INTRODUCTION: Primary aldosteronism is the most common form of secondary hypertension and blood pressure salt sensitivity. In the setting of hyperaldosteronism and a high-salt diet, disturbances in tissue sodium and potassium levels may contribute to salt sensitivity. This study aimed to determine whether aldosterone-dependent changes in tissue and plasma sodium and potassium concentrations occur before or after the development of salt sensitivity and hypertension in a rat model of primary aldosteronism. Previous studies in this model show that aldosterone-dependent salt sensitivity develops after 7-10 days on a high-salt diet. A secondary objective was to investigate differences in skin gene expression between aldosterone-treated rats and vehicle-treated controls. METHODS: Unilaterally nephrectomized male Sprague-Dawley rats received continuous infusions of aldosterone or vehicle while being fed a high-salt diet. Electrolyte concentrations in plasma, carcass, and skin were measured after 2 and 14 days of high-salt feeding. Tissue sodium and potassium concentrations were determined by atomic absorption spectroscopy and expressed as mmol/g tissue dry weight, while plasma ions (mmol/L) were measured using ion-selective electrodes. RNA sequencing (RNAseq) was used to identify differentially expressed genes in the skin, and gene set enrichment analysis (GSEA) was performed to explore biological processes associated with aldosterone treatment. RESULTS: After 2 days on the high-salt diet, aldosterone-treated rats showed significantly lower skin and plasma potassium concentrations compared to vehicle-treated controls, while sodium concentrations in the carcass, skin, and plasma did not differ significantly. At 14 days, aldosterone-treated rats continued to exhibit lower plasma potassium levels, although skin potassium differences were no longer significant. Carcass sodium concentrations were significantly higher in aldosterone-treated rats at 14 days. GSEA revealed that, at 2 days, aldosterone treatment affected biological processes related to electrolyte homeostasis and hyperosmotic responses. At 14 days, biological processes related to muscle function and calcium ion transport were significantly altered. CONCLUSION: Aldosterone-treated rats on a high-salt diet for 2 days had lower skin and plasma potassium levels compared to salt-loaded controls, suggesting early potassium depletion precedes significant sodium accumulation and blood pressure increases. These findings raise the possibility that early potassium depletion contributes to the development of aldosterone-induced salt sensitivity. Further studies with detailed time-course analysis will be of interest to elucidate the role of early potassium depletion in increasing vascular resistance and triggering aldosterone-dependent salt sensitivity and hypertension.

• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS: Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US-representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross-sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS: In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION: Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. HIGHLIGHTS: Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition-neuropathology associations. Transportability methods can provide insight into selection bias.

• MeSH
• Alzheimerova nemoc * psychologie   patologie   MeSH
• cerebrovaskulární poruchy * psychologie   patologie   MeSH
• kognice * fyziologie   MeSH
• lidé MeSH
• neuropsychologické testy statistika a číselné údaje   MeSH
• osamocení * psychologie   MeSH
• průřezové studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. METHODS: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. RESULTS: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). DISCUSSION: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. HIGHLIGHTS: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.

• MeSH
• Alzheimerova nemoc genetika   MeSH
• celogenomová asociační studie * MeSH
• demence genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• lidé MeSH
• rizikové faktory MeSH
• vaskulární demence * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host-microorganism interactions. These RORγt+ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt+ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.

