Systematic review and network meta-analysis (NMA) for cladribine tablets in achieving sustained disability improvement (SDI) in multiple sclerosis.

INTRODUCTION: This study was performed to compare probabilities of SDI on the Expanded Disability Status Scale (EDSS) in patients with relapsing-remitting multiple sclerosis (RRMS), treated with cladribine tablets (CT) or fingolimod (FTY), natalizumab (NAT), alemtuzumab (ALE) and ocrelizumab (OCR). CLINICAL RATIONALE FOR THE STUDY: Progression of neurological disability as measured by the EDSS has been a common endpoint in multiple sclerosis (MS) trials. Novel therapies can not only slow this process, but in some patients even reverse it. This effect can be measured by the sustained disability improvement (SDI) - an endpoint that seems to continuously gain importance in clinical practice. Despite that, SDI has rarely been explored as an outcome in MS clinical studies, mostly as post-hoc analyses from randomised trials or as retrospective analyses based on patient registry records. MATERIAL AND METHODS: A systematic review was conducted in Medline, Embase and Cochrane to identify clinical trials (RCT or non-RCT) evaluating 6-month SDI. An indirect comparison via network meta-analysis (NMA) was performed. Bayesian inference with Markov chains Monte Carlo methods were applied. RESULTS: Eight trials presenting SDI results and applicable for NMA were included: six non-RCTs, with control groups selected by propensity score matching, and two RCTs. NMA results revealed that probability of achieving 6-month SDI with CT was significantly higher compared to all other high efficacy disease-modifying drugs with available data - HR (95% Crl - Bayesian Credibility Interval) vs. FTY: 4.98 (2.11-11.79); vs. NAT: 3.12 (1.31-7.27); vs. ALE: 9.29 (3.40-25.21). The main results were confirmed in the sensitivity analyses. CONCLUSIONS: Of all considered therapies, treatment with cladribine tablets was associated with a higher probability of sustained disability improvement in RRMS patients. As this conclusion is based on available clinical data of limited quality, future studies, as well as real-world data, would be valuable to provide further evidence regarding the comparative effectiveness of RRMS therapies.

Effect of honeydew honey addition on the water activity and water holding capacity of kefir in the context of its sensory acceptability.

The aim of the research was to check how the addition of honeydew honey and various compositions of starter cultures affects the water holding capacity, water activity, color, syneresis and consistency of the obtained kefir in the context of its sensory acceptability. In this research, 2.5% and 5% (w/w) honeydew honey was added to the samples of model kefir (K) and commercial kefir (K13). Kefirs differed by the type of used starter cultures and conditions of production. The addition of honeydew honey to kefir resulted in increased water holding capacity and a reduction in water activity. Honeydew honey kefir was characterized by the following flavor: astringent, fruity, pungent and waxy. As the honey content increased, the taste and waxy flavor became sweeter. In the sensory assessment, the attributes of texture and mouthfeel, creaminess, density and firmness, do not change because of the honey amount or storage time of the samples. The use of different starter cultures in kefir production with the addition of honeydew honey impacted texture parameters, resulting in up to a 4.8-fold increased viscosity index.

Cladribine tablets versus other disease-modifying oral drugs in achieving no evidence of disease activity (NEDA) in multiple sclerosis-A systematic review and network meta-analysis.

INTRODUCTION: Assuming full control of the relapsing-remitting multiple sclerosis (RRMS) is the main target for practitioners. Disease control could be defined as no clinical relapse, absence of 3-month confirmed disability progression expressed on the Expanded Disability Status Scale (EDSS), as well as no disease activity on magnetic resonance imaging (MRI). NEDA-3 (no evidence of disease activity) is a composite endpoint used primarily in clinical trials, comprising these 3 measurements of disease activity. The aim of this study is to compare cladribine tablets (CT) with oral disease-modifying drugs (DMDs) - fingolimod (FTY), dimethyl fumarate (DMF), and teriflunomide (TERI) - with regard to NEDA-3 and its clinical (relapse and disability progression) and MRI (no new T1 Gd+ lesions or no new T2 lesions or no enlargement of existing lesions) components occurrence during a 24-month follow-up. METHODS: In June 2018, a systematic review of MEDLINE, Embase and Cochrane database was performed. Due to the lack of head-to-head trials directly comparing cladribine tablets to oral drugs of interest, an indirect network meta-analysis (NMA) was applied, with placebo as a common comparator. NMA was performed with Bayesian approach and Markov chain Monte Carlo (MCMC) method for estimating posterior distributions. Additional data used in the analysis were taken from conference abstracts or post hoc analyses of pooled data from the clinical studies. RESULTS: Six randomised clinical trials (RCTs) presenting NEDA, with active treatment compared to placebo, were included in the NMA: CLARITY (CT), FREEDOMS and FREEDOMS II (FTY), CONFIRM and DEFINE (DMF) and TEMSO (TERI). The rate of NEDA-3 was significantly higher in cladribine tablets vs DMF: OR (odds ratio)=1.76 (95% CrI [credible intervals]: 1.02-3.03) and TERI: OR=2.78 (95% CrI: 1.60-4.83), but not vs FTY. For the MRI NEDA results were as follows - cladribine tablets vs DMF: OR=1.87 (95% CrI: 1.18-2.97); cladribine tablets vs TERI: OR=6.59 (95% CrI: 4.32-10.09); cladribine tablets vs FTY: OR=1.58 (95% CrI: 1.10-2.29). The comparison of clinical NEDA did not reach significance vs either DMF or TERI and evaluation vs FTY was not possible because of lack of data. CONCLUSIONS: Cladribine in the form of tablets was significantly more effective in achieving NEDA-3 than DMF and TERI, but there was no significant difference vs FTY. Cladribine tablets was more effective than all oral comparators considering the MRI NEDA. For clinical NEDA, the superiority vs DMF and vs TERI was not confirmed, and vs FTY evaluation was not possible.

