DRESS syndrom (z anglického Drug Reaction with Eosinophilia and Systemic Symptoms) je závažnou pozdní reakcí na některá léčiva, která může být potenciálně životu nebezpečná. Projevuje se většinou celotělovým exantémem, změnami v krevním obrazu a postižením orgánů, především jater a ledvin. Zde popisujeme případ polymorbidní pacientky ve vyšším věku s kožním postižením a selháním ledvin po užívání alopurinolu, u níž včasná diagnostika a adekvátní léčba vedla k obnovení renálních funkcí. Zásadním diagnostickým ukazatelem byla eosinofilie.
DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe late drug reaction, which can be potentially life threatening. It usually manifests itself as a whole-body exanthema, changes in blood count and organ involvement, especially the liver and kidneys. Here, we describe a case of a polymorbid elderly patient with skin involvement and renal failure related to the use of allopurinol. Early diagnosis and adequate treatment led to restoration of renal function. Eosinophilia was a crucial diagnostic indicator.
- MeSH
- alopurinol škodlivé účinky MeSH
- eozinofilie diagnóza etiologie MeSH
- komorbidita MeSH
- lékový hypersenzitivní syndrom * diagnóza etiologie komplikace terapie MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- renální insuficience etiologie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Glukokortikoidy jsou skupinou léků, která je používána k léčbě celé řady imunitně podmíněných chorob a stavů v mnoha oborech, včetně akutních stavů. Jedná se na jedné straně o velmi efektivní léky, které však na druhé straně mají i mnoho nežádoucích účinků, zejména při jejich dlouhodobém užívání a ve vyšších dávkách. Ve sdělení předkládáme přehled poznatků a evidenci o kardiovaskulárních rizicích léčby glukortikoidy a jejich klinických formách, které jsou stále vnímány spíše v kontextu klasických rizikových faktorů kardiovaskulárních onemocnění, jako je hypertenze, dyslipidemie apod.
Glucocorticoids are a group of drugs used to treat a wide range of immune-mediated diseases and conditions in many fields, including acute conditions. On the one hand, they are very effective drugs, but on the other hand, they also have many side effects, especially when used for long periods of time and at higher doses. In this communication, we present a review of the knowledge and evidence on the cardiovascular risks of glucocorticoid treatment and their clinical forms, which are still perceived more in the context of classical risk factors for cardiovascular disease, such as hypertension, dyslipidemia, etc.
Rabdomyolýza je potenciálně život ohrožující syndrom charakterizovaný nekrózou svalových buněk a uvolněním intracelulárního obsahu do cirkulace. Akutní poškození ledvin představuje jednu z jeho nejzávažnějších komplikací. Odhalení vyvolávajícího faktoru vyžaduje v některých případech značné diagnostické úsilí, jak dokumentuje i popisované kazuistické sdělení. Základ terapie tvoří, kromě ovlivnění samotné příčiny, časná a poměrně agresivní rehydratační terapie. V nejzávažnějších případech je nezbytná náhrada funkce ledvin, která se řídí renálními indikacemi. Eliminace samotného myoglobinu je ale při konvenční dialýze (i s použitím high‐flux dialyzačních membrán) vzhledem k jeho molekulové velikosti (17kDa) nedostatečná. Významným krokem ke zlepšení eliminace myoglobinu při rabdomyolýze se stalo použití inovativních dialyzačních membrán propustných i pro látky s vyšší molekulovou hmotností, takzvané medium cut‐off (MCO), či high cut‐off (HCO) membrány. Jejich využití bylo v případě popisované pacientky klíčovým momentem při snaze o zvrácení akutního poškození ledvin s oligurií, hypervolemií a dalšími provázejícími komplikacemi. Došlo k signifikantnímu poklesu myoglobinu v cirkulaci, rychlému zlepšení renálních funkcí a celkového klinického stavu.
Rhabdomyolysis is a potentially life-threatening syndrome characterized by necrosis of muscle cells and release of intracellular contents into the circulation. Acute kidney injury represents one of its most serious complications. The detection of the causative factor requires considerable diagnostic effort in some cases, as documented in the case report. The basis of therapy, in addition to affecting the cause itself, is early and relatively aggressive rehydration therapy. In the most severe cases, replacement of renal function is necessary, guided by renal indications. However, elimination of myoglobin itself is insufficient in conventional dialysis (even with the use of high-flux dialysis membranes) due to its molecular size (17kDa). The use of innovative dialysis membranes permeable to higher molecular weight substances, the so-called medium cut-off (MCO) or high cut-off (HCO) membranes, has become an important step towards improving myoglobin elimination in rhabdomyolysis. In the case of the described patient, their use was a key moment in the attempt to reverse acute kidney injury with oliguria, hypervolaemia and other accompanying complications. There was a significant decrease in circulating myoglobin, rapid improvement in renal function and overall clinical status.