• MeSH
• antigen prezentující buňky metabolismus   MeSH
• endoteliální buňky MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 * metabolismus   MeSH
• lidé MeSH
• lymfocyty * MeSH
• přirozená imunita MeSH
• transportní proteiny metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Súčasné trendy projekcie liečiv významne reflektujú tzv. privilegované zoskupenia ako základné (tzv. jadrové) štruktúrne fragmenty s rozhodujúcim vplyvom na afinitu k vhodne zvoleným biologickým cieľom, účinok, selektivitu aj toxikologické charakteristiky týchto liečiv a perspektívnych kandidátov na liečivá. Fruquintinib (1) je nový syntetický selektívny inhibítor izoforiem receptora vaskulárneho endotelového rastového faktora (z angl. vascular endothelial growth factor receptor; VEGFR), t. j. VEGFR-1, VEGFR-2 a VEGFR-3. Terapeutikum (1) obsahuje planárne bicyklické heteroaromatické jadro, v ktorom sú vhodne inkorporované dva atómy dusíka, základný (jadrový) bicyklický heteroaromatický kruh – privilegované (substituované) benzofuránové zoskupenie a skupinu pôsobiacu ako donor a akceptor väzby vodíkovým mostíkom (VVM), t. j. amidové funkčné zoskupenie. Fruquintinib (1) bol prvýkrát schválený v Číne pre liečbu metastázujúceho kolorektálneho karcinómu, závažného nádorového ochorenia s vysokou mortalitou. Táto prehľadová publikácia ponúkla stručný pohľad na tému privilegovaných štruktúr, ich niekoľkých parametrov, ktorých rozsah približuje tzv. liečivu podobné (drug-like) vlastnosti, farmakodynamické charakteristiky fruquintinibu (1) a rôzne in silico-deskriptory definujúce štruktúrne a fyzikálno-chemické vlastnosti tohto liečiva (molekulová hmotnosť, počet ťažkých atómov, počet aromatických tažkých atómov, frakcia C-atómov v sp3-hybridizovanom stave, počet akceptorov VVM, počet donorov VVM, celkový polárny povrch, molekulová refrakcia, molekulový objem aj parametre lipofility a rozpustnosti). Niektoré z týchto deskriptorov súviseli s farmakokinetikou aj distribúciou fruquintinibu (1) a navyše by mohli pomôcť predikovať jeho schopnosť pasívne prechádzať hematoencefalickou bariérou (HEB). V publikácii sa hodnotila aj eventuálna súvislosť medzi indukčným potenciálom liečiva (1) voči izoenzýmom cytochrómu P450 (CYP1A2 a CYP3A4) a jeho pasívnym transportom do centrálneho nervového systému via HEB. Stručne boli takisto načrtnuté súčasné klinické skúsenosti s fruquintinibom (1) a budúce liečebné možnosti tohto terapeutika.

Current trends in drug design notably consider so-called privileged scaffolds as the core structural fragments with decisive impact on affinity to properly chosen biological targets, potency, selectivity and toxicological characteristics of drugs and prospective drug candidates. Fruquintinib (1) is a novel synthetic selective inhibitor of vascular endothelial growth factor receptor (VEGFR) isoforms, i.e., VEGFR-1, VEGFR-2 and VEGFR-3. The therapeutic agent (1) consists of a flat bicyclic heteroaromatic ring, in which two nitrogens are suitablyincorporated, a core bicyclic heteroaromatic ring – privileged (substituted) benzofuran scaffold, and a pair of hydrogen bond (H-bond) donor and acceptor group, i.e., amide functional moiety. Fruquintinib (1) was first approved in China for the treatment of metastatic colorectal cancer, a severe malignant disease with a high mortality rate. The review article offered a brief insight into the topic of privileged structures, their drug- -like ranges of several parameters, pharmacodynamic characteristics of fruquintinib (1) and various in silico descriptors characterizing drug’s structural and physicochemical properties (molecular weight, number of heavy atoms, number of aromatic heavy atoms, fraction of sp3 C-atoms, number of H-bond acceptors, number of H-bond donors, total polar surface area, molar refractivity, molecular volume as well as parameters of lipophilicity and solubility). Some of these descriptors were related to pharmacokinetics and distribution of fruquintinib (1), and, in addition, might help predict its ability to cross passively the blood–brain barrier (BBB). Moreover, a possible connection between the induction potential on cytochrome P450 isoenzymes (CYP1A2 and CYP3A4) and passive transport of a given drug into the central nervous system via BBB was investigated. Current clinical experience and future directions regarding of fruquintinib (1) were also briefly outlined.

• Klíčová slova
• fruquintinib,
• MeSH
• benzofurany farmakologie   MeSH
• chinazoliny farmakologie   MeSH
• farmakokinetika MeSH
• lidé MeSH
• protinádorové látky * farmakokinetika   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH

Úvod: Potíže pacientů se syndromem diabetické nohy jsou nejčastěji způsobeny periferní neuropatií a vaskulopatií. Při mikroangiopatii dochází k poruše funkce prekapilárních sfinkterů, otevírají se arteriovenózní zkraty a dochází k venostáze. Tyto poruchy mohou mít za následek zvýšenou tvorbu intersticiální tekutiny, která může stav tkání dále zhoršovat. Proto jsme se rozhodli u těchto pacientů otestovat funkci lymfatického systému. Materiál a metoda: Do souboru jsme zařadili 13 pacientů se syndromem diabetické nohy bez kožního defektu. Jednalo se o 9 žen a 4 muže průměrného věku 64 let. Z vlastní databáze pacientů bez diabetu jsme vybrali stejně početnou kontrolní skupinu stejného věku a pohlaví. Lymfoscintigrafie byla provedena standardním způsobem po aplikaci radiokoloidu do podkoží distální části nártů. Snímali jsme ihned po aplikaci, po 30 minutách klidu a po 30 minutách chůze. Vypočítali jsme transportní kapacitu lymfatického systému jako procento koloidu akumulovaného v tříselných uzlinách. Pro srovnání obou souborů jsme použili párový t-test. Výsledky: Průměrná transportní kapacita u diabetiků na pravé a levé DK v klidu a po zátěži chůzí byla 4,4 %, 4,8 %, 18,6 %, 19,5 %, u pacientů bez diabetu 0,4 %, 0,3 %, 4,8 % a 2,9 % (p = 0,000–0,007). Závěr: Transportní kapacita lymfatického systému dolních končetin je u diabetiků se syndromem diabetické nohy několikanásobně vyšší ve srovnání s pacienty bez diabetu. Na druhou stranu je ale jejich rezerva transportní kapacity několikanásobně nižší než u pacientů bez diabetu. Jsme přesvědčeni, že je to způsobeno přetížením lymfatického systému v důsledku zvýšené tvorby intersticiální tekutiny, což se může podílet na komplikacích.

Introduction: Lymphatic system can play an important role in the development of some pathological processes in diabetic foot syndrome. It is associated with neurological abnormalities and various degree of peripheral vascular disease in the lower limbs which can increase the amount of interstitial fluid. We, therefore, tested function of lymphatic system of lower extremities in diabetic patients. Material and methods: We evaluated 13 diabetic patients (4 male, 9 female, average age 64 years) with diabetic foot syndrome without skin defect. We selected control group (13 matched patients without diabetes) from our historical database. Lymphoscintigraphy was performed after subcutaneous injection of radio-colloid in the web spaces of the feet. Static images were performed immediately post injection, 30 minutes post injection at rest and after 30 minutes of walking. The transport capacity (percentage of the injected dose accumulated in the regional lymph nodes) was then calculated. Paired t-test was used for comparison. Results: Mean transport capacity in diabetic and non-diabetic pts on the right and left side at rest and after stress was 4.4%, 18.6%, 4.8%, 19.5%, 0.4%, 4.8%, 0.3%, and 2.9%, respectively (p=0.000–0.007). Rest transport capacity in diabetics was at the level of stress transport capacity in non-diabetics while transport capacity reserve in non-diabetic pts was twice as higher as in diabetics. Conclusion: Transport capacity of lymphatic system of both lower extremities at rest is much higher in diabetic patients comparing to patients without diabetes while their transport capacity reserve is much lower. We believe this is a sign of overload of lymphatics due to increased amount of interstitial fluid which can contribute to development of diabetic foot syndrome.

• Klíčová slova
• transportní kapacita,
• MeSH
• diabetická noha * MeSH
• dospělí MeSH
• klinická studie jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatický systém * MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH

• MeSH
• dítě MeSH
• péče o pacienty v kritickém stavu MeSH
• terapie náhlých příhod MeSH
• Check Tag
• dítě MeSH

• Konspekt
• Pediatrie
• NLK Obory
• pediatrie
• urgentní lékařství
• NLK Publikační typ
• kolektivní monografie

BACKGROUND: The etiopathogenesis of abdominal aortic aneurysm (AAA) is still unclarified, but vascular inflammation and matrix metalloproteases activation have a recognized role in AAA development and progression. Circulating lipoproteins are involved in tissue inflammation and repair, particularly through the regulation of intracellular cholesterol, whose excess is associated to cell damage and proinflammatory activation. We analyzed lipoprotein metabolism and function in AAA and in control vasculopathic patients, to highlight possible non-atherosclerosis-related, specific abnormalities. METHODS: We measured fluorometrically serum esterified/total cholesterol ratio, as an index of lecithin-cholesterol acyltransferase (LCAT) activity, and cholesteryl ester transfer protein (CETP) activity in patients referred to vascular surgery either for AAA (n=30) or stenotic aortic/peripheral atherosclerosis (n=21) having similar burden of cardiovascular risk factors and disease. We measured high-density lipoprotein (HDL)-cholesterol efflux capacity (CEC), through the ATP-binding cassette G1 (ABCG1) and A1 (ABCA1) pathways and serum cell cholesterol loading capacity (CLC), by radioisotopic and fluorimetric methods, respectively. RESULTS: We found higher LCAT (+23%; p < 0.0001) and CETP (+49%; p < 0.0001) activity in AAA sera. HDL ABCG1-CEC was lower (-16%; p < 0.001) and ABCA1-CEC was higher (+31.7%; p < 0.0001) in AAA. Stratification suggests that smoking may partly contribute to these modifications. CEC and CETP activity correlated with CLC only in AAA. CONCLUSIONS: We demonstrated that compared to patients with stenotic atherosclerosis, patients with AAA had altered HDL metabolism and functions involved in their anti-inflammatory and tissue repair activity, particularly through the ABCG1-related intracellular signaling. Clarifying the relevance of this mechanism for AAA evolution might help in developing new diagnostic parameters and therapeutic targets for the early management of this condition.

• MeSH
• adenosintrifosfát MeSH
• aneurysma břišní aorty * MeSH
• antiflogistika MeSH
• ateroskleróza * MeSH
• cholesterol metabolismus   MeSH
• cholesterolacyltransferasa metabolismus   MeSH
• HDL-cholesterol MeSH
• homeostáza MeSH
• lecitiny MeSH
• lidé MeSH
• lipoproteiny metabolismus   MeSH
• metaloproteasy metabolismus   MeSH
• transportní proteiny pro estery cholesterolu MeSH
• zánět metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Several studies have been published in the last decade on the effects of low glucose degradation product (GDP) neutral pH (L-GDP/N-pH) dialysis solutions on peritoneal morphology and function during the long-term PD treatment. Compared to conventional solutions, the impact of these solutions on the morphological and functional alterations of the peritoneal membrane is discussed, including those of effluent proteins that reflect the status of peritoneal tissues. Long-term PD with conventional solutions is associated with the loss of mesothelium, submesothelial and interstitial fibrosis, vasculopathy, and deposition of advanced glycosylation end products (AGEs). L-GDP/N-pH solutions mitigate these alterations, although vasculopathy and AGE deposition are still present. Increased vascular density was found in some studies. Small solute transport increases with PD duration on conventional solutions. Initially, higher values are present on L-GDP/N-pH treatment, but these may be reversible and remain stable with PD duration. Consequently, ultrafiltration (UF) is lower initially but remains stable thereafter. At 5 years, UF and small pore fluid transport are higher, while free water transport decreased only slightly during follow-up. Cancer antigen 125 was initially higher on L-GDP/N-pH solutions, suggesting better mesothelial preservation but decreased during follow-up. Therefore, L-GDP/N-pH solutions may not prevent but reduce and retard the peritoneal alterations induced by continuous exposure to glucose-based dialysis fluids.

• MeSH
• dialyzační roztoky metabolismus   MeSH
• glukosa metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• peritoneální dialýza * škodlivé účinky   MeSH
• peritoneum metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. RESULTS: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). CONCLUSIONS: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

• MeSH
• bipolární porucha genetika   MeSH
• celogenomová asociační studie MeSH
• depresivní porucha unipolární * genetika   MeSH
• endoteliální buňky MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• pohlavní dimorfismus * MeSH
• psychotické poruchy * genetika   MeSH
• receptory vaskulárního endoteliálního růstového faktoru MeSH
• schizofrenie genetika   MeSH
• sulfurtransferasy MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH