Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.

• MeSH
• Anti-Inflammatory Agents pharmacology   chemistry   MeSH
• Dexamethasone * pharmacology   chemistry   analogs & derivatives   MeSH
• Liver * drug effects   metabolism   MeSH
• Polylactic Acid-Polyglycolic Acid Copolymer * chemistry   MeSH
• Macrophages * drug effects   metabolism   MeSH
• Mice MeSH
• Nanospheres * chemistry   MeSH
• Drug Carriers chemistry   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

While there is substantial research on what people want in their romantic and sexual partners, much of this work focuses on WEIRD, youthful samples, fails to consider the role of undesirable characteristics (i.e., things people do not want in partners) at all, or in conjunction with desirable characteristics (i.e., things people do want in partners), and may be overly reliant on psychometric approaches to pivotal variables in mating psychology like mate value and sociosexuality. In a nationally representative (online) sample of 2280 people from Czechia (aged between 18 and 50 years old), we examined linear and quadratic age, education, and self-perceived mate value (desirability) effects on the desired levels in mate choice of eight undesirable and seven desirable characteristics in men and women in relation to ostensible metrics of mate value. Self-perceived mate value alone explained little variance (men 1%, women 2%), while all mate value and mating strategy indicators together explained little variance of mate preferences and aversions (men 3%, women 5%). Desirable characteristics were better explained by mate value than undesirable ones. Our results are in line with evolutionary predictions suggesting that women are more demanding. Also, more qualities to offer correlate with more expectations in a partner.

• MeSH
• Adult MeSH
• Interpersonal Relations MeSH
• Middle Aged MeSH
• Humans MeSH
• Marriage psychology   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Surveys and Questionnaires MeSH
• Self Concept MeSH
• Sexual Behavior psychology   MeSH
• Sexual Partners * psychology   MeSH
• Choice Behavior MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Úvod a cíl studie: Uterinní NK (uNK) buňky jsou specializovanou subpopulací NK (natural killer) lymfocytů nacházejících se v endometriu. Hrají klíčovou roli v regulaci imunitní odpovědi a v procesu implantace embrya. Cílem této studie je retrospektivní analýza výsledků léčby metodou in vitro fertilizace (IVF) v souboru žen, které podstoupily imunofenotypizaci uNK buněk a na základě výsledků tohoto vyšetření byly, nebo nebyly léčeny imunomodulační terapií. Metody: Studie zahrnovala 122 pacientek, které podstoupily imunofenotypizaci uNK buněk v období od dubna do prosince 2023. Imunofenotypizace byla provedena metodou průtokové cytometrie. Pacientky byly roztříděny do čtyř skupin dle fenotypu uNK buněk: normální nálezy, nízké absolutní a relativní počty uNK (LOW-IMMUNE profil), nízké počty uNK v kombinaci s nežádoucím posunem směrem k cytotoxickému uNKdim imunofenotypu (MIXED-IMMUNE profil) a normální počty uNK, ale nežádoucí posun v poměru cytotoxických a regulačních uNK s cytotoxickým fenotypem (OVER-IMMUNE profil). Byly hodnoceny výsledky embryotransferu a výskyt potratů do ukončeného 12. týdne těhotenství v jednotlivých skupinách. Výsledky: Nejvyšší míra dosažení klinické gravidity byla nalezena v léčené skupině OVER- -IMMUNE (70 %), následované skupinou MIXED-IMMUNE (60 %). Skupina LOW-IMMUNE se od neléčené NORMAL skupiny signifikantně nelišila (p = 0,205). Nedostatečná imunitní aktivace (LOW-IMMUNE profil) byla signifikantně nejčastěji sdružena s prvotrimestrální těhotenskou ztrátou (p < 0,0001). Závěr: Tato studie přináší nové poznatky o potenciálu imunofenotypizace uNK buněk a následné imunomodulační terapie v léčbě poruch plodnosti. Ačkoli výsledky naznačují možné klinické přínosy, je zapotřebí dalšího výzkumu k potvrzení těchto zjištění a k objasnění mechanizmů, které vedou ke zlepšení výsledků léčby technikami asistované reprodukce.

Introduction and objective: Uterine NK (uNK) cells, a specialized subpopulation of natural killer (NK) lymphocytes located in the endometrium, play a crucial role in regulating the immune response and in the process of embryo implantation. This study aims to retrospectively analyze the outcomes of in vitro fertilization (IVF) treatment in a cohort of women who underwent uNK cell immunophenotyping with subsequent immunomodulatory therapy applied based on the results. Methods: The study included 122 patients who underwent uNK cell immunophenotyping between April and December 2023. Immunophenotyping was performed using flow cytometry. Patients were categorized into four groups according to their uNK cell phenotypes: normal findings, low absolute and relative numbers of uNK cells (LOW-IMMUNE profile), low numbers of uNK cells combined with the shift towards the cytotoxic uNKc dim immunophenotype (MIXED-IMMUNE profile), and normal numbers of uNK cells, but an undesirable shift in the ratio of cytotoxic to regulatory uNK cells towards the cytotoxic uNK dim phenotype (OVER-IMMUNE profile). Embryo transfer outcomes and the occurrence of miscarriages up to the 12th week of pregnancy were evaluated in each group. Results: The highest clinical pregnancy rate was observed in the treated OVER-IMMUNE group (70%), fol lowed by the MIXED-IMMUNE group (60%). The LOW-IMMUNE group did not differ significantly from the untreated NORMAL group (P = 0.205). Insufficient immune activation (LOW-IMMUNE profile) was significantly associated with first-trimester pregnancy loss (P < 0.0001). Conclusion: This study provides new insights into the potential benefits of uNK cell immunophenotyping and subsequent immunomodulatory therapy in treating fertility disorders. While the results indicate possible clinical advantages, further research is necessary to confirm these findings and elucidate the mechanisms leading to improved outcomes in assisted reproductive techniques.

• Keywords
• uterinní NK buňky, imunofenotypizace lymfocytů, opakované selhání implantace,
• MeSH
• Killer Cells, Natural MeSH
• Endometrium cytology   MeSH
• Fertilization in Vitro * MeSH
• Abortion, Habitual MeSH
• Immunophenotyping MeSH
• Immunomodulation MeSH
• Humans MeSH
• Flow Cytometry methods   MeSH
• Retrospective Studies MeSH
• Infertility, Female * MeSH
• Check Tag
• Humans MeSH
• Female MeSH

BACKGROUND AND OBJECTIVE: We present a summary of the 2025 update for the European Association of Urology (EAU) guidelines for upper urinary tract urothelial carcinoma (UTUC). The aim is to provide practical recommendations on the clinical management of UTUC with a focus on diagnosis, treatment, and follow-up. METHODS: For the 2025 guidelines on UTUC, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences. KEY FINDINGS AND LIMITATIONS: Key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with UTUC. The guidelines stress the importance of appropriate treatment taking into account patient values and preferences. Key updates in the 2025 UTUC guidelines include: significant changes to the recommendations for UTUC diagnosis; complete revision of the sections addressing risk stratification, ureteroscopy, and the surgical approach for radical nephroureterectomy; addition of four new recommendations, two related to kidney-sparing management of localised low-risk UTUC and a further two related to management of high-risk nonmetastatic UTUC; a review and adaptation of recommendation for UTUC follow-up; and addition of a new section addressing quality indicators for UTUC management. CONCLUSIONS AND CLINICAL IMPLICATIONS: This overview of the 2025 EAU guidelines on UTUC offers valuable insights into risk factors, diagnosis, classification, treatment, and follow-up for UTUC. The guidelines contain information on the management of individual patients according to the current best evidence and are designed for effective integration in clinical practice.

• MeSH
• Carcinoma, Transitional Cell * therapy   diagnosis   MeSH
• Humans MeSH
• Kidney Neoplasms * therapy   diagnosis   MeSH
• Ureteral Neoplasms * therapy   diagnosis   MeSH
• Societies, Medical MeSH
• Urology standards   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Practice Guideline MeSH
• Geographicals
• Europe MeSH

For the treatment of bilateral limbal stem cell deficiency (LSCD), cell therapy with transplantation of cultivated oral mucosa epithelial cells (COMET) is a promising alternative. Although not yet established, current protocols on the cultivation of oral mucosal epithelial cell (OMECs) sheets are based mainly on substrates and xenobiotic additives that may lead to variable outcomes and undesirable immune responses by the patient. The aim of this study was to characterize OMECs cultivated in xenobiotic-free media (XF) seeded on fibrin gel, in comparison to conventional complex (COM) medium. Oral mucosal biopsies were retrieved from 31 donors. After cultivation in COM or XF medium, OMECs were compared based on growth kinetics, morphology, cell size and viability. Using immunofluorescence and gene expression analyses, the degree of stemness, proliferation and differentiation was evaluated in OMEC cultures. Our findings showed that although OMECs showed a similar morphology and viability, and comparable growth kinetics, immunofluorescence revealed the preservation of stemness (p63 + p40 positivity in cells ≤11 μm) and proliferation in both COM and XF. Gene expression analyses showed that keratin (K)13 and K15 expression levels were significantly higher in XF (adj. p < 0.001), but otherwise COM and XF-treated OMECs had comparable transcriptional profiles in a panel of stemness, proliferation and differentiation genes. These results demonstrate the feasibility of culturing OMECs on fibrin gel without xenogeneic additives, while maintaining their undifferentiated state and preserving stemness. In conclusion, both in terms of results and methodology, the procedures presented here are suitable for implementation in clinical practice.