The Influence of the Flow of Detergent and Donor Characteristics on the Extracellular Matrix Composition After Human Pancreas Decellularization.

INTRODUCTION: The extracellular matrix (ECM) consists, among others, of polysaccharides, glycosaminoglycans, and proteins. It is being increasingly used in tissue bioengineering. Obtaining ECM of the highest quality through decellularization is a big challenge because of some differences in organ structure. To deprive organs of the cellular part, chemical, enzymatic, or mechanical methods are used. After decellularization, we get a scaffold made of a variety of proteins, and it is the role of these proteins that can significantly affect the maintenance of the spatial structure and be a suitable environment for cells to rebuild a specific organ. AIM: Estimation of the detergent (Triton X-100) flow parameters and anthropometric donors' decellularization process accuracy on the final ECM composition. MATERIALS: Five human pancreata, rejected from transplantation, were used for decellularization. All organs were harvested from brain-dead donors age 13 to 60 years. METHODS: Decellularization was carried out using the flow method with Triton X-100 as an active agent. The experiment compared 5 different flow values. After decellularization, an assessment of the final DNA concentration and the protein composition was performed. Results were compared to anthropometric data of donors. In addition, a microscopic analysis was also carried out. RESULTS: The best results were obtained using a flow of 120 mL/minute. A higher detergent flow was associated with a lower concentration of residual DNA in scaffold. Analysis of the protein profile with anthropometric data has shown that LAM A2 was increasing with age and LAMA5 was decreasing. Being overweight was associated with a higher proportion of COL1 and 4 and a smaller proportion of COL6.

Color Stability of Fermented Mare's Milk and a Fermented Beverage from Cow's Milk Adapted to Mare's Milk Composition.

Color is important for the consumer when making a purchase decision. Mare's milk and, thus, fermented mare's milk is little known to consumers. Thus, it is worth presenting research showing the extent of color change during the production and storage of mare's milk. Herein, we examined the range of color changes in mare's milk and cow's milks adapted to mare's milk composition. These samples were further fermented and stored for 3 weeks at 5 ± 1 °C. Starter cultures containing Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus were used for fermentation. Mare's milk reached the required pH of 4.5 during fermentation faster (255 min) than cow's milk (300 min). After fermentation, mare's milk compared to cow's milk and adapted cow's milk had lower titratable acidity (0.75%) and firmness (145. 6 |(g∙s)|). The water holding capacity (95.6%) and number of Lactobacillus (7.71 log CFU/mL) and Streptocococcus (7.20 log CFU/mL) in mare's and other's milks were the same. Mare's milk was furthest from the ideal white (WI) color, with its chrome (C*) being 1.5-times larger than cow's milk. However, fermented mare's milk was darker than the fermented adapted milk and cow's milk by 36% and 58%, respectively. Storage caused a decrease in the WI, C*, and yellowness index (YI). The fermented mare's milk color stability during production and storage was less than that of fermented cow's milk. After 3 weeks storage, it was observed that the titratable acidity increased to 1.05%, and the pH decreased to 4.3 in fermented mare's milk. The water holding capacity decreased but was still higher compared to fermented cow's milk.

Kinetics of lactose hydrolysis and galactooligosaccharides formation in beverages based on goat's milk and its permeate.

The aim of this work was the analysis of galactooligosaccharides (GOS) formation in a model mixture of goat's milk and its permeate from microfiltration and further concentration by ultrafiltration based on the hydrolysis and transgalactosylation of lactose under various temperature and time regimes. These reactions were catalyzed by a ß-galactosidase from Kluyveromyces lactis. Simultaneous hydrolysis and transgalactosylation of the milk lactose was carried out at 37, 40, and 43 °C for 6 h. The maximum GOS content in the mixture was obtained at 37 °C after 20 min. It was 6.9% of the total sugars and the degree of lactose hydrolysis was 13.3%. This was about 10% more GOS than in milk. The mixture containing GOS had a faster maximum acidification rate, 33% greater than before transgalactosylation.

[Pragmatic randomized controlled trials as a source of data in the assessment of effectiveness of medical technology]. / Pragmatyczne badania kliniczne z randomizacja jako zródlo danych w ocenie efektywnosci praktycznej technologii medycznych.