- MeSH
- akutní poškození ledvin terapie MeSH
- dialýza ledvin MeSH
- hydratace organismu MeSH
- lidé MeSH
- rhabdomyolýza * etiologie komplikace terapie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Proteins are naturally formed by domains edging their functional and structural properties. A domain out of the context of an entire protein can retain its structure and to some extent also function on its own. These properties rationalize construction of artificial fusion multidomain proteins with unique combination of various functions. Information on the specific functional and structural characteristics of individual domains in the context of new artificial fusion proteins is inevitably encoded in sequential order of composing domains defining their mutual spatial positions. So the challenges in designing new proteins with new domain combinations lie dominantly in structure/function prediction and its context dependency. Despite the enormous body of publications on artificial fusion proteins, the task of their structure/function prediction is complex and nontrivial. The degree of spatial freedom facilitated by a linker between domains and their mutual orientation driven by noncovalent interactions is beyond a simple and straightforward methodology to predict their structure with reasonable accuracy. In the presented manuscript, we tested methodology using available modeling tools and computational methods. We show that the process and methodology of such prediction are not straightforward and must be done with care even when recently introduced AlphaFold II is used. We also addressed a question of benchmarking standards for prediction of multidomain protein structures-x-ray or Nuclear Magnetic Resonance experiments. On the study of six two-domain protein chimeras as well as their composing domains and their x-ray structures selected from PDB, we conclude that the major obstacle for justified prediction is inappropriate sampling of the conformational space by the explored methods. On the other hands, we can still address particular steps of the methodology and improve the process of chimera proteins prediction.
The earliest proteins had to rely on amino acids available on early Earth before the biosynthetic pathways for more complex amino acids evolved. In extant proteins, a significant fraction of the 'late' amino acids (such as Arg, Lys, His, Cys, Trp and Tyr) belong to essential catalytic and structure-stabilizing residues. How (or if) early proteins could sustain an early biosphere has been a major puzzle. Here, we analysed two combinatorial protein libraries representing proxies of the available sequence space at two different evolutionary stages. The first is composed of the entire alphabet of 20 amino acids while the second one consists of only 10 residues (ASDGLIPTEV) representing a consensus view of plausibly available amino acids through prebiotic chemistry. We show that compact conformations resistant to proteolysis are surprisingly similarly abundant in both libraries. In addition, the early alphabet proteins are inherently more soluble and refoldable, independent of the general Hsp70 chaperone activity. By contrast, chaperones significantly increase the otherwise poor solubility of the modern alphabet proteins suggesting their coevolution with the amino acid repertoire. Our work indicates that while both early and modern amino acids are predisposed to supporting protein structure, they do so with different biophysical properties and via different mechanisms.
- MeSH
- aminokyseliny * chemie MeSH
- prebiotika * MeSH
- proteiny chemie MeSH
- sbalování proteinů MeSH
- Publikační typ
- časopisecké články MeSH
Constantly increasing attention to bioengineered proteins has led to the rapid development of new functional targets. Here we present the biophysical and functional characteristics of the newly designed CaM/AMBN-Ct fusion protein. The two-domain artificial target consists of calmodulin (CaM) and ameloblastin C-terminus (AMBN-Ct). CaM as a well-characterized calcium ions (Ca2+) binding protein offers plenty of options in terms of Ca2+ detection in biomedicine and biotechnologies. Highly negatively charged AMBN-Ct belongs to intrinsically disordered proteins (IDPs). CaM/AMBN-Ct was designed to open new ways of communication synergies between the domains with potential functional improvement. The character and function of CaM/AMBN-Ct were explored by biophysical and molecular modelling methods. Experimental studies have revealed increased stability and preserved CaM/AMBN-Ct function. The results of molecular dynamic simulations (MDs) outlined different interface patterns between the domains with potential allosteric communication within the fusion.
- MeSH
- kalmodulin chemie MeSH
- lidé MeSH
- molekulární modely MeSH
- proteiny zubní skloviny chemie metabolismus MeSH
- sekvence aminokyselin genetika MeSH
- vápník chemie MeSH
- vazba proteinů fyziologie MeSH
- vazebná místa fyziologie MeSH
- vnitřně neuspořádané proteiny chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Ameloblastin (Ambn) as an intrinsically disordered protein (IDP) stands for an important role in the formation of enamel-the hardest biomineralized tissue commonly formed in vertebrates. The human ameloblastin (AMBN) is expressed in two isoforms: full-length isoform I (AMBN ISO I) and isoform II (AMBN ISO II), which is about 15 amino acid residues shorter than AMBN ISO I. The significant feature of AMBN-its oligomerization ability-is enabled due to a specific sequence encoded by exon 5 present at the N-terminal part in both known isoforms. In this study, we characterized AMBN ISO I and AMBN ISO II by biochemical and biophysical methods to determine their common features and differences. We confirmed that both AMBN ISO I and AMBN ISO II form oligomers in in vitro conditions. Due to an important role of AMBN in biomineralization, we further addressed the calcium (Ca2+)-binding properties of AMBN ISO I and ISO II. The binding properties of AMBN to Ca2+ may explain the role of AMBN in biomineralization and more generally in Ca2+ homeostasis processes.
- MeSH
- biologické modely MeSH
- hydrodynamika MeSH
- lidé MeSH
- multimerizace proteinu MeSH
- protein - isoformy MeSH
- proteiny vázající vápník chemie metabolismus MeSH
- proteiny zubní skloviny chemie metabolismus MeSH
- spektrální analýza MeSH
- teplota MeSH
- vápník metabolismus MeSH
- vazba proteinů MeSH
- vnitřně neuspořádané proteiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Domains are distinct units within proteins that typically can fold independently into recognizable three-dimensional structures to facilitate their functions. The structural and functional independence of protein domains is reflected by their apparent modularity in the context of multi-domain proteins. In this work, we examined the coupling of evolution of domain sequences co-occurring within multi-domain proteins to see if it proceeds independently, or in a coordinated manner. We used continuous information theory measures to assess the extent of correlated mutations among domains in multi-domain proteins from organisms across the tree of life. In all multi-domain architectures we examined, domains co-occurring within protein sequences had to some degree undergone concerted evolution. This finding challenges the notion of complete modularity and independence of protein domains, providing new perspective on the evolution of protein sequence and function.