• MeSH
• Cell Differentiation MeSH
• Cell Culture Techniques * MeSH
• Limbal Stem Cell Deficiency MeSH
• Adult MeSH
• Epithelial Cells * metabolism   drug effects   MeSH
• Fibrin * MeSH
• Gels MeSH
• Stem Cells * metabolism   cytology   MeSH
• Culture Media MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Limbus Corneae * cytology   pathology   metabolism   MeSH
• Corneal Diseases pathology   drug therapy   metabolism   MeSH
• Cell Proliferation drug effects   MeSH
• Epithelium, Corneal metabolism   cytology   drug effects   pathology   MeSH
• Aged MeSH
• Stem Cell Transplantation methods   MeSH
• Mouth Mucosa * cytology   MeSH
• Cell Survival MeSH
• Xenobiotics pharmacology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: In the current era of targeted axillary dissection (TAD), there are still cases where axillary lymph node dissection (ALND) is indicated, but histopathological examination confirms the regression of nodal metastases (ypN0). In this situation, ALND may represent undesirable overtreatment. METHODS: A retrospective study at the Comprehensive Cancer Centre was conducted based on a prospectively maintained database. Patients who underwent surgery after neoadjuvant chemotherapy (NAC) between 2020 and 2023 were selected, specifically those for whom ALND was directly indicated after NAC. Subsequently, clinical-pathological characteristics were compared between cases with ypN0 and those with persistent metastases (ypN+). The reasons for indicating ALND in ypN0 cases were extracted from the medical records. RESULTS: ALND was indicated in 118 cases across 117 patients, of which ypN0 was observed in 44 cases (37%). There were significantly more ypN0 cases for inflammatory carcinomas (68%), the non-luminal HER2-positive phenotype (76%), and carcinomas with histopathological regression of the primary tumor (76%) or the persistence of only the non-invasive component of ypTis (67%). Typical reasons for ALND in ypN0 cases included inflammatory carcinoma (n = 13, 29.5%), locally advanced carcinoma (n = 5, 11.4%), occult carcinoma (n = 2, 4.5%), or persistent lymphadenopathy on ultrasound examination after NAC, especially in the tumor phenotypes HER2-positive and triple-negative breast cancer (TNBC) (n = 8, 18.2%). CONCLUSIONS: Through real-world evidence data analysis, subgroups of breast cancer patients treated with NAC were identified who may experience surgical overtreatment in the axilla. These include patients with inflammatory carcinoma, locally advanced carcinoma, occult carcinoma, or patients with persistent lymphadenopathy on US examination after NAC, particularly in the tumor phenotypes HER2-positive and TNBC.

• Publication type
• Journal Article MeSH

BACKGROUND: Inappropriate therapy (IAT) is an undesirable side effect of implantable cardiac defibrillator (ICD) therapy. Early studies with the subcutaneous ICD (S-ICD) showed relatively high inappropriate shock (IAS) rates. The PRAETORIAN (Prospective Randomized Comparison of Subcutaneous and Transvenous Implantable Cardioverter Defibrillator Therapy) trial demonstrated that the S-ICD is noninferior to the transvenous ICD (TV-ICD) with regard to the combined end point of IAS and complications. This secondary analyses evaluates all IAT in the PRAETORIAN trial. METHODS: This international, multicenter trial randomized 849 patients with an indication for ICD therapy between S-ICD (n=426) and TV-ICD therapy (n=423). ICD programming was mandated by protocol. All analysis were performed in the modified intention-to-treat population. RESULTS: In both groups 42 patients experienced IAT (48-month Kaplan-Meier estimated cumulative incidence, 9.9% and 10.1%, respectively; hazard ratio (HR), 0.99 [95% CI, 0.65-1.52]; P=0.97). There was no significant difference in patients experiencing IAS between both groups (P=0.14). In the S-ICD group, 81 IAT episodes with 124 IAS and 1 inappropriate antitachycardia pacing occurred versus 89 IAT episodes with 130 IAS and 124 inappropriate antitachycardia pacing in the TV-ICD group. IAT episodes were most frequently caused by supraventricular tachycardias in the TV-ICD group (n=83/89) versus cardiac oversensing in the S-ICD group (n=40/81). In the TV-ICD group, a baseline heart rate >80 bpm (HR, 1.99 [95% CI, 1.05-3.76]; P=0.03), a history of atrial fibrillation (HR, 2.66 [95% CI, 1.41-5.02]; P=0.003), and smoking (HR, 2.46 [95% CI, 1.31-4.09]; P=0.005) were independent predictors for IAT. A QRS duration >120 ms was an independent predictor for IAT caused by cardiac oversensing in the S-ICD group (HR, 3.13 [95% CI, 1.34-7.31]; P=0.008). Post-IAS interventions significantly reduced IAS recurrence in both groups (P=0.046). CONCLUSIONS: There was no significant difference in IAT and IAS rates between the S-ICD and TV-ICD in a conventional ICD population, but causes and predictors for IAT differed between the devices. After the first IAS, an intervention significantly reduced the recurrence rate of IAS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01296022.

• MeSH
• Time Factors MeSH
• Defibrillators, Implantable * MeSH
• Electric Countershock * instrumentation   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH

Background/Objectives: As musculoskeletal injuries in gastroenterologists related to the performance of endoscopic procedures are on the rise, solutions and new approaches are needed to prevent these undesired outcomes. In our study, we evaluated an approach to ergonomic challenges in the form of a belt-like endoscope holder designed to redistribute the weight of the endoscope across the whole body of the practitioner. The aim of the study was to determine how the use of this holder affected the body posture of practitioners during endoscopy. Methods: We designed a special endoscopic model that emulates basic endoscopic movement and maneuvers. With the use of the MoCap camera system, we recorded experienced endoscopists exercising a standardized set of tasks with and without the holder. Results: Following video and statistical analyses, the most significant differences were observed in the position of the left arm which pointed to a more relaxed arm position. Conclusions: The ergonomic benefits of the belt holder in this model merit testing in the clinical setting to evaluate its effectiveness and prevention of musculoskeletal injuries in GI endoscopy.

• Publication type
• Journal Article MeSH

We aimed to prepare novel dibenzo [a,d][7]annulen derivatives that act on N-methyl-d-aspartate (NMDA) receptors with potential neuroprotective effects. Our approach involved modifying the tropane moiety of MK-801, a potent open-channel blocker known for its psychomimetic side effects, by introducing a seven-membered ring with substituted base moieties specifically to alleviate these undesirable effects. Our in silico analyses showed that these derivatives should have high gastrointestinal absorption and cross the blood-brain barrier (BBB). Our pharmacokinetic studies in rats supported this conclusion and confirmed the ability of leading compounds 3l and 6f to penetrate the BBB. Electrophysiological experiments showed that all compounds exhibited different inhibitory activity towards the two major NMDA receptor subtypes, GluN1/GluN2A and GluN1/GluN2B. Of the selected compounds intentionally differing in the inhibitory efficacy, 6f showed high relative inhibition (∼90 % for GluN1/GluN2A), while 3l showed moderate inhibition (∼50 %). An in vivo toxicity study determined that compounds 3l and 6f were safe at 10 mg/kg doses with no adverse effects. Behavioral studies demonstrated that these compounds did not induce hyperlocomotion or impair prepulse inhibition of startle response in rats. Neuroprotective assays using a model of NMDA-induced hippocampal neurodegeneration showed that compound 3l at a concentration of 30 μM significantly reduced hippocampal damage in rats. These results suggest that these novel dibenzo [a,d][7]annulen derivatives are promising candidates for developing NMDA receptor-targeted therapies with minimal psychotomimetic side effects.

• MeSH
• Dizocilpine Maleate * pharmacology   MeSH
• Blood-Brain Barrier metabolism   drug effects   MeSH
• Rats MeSH
• Humans MeSH
• Molecular Structure MeSH
• Neuroprotective Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Rats, Sprague-Dawley MeSH
• Receptors, N-Methyl-D-Aspartate * antagonists & inhibitors   metabolism   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The pregnane X receptor (PXR) is a key regulator of metabolism, but the mechanisms underlying its antagonism remain unclear. Garcia-Maldonado et al. reported potent new antagonists and their co-crystal structures, revealing molecular determinants of PXR antagonism and paving the way for developing antagonists as therapeutics and preventing undesirable PXR activation.

• MeSH
• Humans MeSH
• Pregnane X Receptor * antagonists & inhibitors   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH