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The key DNA repair enzyme DNA-PKcs has several and important cellular functions. Loss of DNA-PKcs activity in mice has revealed essential roles in immune and nervous systems. In humans, DNA-PKcs is a critical factor for brain development and function since mutation of the prkdc gene causes severe neurological deficits such as microcephaly and seizures, predicting yet unknown roles of DNA-PKcs in neurons. Here we show that DNA-PKcs modulates synaptic plasticity. We demonstrate that DNA-PKcs localizes at synapses and phosphorylates PSD-95 at newly identified residues controlling PSD-95 protein stability. DNA-PKcs -/- mice are characterized by impaired Long-Term Potentiation (LTP), changes in neuronal morphology, and reduced levels of postsynaptic proteins. A PSD-95 mutant that is constitutively phosphorylated rescues LTP impairment when over-expressed in DNA-PKcs -/- mice. Our study identifies an emergent physiological function of DNA-PKcs in regulating neuronal plasticity, beyond genome stability.
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Proteína Quinase Ativada por DNA , Proteína 4 Homóloga a Disks-Large , Potenciação de Longa Duração , Plasticidade Neuronal , Estabilidade Proteica , Animais , Fosforilação , Proteína Quinase Ativada por DNA/metabolismo , Proteína Quinase Ativada por DNA/genética , Camundongos , Proteína 4 Homóloga a Disks-Large/metabolismo , Proteína 4 Homóloga a Disks-Large/genética , Neurônios/metabolismo , Camundongos Knockout , Humanos , Sinapses/metabolismo , Reparo do DNA , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Proteínas de Ligação a DNARESUMO
OBJECTIVES: Scanty data on the anti- SARS-CoV-2 IgG level decay after two-dose BNT162b2 vaccination have been published in patients with psoriatic arthritis (PsA) on TNF inhibitors (TNFi). Similarly, no reports on the immunogenicity of a booster dose in such patients have been provided yet.We aimed to investigate the IgG level decay after two-dose BNT162b2 vaccination and the immunogenicity and safety of the booster dose in PsA patients on TNFi. METHODS: Forty patients with classified PsA on TNFi undergoing booster dose with the BNT162b2 mRNA SARS- CoV-2 vaccine (BioNTech/Pfizer) were enrolled. Fifteen days after the third shot, serum IgG levels against SARS-CoV-2 (Abbott®ARCHITECT i2000SR, positivity cut-off 50 AU/mL) were assayed in all patients. Clinimetrics and treatment data were gathered. TNFi treatment was not discontinued. Sera from healthcare professionals were considered as healthy controls for 1:1 propensity score-matching. Student's t-test and logistic regression were used for investigating differences in immunogenicity between groups and predictors of antibody response. RESULTS: Even though the decay of IgG levels showed similar magnitude between groups, PsA patients had a lower IgG level than matched controls at 4 months after two-dose vaccination (2009.22±4050.22 vs. 6206.59±4968.33 AU/mL, respectively p=0.0006). Booster dose restored IgG levels to a similar extent in both groups (15846.47±12876.48 vs. 20374.46±12797.08 AU/ml p=0.20, respectively). Clinical Disease Activity Index (CDAI) did not change before and after vaccination (6.68±4.38 vs. 4.95±4.20, p=0.19). CONCLUSIONS: A BNT162b2 booster dose should be recommended in PsA patients on TNFi as its administration restores anti-SARS-CoV-2 IgG levels similar to healthy individuals.
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Artrite Psoriásica , COVID-19 , Humanos , Vacina BNT162 , SARS-CoV-2 , Inibidores do Fator de Necrose Tumoral , Vacinas contra COVID-19 , Anticorpos Antivirais , Imunoglobulina G , Imunogenicidade da Vacina , Vacinação , Vacinas de mRNARESUMO
A thorough study on the amidation conditions of N-acetyl-l-phenylalanine using TBTU and various bases is reported for the synthesis of 2-(N-acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA), a promising drug for the treatment of joints diseases. TBTU-mediated diastereoselective amidation reaction with 1,3,4,6-tetra-O-acetyl-ß-d-glucosamine always gave racemization of N-acetyl-l-phenylalanine. The stereochemical retention under amidation conditions was studied in detail in the presence of difference bases and via other control experiments, evidencing the possibility to reduce racemization using pyridine as base.