Acquisition of scientific data needed to make rational decisions about health policy has became an important tool in determining the validity of the financing methods of treatment from public funds under the health technology assessment (HTA). The primary source of scientific evidence for health technology assessment are randomized controlled trials (RCTs, explanatory trials evaluating the efficacy), because of their features reducing methodological bias (e.g. randomization or blindness). These features may become a disadvantage, which seriously reduces the possibility of transfer of the results and conclusions to the level of routine practice. In this situation an important role begin to play studies that provide data on effectiveness-observational studies, registries and pragmatic randomized controlled trials (pRCTs).

miRNEST database: an integrative approach in microRNA search and annotation.

Despite accumulating data on animal and plant microRNAs and their functions, existing public miRNA resources usually collect miRNAs from a very limited number of species. A lot of microRNAs, including those from model organisms, remain undiscovered. As a result there is a continuous need to search for new microRNAs. We present miRNEST (http://mirnest.amu.edu.pl), a comprehensive database of animal, plant and virus microRNAs. The core part of the database is built from our miRNA predictions conducted on Expressed Sequence Tags of 225 animal and 202 plant species. The miRNA search was performed based on sequence similarity and as many as 10,004 miRNA candidates in 221 animal and 199 plant species were discovered. Out of them only 299 have already been deposited in miRBase. Additionally, miRNEST has been integrated with external miRNA data from literature and 13 databases, which includes miRNA sequences, small RNA sequencing data, expression, polymorphisms and targets data as well as links to external miRNA resources, whenever applicable. All this makes miRNEST a considerable miRNA resource in a sense of number of species (544) that integrates a scattered miRNA data into a uniform format with a user-friendly web interface.

[Humanin and its derivatives as peptides with potential antiapoptotic and confirmed neuroprotective activities]. / Humanina i jej analogi jako peptydy o potencjalnym dzialaniu antyapoptotycznym i potwierdzonych wlasciwosciach neuroprotekcyjnych.

Humanin (HN) is a newly discovered 24-amino acid peptide, which may suppress neuronal cell death. HN cDNA includes the open reading frame (HN-ORF) of 75 bases, located 950 bases downstream of the 5' end of the HN cDNA. It was demonstrated that HN cDNA is 99% identical with mitochondrial DNA (mtDNA) sequence. HN homologues have been identified as expressed sequence tags (ESTs) in rat and nematode. Certain regions homologous to the HN cDNA exist on human chromosomes. HN forms homodimers and multimers and this seems to be essential for the peptide functions. HN acts as a ligand for formyl peptide receptor-like 1 (FPRL1) and 2 (FPRL2). It was demonstrated that HN plays a protective role by an antiapoptotic activity interfering with Bax activation, and suppressing Bax-dependent apoptosis. HN is also shown to suppress the c-Jun N-terminal kinase (JNK) and ASK/JNK-mediated neuronal cell death. Several studies also confirm that HN could be important in prevention of angiopathy-associated Alzheimer's disease dementia, diseases related to mitochondrial dysfunction (MELAS), and other types of beta-amyloid accumulation associated neurodegeneration. A very recent study demonstrated a pluripotent cytoprotective effect and mechanisms of HNs in cells other than from the CNS, such as germ cells, or panreatic b-cells, and potent physiological consequences that result from HN interaction with IGFBP3 and STAT3. The in vivo studies suggest that humanin may protect against cognitive impairment, also due to ischemia/reperfusion injury.

Humanins, the neuroprotective and cytoprotective peptides with antiapoptotic and anti-inflammatory properties.

Humanin (HN) is a newly discovered 24-amino acid peptide, which may suppress neuronal cell death. HN cDNA includes an open reading frame (HN-ORF) of 75 bases located 950 bases downstream of the 5' end of the HN cDNA. It has been demonstrated that HN cDNA is 99% identical to the mitochondrial DNA (mtDNA) sequence. HN homologs have been identified as expressed sequence tags (ESTs) in both rats and nematodes. Certain regions that are homologous to the HN cDNA exist on human chromosomes. HN forms homodimers and multimers and this action seems to be essential for peptide function. HN acts as a ligand for formyl peptide receptor-like 1 (FPRL1) and 2 (FPRL2). It has been demonstrated that HN plays a protective role through its antiapoptotic activity that interferes with Bax activation, which suppresses Bax-dependent apoptosis. HN has also been shown to suppress the c-Jun N-terminal kinase (JNK) and ASK/JNK-mediated neuronal cell death. Several studies have also confirmed that HN could be important in the prevention of angiopathy-associated Alzheimer's disease dementia, diseases related to mitochondrial dysfunction (MELAS), and other types of ß-amyloid accumulation-associated neurodegeneration. Avery recent study demonstrated a pluripotent cytoprotective effect and mechanisms of HNs in cells not from the CNS, such as germ cells or pancreatic ß-cells, and the potent physiological consequences that result from HN interaction with IGFBP3 and STAT3. In vivo studies suggest that HN may also protect against cognitive impairment due to ischemia/reperfusion injury.