• MeSH
• Quantum Theory MeSH
• Humans MeSH
• Mind-Body Relations, Metaphysical MeSH
• Disease MeSH
• Consciousness MeSH
• Check Tag
• Humans MeSH

V kazuistike analyzujeme príčinu nízkeho time in range u 66-ročného, pravidelne športujúceho pacienta s diabetes mellitus 1. typu v trvaní 17 rokov a anamnézou chronického srdcového zlyhávania používajúceho kontinuálny monitoring glykémií.

In the case report, we analyse the cause of a low time in range in a 66-year-old regularly exercising patient with type 1 diabetes mellitus lasting for 17 years and a history of chronic heart failure, and using continuous blood glucose monitoring.

Cytochalasans are known as inhibitors of actin polymerization and for their cytotoxic and migrastatic activity. In this study, we synthesized a series of cytochalasin derivatives that lack a macrocyclic moiety, a structural element traditionally considered essential for their biological activity. We focused on substituting the macrocycle with simple aryl-containing sidechains, and we have also synthesized compounds with different substitution patterns on the cytochalasin core. The cytochalasin analogues were screened for their migrastatic and cytotoxic activity. Compound 24 which shares the substitution pattern with natural cytochalasins B and D exhibited not only significant in vitro migrastatic activity towards BLM cells but also demonstrated inhibition of actin polymerization, with no cytotoxic effect observed at 50 μM concentration. Our results demonstrate that even compounds lacking the macrocyclic moiety can exhibit biological activities, albeit less pronounced than those of natural cytochalasins. However, our findings emphasize the pivotal role of substituting the core structure in switching between migrastatic activity and cytotoxicity. These findings hold significant promise for further development of easily accessible cytochalasan analogues as novel migrastatic agents.

• Publication type
• Journal Article MeSH

INTRODUCTION: Postoperative constipation (PC) in patients with imperforate anus and perineal fistula (PF) has been reported in up to 60%. Histological studies of PF revealed innervation anomalies which seem to be one of the reasons for PC. Perioperative histologically controlled fistula resection (PHCFR) allows appropriate resection of PF and pull-down normoganglionic rectum at the time of posterior sagittal anorectoplasty (PSARP). MATERIALS AND METHODS: A total of 665 patients with anorectal malformations underwent surgery between 1991 and 2021. Of these, 364 presented PF; 92 out of them (41 F) were studied. Patients with sacral and spinal cord anomalies, neurological disorders, and cut-back anoplasty were excluded. PSARP was done on all patients. Hematoxylin-eosin staining and NADH Tetrazolium-reductase histochemical method were used. Four and more ganglion cells in the myenteric plexus represented a sufficient length of the resection. The continence was scored according to the modified Krickenbeck scoring system. Final scores ranged from 1 to 7 points. Values are given as median. RESULTS: A total of 65 (70.7%) patients presented an aganglionic segment in PF, and 27 patients presented hypoganglionosis. The median length of the resected fistula was 25 mm (interquartile range [IQR]: 20-30). The median total continence score was 7 (IQR: 6-7). Post-op constipation was observed in 6/92 (6.5%) patients. CONCLUSION: PHCFR diminished PC to 6.5% of patients.

• MeSH
• Anus, Imperforate * surgery   MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Infant, Newborn MeSH
• Perineum surgery   MeSH
• Postoperative Complications etiology   MeSH
• Child, Preschool MeSH
• Rectal Fistula * surgery   MeSH
• Rectum surgery   abnormalities   MeSH
• Retrospective Studies MeSH
• Treatment Outcome MeSH
• Constipation etiology   surgery   MeSH
• Plastic Surgery Procedures methods   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Infant, Newborn MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

G-quadruplexes (G4s) formed within RNA are emerging as promising targets for therapeutic intervention in cancer, neurodegenerative disorders and infectious diseases. Sequences containing a succession of short GG blocks, or uneven G-tract lengths unable to form three-tetrad G4s (GG motifs), are overwhelmingly more frequent than canonical motifs involving multiple GGG blocks. We recently showed that DNA is not able to form stable two-tetrad intramolecular parallel G4s. Whether RNA GG motifs can form intramolecular G4s under physiological conditions and play regulatory roles remains a burning question. In this study, we performed a systematic analysis and experimental evaluation of a number of biologically important RNA regions involving RNA GG motifs. We show that most of these motifs do not form stable intramolecular G4s but need to dimerize to form stable G4 structures. The strong tendency of RNA GG motif G4s to associate may participate in RNA-based aggregation under conditions of cellular stress.

• MeSH
• Dimerization MeSH
• G-Quadruplexes * MeSH
• Transcription, Genetic MeSH
• Humans MeSH
• Nucleotide Motifs * MeSH
• RNA * chemistry   metabolism   genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

DNA double-strand breaks (DSBs) represent a lethal form of DNA damage that can trigger cell death or initiate oncogenesis. The activity of RNA polymerase II (RNAPII) at the break site is required for efficient DSB repair. However, the regulatory mechanisms governing the transcription cycle at DSBs are not well understood. Here, we show that Integrator complex subunit 6 (INTS6) associates with the heterotrimeric sensor of ssDNA (SOSS1) complex (comprising INTS3, INIP and hSSB1) to form the tetrameric SOSS1 complex. INTS6 binds to DNA:RNA hybrids and promotes Protein Phosphatase 2A (PP2A) recruitment to DSBs, facilitating the dephosphorylation of RNAPII. Furthermore, INTS6 prevents the accumulation of damage-associated RNA transcripts (DARTs) and the stabilization of DNA:RNA hybrids at DSB sites. INTS6 interacts with and promotes the recruitment of senataxin (SETX) to DSBs, facilitating the resolution of DNA:RNA hybrids/R-loops. Our results underscore the significance of the tetrameric SOSS1 complex in the autoregulation of DNA:RNA hybrids and efficient DNA repair.

• MeSH
• DNA-Binding Proteins metabolism   MeSH
• DNA Helicases metabolism   genetics   MeSH
• DNA * metabolism   chemistry   MeSH
• DNA Breaks, Double-Stranded * MeSH
• Phosphorylation MeSH
• Homeostasis genetics   MeSH
• Humans MeSH
• DNA Repair * MeSH
• Protein Phosphatase 2 metabolism   genetics   MeSH
• R-Loop Structures MeSH
• RNA Helicases metabolism   genetics   MeSH
• RNA Polymerase II * metabolism   MeSH
• RNA * metabolism   genetics   chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The use of temporary mechanical circulatory support (tMCS) in cardiogenic shock patients has increased during the last decades with most management strategies relying on observational studies and expert opinion, including hemodynamic monitoring, device selection, and timing of support institution/duration. In this context, imaging has a pivotal role throughout the patient pathway, from identification to initiation, monitoring, and weaning. This manuscript summarizes the consensus of an expert panel from the European Society of Cardiology Association for Acute CardioVascular Care, the European Association of CardioVascular Imaging, and the European Extracorporeal Life Support Organization, providing the rationale for and practical guidance of imaging to tMCS based on existing evidence and consensus on best current practice.

• MeSH
• Adult MeSH
• Shock, Cardiogenic * therapy   diagnostic imaging   MeSH
• Consensus * MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation MeSH
• Heart-Assist Devices * MeSH
• Societies, Medical MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Consensus Development Conference MeSH
• Review MeSH
• Geographicals
• Europe MeSH

BACKGROUND: Activation of nuclear factor-kappa B (NF-κB) signalling is key in the pathogenesis of chronic kidney disease (CKD). However, a certain level of NF-κB activity is necessary to enable tissue repair. METHODS: The relationship between activated and inactivated NF-κB signaling and the pathogenesis of CKD was investigated using mouse models of NF-κB partial inactivation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into alanine) and activation (mutating cysteine at position 59 of the sixth exon on the NF-κB gene into serine). RESULTS: The density of CD3, CD8, CD68 positive cells, as well as the expression of interleukin 6, Tumor necrosis factor receptor associated factor 1 and Nef-associated factor 1 in the kidney tissues of NF-κBC59A mice were reduced, whereas an opposing pattern was observed in the NF-κBC59S mice. Blood pressure, kidney fibrosis (analyzed by periodic acid-Schiff, Masson trichrome and Sirius Red staining, as well as α-SMA immunofluorescence), serum creatinine and urinary albumin-to-creatinine ratio are markedly increased in NF-κB-activated and -inactivated mice compared with controls. Transmission electron microscopy indicated that the glomerular basement membrane was thicker in both NF-κBC59A and NF-κBC59S mice compared with wild-type mice. CONCLUSIONS: Using mice models with partially activated and inactivated NF-κB pathways suggests that there is an apparently U-shaped relationship between blood pressure, kidney function as well as morphology and the activation of the NF-κB pathway. A certain optimal activity of the NF-κB pathway seems to be important to maintain optimal kidney function and morphology.

• MeSH
• Renal Insufficiency, Chronic metabolism   pathology   etiology   MeSH
• Fibrosis MeSH
• Hypertension * metabolism   etiology   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• NF-kappa B * metabolism   MeSH
• Signal Transduction * MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND AND PURPOSE: We evaluated whether there was a difference in the occurrence of relapses pre- and post-COVID-19 vaccination in a nationwide cohort of Danish patients with relapsing multiple sclerosis. METHODS: We conducted a population-based, nationwide cohort study with a cutoff date of 1 October 2022. We used McNemar tests to assess changes in the proportion of patients with recorded relapses within 90 days and 180 days before and after first vaccine dose, and a negative binomial regression model to compare the 90 and 180 days postvaccination annualized relapse rate (ARR) to the 360 days prevaccination ARR. Multivariate Cox regression was used to estimate relapse risk factors. RESULTS: We identified 8169 vaccinated (87.3% Comirnaty) patients without a recorded history of a positive COVID-19 test. We did not find statistically significant changes in the proportion of patients with relapses in the 90 days (1.3% vs. 1.4% of patients, p = 0.627) and 180 days (2.7% vs. 2.6% of patients, p = 0.918) pre- and postvaccination. Also, a comparison of the ARR 360 days before (0.064, 95% confidence interval [CI] = 0.058-0.070) with the ARR 90 (0.057, 95% CI = 0.047-0.069, p = 0.285) and 180 (0.055, 95% CI = 0.048-0.063, p = 0.060) days after vaccination did not show statistically significant differences. Lower age, higher Expanded Disability Status Scale score, and relapse within 360 days before vaccination were associated with a higher risk of relapse. CONCLUSIONS: We did not find evidence of increased relapse activity following the administration of the first dose of the COVID-19 vaccine.

• MeSH
• Chronic Disease MeSH
• COVID-19 * prevention & control   MeSH
• Cohort Studies MeSH
• Humans MeSH
• Recurrence MeSH
• Multiple Sclerosis, Relapsing-Remitting * MeSH
• Multiple Sclerosis * MeSH
• Vaccination MeSH
• COVID-19 Vaccines therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Denmark MeSH

BACKGROUND: To date there remains much ambiguity in the literature regarding the immunological interplay between SARS-CoV-2 and HIV and the true risk posed to coinfected individuals. There has been little conclusive data regarding the use of CD4 cell count and HIV viral load stratification as predictors of COVID-19 severity in this cohort. METHODS: We performed a retrospective, observational cohort study on people living with HIV (PLWH) who contracted COVID-19 in central and eastern Europe. We enrolled 536 patients from 16 countries using an online survey. We evaluated patient demographics, HIV characteristics and COVID-19 presentation and outcomes. Statistical analysis was performed using SPSS 20.1. RESULTS: The majority of the study cohort were male (76.4%) and 152 (28.3%) had a significant medical comorbidity. Median CD4 cell count at COVID-19 diagnosis was 605 cells/μL [interquartile range (IQR) 409-824]. The majority of patients on antiretroviral therapy (ART) were virally suppressed (92%). In univariate analysis, CD4 cell count <350 cells/μL was associated with higher rates of hospitalization (p < 0.0001) and respiratory failure (p < 0.0001). Univariate and multivariate analyses found that an undetectable HIV VL was associated with a lower rate of hospitalization (p < 0.0001), respiratory failure (p < 0.0001), ICU admission or death (p < 0.0001), and with a higher chance of full recovery (p < 0.0001). CONCLUSION: We can conclude that detectable HIV viral load was an independent risk factor for severe COVID-19 illness and can be used as a prognostic indicator in this cohort.

• MeSH
• COVID-19 * epidemiology   complications   MeSH
• HIV Infections * complications   drug therapy   epidemiology   MeSH
• Humans MeSH
• CD4 Lymphocyte Count MeSH
• Respiratory Insufficiency * MeSH
• Retrospective Studies MeSH
• SARS-CoV-2 MeSH
• COVID-19 Testing MeSH
• Viral Load MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Geographicals
• Europe, Eastern MeSH