched by propensity score to 20,334 highly compliant statin initiators in 2004-2005 and followed until the end of 2010. Within 59,597 statin users and nonusers in a multivariable model, hypothyroidism and subclinical hypothyroidism carried an increased risk for DM (RR 1.53 [95% CI 1.31-1.79] and 1.75 [1.40-2.18], respectively). Hypothyroidism increased DM risk irrespective of statin treatment (RR 2.06 [1.42-2.99] and 1.66 [1.05-2.64] in statin users and nonusers, respectively). Subclinical hypothyroidism risk for DM was prominent only upon statin use (RR 1.94 [1.13-3.34] and 1.20 [0.52-2.75] in statin users and nonusers, respectively). Patients with hypothyroidism treated with thyroid hormone replacement therapy were not at increased risk for DM. CONCLUSIONS: Hypothyroidism is a risk factor for DM. Subclinical hypothyroidism-associated risk for DM is prominent only upon statin use. Identifying and treating hypothyroidism and subclinical hypothyroidism might reduce DM risk. Future clinical studies are needed to confirm the findings.

From depression to neurodegeneration and heart failure: re-examining the potential of MAO inhibitors.

Initially introduced in the 1950s for treating depression, monoamine oxidase (MAO) inhibitors were gradually abandoned, mainly owing to their potential for drug-drug and drug-food interactions, the most widely known being with tyramine-containing food (the 'cheese' effect). Since then, more selective MAO-A or MAO-B inhibitors have been developed with substantially reduced risks, and have been approved for the treatment of depression and Parkinson's disease, respectively. Recent research suggests that some of these drugs also have neuroprotective properties, while preclinical evidence expands the spectrum of potential indications to heart failure, renal diseases and multiple sclerosis. In this article, the authors review the relevance of MAO isoforms to disease, and they also outline current research and development efforts in this class of drugs, including newer multipotent compounds.

Drug repurposing and adverse event prediction using high-throughput literature analysis.

Drug repurposing is the process of using existing drugs in indications other than the ones they were originally designed for. It is an area of significant recent activity due to the mounting costs of traditional drug development and scarcity of new chemical entities brought to the market by bio-pharmaceutical companies. By selecting drugs that already satisfy basic toxicity, ADME and related criteria, drug repurposing promises to deliver significant value at reduced cost and in dramatically shorter time frames than is normally the case for the drug development process. The same process that results in drug repurposing can also be used for the prediction of adverse events of known or novel drugs. The analytics method is based on the description of the mechanism of action of a drug, which is then compared to the molecular mechanisms underlying all known adverse events. This review will focus on those approaches to drug repurposing and adverse event prediction that are based on the biomedical literature. Such approaches typically begin with an analysis of the literature and aim to reveal indirect relationships among seemingly unconnected biomedical entities such as genes, signaling pathways, physiological processes, and diseases. Networks of associations of these entities allow the uncovering of the molecular mechanisms underlying a disease, better understanding of the biological effects of a drug and the evaluation of its benefit/risk profile. In silico results can be tested in relevant cellular and animal models and, eventually, in clinical trials.

Localisation of cervical spinal cord compression by TMS and MRI.

The authors set out to study the role of transcranial magnetic stimulation (TMS) in the pre-surgical assessment of patients with cervical spondylotic myelopathy. Central motor conduction time (CMCT) was calculated in 50 patients and 50 controls by recording muscle evoked potentials from upper limb muscles. The level of spinal cord compression was determined according to the pattern of CMCT prolongation and compared with the level disclosed by MRI. Direct comparison of the TMS and MRI results was possible in 42 cases and agreement was noted in 25 (59.5%). In the 23 patients in whom the two methods did not give convergent findings, post-operative data were used in order to determine the actual level of compression. This level was correctly indicated by TMS in 87.5% of cases and by MRI in 12.5%. TMS is a neurophysiological tool that can complement existing methods for determining the level of cervical spinal cord compression.

Vestibular evoked myogenic potential eliciting in normal subjects: comparison of four different methods.

OBJECTIVE: Vestibular evoked myogenic potential (VEMP) recording is a new method for testing the otolith receptors and vestibulospinal pathways. The aim of this study was to evaluate the characteristics of VEMP using four different techniques to find reasons to prefer one type of recording over the others. MATERIAL AND METHODS: Twenty healthy persons, 10 males and 10 females with ages ranging from 20 to 57 years (mean age 41 years), were enrolled in this study. Eliciting of VEMPs by using monaural or binaural acoustic stimulation and unilateral or bilateral SCM contraction was evaluated; 105 dB NHL acoustic stimulation consisting of 145 dB rarefaction clicks was applied. Latencies of p13, n23, n34, p44 peaks; amplitudes p13-n23 and n34-p44; and interaural amplitude differences (IADs) were assessed. RESULTS: All four methods elicited constant and evident waveforms. The reliability coefficients of amplitudes were high for all four methods and for both waves. However, the higher scores of reliability appeared for the monaural-ipsilateral recording. The results indicated no statistically significant difference between the right and left sides for all four types of VEMP eliciting. No correlation was found between IAD13-23 and IAD34-44 for all four methods. Statistically significant differences were found only for n23 latency among the four methods. CONCLUSIONS: Although no evidence to reject or strongly favour a specific method was found, the monaural-ipsilateral recording was associated with some advantages.

On the calculation of transcallosal conduction time using transcranial magnetic stimulation.

Transcallosal conduction time (TCT), based on the results of transcranial magnetic stimulation studies, is currently calculated as a function of the ipsilateral silent period (iSP) and of the motor evoked potential (MEP) obtained from a target muscle (TCTcurrent = iSP latency - MEP latency). We argue that this measure overestimates TCT and may lead to a bias in statistical group comparisons. We propose an alternative measure, TCTproposed, which we defined as TCTproposed = iSP latency - cSP latency, where cSP is the contralateral silent period. We report our results on the comparison of the two measures in twenty healthy individuals and provide a theoretical basis for TCTproposed.