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Glucosamina , Glucose , Anti-Inflamatórios , DesoxiglucoseRESUMO
INTRODUCTION: The worldwide spread of SARS-COV2 had led to a delay in treatment of numerous urological pathologies, even in emergency conditions. We therefore sought to determine whether the timing of diagnosis and treatment and the postoperative outcome of patients with testicular torsion had been changed during the COVID pandemic. MATERIALS AND METHODS: We considered all patients evaluated in the emergency department (ED) for testicular torsion from February 2018 to August 2019 (pre-COVID period) and from February 2020 to August 2021 (during COVID pandemic). All patients underwent clinical and ultrasound evaluation and subsequently scrotal exploration. Primary outcomes were the time differences from pain onset to ED presentation and from ED presentation to surgical treatment. We also investigated whether the number or orchiectomies required changed during the pandemic. RESULTS: A total of 54 patients were divided in two groups: 40 patients in pre-COVID-19 group and 14 in the COVID-19 cohort. Mean time from symptoms onset to ED access was longer during the pandemic (4.2 ± 5.7 versus 39.6 ± 37.3 hours, p = 0.009). Mean time from ED access to surgery was similar (2.9 ± 1.1 versus 4.2 ± 2.3, p = 0.355). In addition, the number of orchiectomies was higher in COVID-19 group (2.5% versus 28.6%, p < 0.01), compared to a lower number of detorsions (97.5% versus 71.4%, p < 0.01). Elapsed time from pain onset to surgery was directly correlated with the increased white blood cell (WBC) count after surgery (r = 0.399, p = 0.002). DISCUSSION AND CONCLUSIONS: The current study identifies a significant delay in presentation of testicular torsion which resulted in a significant increase in orchiectomies with the expected decreased in detorsion/orchiopexy. In addition, there was an increase in the WBC at presentation associated with delayed presentation.
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COVID-19 , Torção do Cordão Espermático , Adulto , Humanos , Masculino , Orquiectomia/métodos , Dor/cirurgia , Pandemias , RNA Viral , Estudos Retrospectivos , SARS-CoV-2 , Torção do Cordão Espermático/diagnóstico , Torção do Cordão Espermático/epidemiologia , Torção do Cordão Espermático/cirurgia , Resultado do TratamentoRESUMO
In the preregistration trial, data on efficacy of BNT162b2 mRNA vaccine against SARS-CoV-2 infection were not collected. This study aimed to evaluate vaccine effectiveness (VE) against documented infection. Bari Policlinico University Hospital health care workers (HCWs) who completed the vaccination schedule were matched with HCWs who had refused vaccination. VE for documented infection was 61.9% (95% confidence interval [CI], 19.2%-82.0%) 14-20 days after first dose, 87.9% (95% CI, 51.7%-97.0%) 21-27 days after first dose, and 96.0% (95% CI, 82.2%-99.1%) 7 or more days after second dose. Unvaccinated HCWs remain a concern in the context of the pandemic emergency.
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Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Adulto , Idoso , Vacina BNT162 , Estudos de Coortes , Feminino , Pessoal de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
Nowadays natural biopolymers have a wide variety of uses in various industrial applications, such as food, adhesives and composite materials. Among them, cellulose has attracted the interest of researchers due to its properties: high strength and flexibility, biocompatibility and nontoxicity. Despite that, in many cases its practical use is limited because of poor solubility and/or an unsuitable hydrophilic/hydrophobic balance. In this context, enzymatic modification appears as a powerful strategy to overcome these problems through selective, green and environmentally friendly processes. This minireview discusses the different methods developed for the enzymatic modification of cellulose, emphasizing the type of reaction, the enzymes used (laccases, esterases, lipases, hexokinases, etc.), and the properties and applications of the cellulose derivatives obtained. Considering that cellulose is the most abundant natural polymer on Earth and can be derived from residual lignocellulosic biomass, the impact of its use in bio-based process following the logic of the circular economy is relevant.
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Celulose/metabolismo , Hexoquinase/metabolismo , Lacase/metabolismo , Acilação , Biocatálise , Celulose/química , Óxidos N-Cíclicos/química , Química Verde , Hidrolases/metabolismo , Oxirredução , FosforilaçãoRESUMO
We report on the thermodynamic, structural, and dynamic properties of a recently proposed deep eutectic solvent, formed by choline acetate (ChAc) and urea (U) at the stoichiometric ratio 1:2, hereinafter indicated as ChAc:U. Although the crystalline phase melts at 36-38 °C depending on the heating rate, ChAc:U can be easily supercooled at sub-ambient conditions, thus maintaining at the liquid state, with a glass-liquid transition at about -50 °C. Synchrotron high energy x-ray scattering experiments provide the experimental data for supporting a reverse Monte Carlo analysis to extract structural information at the atomistic level. This exploration of the liquid structure of ChAc:U reveals the major role played by hydrogen bonding in determining interspecies correlations: both acetate and urea are strong hydrogen bond acceptor sites, while both choline hydroxyl and urea act as HB donors. All ChAc:U moieties are involved in mutual interactions, with acetate and urea strongly interacting through hydrogen bonding, while choline being mostly involved in van der Waals mediated interactions. Such a structural situation is mirrored by the dynamic evidences obtained by means of 1H nuclear magnetic resonance techniques, which show how urea and acetate species experience higher translational activation energy than choline, fingerprinting their stronger commitments into the extended hydrogen bonding network established in ChAc:U.
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OBJECTIVE: The theoretical advantages of augmented reality (AR) with diffusion tensor imaging (DTI)-based high-definition fiber tractography (HDFT) and sodium fluorescein (F) in high-grade glioma (HGG) surgery have not been investigated in detail. In this study, the authors aimed to evaluate the safety and efficacy profiles of HDFT-F microscope-based AR cytoreductive surgery for newly diagnosed supratentorial HGGs. METHODS: Data of patients with newly diagnosed supratentorial HGGs who underwent surgery using the AR HDFT-F technique were reviewed and compared with those of a cohort of patients who underwent conventional white-light surgery assisted by infrared neuronavigation. The safety and efficacy of the techniques were reported based on the postoperative Neurological Assessment in Neuro-Oncology (NANO) scores, extent of resection (EOR), and Kaplan-Meier curves, respectively. The chi-square test was conducted for categorical variables. A p value < 0.05 was considered statistically significant. RESULTS: A total of 54 patients underwent surgery using the AR HDFT-F technique, and 63 underwent conventional white-light surgery assisted by infrared neuronavigation. The mean postoperative NANO scores were 3.8 ± 2 and 5.2 ± 4 in the AR HDFT-F group and control group, respectively (p < 0.05). The EOR was higher in the AR HDFT-F group (p < 0.05) than in the control group. With a mean follow-up of 12.2 months, the rate of progression-free survival (PFS) was longer in the study group (log-rank test, p = 0.006) than in the control group. Moreover, the complication rates were 9.2% and 9.5% in the study and control groups, respectively. CONCLUSIONS: Overall, AR HDFT-F-assisted surgery is safe and effective in maximizing the EOR and PFS rate for patients with newly diagnosed supratentorial HGGs, and in optimizing patient functional outcomes.
