Transcriptional Dysregulation in Huntington's Disease: The Role in Pathogenesis and Potency for Pharmacological Targeting.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene that encodes a critical cell regulatory protein, huntingtin (Htt). The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats causes improper folding of functional proteins and is an initial trigger of pathological changes in the brain. Recent research has indicated that the functional dysregulation of many transcription factors underlies the neurodegenerative processes that accompany HD. These disturbances are caused not only by the loss of wild-type Htt (WT Htt) function but also by the occurrence of abnormalities that result from the action of mutant Htt (mHtt). In this review, we aim to describe the role of transcription factors that are currently thought to be strongly associated with HD pathogenesis, namely, RE1-silencing transcription factor, also known as neuron-restrictive silencer factor (REST/NRSF), forkhead box proteins (FOXPs), peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1α), heat shock transcription factor 1 (HSF1), and nuclear factor κ light-chain-enhancer of activated B cells (NF- κB). We also take into account the role of these factors in the phenotype of HD as well as potential pharmacological interventions targeting the analyzed proteins. Furthermore, we considered whether molecular manipulation resulting in changes in transcription factor function may have clinical potency for treating HD.

The mean platelet volume on admission predicts unfavorable stroke outcomes in patients treated with IV thrombolysis.

PURPOSE: The role of biomarkers in the prediction of acute ischemic stroke (AIS) outcome or response to thrombolytic therapy (with recombinant tissue plasminogen activator [rt-PA]) remains limited. The aim of this study was to evaluate whether mean platelet volume (MPV) could predict short-term functional outcome in patients with AIS following rt-PA treatment. PATIENTS AND METHODS: This was a retrospective analysis of 237 AIS patients (mean age 71.04±0.8 years, 50.6% women) consecutively admitted to a tertiary care center between 2011 and 2015. RESULTS: The mean MPV in the cohort was 9.8±0.35 fL (lowest tertile <7.29 fL, median 7.29-8.8 fL, and highest tertile >8.8 fL). Patients in the lowest tertile compared to median and highest tertiles were less often dependent (modified Rankin scale [mRS] ≥3) at admission (87.2% vs 96.1% and 96.1%, respectively, P=0.04) and less often had a poor stroke outcome (mRS 4-6) at discharge (28.2% vs 55.3% and 44.7%, P<0.01). However, there was no significant difference between tertiles with regard to AIS etiology, CT (Alberta Stroke Program Early CT) score, frequency of stroke due to large artery occlusion, risk of secondary hemorrhage, and early neurologic deterioration. Multivariable analysis after adjustment for confounders showed that patients in the second and third tertiles had a significantly higher risk of poor stroke outcome (OR =1.9, 95% CI =1.01-4), lack of early improvement (OR =1.91, 95% CI =1.05-3.47), lower chance of good outcome (mRS 0-2; OR =0.38, 95% CI =0.18-0.78), or minor stroke at discharge (OR =0.47, 95% CI =0.26-0.84). Receiver operating characteristic analysis for prediction of poor stroke outcome showed that the optimal cut-off point of MPV was 8.8 fL (area under the curve 0.586 [0.512-0.659], P=0.03) with a sensitivity of 82.7% and a specificity of 43.9%. CONCLUSION: Disabling or fatal ischemic stroke in thrombolyzed patients was observed more often in patients with high admission MPV. The prognostic value of MPV was independent of other well-defined individual risk factors.

Effectiveness of dimethyl fumarate as first line therapy in MS patients - one center real life observation study.

Interferon ß, glatiramer acetate and dimethyl fumarate are first line of disease-modifying therapies for patients who have got relapsingremitting multiple sclerosis (RRMS). Currently, there are no precise guidelines for modifying treatment. This is the individual decision of the attending physician, which should take into account both the clinical course of the disease and the patient's preferences. Therefore, possible findings of this study may potentially improve treatment strategy and could be helpful for the clinicians to select the most appropriate therapy. AIM: The aim of this study was to evaluate and compare activity of multiple sclerosis one year before and one year after switching treatment from interferon ß or glatiramer acetate to dimethyl fumarate. The reasons for treatment modification and impact of these reasons on therapy effectiveness were studied as a secondary outcome. MATERIALS AND METHODS: This observational and retrospective study among patients with RRMS lasted for 2 years and was conducted at one medical center. Participants of the study were aged 19-61 years. All of them had been initially treated with disease-modifying drugs (DMDs) by injection: interferon or glatiramer acetate. After one-year observation patients switched therapy to dimethyl fumarate (DMF) for various reasons. RESULTS: 62 adult patients received interferon beta or glatiramer acetate in the first year. After a year all of them switched from that therapy to dimethyl fumarate. Patients in all treatment groups had similar demographic and clinical characteristics at baseline. The most common reason for change in interferon ß group were adverse effects or clinical ineffectiveness. Patients from glatiramer acetate group most often changed their therapy due to new lesions on MRI scans. Presented study shows a statistically significant decrease in radiological relapse when changing treatment from glatiramer acetate to dimethyl fumarate. At the same time, switching from interferon to dimethyl fumarate reduced the number of clinical relapses. There was no statistically significant difference in EDSS scores before and after treatment change in interferons' ß and glatiramer acetate's groups. CONCLUSIONS: The results of our study show that patients with progression of the disease should be treated with another medication. Further research is necessary to develop therapeutic position that supports therapeutic decision in an early period of MS. The observation of the presented group of patients will be continued.