Search

Abstract Background The primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs. Methods This was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H+/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers. Results Our findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 2.5. This supports the hypothesis of the presence of the H+/OC antiporter system at the blood–brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean Kp,uu,LV values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean Kp,uu,lumbarCSF of 1.5. LPS challenge caused a slight decrease in Kp,uu,LV, while Kp,uu,lumbarCSF remained unaffected. Conclusions This study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings.

Abstract Background Triptans are potent 5-HT1B/1D/1F receptor agonists used in migraine therapy, thought to act through peripheral mechanisms. It remains unclear whether triptans cross the blood-brain barrier (BBB) sufficiently to stimulate central 5-HT1B/1D/1F receptors. This study investigates the disposition of eletriptan and sumatriptan in central nervous system (CNS) and peripheral nervous system (PNS) regions and predicts regional 5-HT1B/1D/1F receptor occupancies at clinically relevant concentrations. Methods Using the Combinatory Mapping Approach (CMA) for regions of interest (ROI), we assessed the unbound tissue-to-plasma concentration ratio (Kp, uu, ROI) in rats at steady state across CNS (hypothalamus, brain stem, cerebellum, frontal cortex, parietal cortex, striatum, hippocampus, whole brain, and spinal cord) and PNS (trigeminal ganglion and sciatic nerve) regions. We used Kp, uu, ROI values to estimate unbound target-site concentrations and 5-HT1B/1D/1F receptor occupancies in humans. Results We observed heterogenous triptan transport across CNS and PNS regions with the highest extent of unbound drug transport across the blood-nerve barrier in the trigeminal ganglion (Kp, uu, TG: eletriptan: 0.519, and sumatriptan: 0.923). Both drugs displayed restricted entry across the BBB (Kp, uu, whole brain: eletriptan: 0.058, and sumatriptan: 0.045) combined with high inter-regional variability. We estimated near-complete receptor occupancy in the trigeminal ganglion, while lower occupancies were observed in the whole brain, irrespective of the drug or receptor subtype. For instance, eletriptan was predicted to achieve 84% 5-HT1B receptor occupancy in the trigeminal ganglion and 37% in the whole brain at clinically relevant concentrations. Conclusions This study suggests that despite low BBB transport, both eletriptan and sumatriptan achieve unbound concentrations sufficient to stimulate 5-HT1B, 5-HT1D, and 5-HT1F receptors not only in the trigeminal ganglion, but also in the CNS. Further research is needed to determine whether central mechanisms contribute to triptan’s antimigraine effect and/or side effects. Graphical Abstract

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG). The prevalence of CIPN in patients receiving paclitaxel formulated i) in polyethylated castor oil with ethanol (CreEL-PTX), ii) as albumin-bound (nab-PTX), and iii) in XR17 micelles (micellar-PTX), is unexpectedly varying. We hypothesize that the discrepancy in CIPN prevalence could be governed by differences in the extent of paclitaxel distribution across blood-to-tissue barriers at the CIPN-sites, caused by the specific formulation.MethodsThe recently developed Combinatory Mapping Approach for CIPN was used to determine the unbound tissue-to-plasma concentration ratio Kp,uu,tissue, after a 4-h infusion of 4 mg/kg CreEL-PTX, 4 mg/kg nab-PTX or 1 mg/kg micellar-PTX in male and female Sprague Dawley rats. Kp,uu,tissue was determined in conventional (DRG, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN-sites.ResultsBased on our data, the Cremophor-free paclitaxel formulations were associated with a higher distribution of paclitaxel to CIPN-sites than CreEL-PTX, e.g., Kp,uu,DRG of 0.70 and 0.60 for nab-PTX and micellar-PTX, respectively, in comparison to 0.27 for CreEL-PTX (p < 0.01). In addition, the fraction of unbound paclitaxel in plasma was on average 1.6-fold higher in nab- and micellar PTX arms and equal to 0.061 and 0.065, respectively, compared to 0.039 for the CreEL-PTX treatment arm (p < 0.0001).DiscussionIn the case of similar unbound paclitaxel concentration in the plasma of patients and assumed species-independent extent of paclitaxel transport across the barriers, nab- and micellar-PTX formulations can lead to higher paclitaxel exposure at CIPN-sites in comparison to CreEL-PTX.

Familial Mediterranean fever (FMF) is an autosomal recessive disease distributed among populations of Mediterranean origin – Armenians, Sephardi Jews, Arabs, Turks. There are numerous clinical observations regarding combination of FMF, as a classical representative of autoinflammatory diseases, with systemic diseases of connective tissue. Seronegative spondyloarthritis (SpA) are the most interesting disorders from this point of view, as far as sacroiliitis – an essential feature of SpA, may also present as a part of joint syndrome in FMF. The main objective of this clinical study was the investigation of the peculiarities of courses of FMF and SpA in case of their coexistence. We studied 126 patients with FMF, SpA and coexistence of both. According to results, patients with the overlap of FMF with SpA had relatively milder course of disease in comparison with each disease separately. Comparative clinical and instrumental characteristics of FMF-associated disorders had shown that in FMF-SpA overlap the symptoms of both diseases are less severe.

Cellular events require the spatiotemporal interplay between actin assembly and actin disassembly. Yet, how different factors promote the integration of these two opposing processes is unclear. In particular, cellular monomeric (G)-actin is complexed with profilin, which inhibits spontaneous actin nucleation but fuels actin filament (F-actin) assembly by elongation-promoting factors (formins, Ena/VASP). In contrast, site-specific F-actin oxidation by Mical promotes F-actin disassembly and release of polymerization-impaired Mical-oxidized (Mox)-G-actin. Here we find that these two opposing processes connect with one another to orchestrate actin/cellular remodeling. Specifically, we find that profilin binds Mox-G-actin, yet these complexes do not fuel elongation factors'-mediated F-actin assembly, but instead inhibit polymerization and promote further Mox-F-actin disassembly. Using Drosophila as a model system, we show that similar profilin-Mical connections occur in vivo - where they underlie F-actin/cellular remodeling that accompanies Semaphorin-Plexin cellular/axon repulsion. Thus, profilin and Mical combine to impair F-actin assembly and promote F-actin disassembly, while concomitantly facilitating cellular remodeling and plasticity.

Sarcoidosis is a complex multisystem inflammatory granulomatous disease that can affect any organ, with a wide range of clinical presentations. A significant number of patients with systemic sarcoidosis may also have cardiac involvement. Clinical manifestations of cardiac sarcoidosis can include various rhythm and conduction disturbances, as well as heart failure.The structure of sarcoid granulomas is similar to that of tuberculous granulomas, but in contrast, they lack caseous necrosis. Tissue changes in sarcoidosis tissues depend on the stage of development of the disease, progressing from pathological process: macrophage-lymphocytic infiltration to epithelioid cell granuloma formation, and fibrosis. Granulomas can be found in any part of the myocardium, with the most common locations being the free wall of the left ventricle, the basal part of the interventricular septum, and the interatrial septum. Vasculopathy of the pulmonary circulation and coronary arteries is often observed.Advancements in diagnostic imaging techniques, such as computer tomography and magnetic resonance imaging, have facilitated the verification of cardiac sarcoidosis. This article presents an analysis of updated information on cardiac sarcoidosis by a multidisciplinary working group.

Abstract Background There is not a prevailing consensus on appropriate antibiotic choice, route, and duration in the treatment of bacterial pleural empyema after appropriate source control. Professional society guidelines note the lack of comparative trials with which to guide recommendations. We assessed clinical outcomes in the treatment of known and suspected empyema based upon three aspects of antibiotic use: (1) total duration, (2) duration of intravenous (IV) antibiotics, and (3) duration of anti-anaerobic antibiotics. Methods We performed a hypothesis-generating retrospective chart review analysis of 355 adult inpatients who had pleural drainage, via either chest tube or surgical intervention, for known or suspected empyema. The primary outcome variable was clinician assessment of resolution or lack thereof. The secondary outcomes were death within 90 days, hospital readmission within 30 days for empyema, and all-cause hospital readmission within 30 days. Mann-Whitney U test was used to compare outcomes with regard to these variables. Results None of the independent variables was significantly associated with a difference in clinical resolution rate despite trends for total antibiotic duration and anti-anaerobic antibiotic duration. None of the independent variables was associated with mortality. Longer total antibiotic duration was associated with lower readmission rate for empyema (median 17 [interquartile range 11–28] antibiotic days in non-readmission group vs. 13 [6-15] days in readmission group), with a non-significant trend for all-cause readmission rate (17 [11–28] days vs. 14 [9–21] days). IV antibiotic duration was not associated with a difference in any of the defined outcomes. Longer duration of anti-anaerobic antibiotics was associated with both lower all-cause readmission (8.5 [0–17] vs. 2 [0–11]) and lower readmission rate for empyema (8 [0–17] vs. 2 [0–3]). Conclusion Our data support the premise that routine use of anti-anaerobic antibiotics is indicated in the treatment of pleural empyema. However, our study casts doubt on the benefits of extended IV rather than oral antibiotics in the treatment of empyema. This represents a target for future investigation that could potentially limit complications associated with the excessive use of IV antibiotics.