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Realidade Aumentada , Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Imagem de Tensor de Difusão , Fluoresceína , Glioma/diagnóstico por imagem , Glioma/cirurgia , HumanosRESUMO
Synthetic amorphous silica (SAS) nanomaterial - consisting of aggregates and agglomerates of primary silicon dioxide (SiO2) particles in the nanorange (<100 nm) - is commonly used as excipient in pharmaceuticals, in cosmetics and as food additive (E551). The available data suggest that SAS nanoparticles (NP) after intravenous (IV) exposure persist in liver and spleen; however, insufficient data exist to verify whether SAS may also induce adverse effects. The aim of the present study was to verify the potential long-term effects of SAS NP (NM-203) on spleen and liver as target organs following short-term exposure. Adult male and female Sprague-Dawley rats were treated by IV injection in the tail vein with a single (1-day) dose (SD) and repeated (5-day) doses (RD) of 20 mg/kg bw per day of SAS dispersed in sterile saline solution as vehicle. Histopathological examinations of target organs were performed after 90 days. Tissue biodistribution and full characterization of NM-203, primary particle size 13-45 nm, was performed within the framework of the Nanogenotox project. No mortality or general toxicity occurred; histopathological analysis showed splenomegaly in the RD group accompanied by inflammatory granulomas in both sexes. Granulomas were also present in liver parenchyma in the RD (both sexes) and SD groups (male only). The histopathological results indicated that SAS NP have the potential to persist and induce sex-specific chronic inflammatory lesions in spleen and liver upon short-term treatment. Overall, the data showed that the widespread use of silica in drugs might elicit chronic reactions in spleen and liver prompting to the need of further investigations on the safety of SAS NP.[Formula: see text].
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Fígado/efeitos dos fármacos , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Baço/efeitos dos fármacos , Administração Intravenosa , Animais , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Distribuição TecidualRESUMO
Respirable Crystalline Silica (RCS) is a hazardous substance with known effects that can be well correlated with exposure levels that still persist in many traditional sectors, such as construction or stone processing. In the past decade, exposure scenarios for RCS have been found in the sector of artificial stone processing. The aim of this study is to evaluate the levels of RCS in facilities specialized in the production of artificial stone countertops and other accessories for the furnishing of kitchens, bathrooms, and offices after the introduction of some preventive technical measures such as wet processing or local exhaust ventilation systems. The study involved 51 subjects in four facilities. Personal silica exposure assessment was carried out using GS3 cyclones positioned in the breathing zone during the work shift. Quantitative determination of silica was carried out by X-ray diffraction analysis. Respirable dust levels were in the range 0.046-1.154 mg/m3 with RCS levels within the range <0.003-0.098 mg/m3. The highest exposure was found in dry finishing operations. Although there was a remarkable reduction in RCS exposure levels compared to what was observed in the past before the introduction of preventive measures, the data still showed hazardous exposure levels for some of the monitored activities.
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Poluentes Ocupacionais do Ar , Exposição Ocupacional , Poluentes Ocupacionais do Ar/análise , Poeira/análise , Humanos , Exposição por Inalação/análise , Exposição Ocupacional/análise , Dióxido de Silício/análiseRESUMO
Wound healing is a dynamic process that can be seriously delayed by many factors including infectious complications. The development of dressings with intrinsic wound healing activity and/or releasing bioactive compounds may help with addressing such an issue. In this study, hyaluronic acid (HA) at different percentages (1-35%) was used to modify chitosan (CS) biological and physico-chemical properties in order to obtain 2D-matrices able to promote healing and protect from infection. HA incorporation in the CS matrix decreased film transparency and homogeneity, but improved film water uptake and surface wettability. The water vapor transmission rate (WVTR) increased up to a 5% HA content, where it reached the highest value (672 g/m2 day), and decreased for higher HA contents. At all of the tested HA concentrations, HA affected mechanical properties providing matrices more flexible than pure CS with benefit for wound care. Pure CS films permitted S. epidermidis adhesion and biofilm formation. That was not true for CS/HA matrices, where HA at concentrations equal to or greater than 5% was able to avoid S. epidermidis adhesion. Fibroblasts adhesion also took benefit from the HA presence in the film, especially at 5% content, where the best adhesion and proliferation was found.
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Bandagens , Quitosana , Fibroblastos/metabolismo , Ácido Hialurônico , Membranas Artificiais , Staphylococcus epidermidis/crescimento & desenvolvimento , Aderência Bacteriana , Adesão Celular , Células Cultivadas , Fibroblastos/microbiologia , Fibroblastos/patologia , Humanos , MasculinoRESUMO
INTRODUCTION: Outbreaks of silicosis have bene recently reported in artificial stone workers. AIM: To describe the features of silicosis in quartz conglomerate workers in North-Eastern Italy. METHODS: Active search of pneumoconiosis was performed in 11 companies of North-Eastern Italy involved in the fabrication of quartz conglomerate countertops. Occupational history, lung function tests, chest X-ray and high resolution computed tomography (HRCT) were performed. In selected cases, trans-bronchial biopsies were taken for histological evaluation and identification of silica crystals in the tissue. Cumulative exposure to crystalline silica was estimated. RESULTS: We recruited 45 workers and 24 cases of silicosis were diagnosed. Mean age at diagnosis was 43 years and duration of exposure to quartz conglomerate dust was 3.5 to 20 years. The average silica cumulative exposure was 4.3 mg/m3/y. Abnormal findings were detected in 42% of chest X-rays, in 33% of spirometry and 50% of carbon monoxide lung diffusion (DLco). HRCTs were abnormal in all cases showing well-defined rounded opacities, irregular/linear intralobular opacities and bilateral enlarged mediastinal lymph-nodes. Histological findings consistent with silicosis were observed in 24 cases. Numerous silica particles (diameter 0.1-5 µm) were identified in lung tissue. CONCLUSIONS: We reported an unexpected high incidence of silicosis in Italian workers exposed to quartz conglomerate dust. The results suggest that chest HRCT is indicated for screening of workers with high exposure to silica and DLco should be added to spirometry in health surveillance. More rigorous application of safety regulations and more effective preventive interventions at work are necessary.
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Exposição Ocupacional , Pneumoconiose , Quartzo , Silicose , Adulto , Poeira , Humanos , Itália , Quartzo/toxicidade , Dióxido de SilícioRESUMO
Despite advances in material sciences and clinical procedures for surgical hygiene, medical device implantation still exposes patients to the risk of developing local or systemic infections. The development of efficacious antimicrobial/antifouling materials may help with addressing such an issue. In this framework, polyethylene glycol (PEG)-grafted segmented polyurethanes were synthesized, physico-chemically characterized, and evaluated with respect to their bacterial fouling-resistance properties. PEG grafting significantly altered the polymer bulk and surface properties. Specifically, the PEG-grafted polyurethanes possessed a more pronounced hard/soft phase segregated microstructure, which contributed to improving the mechanical resistance of the polymers. The better flexibility of the soft phase in the PEG-functionalized polyurethanes compared to the pristine polyurethane (PU) was presumably also responsible for the higher ability of the polymer to uptake water. Additionally, dynamic contact angle measurements evidenced phenomena of surface reorganization of the PEG-functionalized polyurethanes, presumably involving the exposition of the polar PEG chains towards water. As a consequence, Staphylococcus epidermidis initial adhesion onto the surface of the PEG-functionalized PU was essentially inhibited. That was not true for the pristine PU. Biofilm formation was also strongly reduced.
