THE PAIR-WISE LINEAR CLASSIFIER AND THE K-NN RULE IN APPLICATION TO ALS PROGRESSION DIFFERENTIATION

The two kinds of classifier based on the k-NN rule, the standard and the parallel version, were used for recognition of severity of ALS disease. In case of the second classifier version, feature selection was done separately for each pair of classes. The error rate, estimated by the leave one out method, was used as a criterion as for determination the optimum values of k's as well as for feature selection. All features selected in this manner were used in the standard and in the parallel classifier based on k-NN rule. Furthermore, only for the verification purpose, the linear classifier was applied. For this kind of classifier the error rates were calculated by use the training set also as a testing one. The linear classifier was trained by the error correction algorithm with a modified stop condition. The data set concerned with the healthy subjects and patients with amyotrophic lateral sclerosis (ALS). The set of several biomarkers such as erythropoietin, matrix metalloproteinases and their tissue inhibitors measured in serum and cerebrospinal fluid (CSF) were treated as features. It was shown that CSF biomarkers were very sensitive for the ALS progress

Tissue inhibitors of matrix metalloproteinases in serum are cardiac biomarkers in Emery-Dreifuss muscular dystrophy

Wstęp: Tkankowe inhibitory metaloproteinaz macierzy (TIMPs) są zaangażowane w patogenezę chorób układu sercowo-naczyniowego. Dotychczas nie badano stężenia TIMPs u pacjentów z kardiomiopatią rozstrzeniową w przebiegu dystrofii mięśniowej Emery’ego-Dreifussa (EDMD). Cel: Celem badania było określenie stężenia TIMPs w surowicy pacjentów z EDMD w celu rozstrzygnięcia, czy mogłyby stanowić biomarker dysfunkcji mięśnia sercowego na wczesnych etapach choroby i pomóc w wykrywaniu kardiomiopatii w okresie przedklinicznym. Metody: Zbadano 25 pacjentów z EDMD związaną z mutacją w genie laminy A/C (AD-EDMD) lub w genie emeryny (X-EDMD) oraz 20 zdrowych osób z grupy kontrolnej, dobranych pod względem wieku. Stężenia TIMP-1, -2, -3 w surowicy określono za pomocą testu immunoenzymatycznego ELISA z odpowiednimi przeciwciałami. Wyniki: Stężenia TIMP-1 w surowicy były prawidłowe u chorych z AD-EDMD, a zwiększone u większości pacjentów z X-EDMD. Stężenie TIMP-2 w surowicy było obniżone u 25% i /21% chorych, odpowiednio, z AD-EDMD i X-EDMD. Stężenie TIMP-3 było znamiennie obniżone u wszystkich badanych pacjentów. Krzywe ROC wskazywały, że spośród wszystkich zbadanych TIMPs pod względem czułości i specyficzności TIMP-3 (a w mniejszym stopniu TIMP-2) jest najlepszym biomarkerem uszkodzenia mięśnia sercowego u chorych z EDMD. Wnioski: Uzyskane wyniki wskazują, że u chorych z EDMD stężenia TIMP-3 w surowicy, a w niektórych przypadkach także TIMP-2, są obniżone. Obserwowany spadek może się wiązać z niekorzystnym wpływem na metaloproteinazy macierzy oraz remodelowaniem macierzy miokardium. Specyficzny spadek stężenia TIMP-3 w surowicy chorych wskazuje, że biomarker ten mógłby być użyteczny we wczesnej detekcji zajęcia mięśnia sercowego w EDMD. Regulacja w górę TIMP-1 u większości pacjentów z X-EDMD wskazuje na zwiększony obrót macierzy zewnątrzkomórkowej, zaś obserwowane remodelowanie tkanki może uczestniczyć w rozwoju zaburzeń rytmu serca, często stwierdzanych w tej postaci choroby.  Background: Tissue inhibitors of matrix metalloproteinases (TIMPs) are known to be involved in cardiovascular diseases. Hitherto, they have not been examined in dilated cardiomyopathy in the course of Emery-Dreifuss muscular dystrophy (EDMD). Aim: To define TIMPs in serum because they might help in defining cardiac dysfunction at the early cardiological stages of this disease and detect preclinical stages of cardiomyopathy. Methods: Twenty-five EDMD patients connected with lamin A/C (AD-EDMD) or emerin (X-EDMD) deficiency and 20 healthy age-matched controls were examined. The serum levels of the tissue inhibitors TIMP-1, -2, -3 were quantified using the ELISA sandwich immunoassay procedure with appropriate antibodies. Results: Serum levels of TIMP-1 were normal in autosomal AD-EDMD and increased in the majority of X-linked EDMD. The level of TIMP-2 was decreased in 25%/21% of AD-EDMD/X-EDMD cases. TIMP-3 serum level was significantly reduced in all the examined patients. Receiver operating curves indicated that in terms of sensitivity and specificity characteristics the performance of TIMP-3 (less that of TIMP-2) makes them the best markers of cardiac involvement among the examined TIMPs. Conclusions: Evidence shows that the levels of TIMP-3, and in some cases also TIMP-2, are decreased in EDMD. The decrease might be associated with an adverse effect on matrix metalloproteinases and remodelling of the myocardial matrix. The specific decrease of TIMP-3 indicates that this biomarker might help in early detection of cardiac involvement in EDMD. Up-regulation of TIMP-1 in the majority of patients with X-EDMD indicates increased myocardial extracellular matrix turnover, early onset of tissue remodelling, and may contribute to arrhythmia, frequently occurring in this form of the disease.