Dendritic spines (DS) are actin-rich postsynaptic terminals of neurons that are critical for higher-order brain functions. Maturation of DS is accompanied by a change in actin architecture from linear to branched filamentous structures. Presumably, the underlying cause of this is a switch in a mode of actin assembly from formin-driven to Arp2/3-mediated via an undefined mechanism. Here we present data suggesting that neuron-specific actin-binding drebrin A may be a part of such a switch. It is well documented that DS are highly enriched in drebrin A, which is critical for their plasticity and function. At the same time, mDia2 is known to mediate the formation of filopodia-type (immature) spines. We found that neuronal drebrin A directly interacts with mDia2 formin. Drebrin inhibits formin-mediated nucleation of actin and abolishes mDia2-induced actin bundling. Using truncated protein constructs we identified the domain requirements for drebrin-mDia2 interaction. We hypothesize that accumulation of drebrin A in DS (that coincides with spine maturation) leads to inhibition of mDia2-driven actin polymerization and, therefore, may contribute to a change in actin architecture from linear to branched filaments.

Actin-based structures in cells and tissues are built and maintained through a poorly understood balance between assembly and disassembly. Here, our findings provide insights into how factors known to promote these opposing effects dynamically integrate to shape cells and tissue systems.

Summary: Philadelphia chromosome (Ph)‐like acute lymphoblastic leukaemia (ALL) is a high‐risk subtype with a gene expression profile similar to Ph‐positive ALL, due to activation of tyrosine kinase signalling. To understand the clinical implications of Ph‐like ALL, this single‐centre retrospective study evaluates outcomes in 268 adults, largely Hispanic ALL patients treated between 2013 and 2024, with a subgroup analysis of 139 haematopoietic stem cell transplantation (HSCT) patients. ALL subtypes included 68 (25.4%) Ph‐like, 89 (33.2%) Ph‐positive, and 111 (41.4%) Ph‐negative. Ph‐like patients were the youngest age at diagnosis (p = 0.007), most likely to have refractory disease (p < 0.001), and least likely to achieve minimal residual disease (MRD) negativity after induction (p = 0.031). Relative to Ph‐negative ALL, Ph‐like achieved worse event‐free survival (EFS) (HR = 1.66; 95% CI 1.12–2.46; p = 0.012), whereas Ph‐positive had improved EFS (HR = 0.60; 95% CI 0.38–0.93; p = 0.024) and cumulative incidence of relapse (CIR) (HR = 0.59; 95% CI 0.35–0.99; p = 0.046). Within the transplant subgroup, Ph status did not impact disease‐free survival (DFS), CIR, or overall survival (OS). However, patients who received blinatumomab within 1‐year pre‐HSCT had improved DFS (HR = 0.43; 95% CI 0.20–0.94; p = 0.034) and CIR (HR = 0.26; 95% CI 0.09–0.75; p = 0.13). In conclusion, our data suggest that Ph‐like is less likely to respond to standard induction therapy and HSCT may result in similar survival outcomes to Ph‐negative ALL. [ABSTRACT FROM AUTHOR]

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG). The prevalence of CIPN in patients receiving paclitaxel formulated i) in polyethylated castor oil with ethanol (CreEL-PTX), ii) as albumin-bound (nab-PTX), and iii) in XR17 micelles (micellar-PTX), is unexpectedly varying. We hypothesize that the discrepancy in CIPN prevalence could be governed by differences in the extent of paclitaxel distribution across blood-to-tissue barriers at the CIPN-sites, caused by the specific formulation. Methods: The recently developed Combinatory Mapping Approach for CIPN was used to determine the unbound tissue-to-plasma concentration ratio Kp,uu,tissue, after a 4-h infusion of 4 mg/kg CreEL-PTX, 4 mg/kg nab-PTX or 1 mg/kg micellar-PTX in male and female Sprague Dawley rats. Kp,uu,tissue was determined in conventional (DRG, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN-sites. Results: Based on our data, the Cremophor-free paclitaxel formulations were associated with a higher distribution of paclitaxel to CIPN-sites than CreEL-PTX, e.g., Kp,uu,DRG of 0.70 and 0.60 for nab-PTX and micellar-PTX, respectively, in comparison to 0.27 for CreEL-PTX (p < 0.01). In addition, the fraction of unbound paclitaxel in plasma was on average 1.6-fold higher in nab- and micellar PTX arms and equal to 0.061 and 0.065, respectively, compared to 0.039 for the CreEL-PTX treatment arm (p < 0.0001). Discussion: In the case of similar unbound paclitaxel concentration in the plasma of patients and assumed species-independent extent of paclitaxel transport across the barriers, nab- and micellar-PTX formulations can lead to higher paclitaxel exposure at CIPN-sites in comparison to CreEL-PTX. [ABSTRACT FROM AUTHOR]

Background: The primary objective of this study was to advance our understanding of active drug uptake at brain barriers in higher species than rodents, by examining oxycodone brain concentrations in pigs. Methods: This was investigated by a microdialysis study in healthy and endotoxemic conditions to increase the understanding of inter-species translation of putative proton-coupled organic cation (H+/OC) antiporter-mediated central nervous system (CNS) drug delivery in health and pathology, and facilitate the extrapolation to humans for improved CNS drug treatment in patients. Additionally, we sought to evaluate the efficacy of lumbar cerebrospinal fluid (CSF) exposure readout as a proxy for brain unbound interstitial fluid (ISF) concentrations. By simultaneously monitoring unbound concentrations in blood, the frontal cortical area, the lateral ventricle (LV), and the lumbar intrathecal space in healthy and lipopolysaccharide (LPS)-induced inflammation states within the same animal, we achieved exceptional spatiotemporal resolution in mapping oxycodone transport across CNS barriers. Results: Our findings provide novel evidence of higher unbound oxycodone concentrations in brain ISF compared to blood, yielding an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 2.5. This supports the hypothesis of the presence of the H+/OC antiporter system at the blood–brain barrier (BBB) in pigs. Despite significant physiological changes, reflected in pig Sequential Organ Failure Assessment, pSOFA scores, oxycodone blood concentrations and its active net uptake across the BBB remained nearly unchanged during three hours of i.v. infusion of 4 µg/kg/h LPS from Escherichia coli (O111:B4). Mean Kp,uu,LV values indicated active uptake also at the blood-CSF barrier in healthy and endotoxemic pigs. Lumbar CSF concentrations showed minimal inter-individual variability during the experiment, with a mean Kp,uu,lumbarCSF of 1.5. LPS challenge caused a slight decrease in Kp,uu,LV, while Kp,uu,lumbarCSF remained unaffected. Conclusions: This study enhances our understanding of oxycodone pharmacokinetics and CNS drug delivery in both healthy and inflamed conditions, providing crucial insights for translating these findings to clinical settings. [ABSTRACT FROM AUTHOR]

Extra-curricular activities have been encouraged to support foundation program students’ positive attitude to learning and their smooth transition into the higher education system with better academic and social performances. This paper discusses the study that explores the potential benefits of foundation program students’ involvement in extracurricular activities from the perspective of teachers who develop, lead and facilitate them at the Centre for Preparatory Studies of Sultan Qaboos University in Oman In particular, the study focuses on how teachers perceive the effects of extracurricular activities on student performance in relation to eight key areas, namely development of students’ language skills and academic performance, development of communicative competency, students’ needs and interests, students’ self-esteem and self-confidence, students’ motivation and positive attitudes towards learning, extracurricular activities in the framework of the foundation program curriculum, cross-cultural experiences, and transitional challenges. The results indicate that extracurricular activities play a valuable role in helping foundation program students adjust to higher education environment and function more easily in English. However, more student involvement and additional assistance to students are needed in order to boost their motivation and increase engagement in their own learning experiences.

Aim. Determination of the concentration of interleukin-10 (IL-10) and interleukin-6 (IL-6) in serum of patients with periodic disease (PD) before and after treatment with colchicin, as well as the identification of correlation between the indicators of these parameters. Materials and methods. We examined 188 patients with PD (89 men, 99 women) aged from 12 to 69 years, as well as 44 patients with rheumatoid arthritis (RA) as a comparison group and 41 healthy people of the control group. Patients were divided into groups: 1 - PD colchicinotherapy patients with seizures without amyloidosis that do not respond to treatment maximum dose of colchicine 2.0 mg/day; 2nd-PD patients without amyloidosis, not responding to treatment 1.5 mg/day colchicine; 3rd - PD patients that responds to certain doses of colchicine (0.5 to 2.0 mg/day); 4th - PD patients without amyloidosis who did not receive treatment; 5-I of the healthy persons of the control group; 6-I - RA patients. The concentration of IL-10 in blood serum was determined by enzyme immunoassay ELISA, and IL-6 - immunochemiluminescent method. For statistical processing the computer program SPSS is used. The results were considered statistically significant at the level of reliability p