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1.
Int J Mol Sci ; 25(2)2024 Jan 21.
Article in English | MEDLINE | ID: mdl-38279301

ABSTRACT

Hypericum perforatum (St. John's wort) has been described to be beneficial for the treatment of Alzheimer's disease (AD). Different extractions have demonstrated efficiency in mice and humans, esp. extracts with a low hypericin and hyperforin content to reduce side effects such as phototoxicity. In order to systematically elucidate the therapeutic effects of H. perforatum extracts with different polarities, APP-transgenic mice were treated with a total ethanol extract (TE), a polar extract obtained from TE, and an apolar supercritical CO2 (scCO2) extract. The scCO2 extract was formulated with silicon dioxide (SiO2) for better oral application. APP-transgenic mice were treated with several extracts (total, polar, apolar) at different concentrations. We established an early treatment paradigm from the age of 40 days until the age of 80 days, starting before the onset of cerebral ß-amyloid (Aß) deposition at 45 days of age. Their effects on intracerebral soluble and insoluble Aß were analyzed using biochemical analyses. Our study confirms that the scCO2H. perforatum formulation shows better biological activity against Aß-related pathological effects than the TE or polar extracts. Clinically, the treatment resulted in a dose-dependent improvement in food intake with augmentation of the body weight, and, biochemically, it resulted in a significant reduction in both soluble and insoluble Aß (-27% and -25%, respectively). We therefore recommend apolar H. perforatum extracts for the early oral treatment of patients with mild cognitive impairment or early AD.


Subject(s)
Alzheimer Disease , Hypericum , Humans , Mice , Animals , Infant , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plant Extracts/chemistry , Phytotherapy , Hypericum/chemistry , Alzheimer Disease/drug therapy , Alzheimer Disease/chemically induced , Silicon Dioxide/therapeutic use , Amyloid beta-Peptides/toxicity , Mice, Transgenic
2.
Hematol Oncol ; 41(1): 16-25, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36238977

ABSTRACT

Main aim of this systematic review is to quantify the risk and identify predictors of clinical evolution of SARS-CoV-2 in hematological patients compared to different control populations. Two independent reviewers screened the literature assessing clinical outcomes of SARS-CoV-2 infection in adult patients with active hematological malignancies published up to June 2021. Primary outcome was COVID-19 related mortality, secondary outcomes were hospital and intensive-care admission, mechanical ventilation (MV), and thromboembolic events. Variables related to study setting, baseline patients' demographic, comorbidities, underlying hematological disease, ongoing chemotherapy, COVID-19 presentation, and treatments were extracted. A total of 67 studies including 10,061 hematological patients and 111,143 controls were included. Most of the studies were retrospective cohorts (51 studies, 76%) and only 19 (13%) provided data for a control group. A significant increased risk of clinical progression in the hematological population compared to the controls was found in terms of COVID-19 related mortality (OR, 2.12; 95% CI, 1.77-2.54), hospitalization (OR, 1.98; 95% CI, 1.15-3.43), intensive-care admission (OR, 1.77; 95% CI, 1.38-2.26), and MV (OR, 2.17; 95% CI, 1.71-2.75). The risk remained significantly higher in the subgroup analysis comparing hematological patients versus solid cancer. Meta-regression analysis of uncontrolled studies showed that older age, male sex, and hypertension were significantly related to worse clinical outcomes of COVID-19 in hematological population. Older age and hypertension were found to be associated also to thromboembolic events. In conclusion, hematological patients have a higher risk of COVID-19 clinical progression compared to both the general population and to patients with solid cancer.


Subject(s)
COVID-19 , Hypertension , Neoplasms , Adult , Humans , Male , SARS-CoV-2 , Retrospective Studies , Disease Progression
3.
Sensors (Basel) ; 22(22)2022 Nov 18.
Article in English | MEDLINE | ID: mdl-36433548

ABSTRACT

Aceclofenac (ACL) is an anti-inflammatory drug, which is taken by patients who mainly suffer from rheumatoid conditions. In this work, we propose a new voltammetric method that allows the determination of ACL in pharmaceutics, urine, and plasma. As a working electrode, a glassy carbon electrode (GCE) modified with carbon nanofibers, carbon nanotubes, and NiCo nanoparticles (eCNF/CNT/NiCo-GCE) was used. The mentioned sensors are characterized by good repeatability and sensitivity, and their process of preparation is simple, fast, and cost-effective. Instrumental and method parameters were optimized, and the influence of interferences was investigated. To validate the analytical performance of the method, calibration was conducted. Good linearity was obtained (0.05-1.4 µM, r = 0.998), as well as excellent limit of detection (LOD) and limit of quantification (LOQ) values (0.7 nM and 2.1 nM, respectively). Calculated recoveries that were in the range of 98%-105% indicate that this method is accurate and might be used in routine laboratory practice.


Subject(s)
Nanocomposites , Nanotubes, Carbon , Humans , Electrodes , Diclofenac
4.
Cities ; 121: 103453, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34566232

ABSTRACT

This study provides new insights into how local governments (LGs) manage pandemic-related crisis communication with citizens on their social media (SM) profiles. We analyze over 3000 posts published on SM profiles of selected LGs in Poland to get insights on rhetorical communication strategies during the COVID-19 pandemic. We document LGs as they go beyond the simple transmission of information to citizens and use SM in an engaging and educational manner. We found three types of rhetorical strategies and their resonance with the public. Our analysis suggests that LGs are likely to apply the Together communication strategy, which is the most engaging.

5.
J Neurochem ; 158(2): 500-521, 2021 07.
Article in English | MEDLINE | ID: mdl-33899944

ABSTRACT

In healthy conditions, pannexin-1 (Panx-1) channels are in a close state, but in several pathological conditions, including human immunodeficiency virus-1 (HIV) and NeuroHIV, the channel becomes open. However, the mechanism or contribution of Panx-1 channels to the HIV pathogenesis and NeuroHIV is unknown. To determine the contribution of Panx-1 channels to the pathogenesis of NeuroHIV, we used a well-established model of simian immunodeficiency virus (SIV) infection in macaques (Macaca mulatta) in the presence of and absence of a Panx-1 blocker to later examine the synaptic/axonal compromise induced for the virus. Using Golgi's staining, we demonstrated that SIV infection compromised synaptic and axonal structures, especially in the white matter. Blocking Panx-1 channels after SIV infection prevented the synaptic and axonal compromise induced by the virus, especially by maintaining the more complex synapses. Our data demonstrated that targeting Panx-1 channels can prevent and maybe revert brain synaptic compromise induced by SIV infection.


Subject(s)
Connexins/metabolism , HIV Infections/metabolism , HIV-1 , Nerve Tissue Proteins/metabolism , Neurons/pathology , Simian Acquired Immunodeficiency Syndrome/metabolism , Synapses/pathology , Animals , Axons/pathology , Connexins/antagonists & inhibitors , Dendritic Spines/pathology , Gray Matter/pathology , Humans , Macaca mulatta , Nerve Tissue Proteins/antagonists & inhibitors , Virus Replication , White Matter/pathology
6.
BMC Infect Dis ; 21(1): 883, 2021 Aug 28.
Article in English | MEDLINE | ID: mdl-34454452

ABSTRACT

BACKGROUND: A major limitation of current predictive prognostic models in patients with COVID-19 is the heterogeneity of population in terms of disease stage and duration. This study aims at identifying a panel of clinical and laboratory parameters that at day-5 of symptoms onset could predict disease progression in hospitalized patients with COVID-19. METHODS: Prospective cohort study on hospitalized adult patients with COVID-19. Patient-level epidemiological, clinical, and laboratory data were collected at fixed time-points: day 5, 10, and 15 from symptoms onset. COVID-19 progression was defined as in-hospital death and/or transfer to ICU and/or respiratory failure (PaO2/FiO2 ratio < 200) within day-11 of symptoms onset. Multivariate regression was performed to identify predictors of COVID-19 progression. A model assessed at day-5 of symptoms onset including male sex, age > 65 years, dyspnoea, cardiovascular disease, and at least three abnormal laboratory parameters among CRP (> 80 U/L), ALT (> 40 U/L), NLR (> 4.5), LDH (> 250 U/L), and CK (> 80 U/L) was proposed. Discrimination power was assessed by computing area under the receiver operating characteristic (AUC) values. RESULTS: A total of 235 patients with COVID-19 were prospectively included in a 3-month period. The majority of patients were male (148, 63%) and the mean age was 71 (SD 15.9). One hundred and ninety patients (81%) suffered from at least one underlying illness, most frequently cardiovascular disease (47%), neurological/psychiatric disorders (35%), and diabetes (21%). Among them 88 (37%) experienced COVID-19 progression. The proposed model showed an AUC of 0.73 (95% CI 0.66-0.81) for predicting disease progression by day-11. CONCLUSION: An easy-to-use panel of laboratory/clinical parameters computed at day-5 of symptoms onset predicts, with fair discrimination ability, COVID-19 progression. Assessment of these features at day-5 of symptoms onset could facilitate clinicians' decision making. The model can also play a role as a tool to increase homogeneity of population in clinical trials on COVID-19 treatment in hospitalized patients.


Subject(s)
COVID-19 Drug Treatment , Aged , Female , Hospital Mortality , Humans , Male , Prospective Studies , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
7.
AAPS PharmSciTech ; 22(3): 109, 2021 Mar 14.
Article in English | MEDLINE | ID: mdl-33718994

ABSTRACT

Hydrogel wound dressings are highly effective in the therapy of wounds. Yet, most of them do not contain any active ingredient that could accelerate healing. The aim of this study was to prepare hydrophilic active dressings loaded with an anti-inflammatory compound - trans-resveratrol (RSV) of hydrophobic properties. A special attention was paid to select such a technological strategy that could both reduce the risk of irritation at the application site and ensure the homogeneity of the final hydrogel. RSV dissolved in Labrasol was combined with an aqueous sol of poly(vinyl) alcohol (PVA), containing propylene glycol (PG) as a plasticizer. This sol was transformed into a gel under six consecutive cycles of freezing (-80 °C) and thawing (RT). White, uniform and elastic membranes were successfully produced. Their critical features, namely microstructure, mechanical properties, water uptake and RSV release were studied using SEM, DSC, MRI, texture analyser and Franz-diffusion cells. The cryogels made of 8 % of PVA showed optimal tensile strength (0.22 MPa) and elasticity (0.082 MPa). The application of MRI enabled to elucidate mass transport related phenomena in this complex system at the molecular (detection of PG, confinement effects related to pore size) as well as at the macro level (swelling). The controlled release of RSV from membranes was observed for 48 h with mean dissolution time of 18 h and dissolution efficiency of 35 %. All in all, these cryogels could be considered as a promising new active wound dressings.


Subject(s)
Cryogels/chemical synthesis , Polyvinyl Alcohol/chemical synthesis , Resveratrol/chemical synthesis , Wound Healing , Antioxidants/administration & dosage , Antioxidants/chemical synthesis , Antioxidants/pharmacokinetics , Bandages, Hydrocolloid , Cryogels/administration & dosage , Cryogels/pharmacokinetics , Polyvinyl Alcohol/administration & dosage , Polyvinyl Alcohol/pharmacokinetics , Resveratrol/administration & dosage , Resveratrol/pharmacokinetics , Tensile Strength/drug effects , Tensile Strength/physiology , Wound Healing/drug effects , Wound Healing/physiology
8.
Sensors (Basel) ; 21(1)2020 Dec 24.
Article in English | MEDLINE | ID: mdl-33374345

ABSTRACT

A new, highly sensitive Adsorptive Stripping Voltammetric method for levodopa determination was developed. As a working electrode, the glassy carbon electrode (GCE) modified with carbon black (CB), RuO2·xH2O (RuO2) and Nafion was used (CB-RuO2-Nafion GCE). Levodopa signal obtained on the modified electrode was 12 times higher compared to GCE. During research, instrumental parameters were optimized: sampling time ts = 10 ms, waiting time tw = 10 ms, step potential Es = 5 mV and pulse amplitude ΔE = 50 mV. Preconcentration potential Eprec was equal to 0 mV. The best results were obtained in 0.025 M perchloric acid (approx. pH 1.4). Signal repeatability measured on the CB-RuO2-Nafion modified electrode for 0.2 µM of levodopa was equal to 2.1% (levodopa concentration 1 µM, n = 5). Linearity of the method was achieved in the concentration range from 1 to 8 µM. Limit of detection was equal to 17 nM. Recoveries calculated for pharmaceutical products and tap water measurements were in the range 102-105%, which confirms the accuracy of the developed. The applicability of the method was confirmed by analysis of pharmaceutical products and tap water samples. Based on obtained results, it might be concluded that the developed voltammetric method could be a useful tool in routine drug analysis.


Subject(s)
Levodopa/analysis , Carbon , Electrodes , Fluorocarbon Polymers , Ruthenium Compounds/chemistry , Soot
9.
J Neurochem ; 151(5): 558-569, 2019 12.
Article in English | MEDLINE | ID: mdl-31381153

ABSTRACT

Chemical and electrical synapses are the two major communication systems that permit cell-to-cell communication within the nervous system. Although most studies are focused on chemical synapses (glutamate, γ-aminobutyric acid, and other neurotransmitters), clearly both types of synapses interact and cooperate to allow the coordination of several cell functions within the nervous system. The pineal gland has limited independent axonal innervation and not every cell has access to nerve terminals. Thus, additional communication systems, such as gap junctions, have been postulated to coordinate metabolism and signaling. Using acutely isolated glands and dissociated cells, we found that gap junctions spread glycogenolytic signals from cells containing adrenoreceptors to the entire gland lacking these receptors. Our data using glycogen and lactate quantification, electrical stimulation, and high-performance liquid chromatography with electrochemical detection, demonstrate that gap junctional communication between cells of the rat pineal gland allows cell-to-cell propagation of norepinephrine-induced signal that promotes glycogenolysis throughout the entire gland. Thus, the interplay of both synapses is essential for coordinating glycogen metabolism and lactate production in the pineal gland.


Subject(s)
Cell Communication/physiology , Electrical Synapses/metabolism , Glycogenolysis/physiology , Norepinephrine/metabolism , Pineal Gland/metabolism , Animals , Female , Male , Rats , Rats, Sprague-Dawley
10.
Biopolymers ; 107(4)2017 Apr.
Article in English | MEDLINE | ID: mdl-27858985

ABSTRACT

The bacterial ribosome has many functional ribosomal RNA (rRNA) sites. We have computationally analyzed the rRNA regions involved in the interactions between the 30S and 50S subunits. Various properties of rRNA such as solvent accessibility, opening energy, hydrogen bonding pattern, van der Waals energy, thermodynamic stability were determined. Based on these properties we selected rRNA targets for hybridization with complementary 2'-O-methyl oligoribonucleotides (2'-OMe RNAs). Further, the inhibition efficiencies of the designed ribosome-interfering 2'-OMe RNAs were tested using a ß-galactosidase assay in a translation system based on the E. coli extract. Several of the oligonucleotides displayed IC50 values below 1 µM, which were in a similar range as those determined for known ribosome inhibitors, tetracycline and pactamycin. The calculated opening and van der Waals stacking energies of the rRNA targets correlated best with the inhibitory efficiencies of 2'-OMe RNAs. Moreover, the binding affinities of several oligonucleotides to both 70S ribosomes and isolated 30S and 50S subunits were measured using a double-filter retention assay. Further, we applied heat-shock chemical transformation to introduce 2'-OMe RNAs to E. coli cells and verify inhibition of bacterial growth. We observed high correlation between IC50 in the cell-free extract and bacterial growth inhibition. Overall, the results suggest that the computational analysis of potential rRNA targets within the conformationally dynamic regions of inter-subunit bridges can help design efficient antisense oligomers to probe the ribosome function.


Subject(s)
Oligonucleotides/metabolism , RNA, Ribosomal/metabolism , Base Sequence , Binding Sites , Computer-Aided Design , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli/metabolism , Nucleic Acid Conformation , Oligonucleotides/chemistry , Pactamycin/chemistry , Pactamycin/metabolism , Pactamycin/pharmacology , Protein Binding , Protein Biosynthesis/drug effects , Protein Structure, Tertiary , RNA, Ribosomal/antagonists & inhibitors , RNA, Ribosomal/chemistry , Ribosome Subunits, Large, Bacterial/chemistry , Ribosome Subunits, Large, Bacterial/metabolism , Ribosome Subunits, Small, Bacterial/chemistry , Ribosome Subunits, Small, Bacterial/metabolism
11.
PLoS Comput Biol ; 12(6): e1004957, 2016 06.
Article in English | MEDLINE | ID: mdl-27327495

ABSTRACT

There is increasing interest in employing shotgun sequencing, rather than amplicon sequencing, to analyze microbiome samples. Typical projects may involve hundreds of samples and billions of sequencing reads. The comparison of such samples against a protein reference database generates billions of alignments and the analysis of such data is computationally challenging. To address this, we have substantially rewritten and extended our widely-used microbiome analysis tool MEGAN so as to facilitate the interactive analysis of the taxonomic and functional content of very large microbiome datasets. Other new features include a functional classifier called InterPro2GO, gene-centric read assembly, principal coordinate analysis of taxonomy and function, and support for metadata. The new program is called MEGAN Community Edition (CE) and is open source. By integrating MEGAN CE with our high-throughput DNA-to-protein alignment tool DIAMOND and by providing a new program MeganServer that allows access to metagenome analysis files hosted on a server, we provide a straightforward, yet powerful and complete pipeline for the analysis of metagenome shotgun sequences. We illustrate how to perform a full-scale computational analysis of a metagenomic sequencing project, involving 12 samples and 800 million reads, in less than three days on a single server. All source code is available here: https://github.com/danielhuson/megan-ce.


Subject(s)
Genome, Bacterial/genetics , Metagenome/genetics , Microbiota/genetics , Sequence Analysis, DNA/methods , Software , High-Throughput Nucleotide Sequencing , User-Computer Interface
12.
Nucleic Acids Res ; 43(17): e114, 2015 Sep 30.
Article in English | MEDLINE | ID: mdl-26024667

ABSTRACT

Structural biology experiments and structure prediction tools have provided many high-resolution three-dimensional structures of nucleic acids. Also, molecular dynamics force field parameters have been adapted to simulating charged and flexible nucleic acid structures on microsecond time scales. Therefore, we can generate the dynamics of DNA or RNA molecules, but we still lack adequate tools for the analysis of the resulting huge amounts of data. We present MINT (Motif Identifier for Nucleic acids Trajectory) - an automatic tool for analyzing three-dimensional structures of RNA and DNA, and their full-atom molecular dynamics trajectories or other conformation sets (e.g. X-ray or nuclear magnetic resonance-derived structures). For each RNA or DNA conformation MINT determines the hydrogen bonding network resolving the base pairing patterns, identifies secondary structure motifs (helices, junctions, loops, etc.) and pseudoknots. MINT also estimates the energy of stacking and phosphate anion-base interactions. For many conformations, as in a molecular dynamics trajectory, MINT provides averages of the above structural and energetic features and their evolution. We show MINT functionality based on all-atom explicit solvent molecular dynamics trajectory of the 30S ribosomal subunit.


Subject(s)
DNA/chemistry , RNA/chemistry , Software , Hydrogen Bonding , Nucleic Acid Conformation , Nucleotide Motifs , Nucleotides/chemistry , RNA, Ribosomal, 16S/chemistry , Ribosome Subunits, Small, Bacterial/chemistry
13.
iScience ; 27(3): 109236, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38487019

ABSTRACT

HIV-associated neurological compromise is observed in more than half of all people with HIV (PWH), even under antiretroviral therapy (ART). The mechanism has been associated with the early transmigration of HIV-infected monocytes across the BBB in a CCL2 and HIV replication-dependent manner. However, the mechanisms of chronic brain damage are unknown. We demonstrate that all PWH under ART have elevated circulating ATP levels that correlate with the onset of cognitive impairment even in the absence of a circulating virus. Serum ATP levels found in PWH with the most severe neurocognitive impairment trigger the transcellular migration of HIV-infected leukocytes across the BBB in a JAM-A and LFA-1-dependent manner. We propose that targeting transcellular leukocyte transmigration could reduce or prevent the devastating consequences of HIV within the brains of PWH under ART.

14.
Microorganisms ; 12(1)2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38257958

ABSTRACT

COVID-19 has been associated with having a negative impact on patients' gut microbiome during both active disease and in the post-acute phase. In acute COVID-19, rapid alteration of the gut microbiome composition was observed, showing on one side a reduction in beneficial symbionts (e.g., Roseburia, Lachnospiraceae) and on the other side an increase in opportunistic pathogens such as Enterococcus and Proteobacteria. Alpha diversity tends to decrease, especially initially with symptom onset and hospital admission. Although clinical recovery appears to align with improved gut homeostasis, this process could take several weeks, even in mild infections. Moreover, patients with COVID-19 post-acute syndrome showed changes in gut microbiome composition, with specific signatures associated with decreased respiratory function up to 12 months following acute disease. Potential treatments, especially probiotic-based therapy, are under investigation. Open questions remain on the possibility to use gut microbiome data to predict disease progression and on potential confounders that may impair result interpretation (e.g., concomitant therapies in the acute phase; reinfection, vaccines, and occurrence of novel conditions or diseases in the post-acute syndrome). Understanding the relationships between gut microbiome dynamics and disease progression may contribute to better understanding post-COVID syndrome pathogenesis or inform personalized treatment that can affect specific targets or microbiome markers.

15.
Stud Health Technol Inform ; 309: 133-134, 2023 Oct 20.
Article in English | MEDLINE | ID: mdl-37869823

ABSTRACT

Within the HORIZON 2020 project ORCHESTRA, patient data from numerous clinical studies in Europe related to COVID-19 were harmonized to create new knowledge on the disease. In this article, we describe the ecosystem that was established for the management of data collected and contributed by project partners. Study protocols elements were mapped to interoperability standards to establish a common terminology. That served as the basis of identifying common concepts used across several studies. Harmonized data were used to perform analysis directly on a central database and also through federated analysis when data was not permitted to leave the local server(s). This ecosystem facilitates the answering of research questions and generation of new knowledge available for the scientific community.


Subject(s)
Data Management , Humans , Databases, Factual , Europe
16.
Materials (Basel) ; 16(3)2023 Jan 28.
Article in English | MEDLINE | ID: mdl-36770123

ABSTRACT

The significance of ion activity in transport through a porous concrete material sample with steel rebar in its center and bathing solution is presented. For the first time, different conventions and models of ion activity are compared in their significance and influence on the ion fluxes. The study closes an interpretational gap between ion activity in a stand-alone (stagnant) electrolyte solution and ion transport (dynamic) through concrete pores. Ionic activity models developed in stationary systems, namely, the Debye-Hückel (DH), extended DH, Davies, Truesdell-Jones, and Pitzer models, were used for modeling the transport of ions driven through the activity gradient. The activities of ions are incorporated into a frame of the Nernst-Planck-Poisson (NPP) equations. Calculations were done with COMSOL software for a real concrete microstructure determined by X-ray computed tomography. The concentration profiles of four ions (Na+, Cl-, K+, OH-), the ionic strength, and the electric potential in mortar (with pores) and concrete samples (with aggregates and pores) are presented and compared. The Pitzer equation gave the most reliable results for all systems studied. The difference between the concentration profiles calculated with this equation and with the assumption of the ideality of the solution is negligible while the potential profiles are clearly distinguishable.

17.
Materials (Basel) ; 16(14)2023 Jul 19.
Article in English | MEDLINE | ID: mdl-37512370

ABSTRACT

Corrosion of steel reinforcements in concrete constructions is a worldwide problem. To assess the degradation of rebars in reinforced concrete, an accurate description of electric current, potential and concentrations of various species present in the concrete matrix is necessary. Although the concrete matrix is a heterogeneous porous material with intricate microstructure, mass transport has been treated in a homogeneous material so far, modifying bulk transport coefficients by additional factors (porosity, constrictivity, tortuosity), which led to so-called effective coefficients (e.g., diffusivity). This study presents an approach where the real 3D microstructure of concrete is obtained from high-resolution X-ray computed tomography (XCT), processed to generate a mesh for finite element method (FEM) computations, and finally combined with a multi-species system of transport and electric potential equations. This methodology allows for a more realistic description of ion movements and reactions in the bulk concrete and on the rebar surface and, consequently, a better evaluation of anodic and cathodic currents, ultimately responsible for the loss of reinforcement mass and its location. The results of this study are compared with a state-of-the-art model and numerical calculations for 2D and 3D geometries.

18.
Biology (Basel) ; 12(7)2023 Jun 29.
Article in English | MEDLINE | ID: mdl-37508364

ABSTRACT

Alzheimer's disease (AD), the leading cause of dementia, is a growing health issue with very limited treatment options. To meet the need for novel therapeutics, existing drugs with additional preferred pharmacological profiles could be recruited. This strategy is known as 'drug repurposing'. Here, we describe dimethyl fumarate (DMF), a drug approved to treat multiple sclerosis (MS), to be tested as a candidate for other brain diseases. We used an APP-transgenic model (APPtg) of senile ß-amyloidosis mice to further investigate the potential of DMF as a novel AD therapeutic. We treated male and female APPtg mice through drinking water at late stages of ß-amyloid (Aß) deposition. We found that DMF treatment did not result in modulating effects on Aß deposition at this stage. Interestingly, we found that glutathione-modified DMF interacts with the ATP-binding cassette transporter ABCC1, an important gatekeeper at the blood-brain and blood-plexus barriers and a key player for Aß export from the brain. Our findings suggest that ABCC1 prevents the effects of DMF, which makes DMF unsuitable as a novel therapeutic drug against AD. The discovered effects of ABCC1 also have implications for DMF treatment of multiple sclerosis.

19.
EClinicalMedicine ; 62: 102107, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37654668

ABSTRACT

Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively). Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials. Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.

20.
Materials (Basel) ; 15(10)2022 May 20.
Article in English | MEDLINE | ID: mdl-35629673

ABSTRACT

A new electrochemical sensor based on hierarchical carbon nanofibers with Ni and Co nanoparticles (eCNF/CNT/NiCo-GCE) was developed. The presented sensor may be characterized by high sensitivity, good electrical conductivity, and electrocatalytic properties. Reproducibility of its preparation expressed as %RSD (relative standard deviation) was equal to 9.7% (n = 5). The repeatability of the signal register on eCNF/CNT/NiCo-GCE was equal to 3.4% (n = 9). The developed sensor was applied in the determination of the antihistamine drug-cetirizine hydrochloride (CTZ). Measurement conditions, such as DPV (differential pulse voltammetry) parameters, supporting electrolyte composition and concentration were optimized. CTZ exhibits a linear response in three concentration ranges: 0.05-6 µM (r = 0.988); 7-32 (r = 0.992); and 42-112 (r = 0.999). Based on the calibration performed, the limit of detection (LOD) and limit of quantification (LOQ) were calculated and were equal to 14 nM and 42 nM, respectively. The applicability of the optimized method for the determination of CTZ was proven by analysis of its concentration in real samples, such as pharmaceutical products and body fluids (urine and plasma). The results were satisfactory and the calculated recoveries (97-115%) suggest that the method may be considered accurate. The obtained results proved that the developed sensor and optimized method may be used in routine laboratory practice.

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