- MeSH
- adherence k farmakoterapii * MeSH
- alopurinol * terapeutické užití MeSH
- antiuratika * terapeutické užití MeSH
- dna (nemoc) farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- oxypurinol * terapeutické užití MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- dopisy MeSH
Genetic variations in urate transporters play a significant role in determining human urate levels and have been implicated in developing hyperuricemia or gout. Polymorphism in the key urate transporters, such as ABCG2, URAT1, or GLUT9 was well-documented in the literature. Therefore in this study, our objective was to determine the frequency and effect of rare nonsynonymous allelic variants of SLC22A11, SLC22A13, and SLC17A1 on urate transport. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined all coding regions and exon-intron boundaries of SLC22A11, SLC22A13, and SLC17A1 using PCR amplification and Sanger sequencing. For comparison, we used a control group consisting of 115 normouricemic subjects. To examine the effects of the rare allelic nonsynonymous variants on the expression, intracellular processing, and urate transporter protein function, we performed a functional characterization using the HEK293A cell line, immunoblotting, fluorescent microscopy, and site directed mutagenesis for preparing variants in vitro. Variants p.V202M (rs201209258), p.R343L (rs75933978), and p.P519L (rs144573306) were identified in the SLC22A11 gene (OAT4 transporter); variants p.R16H (rs72542450), and p.R102H (rs113229654) in the SLC22A13 gene (OAT10 transporter); and the p.W75C variant in the SLC17A1 gene (NPT1 transporter). All variants minimally affected protein levels and cytoplasmic/plasma membrane localization. The functional in vitro assay revealed that contrary to the native proteins, variants p.P519L in OAT4 (p ≤ 0.05), p.R16H in OAT10 (p ≤ 0.05), and p.W75C in the NPT1 transporter (p ≤ 0.01) significantly limited urate transport activity. Our findings contribute to a better understanding of (1) the risk of urate transporter-related hyperuricemia/gout and (2) uric acid handling in the kidneys.
- MeSH
- dna (nemoc) * genetika MeSH
- hyperurikemie * genetika MeSH
- kotransportní proteiny pro sodík a fosfát - typ I * genetika MeSH
- kyselina močová metabolismus MeSH
- lidé MeSH
- přenašeče organických aniontů nezávislé na sodíku * genetika MeSH
- přenašeče organických aniontů * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected ≤ 40 years (HUA ≤ 40) and > 40 years, gout patients with disease onset ≤ 40 years (Gout ≤ 40) and > 40 years, and normouricemic healthy controls (HC). METHODS: Plasma samples were collected from 94 asymptomatic HUA (77% HUA ≤ 40) subjects, 196 gout patients (59% Gout ≤ 40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied. RESULTS: Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA ≤ 40 and Gout ≤ 40 without ULT. Multivariate statistics differentiated HUA ≤ 40 and Gout ≤ 40 groups from HC with an overall accuracy of > 95%. CONCLUSION: Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA ≤ 40 and Gout ≤ 40 patients, together with a correction of this imbalance with ULT.
- MeSH
- antiuratika terapeutické užití MeSH
- dna (nemoc) * diagnóza farmakoterapie MeSH
- hyperurikemie * diagnóza farmakoterapie MeSH
- kyselina močová MeSH
- lidé MeSH
- lipidomika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Oxidative stress supposedly plays a role in the pathogenesis of Parkinson's disease (PD). Uric acid (UA), a powerful antioxidant, is lowered in PD while allantoin, the oxidation product of UA and known biomarker of oxidative stress, was not systematically studied in PD. We aim to compare serum and cerebrospinal fluid (CSF) levels of UA, allantoin, and allantoin/UA ratio in de novo PD patients and controls, and evaluate their associations with clinical severity and the degree of substantia nigra degeneration in PD. We measured serum and CSF levels of UA, allantoin, and allantoin/UA ratio in 86 PD patients (33 females, mean age 57.9 (SD 12.6) years; CSF levels were assessed in 51 patients) and in 40 controls (19 females, 56.7 (14.1) years). PD patients were examined using Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson Disease-Autonomic (SCOPA-AUT), the University of Pennsylvania Smell Identification Test (UPSIT), one-night video-polysomnography, and dopamine transporter single-photon emission computed tomography (DAT-SPECT). Serum allantoin and allantoin/UA ratio were significantly increased in the PD group compared to controls (p < 0.001 and p = 0.002, respectively). Allantoin/UA ratios in serum and CSF were positively associated with the SCOPA-AUT score (p = 0.005 and 0.031, respectively) and RBD presence (p = 0.044 and 0.028, respectively). In conclusion, serum allantoin and allantoin/UA ratio are elevated in patients with de novo PD. Allantoin/UA ratio in serum and CSF is associated with autonomic dysfunction and RBD presence, indicating that higher systemic oxidative stress occurs in PD patients with more diffuse neurodegenerative changes.
- Publikační typ
- časopisecké články MeSH
Paradoxní kožní reakce jsou novou skupinou nežádoucích účinků, které se objevily v souvislosti s užíváním cílených biologických léků. Jsou definovány jako imunitně zprostředkovaná tkáňová reakce, která se objeví během biologické léčby a která je zároveň účinná v terapii daného nežádoucího účinku. Nejčastější kožní paradoxní reakcí je inhibitory TNF indukovaná psoriáza. Ostatní paradoxní reakce jako lichen, ekzematózní projevy, hidradenitis suppurativa, pyoderma gangrenosum nebo granulomatózní kožní léze se vyskytují méně často. Léčba paradoxních reakcí zahrnuje topickou či systémovou léčbu zaměřenou na kožní projev v závislosti na tíži postižení. Ukončení podávání biologického přípravku a jeho záměna za jiný často vede k vymizení paradoxní kožní reakce.
Paradoxical skin reactions are a new class of adverse events that has been associated with biological therapy. They are defined as inflammatory immune-mediated tissue reactions, developing paradoxically during treatment with biologics that are also effective in treating these reactions. The most common paradoxical skin reaction is TNF inhibitors-induced psoriasis. Other paradoxical skin reactions such as lichen planus, eczematous eruptions, hidradenitis suppurativa, pyoderma gangrenosum or granulomatous skin disease occur much more rarely. The treatment of paradoxical skin reactions includes topical or systemic skin-directed therapies, depending on the severity of adverse event. Discontinuation of the biologic therapy and switching to another biologic agent often results in resolution of the paradoxical skin reaction.
- MeSH
- biologická terapie * škodlivé účinky MeSH
- inhibitory TNF škodlivé účinky MeSH
- kůže patologie účinky léků MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The OAT1 (SLC22A6) and OAT3 (SLC22A8) urate transporters are located on the basolateral membrane of the proximal renal tubules, where they ensure the uptake of uric acid from the urine back into the body. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined the coding regions of both genes using PCR amplification and Sanger sequencing. Variants p.P104L (rs11568627) and p.A190T (rs146282438) were identified in the gene for solute carrier family 22 member 6 (SLC22A6) and variants p.R149C (rs45566039), p.V448I (rs11568486) and p.R513Q (rs145474422) in the gene solute carrier family 22 member 8 (SLC22A8). We performed a functional study of these rare non-synonymous variants using the HEK293T cell line. We found that only p.R149C significantly reduced uric acid transport in vitro. Our results could deepen the understanding of uric acid handling in the kidneys and the molecular mechanism of uric acid transport by the OAT family of organic ion transporters.
- MeSH
- biologický transport MeSH
- dna (nemoc) * genetika metabolismus MeSH
- HEK293 buňky MeSH
- hyperurikemie * genetika MeSH
- kyselina močová metabolismus MeSH
- lidé MeSH
- přenašeče organických aniontů nezávislé na sodíku * genetika MeSH
- protein 1 přenášející organické anionty * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Acute anterior uveitis (AAU) is a relatively common extra-musculoskeletal manifestation of axial spondyloarthritis (axSpA); however, data on the prevalence of active sacroiliitis in patients with AAU are limited. METHODS: 102 patients with AAU and 39 healthy subjects (HS) underwent clinical assessment and sacroiliac joint MRI. Patients with absence of active sacroiliitis were reassessed after two years. International Spondyloarthritis Society (ASAS) classification criteria for axSpA (regardless of patient's age) and expert opinion for definitive diagnosis of axSpA were applied. RESULTS: Although chronic back pain was equally present in both groups, bone marrow edema (BME) in SIJ and BME highly suggestive of axSpA was found in 52 (51%) and in 33 (32%) patients with AAU compared with 11 (28%) and none in HS, respectively. Out of all AAU patients, 41 (40%) patients fulfilled the ASAS classification criteria for axSpA, and 29 (28%) patients were considered highly suggestive of axSpA based on clinical features. Two out of the 55 sacroiliitis-negative patients developed active sacroiliitis at the two-year follow-up. CONCLUSIONS: One-third of patients with AAU had active inflammation on SIJ MRI and clinical diagnosis of axSpA. Therefore, patients with AAU, especially those with chronic back pain, should be referred to a rheumatologist, and the examination should be repeated if a new feature of SpA appears.
- Publikační typ
- časopisecké články MeSH
Hyperurikemie je způsobena nerovnováhou mezi tvorbou a vylučováním kyseliny močové. Nejčastější příčinou hyperurikemie je snížené vylučování kyseliny močové v ledvinách. Chronická hyperurikemie může vést k tvorbě krystalů a rozvoji dny. Dna a hyperurikemie jsou podle řady studií asociovány s dalšími onemocněními – např. s arteriální hypertenzí, chronickou renální insuficiencí, diabetes mellitus 2. typu a ischemickou chorobou srdeční. Důsledná léčba chronické hyperurikemie je nutná u pacientů s dnou jako prevence dnavých atak, k zabránění rozvoje tofů či k jejich eliminaci. Z terapeutických možností ovlivnění hyperurikemie se nejvíce používají inhibitory xantinoxidázy, které blokují konečnou fázi enzymatické degradace purinů na kyselinu močovou. Pozornost se znovu obrací také na urikosurika. Vznikají nové léky blokující specifické urátové transportéry podílející se na reabsorpci kyseliny močové v proximálních tubulech ledvin. Mezi inovativní možnosti patří např. pegylované rekombinantní urikázy.
Hyperuricemia is caused by an imbalance between the rates of production and excretion of uric acid. The most common cause of hyperuricemia is decreased uric acid excretion in the kidneys. Chronic hyperuricemia can lead to crystal formation and development of gout. Many studies have shown that gout and hyperuricemia are associated with other diseases, such as arterial hypertension, chronic renal failure, type 2 diabetes mellitus and ischemic heart disease. In patients with gout, the treatment of chronic hyperuricemia is necessary to prevent gout attacks and development of tophi or to eliminate them. The most widely used drugs for hyperuricemia are xanthine oxidase inhibitors, which block the last enzyme involved in uric acid synthesis pathway. Uricosuric agents experience renewed interest. Novel uricosurics, which inhibit specific urate transporters responsible for reabsorption of uric acid in renal proximal tubule, are under development. Newer therapeutic strategies include e.g. pegylated recombinant uricase.
Hyperurikemie je dána nerovnováhou mezi tvorbou a vylučováním kyseliny močové. Nejčastější příčinou hyperurikemie je snížené vylučování kyseliny močové, které zprostředkovávají urátové transportéry, především reabsorpční transportéry urátu URAT1 a glukózy GLUT9 a sekreční transportér ABC (ATP-binding casette) podtřídy G2 (ABCG2) v renálních proximálních tubulech a v případě ABCG2 i v gastrointestinálním traktu. Bylo identifikováno více než 30 genetických lokusů asociovaných s hyperurikemií a dnou, z nichž třetinu tvoří geny pro urátové transportéry. Z farmakologických možností ovlivnění hyperurikemie zůstávají řadu let zlatým standardem inhibitory xanthinoxidázy, které blokují konečnou fázi enzymatické degradace purinů na kyselinu močovou. Pozornost se znovu obrací také na urikosurika. Reabsorpční urátové transportéry v renálních proximálních tubulech jsou cílem vývoje řady nových urikosurik.
Hyperuricemia is caused by an imbalance between endogenous production and excretion of urate. The most common cause of hyperuricemia is decreased excretion of urate. Urate transport is mediated by several transmembrane proteins responsible for reabsorption (mainly URAT1 and GLUT9) and secretion ATP-binding cassette G2 (ABCG2) on the apical and basolateral membranes of the proximal tubules and in the case of ABCG2 also in the gastrointestinal tract. More than 30 genetic loci associated with hyperuricemia and gout have been identified, a third of which are genes for urate transporters. Xanthine oxidase inhibitors, which block the last enzyme involved in the uric acid synthesis pathway, are the most widely used drugs for hyperuricemia. Uricosuric agents experience renewed interest. Urate transporters responsible for the reabsorption of uric acid in renal proximal tubule are the target of the development of several novel uricosurics.
- MeSH
- alopurinol terapeutické užití MeSH
- febuxostat aplikace a dávkování terapeutické užití MeSH
- hyperurikemie * farmakoterapie genetika MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
