Irisin - evidence for benefits resulting from physical activity

Irisin is a myokine with wide metabolic action, which makes it very similar to a hormone. Its serum level depends on the expression of the genes FNDC5 and PGC-1α which, in turn, are induced, among others, by physical activity, especially aerobic exercises. According to many studies, aerobic training lasting for 45-60 minutes significantly increased the level of irisin in blood or muscles, and was considerably more effective than endurance training. Irisin shows protective properties against type 2 diabetes by decreasing insulin-resistance and against atherosclerosis by the improvement of lipid profile and anti-inflammatory action. It helps patients with overweight and obesity struggle with an excess of adipose tissue, and induces the conversion of white adipose tissue to brown. It also improves metabolic profile by the acceleration of metabolism and increase in thermogenesis. This myokine reduces the risk of occurrence of metabolic syndrome. Also, the neuroprotective effect of irisin has been confirmed, which would indicate a tremendous role of physical effort in slowing down the course of neurodegenerative diseases in seniors. In addition, irisin acts through many signal pathways exerting an anti-inflammatory, anti-oxidative, anti-apoptotic and anti-cancer effects, which is a potential therapeutic goal. Unfortunately, further studies concerning irisin are still needed before it can be clinically used. However, already now it may be the tool for psychologists working with persons suffering from overweight, obesity, diabetes, atherosclerosis, metabolic syndrome, neurodegenerative diseases, and many other disorders to motivate them for regular physical effort. DOI: http://dx.doi.org/10.5281/zenodo.338506

Resistance to ceftaroline - 2018 review

Ceftaroline is a new fifth generation cephalosporin, active mostly against Gram-positive cocci, e.g. Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus). It is used in treating acute bacterial skin and skin structure infections, community acquired respiratory tract infections and methicillin-resistant S. aureus bacteremia. The main resistance mechanisms of bacteria to β-lactam antibiotics, including ceftaroline, are mutations in PBP2a, PBP3 and PBP4. Clinically significant resistance has been noted among both archived and newly-isolated strains in a laboratory test using serial passages. Ceftaroline-resistant strains have also been found in patients suffering from cystic fibrosis, ventilator-associated pneumonia and infectious endocarditis. Irresponsible antibiotic treatment using ceftaroline or other antibiotics (due to a possibility of a cross-resistance) can lead to the spread of ceftaroline resistance and, consequently, its loss of value. DOI: http://dx.doi.org/10.5281/zenodo.130443

Current views on the prevention of thromboembolic complications in atrial fibrillation

Atrial fibrillation ( AF) is the most common arrhythmia and a direct cause of thromboembolic complications. The most common site of thrombus formation is the left auricle also referred to as the left atrial appendage (LAA). Pharmacotherapy with vitamin K antagonists (VKA) and non-vitamin K antagonist oral anticoagulants (NOACs) as well as percutaneous and surgical interventions have all been used to prevent these complications. Interventional management is the treatment of choice in patients with contraindications to oral anticoagulants; the efficacy of such management is comparable to that of pharmacotherapy while the risk of adverse events, ie., severe haemorrhage or haemorrhagic stroke, is lower. Hence, some extensions to the existing indications for interventional treatment might be worth considering under specific clinical circumstances. A hybrid therapy combining left atrial appendage occlusion (LAAO) with AF ablation seems to hold particularly notable potential due to high therapeutic efficacy unassociated with a significant increase in complication rates

Use of Tn5-transposon mutagenesis for the identification of potential novel interactors of antimicrobial peptides in E.coli

2008/2009Antimicrobial peptides (AMPs) participate in the immunity of both animals and plants. In mammals, the most important AMP families are defensins and cathelicidins. The only human cathelicidin, LL-37, is a 37-residue, α-helical, cationic peptide with a direct membranolytic antibacterial activity and various immunomodulatory activities. The aim of our research was to establish a procedure based on an E. coli knock-out mutant library in the search for mutations conferring altered susceptibility to AMPs. The library was created by random insertions of Tn5 transposon into the bacterial genome. The selection of low-susceptibility mutants and their identification was first tested with a Bac7-derived peptide, for which at least one interactor had been found. The procedure was then applied for the identification of mutations that modulate the susceptibility of E. coli cells to LL-37 with the aim of dissecting the steps of the peptide's mode of action. The differences between the wild-type and the mutant phenotypes were characterised using assays determining the bacterial culture growth inhibition and killing, as well as cell binding and membrane permeabilisation. In the majority of the isolated Bac7-resistant mutants, Tn5 was inserted in the sbmA gene, confirming previous findings that showed an essential role for the SbmA protein in the internalisation of Bac7, allowing it to exert its antimicrobial activity. Tn5 insertion in the gene waaY, identified in 15 out of 20 resistant mutants selected with LL-37, lowered the peptide’s ability to inhibit bacterial growth and to kill cells, decreased peptide binding to the bacterial surface and membrane permeabilisation. However, it did not alter the susceptibility to other AMPs. WaaY encodes a specific kinase that phosphorylates the Hep II residue in the core region of bacterial lipopolysaccharide. The inactivation of this enzyme determines a decreased negative charge of the outer membrane, which in turn causes a decrease in the peptide’s binding to the cell surface and in its antibacterial activity. The results reveal a putative LPS-binding site for LL-37 and stress the importance of its initial binding to the cell surface for antimicrobial efficacy. The established procedure utilising Tn5 mutants in the search for bacterial mutations conferring resistance to AMPs, proved efficient and opened a previously unreported branch of research on the mode of action of the human cathelicidin.I peptidi antimicrobici (AMP) fanno parte dell'immunità innata sia degli animali che delle piante. Le famiglie di AMP più importanti nei mammiferi sono le defensine e le catelicidine. L'unica catelicidina presente nell'uomo, LL-37, è un peptide lineare e cationico di 37 residui con una conformazione ad α-elica, che esercita un’azione microbicida diretta tramite permeabilizzazione di membrana. In aggiunta, il peptide è anche dotato di una serie di funzioni immunomodulatorie. Lo scopo del lavoro è stato quello di mettere a punto una procedura che utilizza una libreria di mutanti knock-out di E. coli, ottenuta mediante inserzioni casuali del trasposone Tn5 nel genoma batterico, per cercare mutazioni che rendano i batteri resistenti agli AMP. La bontà del metodo è stata prima verificata selezionando e identificando mutanti resistenti al frammento 1-16 del peptide Bac7. Una volta ottenuti i risultati attesi, la procedura è stata applicata all'identificazione di mutazioni che modulino la suscettibilità di E. coli a LL-37, con lo scopo di meglio comprenderne il meccanismo d'azione. I fenotipi wild-type e mutante sono stati caratterizzati usando saggi d'inibizione della crescita batterica, di killing e di capacità del peptide di legarsi ai batteri e di permeabilizzarli. Nella maggioranza dei mutanti resistenti al peptide Bac7 isolati, Tn5 ha inattivato il gene sbmA, confermando risultati precedenti che avevano portato a dimostrare l'importanza della proteina SbmA per l'internalizzazione di Bac7. Nel caso di LL-37, in 15 dei 20 mutanti resistenti selezionati il trasposone ha inattivato il gene waaY, che codifica per una chinasi specifica per la fosforilazione del residuo Hep II della regione core del lipopolisaccaride batterico. La mancata fosforilazione nei mutanti selezionati riduce la carica negativa della superficie batterica, che, a sua volta, diminuisce l'inibizione della crescita, il killing, il legame e la permeabilizzazione delle cellule da LL-37, ma non da altri peptidi, suggerendo che la modificazione abbia alterato specificamente l'attività di LL-37, rivelando un suo putativo sito di legame all’LPS e sottolineando l'importanza del legame iniziale alla superficie cellulare per l'efficacia battericida del peptide. La procedura messa a punto per la ricerca di mutazioni che inducono resistenza agli AMP è risultata efficiente ed ha indicato una nuova via per far luce sulla sequenza di eventi responsabile del meccanismo d'azione della catelicidina umana.XXII Ciclo198

Autonomia jako nadrzędny cel edukacji w ujęciu Aharona Avirama

The article refers to the issue of autonomy as an overriding educational aim and is analyzing the concept of Autonomy-Oriented Education (AOE) by the Israeli philosopher of education, Aharon Aviram. Although the desire for freedom and the need for self-determination is an immanent part of human identity, the project of erecting individual autonomy as a central educational aim is a matter of controversy. According to Aviram the autonomy should be the main educational goal, and postmodern school should encourage young people to develop their personal autonomy, morality and dialogical belonging – three basic humanistic values. To accomplish that, Aviram proposes a total change of the prevailing education system. This paper presents an overview of the assumptions of that conception.Artykuł dotyczy zagadnienia autonomii jako nadrzędnego celu edukacji i prezentuje koncepcję Edukacji Zorientowanej na Autonomię izraelskiego filozofa edukacji, Aharona Avirama. Chociaż pragnienie wolności i potrzeba samostanowienia stanowią immanentną część ludzkiej tożsamości, projekt ustanowienia autonomii jednostki nadrzędnym celem wychowania budzi pewne kontrowersje. Zdaniem Avirama autonomia powinna być zasadniczym celem wychowania, a ponowoczesna szkoła winna wspierać młodych ludzi w kształtowaniu ich osobistej autonomii, moralności i dialogicznej przynależności – trzech podstawowych wartości humanistycznych. Aby to osiągnąć, Aviram proponuje całościową zmianę dominującego systemu edukacyjnego. Niniejszy artykuł prezentuje zarys założeń tej koncepcji

Kalcyfilaksja — śmiertelne powikłanie nie tylko u pacjentów ze schyłkową niewydolnością nerek

We present a fatal case of end-stage renal disease complication that is calciphylaxis, also known as calcific uremic arteriolopathy, characterized by vascular calcification, necrosis of the skin and adipose tissue and constant severe pain of the affected areas.We present a fatal case of end-stage renal disease complication that is calciphylaxis, also known as calcific uremic arteriolopathy, characterized by vascular calcification, necrosis of the skin and adipose tissue and constant severe pain of the affected areas

PRE-binding sites in the MDR of CLL: Potential Tumor Suppressor Regulation

Chronic lymphocytic leukemia [CLL] is the most common adult leukemia and is heterogeneous in clinical presentation. CLL cases present with various chromosomal aberrations, including 11q23, 14q32, 17p, and trisomy 12, with the most common abnormality being deletion of 13q14 [1]. Although monoallelic deletion of 13q14 is common, there is a subset of patients who have complete nullisomy at 13q14, a locus that has been hypothesized to contribute to CLL pa thogenesis [2] due to loss of tumor suppressors [DLEU and miR-15a/16-1].We hypothesized that deletion of both copies of 13q14 would lead to uncontrollable proliferation of CLL cells and a poor prognosis. We examined our 13q14 nullisomy for survival, treatment-free survival, lymphocyte doubling time, and the presence of lymphadenopathy. Furthermore, we compared the gene expression profiles between patients with 13q14 monosomy, nullisomy, or normal karyotype. Our results suggest that patients with 13q nullisomy have a higher incidence of bulky lymphadenopathy [16.6% compared to 10% of monosomy patients], a higher frequency of lymphocyte doubling time [27.7% compared to 7.4% of monosomy patients], and a higher rate of needing treatment [50% compared to 18.5% of monosomy patients]. We observed deletion of DLEU1 and HTR2A, consistent with a gene dosage effect, and observed PRE-binding sites on DLEU1. Patients with homozygous deletion of 13q14 had a worse prognosis compared to heterozygotes. Lastly, the DLEU1 locus is a possible “second hit” loss for CLL progression