Continuing the work developed by our research group, in the present manuscript, we performed a theoretical study of 10 new structures derived from the antivirals cidofovir and ribavirin, as inhibitor prototypes for the enzyme thymidylate kinase from Variola virus (VarTMPK). The proposed structures were subjected to docking calculations, molecular dynamics simulations, and free energy calculations, using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, inside the active sites of VarTMPK and human TMPK (HssTMPK). The docking and molecular dynamic studies pointed to structures 2, 3, 4, 6, and 9 as more selective towards VarTMPK. In addition, the free energy data calculated through the MM-PBSA method, corroborated these results. This suggests that these compounds are potential selective inhibitors of VarTMPK and, thus, can be considered as template molecules to be synthesized and experimentally evaluated against smallpox.
- Publication type
- Journal Article MeSH
Real-world data report worse 3-month clinical outcomes in elderly patients with acute ischemic stroke (AIS) treated with mechanical thrombectomy (MT). The aim was to identify factors influencing clinical outcome in elderly patients with anterior circulation AIS treated with MT (±intravenous thrombolysis (IVT)). In a retrospective, monocentric study, analysis of prospectively collected data of 138 patients (≥80 years) was performed. IVT was an independent negative predictor (OR 0.356; 95% CI: 0.134-0.942) and female sex an independent positive predictor (OR 4.179, 95% CI: 1.300-13.438) of 3-month good clinical outcome (modified Rankin scale 0-2). Female sex was also an independent negative predictor of 3-month mortality (OR 0.244, 95% CI: 0.100-0.599). Other independent negative predictors of 3-month good clinical outcome were older age, lower pre-stroke self-sufficiency, more severe neurological deficit and longer procedural intervals. Mortality was also independently predicted by longer procedural interval and by the occurrence of symptomatic intracerebral hemorrhage (p < 0.05 in all cases). Our results demonstrated, that in patients aged ≥80 years with anterior circulation AIS undergoing MT (±IVT), IVT reduced the chance of 3-month good clinical outcome and female sex was associated with a greater likelihood of 3-month good clinical outcome and lower probability of 3-month mortality.
- Publication type
- Journal Article MeSH
Gait disorders accompany a number of neurological and musculoskeletal disorders that significantly reduce the quality of life. Motion sensors enable high-quality modelling of gait stereotypes. However, they produce large volumes of data, the evaluation of which is a challenge. In this publication, we compare different data reduction methods and classification of reduced data for use in clinical practice. The best accuracy achieved between a group of healthy individuals and patients with ataxic gait extracted from the records of 43 participants (23 ataxic, 20 healthy), forming 418 segments of straight gait pattern, is 98% by random forest classifier preprocessed by t-distributed stochastic neighbour embedding.
- MeSH
- Ataxia diagnosis MeSH
- Gait MeSH
- Quality of Life * MeSH
- Humans MeSH
- Gait Disorders, Neurologic * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Anterior circulation stroke (ACS) is associated with typical symptoms, while posterior circulation stroke (PCS) may cause a wide spectrum of less specific symptoms. We aim to assess the correlation between the initial presentation of acute ischemic stroke (AIS) symptoms and the treatment timeline. Using a retrospective, observational, single-center study, the set consists of 809 AIS patients treated with intravenous thrombolysis (IVT) and/or endovascular treatment (EVT). We investigate the impact of baseline clinical AIS symptoms and the affected vascular territory on recanalization times in patients treated with IVT only and EVT (±IVT). Regarding the IVT-only group, increasing the National Institutes of Health Stroke Scale (NIHSS) score on admission and speech difficulties are associated with shorter (by 1.59 ± 0.76 min per every one-point increase; p = 0.036, and by 24.56 ± 8.42 min; p = 0.004, respectively) and nausea/vomiting with longer (by 43.72 ± 13.13 min; p = 0.001) onset-to-needle times, and vertigo with longer (by 8.58 ± 3.84 min; p = 0.026) door-to-needle times (DNT). Regarding the EVT (±IVT) group, coma is associated with longer (by 22.68 ± 6.05 min; p = 0.0002) DNT, anterior circulation stroke with shorter (by 47.32 ± 16.89 min; p = 0.005) onset-to-groin time, and drooping of the mouth corner with shorter (by 20.79 ± 6.02 min; p = 0.0006) door-to-groin time. Our results demonstrate that treatment is initiated later in strokes with less specific symptoms than in strokes with typical symptoms.
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- Journal Article MeSH
Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world's acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation.
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- Journal Article MeSH
- Review MeSH
Mushroom poisoning has always been a threat to human health. There are a large number of reports about ingestion of poisonous mushrooms every year around the world. It attracts the attention of researchers, especially in the aspects of toxin composition, toxic mechanism and toxin application in poisonous mushroom. Inocybe is a large genus of mushrooms and contains toxic substances including muscarine, psilocybin, psilocin, aeruginascin, lectins and baeocystin. In order to prevent and remedy mushroom poisoning, it is significant to clarify the toxic effects and mechanisms of these bioactive substances. In this review article, we summarize the chemistry, most known toxic effects and mechanisms of major toxic substances in Inocybe mushrooms, especially muscarine, psilocybin and psilocin. Their available toxicity data (different species, different administration routes) published formerly are also summarized. In addition, the treatment and medical application of these toxic substances in Inocybe mushrooms are also discussed. We hope that this review will help understanding of the chemistry and toxicology of Inocybe mushrooms as well as the potential clinical application of its bioactive substances to benefit human beings.
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- Agaricales chemistry metabolism physiology MeSH
- Lectins chemistry pharmacology MeSH
- Humans MeSH
- Muscarine chemistry poisoning toxicity MeSH
- Organophosphorus Compounds chemistry toxicity MeSH
- Mushroom Poisoning etiology therapy MeSH
- Psilocybin analogs & derivatives chemistry poisoning toxicity MeSH
- Tryptamines chemistry toxicity MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND AND OBJECTIVES: Renal elimination of amikacin and other aminoglycosides is slowed down in sepsis-induced acute kidney injury increasing the risk of adverse effects. Since neutrophil gelatinase-associated lipocalin (NGAL) and aminoglycosides share the mechanisms for renal excretion, the predictive power of NGAL was examined towards the changes in amikacin pharmacokinetics during early endotoxemia in anesthetized Wistar rats. METHODS: Endogenous biomarkers of inflammation and acute kidney injury were assessed including NGAL in saline-injected controls and two groups of rats challenged with an intravenous injection of bacterial lipopolysaccharide (5 mg/kg)-a fluid-resuscitated group (LPS) and a fluid-resuscitated group infused intravenously with 8 μg/kg/h terlipressin (LPS-T). Sinistrin and amikacin were infused to measure glomerular filtration rate (GFR) and amikacin clearance (CLam). The investigations included blood gas analysis, chemistry and hematology tests and assessment of urine output, creatinine clearance (CLcr) and sinistrin clearance (CLsini). RESULTS: Within 3 h of injection, systemic and renal inflammatory responses were induced by lipopolysaccharide. Gene and protein expression of NGAL was increased in the kidneys and the concentrations of NGAL in the plasma (pNGAL) and urine rose 4- to 38-fold (P < 0.01). The decreases in CLam and the GFR markers (CLcr, CLsini) were proportional, reflecting the extent to which endotoxemia impaired the major elimination mechanism for the drug. Terlipressin attenuated lipopolysaccharide-induced renal dysfunction (urine output, CLcr, CLsini) and accelerated CLam. The pNGAL showed a strong association with the CLsini (rs = - 0.77, P < 0.0005). Concerning prediction of CLam, pNGAL was comparable to CLcr (mean error - 24%) and inferior to CLsini (mean error - 6.4%), while the measurement of NGAL in urine gave unsatisfactory results. CONCLUSIONS: During early endotoxemia in the rat, pNGAL has a moderate predictive ability towards CLam. Clinical studies should verify whether pNGAL can support individualized dosing of aminoglycosides to septic patients.
- MeSH
- Acute Kidney Injury blood MeSH
- Amikacin blood metabolism pharmacokinetics MeSH
- Biomarkers blood MeSH
- Cytokines MeSH
- Endotoxemia chemically induced MeSH
- Glomerular Filtration Rate physiology MeSH
- Rats MeSH
- Kidney physiopathology MeSH
- Lipocalin-2 blood metabolism urine MeSH
- Lipopolysaccharides pharmacology MeSH
- Metabolic Clearance Rate MeSH
- Urine MeSH
- Models, Animal MeSH
- Oligosaccharides pharmacokinetics MeSH
- Rats, Wistar * MeSH
- Predictive Value of Tests MeSH
- Sepsis drug therapy metabolism MeSH
- Inflammation MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.
- MeSH
- Algorithms MeSH
- Chemical Warfare Agents chemistry MeSH
- Ligands MeSH
- Molecular Conformation MeSH
- Molecular Structure MeSH
- Drug Discovery MeSH
- Ricin antagonists & inhibitors chemistry MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Binding Sites MeSH
- Hydrogen Bonding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
BACKGROUND: The results of treatment for spinal dural arteriovenous fistula (SDAVF) have been controversial. The goal of this study was to compare results of endovascular and surgical treatments to contribute to determining an optimal treatment strategy. METHODS: A retrospective analysis of the set of 24 SDAVF patients (11 in the endovascular and 13 in the surgical group) was performed. The clinical effect (using the modified Rankin scale [mRS]), the radicality, and the number of clinical recurrences as well as the impact of age, the level of impairment, and the duration of symptoms before the treatment were evaluated. RESULTS: The average age was 60.1 ± 8.4 years. The median duration of symptoms before establishing a diagnosis was 12 (1-70) months. Clinical improvement was reported in 11 out of 24 (45.8%) patients (36.4% following embolization and 53.8% following surgery, p = 0.444). Radical performance was achieved in 47.4% of endovascular versus 92.9% of surgical procedures (p = 0.009). Clinical recurrence was reported in 35.3% of patients in the endovascular group, whereas no clinical recurrence was reported in the surgical group (p = 0.0133). The graphical residuum after 1 surgery out of 14 (7.1%) was cured early during the control angiography. Clinical improvement was reported 42.1% of patients with mRS ≤ 3 versus 60% of patients with mRS ≥ 4 and, in 57.1% of patients aged ≥ 60 versus in 30% of patients < 60 years (p > 0.05 in both cases). The impact of the duration of symptoms on the clinical results was not statistically significant. CONCLUSIONS: The surgical treatment of SDAVF appeared to be a more efficient method in terms of the clinical effect, radicality, and lower recurrence rate in comparison with the endovascular treatment. No statistically significant dependence of the clinical result on age, deficit burden, or symptom duration was found.
- MeSH
- Central Nervous System Vascular Malformations surgery therapy MeSH
- Endovascular Procedures adverse effects methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Neurosurgical Procedures adverse effects methods MeSH
- Postoperative Complications epidemiology MeSH
- Aged MeSH
- Embolization, Therapeutic adverse effects methods MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
