O otkupu i iskorišćenju mlijeka u Sloveniji

U mljekarskoj privredi Slovenije se već duže vremena osjeća potreba za analizom današnjeg stanja mljekarstva. Iz takve analize bilo bi moguće izvesti upute za budući rad

ATIC as a link between antirheumatic drugs and regulation of energy metabolism in skeletal muscle

Chronic inflammatory rheumatic diseases, such as rheumatoid arthritis, psoriatic arthritis, and systemic lupus erythematosus, increase the risk of developing insulin resistance, metabolic syndrome, and/or type 2 diabetes. While inflammation is thought to be a major mechanism underlying metabolic dysregulation in rheumatic diseases, antirheumatic drugs that exert direct metabolic effects in addition to suppressing inflammation, might be particularly useful to prevent metabolic complications. Here we review antirheumatic drugs, such as methotrexate, that inhibit ATIC, the final enzyme in the de novo purine biosynthesis, responsible for conversion of ZMP to IMP. Inhibition of ATIC results in accumulation of ZMP, thus promoting activation of AMP-activated kinase (AMPK), a major regulator of cellular energy metabolism and one of the most promising targets for the treatment of insulin resistance and type 2 diabetes. We focus especially on ATIC inhibition and AMPK activation in skeletal muscle as this is the largest and one of the most metabolically active tissues with a major role in glucose homeostasis. As an important site of insulin resistance, skeletal muscle is also one of the main target tissues for pharmacological therapy of type 2 diabetes. Finally, we review the metabolic effects of ATIC-inhibiting antirheumatic drugs and discuss whether these drugs might improve systemic glucose homeostasis by inhibiting ATIC and activating AMPK in skeletal muscle.</p

Osnovna šola s štiriletnim latinskim programom

Predmet obravnave je iz nižjegimnazijskega klasičnega programa leta 1958 rojeni štiriletni osnovnošolski latinski program (ŠOLP) za učence med 11. in 15. letom, ki predstavlja s kulturno-civilizacijskimi vsebinami smotrno obogateno jezikovno jedro zgodnjega humanističnega programa, je zaključena celota in hkrati predpogoj za oživitev gimnazijske nadgradnje. Priložen je predlog programa, kako pomagati javnemu ŠOLP-u z dna, kamor je, do konca osemletke dovolj trdoživ in uspešen, strmoglavil – zaradi neustreznih normativov, ne pomanjkanja interesa – ob uvedbi devetletke in kjer je preživotaril njeno prvo oziroma svojo šesto dekado (2008–2018) ter se vita minima znašel na pragu sedme (2018–)

Učinci imidazolijevih i kloriranih bispiridinijevih oksima povezani s njihovom toksičnosti na stanicama SH-SY5Y

Current research has shown that several imidazolium and chlorinated bispyridinium oximes are cytotoxic and activate different mechanisms or types of cell death. To investigate this further, we analysed interactions between these oximes and acetylcholine receptors (AChRs) and how they affect several signalling pathways to find a relation between the observed toxicities and their effects on these specific targets. Chlorinated bispyridinium oximes caused time-dependent cytotoxicity by inhibiting the phosphorylation of STAT3 and AMPK without decreasing ATP and activated ERK1/2 and p38 MAPK signal cascades. Imidazolium oximes induced a time-independent and significant decrease in ATP and inhibition of the ERK1/2 signalling pathway along with phosphorylation of p38 MAPK, AMPK, and ACC. These pathways are usually triggered by a change in cellular energy status or by external signals, which suggests that oximes interact with some membrane receptors. Interestingly, in silico analysis also indicated that the highest probability of interaction for all of our oximes is with the family of G-coupled membrane receptors (GPCR). Furthermore, our experimental results showed that the tested oximes acted as acetylcholine antagonists for membrane AChRs. Even though oxime interactions with membrane receptors need further research and clarification, our findings suggest that these oximes make promising candidates for the development of specific therapies not only in the field of cholinesterase research but in other fields too, such as anticancer therapy via altering the Ca2+ flux involved in cancer progression.Praćenjem učinka odabranih imidazolijevih i kloriranih bispiridinijevih oksima utvrđeno je da uzrokuju citotoksičnost i aktiviraju različite mehanizme ili tipove stanične smrti. Kako bismo to detaljnije istražili, analizirali smo aktivaciju nekoliko signalnih putova, kao i interakcije acetilkolinskih receptora (AChR) s navedenim oksimima te procijenili može li se opaženi toksični učinak objasniti njihovim utjecajem na ove specifične mete. Rezultati su pokazali da su klorirani bispiridinijevi oksimi prouzročili vremenski-ovisnu citotoksičnost, bez smanjenja razine ATP-a uz aktivaciju ERK1/2 i p38 MAPK-vezanih signalnih kaskada i inhibiciju fosforilacije STAT3 i AMPK proteina. Imidazolijevi oksimi djelovali su vremenski neovisno, uz značajno smanjenje razine ATP-a i inhibiciju ERK1/2 signalnog puta te fosforilaciju p38 MAPK, AMPK i ACC proteina. Navedeni signalni putovi obično se aktiviraju ili promjenom unutarnjega staničnog statusa, osobito energetskoga, ili vanjskim signalima, što upućuje na moguće interakcije oksima s nekim membranskim receptorima. Zanimljivo, in silico analizom procijenjeno je da je najvjerojatnija interakcija testiranih oksima s porodicom G-protein-spregnutih membranskih receptora (GPCR). K tomu, eksperimentalno je potvrđeno da testirani oksimi djeluju kao mogući antagonisti acetilkolina za vezanje na membranske AChR, potvrđujući tako i računalnu in silico procjenu. Iako interakcije ispitanih oksima s membranskim receptorima treba dodatno potvrditi, takve bi ih interakcije učinile kandidatima za razvoj specifičnih terapija u drugim područjima istraživanja, osim u istraživanjima povezanima s kolinesterazama, npr. kao moguće protutumorske lijekove, putem utjecaja na fluks iona Ca2+ uključenoga u progresiju tumora

Poznohalštatska grobova s Kovka nad Hrastnikom v Zasavju

Several metal artefacts came to light in 2015 at Vrtača, a site below the summit of the Kovk hill above Hrastnik. It was a chance find that comprised a Negova helmet, parts of a belt including a hook plate and a socketed axe. The Pokrajinski muzej Celje acquired the artefacts and also investigated the site in 2016. An inhumation burial of a warrior was discovered with additional parts of the belt, a fragment of a fibula and one of a spearhead, as well as a glass bead. Next to it was an inhumation burial of a girl with a necklace of glass beads, pair of bracelets, pair of anklets and a small knife. The grave goods include two significant artefacts. One is a Negova helmet of the Slovenian type, variant Vače, the other a Kovk type belt set with an exceptional hook belt plate. The goods that are latest in date place the burial of both individuals to the early part of the Negova phase. The burials form part of a flat cemetery below the summit of Kovk that held a small hillfort. Together with the group of tumuli at Grobišče, south of the Kovk village that lies southeast of the Kovk hill, they shed additional light on the Iron Age settlement in the Zasavje region of Slovenia.Leta 2015 je bila v Vrtači pod vrhom hriba Kovk nad Hrastnikom naključno odkrita skupina kovinskih predmetov, ki vključuje negovsko čelado, kavljasto pasno spono in druge dele pasne oprave ter tulasto sekiro. Predmete je pridobil Pokrajinski muzej Celje, ki je avgusta 2016 izvedel kontrolno izkopavanje. Odkrit je bil skeletni grob bojevnika z dodatnimi deli pasne oprave, odlomkoma fibule in sulične osti ter stekleno jagodo. Tik ob njem je bil izkopan skeletni grob dekleta z ogrlico iz steklenih jagod, zapestnicama in nanožnicama ter nožičkom. Med predmeti izstopata negovska čelada različice Vače slovenske vrste in pasna oprava vrste Kovk z izjemno kavljasto spono. Najmlajši grobni pridatki določajo čas pokopa obeh oseb v starejšem delu negovske stopnje. Grobova pripadata planemu grobišču pod manjšo utrjeno naselbino na vrhu Kovka. Skupaj s skupino gomil na ledini Grobišče pri Kovku dopolnjujeta vedenje o železnodobni poselitvi Zasavja

Neuronal Agrin Promotes Proliferation of Primary Human Myoblasts in an Age-Dependent Manner

Neuronal agrin, a heparan sulphate proteoglycan secreted by the -motor neurons, promotes the formation and maintenance of the neuromuscular junction by binding to Lrp4 and activating muscle-specific kinase (MuSK). Neuronal agrin also promotes myogenesis by enhancing differentiation and maturation of myotubes, but its effect on proliferating human myoblasts, which are often considered to be unresponsive to agrin, remains unclear. Using primary human myoblasts, we determined that neuronal agrin induced transient dephosphorylation of ERK1/2, while c-Abl, STAT3, and focal adhesion kinase were unresponsive. Gene silencing of Lrp4 and MuSK markedly reduced the BrdU incorporation, suggesting the functional importance of the Lrp4/MuSK complex for myoblast proliferation. Acute and chronic treatments with neuronal agrin increased the proliferation of human myoblasts in old donors, but they did not affect the proliferation of myoblasts in young donors. The C-terminal fragment of agrin which lacks the Lrp4-binding site and cannot activate MuSK had a similar age-dependent effect, indicating that the age-dependent signalling pathways activated by neuronal agrin involve the Lrp4/MuSK receptor complex as well as an Lrp4/MuSK-independent pathway which remained unknown. Collectively, our results highlight an age-dependent role for neuronal agrin in promoting the proliferation of human myoblasts

HIF-1 alpha response to hypoxia is functionally separated from the glucocorticoid stress response in the in vitro regenerating human skeletal muscle

Pirkmajer S, Filipovic D, Mars T, Mis K, Grubic Z. HIF-1 alpha response to hypoxia is functionally separated from the glucocorticoid stress response in the in vitro regenerating human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 299: R1693-R1700, 2010. First published October 13, 2010; doi:10.1152/ajpregu.00133.2010.-Injury of skeletal muscle is followed by muscle regeneration in which new muscle tissue is formed from the proliferating mononuclear myoblasts, and by systemic response to stress that exposes proliferating myoblasts to increased glucocorticoid (GC) concentration. Because of its various causes, hypoxia is a frequent condition affecting skeletal muscle, and therefore both processes, which importantly determine the outcome of the injury, often proceed under hypoxic conditions. It is therefore important to identify and characterize in proliferating human myoblasts: 1) response to hypoxia which is generally organized by hypoxia-inducible factor-1 alpha (HIF-1 alpha); 2) response to GCs which is mediated through the isoforms of glucocorticoid receptors (GRs) and 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs), and 3) the response to GCs under the hypoxic conditions and the influence of this combination on the factors controlling myoblast proliferation. Using real-time PCR, Western blotting, and HIF-1 alpha small-interfering RNA silencing, we demonstrated that cultured human myoblasts possess both, the HIF-1 alpha-based response to hypoxia, and the GC response system composed of GR alpha and types 1 and 2 11 beta-HSDs. However, using combined dexamethasone and hypoxia treatments, we demonstrated that these two systems operate practically without mutual interactions. A seemingly surprising separation of the two systems that both organize response to hypoxic stress can be explained on the evolutionary basis: the phylogenetically older HIF-1 alpha response is a protection at the cellular level, whereas the GC stress response protects the organism as a whole. This necessitates actions, like downregulation of IL-6 secretion and vascular endothelial growth factor, that might not be of direct benefit for the affected myoblasts

Koga, kdaj in kako napotiti k revmatologu

V Sloveniji kljub pomanjkanju revmatologov in s tem daljšimi čakalnimi dobami revmatološkim bolnikom zagotavljamo sodobno obravnavo, ki je primerljiva z delom v najbolj priznanih svetovnih ustanovah. Da visoko raven obravnave tudi vprihodnosti ohranimo, je bistvenega pomena, da so poslane napotnice primerno izpolnjene in opremljene z vsemi podatki, ki jih potrebujemo za ustrezno razvrščanje v čakalno knjigo glede na resnost in vrsto bolezni (triažiranje). V prispevku podajamo osnovna navodila glede napotitev v revmatološko ambulanto s strokovno ustreznimi stopnjami nujnosti