Human Umbilical Cord Blood Treatment in a Mouse Model of ALS: Optimization of Cell Dose

Amyotrophic Lateral Sclerosis (ALS) is a multicausal disease characterized by motor neuron degeneration in the spinal cord and brain. Cell therapy may be a promising new treatment for this devastating disorder. We recently showed that a single low dose (10(6) cells) of mononuclear human umbilical cord blood (MNC hUCB) cells administered intravenously to G93A mice delayed symptom progression and modestly prolonged lifespan. The aim of this pre-clinical translation study is to optimize the dose of MNC hUCB cells to retard disease progression in G93A mice. Three different doses of MNC hUCB cells, 10x10(6), 25x10(6) and 50x10(6), were administered intravenously into pre-symptomatic G93A mice. Motor function tests and various assays to determine cell effects were performed on these mice.Our results showed that a cell dose of 25x10(6) cells significantly increased lifespan of mice by 20-25% and delayed disease progression by 15%. The most beneficial effect on decreasing pro-inflammatory cytokines in the brain and spinal cord was found in this group of mice. Human Th2 cytokines were found in plasma of mice receiving 25x10(6) cells, although prevalent human Th1 cytokines were indicated in mice with 50x10(6) cells. High response of splenic cells to mitogen (PHA) was indicated in mice receiving 25x10(6) (mainly) and 10x10(6) cells. Significantly increased lymphocytes and decreased neutrophils in the peripheral blood were found only in animals receiving 25x10(6) cells. Stable reduction in microglia density in both cervical and lumbar spinal cords was also noted in mice administered with 25x10(6) cells.These results demonstrate that treatment for ALS with an appropriate dose of MNC hUCB cells may provide a neuroprotective effect for motor neurons through active involvement of these cells in modulating the host immune inflammatory system response

Biomarkers in motor neuron disease: A state of the art review

Motor neuron disease can be viewed as an umbrella term describing a heterogeneous group of conditions, all of which are relentlessly progressive and ultimately fatal. The average life expectancy is 2 years, but with a broad range of months to decades. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. It also allows differentiation of the disease population into sub-groups, which serves two general purposes: (a) provides clinicians with information to better guide their patients in terms of disease progression, and (b) guides clinical trial design so that an intervention may be shown to be effective if population variation is controlled for. Biomarkers also have the potential to provide monitoring during clinical trials to ensure target engagement. This review highlights biomarkers that have emerged from the fields of systemic measurements including biochemistry (blood, cerebrospinal fluid, and urine analysis); imaging and electrophysiology, and gives examples of how a combinatorial approach may yield the best results. We emphasize the importance of systematic sample collection and analysis, and the need to correlate biomarker findings with detailed phenotype and genotype data