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Materiais Biocompatíveis/química , Incrustação Biológica/prevenção & controle , Elastômeros/química , Polietilenoglicóis/química , Poliuretanos/química , Aderência Bacteriana , Materiais Biocompatíveis/síntese química , Biofilmes , Elastômeros/síntese química , Humanos , Polietilenoglicóis/síntese química , Poliuretanos/síntese química , Propriedades de SuperfícieRESUMO
This paper describes, for the first time, the use of oxidized buckypaper (BP) as a sorbent membrane of a stir-disc solid phase extraction module. The original device, consisting of a BP disc ( d = 34 mm) enveloped in a polypropylene mesh pouch, was designed to extract organic micropollutants (OMPs) from environmental water samples in dynamic mode. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze the extracts. Several classes of pesticides and pharmaceuticals were chosen as model compounds to evaluate key parameters affecting the recovery rates. To this end, the effects of adsorption time, desorption time, stirring speed, type and volume of solvent, and sample volume were thoroughly examined. After optimization, a novel and in-depth study was conducted to find a correlation between physicochemical properties of the analytes and extraction yields. Recoveries were mainly governed by a combination of log P and p Ka values. As indicated, hydrophilic compounds with log P < 1 showed poor affinity for the oxidized BP, compounds having log P > 1 exhibited recoveries ranging between 50% and 100% depending on their p Ka, while compounds with p Ka between 6 and 7.5 gave low yields irrespective of their log P. The analytical method was also validated and tested as large scale screening method of OMPs in surface waters. The analysis of real samples revealed the presence of some nonsteroidal anti-inflammatory drugs, sulfonamides, and pesticides at low ng L-1 concentration levels with relative standard deviations lower than 8%.
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Papel , Praguicidas/análise , Extração em Fase Sólida , Sulfonamidas/análise , Poluentes Químicos da Água/análise , OxirreduçãoRESUMO
Studies on the role of multipotent mesenchymal stromal cells (MSC) on tumor growth have reported both a tumor promoting and a suppressive effect. The aim of the present study was to determine the effect of MSC isolated from Wharton's jelly of umbilical cord (WJMSC) on lung cancer stem cells (LCSC) derived from human lung tumors: two adenocarcinomas (AC) and two squamous cell carcinomas (SCC). LCSC derived from SCC and AC expressed, to varying extents, the more relevant stem cell markers. The effect of WJMSC on LCSC was investigated in vitro using conditioned medium (WJ-CM): a proliferation increase in AC-LCSC was observed, with an increase in the ALDH+ and in the CD133+ cell population. By contrast, WJ-CM hampered the growth of SCC-LCSC, with an increase in the pre-G1 phase indicating the induction of apoptosis. Furthermore, the ALDH+ and CD133+ population was also reduced. In vivo, subcutaneous co-transplantation of AC-LCSC/WJMSC generated larger tumors than AC-LCSC alone, characterized by an increased percentage of CD133+ and CD166+ cells. By contrast, co-transplantation of WJMSC and SCC-LCSC did not affect the tumor size. Our results strongly suggest that WJMSC exert, both in vitro and in vivo, contrasting effects on LCSC derived from different lung tumor subtypes.
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Neoplasias Pulmonares/classificação , Neoplasias Pulmonares/patologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Neoplásicas/patologia , Geleia de Wharton/citologia , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células , Células Cultivadas , Meios de Cultivo Condicionados/farmacologia , Humanos , Transplante de Células-Tronco Mesenquimais , Camundongos Endogâmicos NOD , Camundongos SCID , Microscopia de Fluorescência , Fenótipo , Tela Subcutânea/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The accumulation of reactive oxygen species (ROS) in microbial biofilms has been recently recognized to play a role in promoting antibiotic resistance in biofilm-growing bacteria. ROS are also over-produced when a medical device is implanted and they can promote device susceptibility to infection or aseptic loosening. High levels of ROS seem also to be responsible for the establishment of chronic wounds.In this study, a novel antioxidant polyacrylate was synthesized and investigated in terms of antimicrobial and antibiofilm activity. The polymer possesses in side-chain hydroxytyrosol (HTy), that is a polyphenolic compound extracted from olive oil wastewaters.The obtained 60 nm in size polymer nanoparticles showed good scavenging and antibacterial activity versus a strain of Staphylococcus epidermidis. Microbial adherence assays evidenced that the hydroxytyrosol-containing polymer was able to significantly reduce bacterial adhesion compared to the control. These findings open novel perspective for a successful use of this antioxidant polymer for the prevention or treatment of biofilm-based infections as those related to medical devices or chronic wounds.
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Antibacterianos/farmacologia , Antioxidantes/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Staphylococcus epidermidis/efeitos dos fármacos , Antibacterianos/química , Antioxidantes/química , Biofilmes/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Álcool Feniletílico/química , Álcool Feniletílico/farmacologia , Staphylococcus epidermidis/crescimento & desenvolvimento , Staphylococcus epidermidis/fisiologiaRESUMO
BACKGROUND: Individuals whose gender identity differs from the biological sex and the social norms are defined as transgender. Sometimes transgender undergo gender affirming hormone therapy, which lasts for the entire life making essential to evaluate its potential long-term effects. Moreover, transgender can represent a susceptible sub-group of population and specific attention is needed in risk assessment, including the development of targeted animal models. Aim of the study is the implementation of a rodent demasculinizing-feminizing model through the setting of appropriate dose of hormone therapy and the selection of specific biomarkers to evaluate the sex transition. Specific attention is paid to thyroid homeostasis due to the close link with reproductive functions. Four male adult rats/group were subcutaneously exposed to three doses plus control of ß-estradiol valerate plus cyproterone acetate at: 0.045 + 0.2 (low), 0.09 + 0.2 (medium) and 0.18 + 0.2 (high) mg/dose, five times/week. The doses were selected considering the most recent recommendations for transgender woman. Sperm count, histopathological analysis (testis, liver, thyroid), testosterone, estradiol, triiodothyronine and thyroid-stimulating hormone serum levels and gene expression of sex dimorphic CYP450 were evaluated. RESULTS: The doses induced feminizing-demasculinizing effects: decreased testosterone serum levels at the corresponding cisgender, increased estradiol, impairment of male reproductive function and reversal of sex-specific CYP liver expression. However, the medium and high doses induced marked liver toxicity and the low dose is considered the best choice, also for long-term studies in risk assessment. The alterations of thyroid indicated follicular cell hypertrophy supported by increased thyroid-stimulating hormone serum levels at the higher doses. CONCLUSIONS: The implementation of animal models that mimic the effects of gender affirming hormone therapy is essential for supporting clinical studies in transgender people and filling data gap in order to ensure an appropriate risk assessment and a more accurate, personalized care for transgender people.
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Pessoas Transgênero , Humanos , Adulto , Masculino , Feminino , Ratos , Animais , Glândula Tireoide , Roedores , Identidade de Gênero , Sêmen , Estradiol/uso terapêutico , Testosterona , TireotropinaRESUMO
2,2',4,4'-tetra-bromodiphenyl ether (BDE-47) is widespread in the environment and biological samples. Its association with health risks is an increasing concern, yet information on BDE-47 immunotoxicity remains limited. This study investigated the impact of BDE-47 on innate and adaptive immune responses through in vitro and in vivo approaches. BDE-47's capacity to directly induce cell responses and modulate responses induced by known stimuli was studied in vitro using the RAW 264.7 murine macrophage cell line and spleen-derived lymphocytes, and in vivo using keyhole limpet hemocyanin (KLH)-immunized BALB/c mice orally administered (28 d) at dose levels (7.5, 15.0 and 30 mg/kg/bw/d) derived from relevant toxicokinetic data from rodent models. RAW 264.7 cells stimulated with lipopolysaccharide (LPS) and exposed to BDE-47 exhibited unchanged cell viability but decreased release of interleukin (IL)-6. Primary splenocytes from naïve mice stimulated with anti-CD3/anti-CD28 antibodies and exposed to BDE-47 showed a significant decrease of IL-17 A and IFNγ production. In vivo data showed that BDE-47 significantly reduced the KLH-specific antibody response. A generally decreasing trend of IFNγ, IL-10 and IL-5 production was observed after in vitro antigen-specific restimulation of spleen cells. Histopathological effects on liver, spleen, small intestine and thyroid were detected at the highest dose in the absence of general toxicity. In addition, the expression of Mm_mir155 and Mm_let7a was induced in livers of exposed mice. The data obtained in this study suggest that exposure to BDE-47 may perturb innate and adaptive immune responses, thus possibly decreasing resistance to bacterial and viral infections.
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Imunidade , Interleucina-6 , Camundongos , Animais , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , HemocianinasRESUMO
Poly(3-hydroxybutyrate-co-3-hydroxyvalerate (P(3HB-co-3HV) copolymers are an attractive class of biopolymers whose properties can be tailored by changing the 3-hydroxyvalerate monomer (3HV) concentration, offering the possibility of counteracting problems related to high crystallinity, brittleness, and processability. However, there are few studies about the effects of 3HV content on the processability of copolymers. The present study aims to provide new insights into the effect of 3HV content on the processing step including common practices like compounding, addition of nucleation agents and/or amorphous polymers as plasticizers. P(3HB-co-3HV)-based films containing 3, 18, and 28 mol % 3HV were processed into films by extrusion and subsequent molding. The characterization results confirmed that increasing the 3HV content from 3 to 28 mol % resulted in a decrease in the melting point (from 175 to 100 °C) and an improvement in mechanical properties (i.e., elongation at break from 7 ± 1% to 120 ± 3%). The behavior of P(3HB-co-3HV) in the presence of additives was also investigated. It was shown that an increase in the 3HV content leads to better miscibility with amorphous polymers.
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BACKGROUND: Since 2021 a recombinant adjuvanted anti-Herpes Zoster vaccine(Recombinant Zoster Vaccine, RZV) is offered in Italy to high-risk patients. Few real-life data about RZV safety are available in target populations. OBJECTIVES: This study investigates Adverse Events Following Immunization(AEFIs), baseline disease flare-ups, and Herpes Zoster (HZ) episodes occurring after RZV administration in a heterogeneous population of fragile patients to design its safety profile. METHODS: This is a retrospective population-based study. RZV-vaccinated patients at Bari Policlinico General Hospital vaccination clinic from October 1st, 2021, to March 31st, 2023, were enrolled. Subjects were screened for reason of RZV eligibility and baseline chronic pathologies. AEFIs occurred in the first 7-days post-vaccination period were collected, and baseline disease flare-ups and post-vaccination HZ episodes were assessed via a 3-month follow-up. RESULTS: Five-hundred-thirty-eight patients were included and total of 1,031 doses were administered. Most patients were vaccinated due to ongoing immunosuppressive therapy(54.65 %); onco-hematological and cardiovascular conditions were the most common chronic baseline pathologies. Out of 1,031 follow-ups, 441 AEFI cases were reported(42.7/100). The most common symptoms were injection site pain/itching(35.60/100), asthenia/malaise(11.44/100), and fever (10.09/100). Four serious AEFIs occurred(0.38/100). Older age, male sex, and history of cardiovascular diseases(OR:0.71; 95CI:0.52-0.98; p-value <0.05) were found to decrease AEFIs risk, while endocrine-metabolic illnesses(OR:1.61; 95CI:1.15-2.26; p-value <0.05) increased it. Twelve patients(2.23 %) reported a flare-up/worsening of their baseline chronic condition within the first three months after vaccination(mean interval 31.75 days, range 0-68 days). Patients with rheumatological illnesses had a higher risk of relapse(OR:16.56; 95CI:3.58-76.56; p-value <0.001), while male sex behaved as a protective factor. Twelve patients who completed the vaccination cycle(2.43%) had at least one HZ episode by the long-term follow-up. CONCLUSIONS: The study demonstrates RZV safety in a significant number of high-risk patients. Hence, RZV should be actively offered as part of tailored vaccination programs to decrease the burden of HZ in fragile populations.