Despite the availability of new drugs on the clinics in recent years, drug-resistant epilepsy remains an unresolved challenge for healthcare, and one-third of epilepsy patients remain refractory to anti-seizure medications. Gene therapy in experimental models has emerged as effective treatment targeting specific neuronal populations in the epileptogenic focus. When combined with an external chemical activator using chemogenetics, it also becomes an "on-demand" treatment. Here, we evaluate a targeted and specific chemogenetic therapy, the PSAM/PSEM system, which holds promise as a potential candidate for clinical application in treating drug-resistant epilepsy. We show that the inert ligand uPSEM817, which selectively activates the chloride-permeable channel PSAM4-GlyR, effectively reduces the number of depolarization-induced action potentials in vitro. This effect is likely due to the shunting of depolarizing currents, as evidenced by decreased membrane resistance in these cells. In organotypic slices, uPSEM817 decreased the number of bursts and peak amplitude of events of spontaneous epileptiform activity. Although administration of uPSEM817 in vivo did not significantly alter electrographic seizures in a male mouse model of temporal lobe epilepsy, it did demonstrate a strong trend toward reducing the frequency of interictal epileptiform discharges. These findings indicate that PSAM4-GlyR-based chemogenetics holds potential as an anti-seizure strategy, although further refinement is necessary to enhance its efficacy.
- MeSH
- akční potenciály účinky léků MeSH
- epilepsie patofyziologie genetika farmakoterapie terapie metabolismus MeSH
- genetická terapie metody MeSH
- hipokampus * metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Many studies have demonstrated the association between low birth weight (LBW) and chronic kidney disease, estimated glomerular filtration rate (eGFR) and kidney volume (KV). However, studies on twins and those investigating numerous perinatal factors beyond LBW, and their associations with various kidney parameters are scarce. METHODS: A two-center cross-sectional study on five-year-old LBW children was conducted between 2021 and 2023. 110 children were enrolled (8 LBW, 58 very LBW (VLBW), 44 extremely LBW (ELBW)); 56 were twins. We examined associations between birth weight (BW), various prenatal, perinatal and postnatal factors, and eGFR, KV, tubular abnormalities and kidney ultrasound abnormalities, both in singletons and twins. RESULTS: In children with ELBW, eGFR correlated with BW (r = 0.55, P = 0.0018), while in those with BW ≥ 1000 g, eGFR remained constant. Other factors associated with decreased eGFR were hypertensive disorder of pregnancy (93.86 vs. 87.26 ml/min/1.73m2, P = 0.0285) in singletons, decreased growth velocity (β = 0.83, P = 0.0277) in twins, and lower total KV (tKV) and relative KV (rKV) in both singletons (r = 0.60, P < 0.0001 for tKV and r = 0.45, P = 0.0010 for rKV) and twins (β = 0.34, P < 0.0001 for tKV and β = 0.23, P = 0.0002 for rKV). Based on the multivariable models excluding KV, BW and gestational age were associated with eGFR in singletons, while male gender, BW, growth velocity, and coffee drinking during pregnancy were associated with eGFR in twins. However, in models that included KV, BW, gestational age and growth velocity were no longer significant. Total KV was associated with BW (r = 0.39, P = 0.0050 for singletons; β = 2.85, P < 0.0001 for twins), body mass index (r = 0.34, P = 0.0145 for singletons; β = 8.44, P < 0.0001 for twins), and growth velocity (β = 1.43, P = 0.0078). Twins born small for gestational age had lower tKV (70.88 vs 89.20 ml, P < 0.0001). Relative KV showed similar associations. Relative kidney volumes were significantly lower for both kidneys compared to the reference population (55.02 vs 65.42 ml/m2, P < 0.0001 for right kidney and 61.12 vs 66.25 ml/m2, P = 0.0015 for left kidney); however, only 8.6% of children had rKV below 10th percentile. CONCLUSION: Many factors affect eGFR and KV, some of them differ between twins and singletons. Based on multivariable models, eGFR seems to be better predicted by KV than by BW and gestational age in LBW children. Relative kidney volumes were significantly lower in our cohort compared to the reference population, but only 8.6% of rKV were below 10th percentile.
- MeSH
- chronická renální insuficience epidemiologie etiologie patofyziologie MeSH
- dvojčata MeSH
- hodnoty glomerulární filtrace * MeSH
- ledviny * diagnostické zobrazování patofyziologie MeSH
- lidé MeSH
- novorozenec s nízkou porodní hmotností * MeSH
- novorozenec MeSH
- porodní hmotnost MeSH
- předškolní dítě MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- těhotenství MeSH
- velikost orgánu MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
BACKGROUND AND AIM: Diabetes has been shown in last decades to be associated with a significantly higher mortality among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary PCI (PPCI). Therefore, the aim of current study was to evaluate the impact of diabetes on times delays, reperfusion and mortality in a contemporary STEMI population undergoing PPCI, including treatment during the COVID pandemic. METHODS AND RESULTS: The ISACS-STEMI COVID-19 is a large-scale retrospective multicenter registry involving PPCI centers from Europe, Latin America, South-East Asia and North-Africa, including patients treated from 1st of March until June 30, 2019 and 2020. Primary study endpoint of this analysis was in-hospital mortality. Secondary endpoints were postprocedural TIMI 0-2 flow and 30-day mortality. Our population is represented by 16083 STEMI patients. A total of 3812 (23,7 %) patients suffered from diabetes. They were older, more often males as compared to non-diabetes. Diabetic patients were less often active smokers and had less often a positive family history of CAD, but they were more often affected by hypertension and hypercholesterolemia, with higher prevalence of previous STEMI and previous CABG. Diabetic patients had longer ischemia time, had more often anterior MI, cardiogenic shock, rescue PCI and multivessel disease. They had less often out-of-hospital cardiac arrest and in-stent thrombosis, received more often a mechanical support, received less often a coronary stent and DES. Diabetes was associated with a significantly impaired postprocedural TIMI flow (TIMI 0-2: 9.8 % vs 7.2 %, adjusted OR [95 % CI] = 1.17 [1.02-1.38], p = 0.024) and higher mortality (in-hospital: 9.1 % vs 4.8 %, Adjusted OR [95 % CI] = 1.70 [1.43-2.02], p < 0.001; 30-day mortality: 10.8 % vs 6 %, Adjusted HR [95 % CI] = 1.46 [1.26-1.68], p < 0.001) as compared to non-diabetes, particularly during the pandemic. CONCLUSIONS: Our study showed that in a contemporary STEMI population undergoing PPCI, diabetes is significantly associated with impaired epicardial reperfusion that translates into higher in-hospital and 30-day mortality, particularly during the pandemic.
- MeSH
- čas zasáhnout při rozvinutí nemoci MeSH
- časové faktory MeSH
- COVID-19 * mortalita epidemiologie MeSH
- diabetes mellitus * mortalita diagnóza epidemiologie MeSH
- hodnocení rizik MeSH
- infarkt myokardu s elevacemi ST úseků * mortalita terapie diagnóza MeSH
- koronární angioplastika * mortalita škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mortalita v nemocnicích MeSH
- registrace MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
The marine environment is considered one of the most important ecosystems with high biodiversity. Microorganisms in this environment are variable and coexist with other marine organisms. The microbes associated with other marine organisms produce compounds with biological activity that may help the host's defense against invading organisms. The symbiotic association of bacteria with marine invertebrates is of ecological and biotechnological importance. Biologically active metabolites isolated from bacteria associated with marine invertebrates are considered potential sources of natural antimicrobial molecules for treating infectious diseases. Many studies have been conducted to screen the antimicrobial activity of metabolites produced by bacteria associated with marine invertebrates. This work provides an overview of the advancements in antimicrobial compound research on bacteria associated with marine invertebrates.
- MeSH
- antibakteriální látky * farmakologie MeSH
- antiinfekční látky * farmakologie metabolismus chemie MeSH
- Bacteria * metabolismus izolace a purifikace chemie MeSH
- bezobratlí * mikrobiologie MeSH
- symbióza MeSH
- vodní organismy * mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND AND OBJECTIVE: While active surveillance (AS) is an alternative to surgical interventions in patients with small renal masses (SRMs), evidence regarding its oncological efficacy is still debated. We aimed to evaluate oncological outcomes for patients with SRMs who underwent AS in comparison to surgical interventions. METHODS: In April 2024, PubMed, Scopus, and Web of Science were queried for comparative studies evaluating AS in patients with SRMs (PROSPERO: CRD42024530299). The primary outcomes were overall (OS) and cancer-specific survival (CSS). A random-effects model was used for quantitative analysis. KEY FINDINGS AND LIMITATIONS: We identified eight eligible studies (three prospective, four retrospective, and one study based on Surveillance, Epidemiology and End Results [SEER] data) involving 4947 patients. Pooling of data with the SEER data set revealed significantly higher OS rates for patients receiving surgical interventions (hazard ratio [HR] 0.73; p = 0.007), especially partial nephrectomy (PN; HR 0.62; p < 0.001). However, in a sensitivity analysis excluding the SEER data set there was no significant difference in OS between AS and surgical interventions overall (HR 0.84; p = 0.3), but the PN subgroup had longer OS than the AS group (HR 0.6; p = 0.002). Only the study based on the SEER data set showed a significant difference in CSS. The main limitations include selection bias in retrospective studies, and classification of interventions in the SEER database study. CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients treated with AS had similar OS to those who underwent surgery or ablation, although caution is needed in interpreting the data owing to the potential for selection bias and variability in AS protocols. Our review reinforces the need for personalized shared decision-making to identify patients with SRMs who are most likely to benefit from AS. PATIENT SUMMARY: For well-selected patients with a small kidney mass suspicious for cancer, active surveillance seems to be a safe alternative to surgery, with similar overall survival. However, the evidence is still limited and more studies are needed to help in identifying the best candidates for active surveillance.
BACKGROUND: As the healthcare sector evolves, Artificial Intelligence's (AI's) potential to enhance laboratory medicine is increasingly recognized. However, the adoption rates and attitudes towards AI across European laboratories have not been comprehensively analyzed. This study aims to fill this gap by surveying European laboratory professionals to assess their current use of AI, the digital infrastructure available, and their attitudes towards future implementations. METHODS: We conducted a methodical survey during October 2023, distributed via EFLM mailing lists. The survey explored six key areas: general characteristics, digital equipment, access to health data, data management, AI advancements, and personal perspectives. We analyzed responses to quantify AI integration and identify barriers to its adoption. RESULTS: From 426 initial responses, 195 were considered after excluding incomplete and non-European entries. The findings revealed limited AI engagement, with significant gaps in necessary digital infrastructure and training. Only 25.6 % of laboratories reported ongoing AI projects. Major barriers included inadequate digital tools, restricted access to comprehensive data, and a lack of AI-related skills among personnel. Notably, a substantial interest in AI training was expressed, indicating a demand for educational initiatives. CONCLUSIONS: Despite the recognized potential of AI to revolutionize laboratory medicine by enhancing diagnostic accuracy and efficiency, European laboratories face substantial challenges. This survey highlights a critical need for strategic investments in educational programs and infrastructure improvements to support AI integration in laboratory medicine across Europe. Future efforts should focus on enhancing data accessibility, upgrading technological tools, and expanding AI training and literacy among professionals. In response, our working group plans to develop and make available online training materials to meet this growing educational demand.
- MeSH
- klinické laboratoře MeSH
- lidé MeSH
- průzkumy a dotazníky MeSH
- umělá inteligence * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
BACKGROUND: Androgen-receptor signaling inhibitors (ARSIs) significantly improve survival in systemic therapy for advanced/metastatic prostate cancer (PCa) patients; however possible central nervous system (CNS) toxicity is an unaddressed concern. We aimed to assess and compare the incidence of CNS-related adverse events (AEs) secondary to the treatment of PCa patients with different ARSIs. MATERIALS: In August 2023, a comprehensive seach was conducted in three databases for randomized controlled trials (RCTs) of PCa patients receiving ARSIs plus ADT. The primary endpoints included mental impairment, cognitive impairment, seizure, fatigue, and falls. RESULTS: Twenty-six RCTs, comprising 20,328 patients, were included in meta-analyses and network meta-analyses (NMAs). ARSIs increased the risk of mental impairment (RR: 1.72; 95% CI, 1.09-2.71), cognitive impairment (RR: 2.25; 95% CI, 1.78-2.86), seizure (RR: 2.20, 95% CI, 1.09-4.45), fatigue (RR: 1.31, 95% CI, 1.20-1.43), and falls (RR: 2.07, 95% CI, 1.60-2.67) compared to standard of care (SOC). Based on NMAs, Enzalutamide showed a significant increase in risk for all assessed CNS-related AEs, while Abiraterone demonstrated significant risk increases in cognitive impairment, fatigue, and falls. Conversely, Darolutamide did not exhibit significant increases in risk for any CNS-related AEs, except for fatigue. CONCLUSIONS: The addition of ARSIs to ADT increased all examined CNS-related AEs compared to SOC. Each ARSI is associated with a distinct profile of CNS-related AEs. Careful patient selection and monitoring for CNS sequelae is necessary to achieve the best quality of life in patients on ARSI + ADT for PCa.
- MeSH
- antagonisté androgenních receptorů * škodlivé účinky aplikace a dávkování terapeutické užití MeSH
- benzamidy MeSH
- fenylthiohydantoin škodlivé účinky aplikace a dávkování MeSH
- lidé MeSH
- nádory prostaty * farmakoterapie patologie MeSH
- nemoci centrálního nervového systému chemicky indukované MeSH
- nitrily MeSH
- pyrazoly MeSH
- randomizované kontrolované studie jako téma MeSH
- síťová metaanalýza * MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- přehledy MeSH
- systematický přehled MeSH
Yeasts are unicellular fungi that occur in a wide range of ecological niches, where they perform numerous functions. Furthermore, these microorganisms are used in industrial processes, food production, and bioremediation. Understanding the physiological and adaptive characteristics of yeasts is of great importance from ecological, biotechnological, and industrial perspectives. In this context, we evaluated the abilities to assimilate and ferment different carbon sources, to produce extracellular hydrolytic enzymes, and to tolerate salt stress, heavy metal stress, and UV-C radiation of two isolates of Eremothecium coryli, isolated from Momordica indica fruits. The two isolates were molecularly identified based on sequencing of the 18S-ITS1-5.8S-ITS2 region. Our isolates were able to assimilate nine carbon sources (dextrose, galactose, mannose, cellobiose, lactose, maltose, sucrose, melezitose, and pectin) and ferment three (glucose, maltose, and sucrose). The highest values of cellular dry weight were observed in the sugars maltose, sucrose, and melezitose. We observed the presence of hyphae and pseudohyphae in all assimilated carbon sources. The two isolates were also capable of producing amylase, catalase, pectinase, and proteases, with the highest values of enzymatic activity found in amylase. Furthermore, the two isolates were able to grow in media supplemented with copper, iron, manganese, nickel, and zinc and to tolerate saline stress in media supplemented with 5% NaCl. However, we observed a decrease in CFU at higher concentrations of these metals and NaCl. We also observed morphological changes in the presence of metals, which include changes in cell shape and cellular dimorphisms. The isolates were sensitive to UV-C radiation in the shortest exposure time (1 min). Our findings reinforce the importance of endophytic yeasts for biotechnological and industrial applications and also help to understand how these microorganisms respond to environmental variations caused by human activities.
- MeSH
- endofyty * izolace a purifikace genetika metabolismus fyziologie klasifikace účinky záření MeSH
- fermentace MeSH
- fylogeneze MeSH
- fyziologický stres * MeSH
- metabolismus sacharidů * MeSH
- ovoce * mikrobiologie MeSH
- Saccharomycetales * izolace a purifikace genetika fyziologie metabolismus účinky záření klasifikace MeSH
- těžké kovy toxicita MeSH
- ultrafialové záření MeSH
- Publikační typ
- časopisecké články MeSH
β-Glucans comprise a group of β-D-glucose polysaccharides (glucans) that occur naturally in the cell walls of bacteria, fungi, and cereals. Its degradation is catalyzed by β-glucanases, enzymes that catalyze the breakdown of β-glucan into cello-oligosaccharides and glucose. These enzymes are classified as endo-glucanases, exo-glucanases, and glucosidases according to their mechanism of action, being the lichenases (β-1,3;1,4-glucanases, EC 3.2.1.73) one of them. Hence, we aimed to enhance lichenase production by Thermothelomyces thermophilus through the application of response surface methodology, using tamarind (Tamarindus indica) and jatoba (Hymenaea courbaril) seeds as carbon sources. The crude extract was immobilized, with a focus on improving lichenase activity, using various ionic supports, including MANAE (monoamine-N-aminoethyl), DEAE (diethylaminoethyl)-cellulose, CM (carboxymethyl)-cellulose, and PEI (polyethyleneimine)-agarose. Regarding lichenase, the optimal conditions yielding the highest activity were determined as 1.5% tamarind seeds, cultivation at 50 °C under static conditions for 72 h. Moreover, transitioning from Erlenmeyer flasks to a bioreactor proved pivotal, resulting in a 2.21-fold increase in activity. Biochemical characterization revealed an optimum temperature of 50 °C and pH of 6.5. However, sustained stability at varying pH and temperature levels was challenging, underscoring the necessity of immobilizing lichenase on ionic supports. Notably, CM-cellulose emerged as the most effective immobilization medium, exhibiting an activity of 1.01 U/g of the derivative (enzyme plus support), marking a substantial enhancement. This study marks the first lichenase immobilization on these chemical supports in existing literature.
- MeSH
- enzymy imobilizované * metabolismus chemie MeSH
- fungální proteiny * metabolismus chemie MeSH
- glykosidhydrolasy * metabolismus chemie biosyntéza MeSH
- koncentrace vodíkových iontů MeSH
- ovoce metabolismus MeSH
- semena rostlinná metabolismus MeSH
- Sordariales MeSH
- stabilita enzymů MeSH
- Tamarindus metabolismus mikrobiologie MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUNDS: SWI/SNF complexes represent a family of multi-subunit chromatin remodelers that are affected by alterations in >20% of human tumors. While mutations of SWI/SNF genes are relatively uncommon in prostate cancer (PCa), the literature suggests that deregulation of various subunits plays a role in prostate tumorigenesis. To assess SWI/SNF functions in a clinical context, we studied the mutually exclusive, paralogue accessory subunits SMARCD1, SMARCD2, and SMARCD3 that are included in every known complex and are sought to confer specificity. METHODS: Performing immunohistochemistry (IHC), the protein levels of the SMARCD family members were measured using a tissue microarray (TMA) comprising malignant samples and matching healthy tissue of non-metastatic PCa patients (n = 168). Moreover, IHC was performed in castration-resistant tumors (n = 9) and lymph node metastases (n = 22). To assess their potential role as molecular biomarkers, SMARCD1 and SMARCD3 protein levels were correlated with clinical parameters such as T stage, Gleason score, biochemical recurrence, and progression-free survival. RESULTS: SMARCD1 protein levels in non-metastatic primary tumors, lymph node metastases, and castration-resistant samples were significantly higher than in benign tissues. Likewise, SMARCD3 protein expression was elevated in tumor tissue and especially lymph node metastases compared to benign samples. While SMARCD1 levels in primary tumors did not exhibit significant associations with any of the tested clinical parameters, SMARCD3 exhibited an inverse correlation with pre-operative PSA levels. Moreover, low SMARCD3 expression was associated with progression to metastasis. CONCLUSIONS: In congruence with previous literature, our results implicate that both SMARCD1 and SMARCD3 may exhibit relevant functions in the context of prostate tumorigenesis. Moreover, our approach suggests a potential role of SMARCD3 as a novel prognostic marker in clinically non-metastatic PCa.
- MeSH
- chromozomální proteiny, nehistonové * genetika metabolismus MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru patologie metabolismus genetika MeSH
- lymfatické metastázy MeSH
- nádorové biomarkery * genetika metabolismus MeSH
- nádory prostaty rezistentní na kastraci patologie genetika metabolismus MeSH
- nádory prostaty * patologie metabolismus genetika MeSH
- prognóza MeSH
- senioři MeSH
- stupeň nádoru MeSH
- transkripční faktory genetika metabolismus MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
