RESUMEN
Lanthanides are indispensable constituents of modern technologies and are often challenging to acquire from natural resources. The demand for REEs is so high that there is a clear need to develop efficient and eco-friendly recycling methods. In the present study, freeze-dried biomass of the polyextremophile Galdieria sulphuraria was employed to recover REEs from spent fluorescent lamps (FL) luminophores by pretreating the freeze-dried biomass with an acid solution to favour ion exchange and enhance the binding sites on the cell surface available for the metal ions. Lanthanides were extracted from the luminophores using sulfuric acid solutions according to standardised procedures, and the effect of biosorbent dosage (0.5-5 mg/ml) and biosorption time (5-60 min) were evaluated. The content of individual REEs in the luminophores and the resulting algal biomass were determined using inductively coupled plasma mass spectrometry (ICP-MS). The most abundant REE in the luminophores was yttrium (287.42 mg/g dm, 91.60% of all REEs), followed by europium (20.98 mg/g, 6.69%); cerium, gadolinium, terbium and lanthanum was in trace. The best biosorption performances were achieved after 5 min and at the lowest biosorbent dosage (0.5 mg/mL). The highest total metal amount corresponded to 41.61 mg/g dried mass, and yttrium was the most adsorbed metal (34.59 mg/g dm, 82.88%), followed by cerium (4.01 mg/g); all other metals were less than 2 mg/g. The rapidity of the biosorption process and the low biosorbent dosage required confirmed this microalga as a promising material for creating an eco-sustainable protocol for recycling REEs.
Asunto(s)
Cerio , Metales de Tierras Raras , Rhodophyta , Metales de Tierras Raras/análisis , Itrio , Metales/metabolismo , Rhodophyta/metabolismoRESUMEN
Immune checkpoint inhibition has revolutionized the treatment of several solid cancers, most notably melanoma and non-small-cell lung cancer (NSCLC). Drugs targeting cytotoxic T lymphocyte antigen (CTLA)-4 and programmed cell death 1 (PD-1) have made their way into routine clinical use; however, this has not been without difficulties. Stimulation of the immune system to target cancer has been found to result in a reduction of self-tolerance, leading to the development of adverse effects that resemble autoimmunity. These adverse effects are erratic in their onset and severity and can theoretically affect any organ type. Several mechanisms for immune-related toxicity have been investigated over recent years; however, no consensus on the cause or prediction of toxicity has been reached. This review seeks to examine reported evidence for possible mechanisms of toxicity, methods for prediction of those at risk and a discussion of future prospects within the field.
Asunto(s)
Antineoplásicos , Antígeno CTLA-4 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas de Neoplasias , Receptor de Muerte Celular Programada 1 , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
BACKGROUND: Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis. METHODS: Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-ß, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3,5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. RESULTS: OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-ß signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. CONCLUSIONS: OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis.
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Cirrosis Hepática/metabolismo , Osteopontina/metabolismo , Células Madre/metabolismo , Animales , Progresión de la Enfermedad , Regulación hacia Abajo/fisiología , Inmunohistoquímica , Hígado/patología , Cirrosis Hepática/patología , Ratones Endogámicos C57BL , Factor de Transcripción SOX9/metabolismo , Factor de Crecimiento Transformador beta/fisiología , Regulación hacia Arriba/fisiología , Cicatrización de Heridas/fisiologíaRESUMEN
Cancer clinical trials enable the development of novel agents for the potential benefit of cancer patients. Enrolment in a trial offers patients the chance of superior efficacy coupled to the risk of unanticipated toxicity. For trial results to be generalisable, the data need to be collected in patients' representative of the general cancer population. Socioeconomic deprivation is associated with poor cancer outcomes. In the developed world, the gap between the most and least deprived is widening. This mini-review explores the evidence regarding socioeconomics and access to cancer trials, highlighting the underrepresentation of deprived patients, and exploring reasons for this disparity.
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Ensayos Clínicos como Asunto/economía , Accesibilidad a los Servicios de Salud/economía , Disparidades en Atención de Salud , Neoplasias/economía , Humanos , Neoplasias/epidemiología , Neoplasias/psicología , Pronóstico , Factores Socioeconómicos , Reino Unido/epidemiologíaRESUMEN
Campylobacter jejuni is the most common cause of bacterial gastroenteritis in humans. The synthesis of cytolethal distending toxin appears essential in the infection process. In this work we evaluated the sequence of lethal events in HeLa cells exposed to cell lysates of two distinct strains, C. jejuni ATCC 33291 and C. jejuni ISS3. C. jejuni cell lysates (CCLys) were added to HeLa cell monolayers which were analysed to detect DNA content, death features, bcl-2 and p53 status, mitochondria/lysosomes network and finally, CD54 and CD59 alterations, compared to cell lysates of C. jejuni 11168H cdtA mutant. We found mitochondria and lysosomes differently targeted by these bacterial lysates. Death, consistent with apoptosis for C. jejuni ATCC 33291 lysate, occurred in a slow way (>48 h); concomitantly HeLa cells increase their endolysosomal compartment, as a consequence of toxin internalization besides a simultaneous and partial lysosomal destabilization. C. jejuni CCLys induces death in HeLa cells mainly via a caspase-dependent mechanism although a p53 lysosomal pathway (also caspase-independent) seems to appear in addition. In C. jejuni ISS3-treated cells, the p53-mediated oxidative degradation of mitochondrial components seems to be lost, inducing the deepest lysosomal alterations. Furthermore, CD59 considerably decreases, suggesting both a degradation or internalisation pathway. CCLys-treated HeLa cells increase CD54 expression on their surface, because of the action of lysate as its double feature of toxin and bacterial peptide. In conclusion, we revealed that C. jejuni CCLys-treated HeLa cells displayed different features, depending on the particular strain.
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Campylobacter jejuni/metabolismo , Lisosomas/metabolismo , Mitocondrias/metabolismo , Apoptosis , Toxinas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Cardiolipinas/metabolismo , Caspasas/metabolismo , Citosol/metabolismo , Endocitosis , Células HeLa , Humanos , Proteína 1 de la Membrana Asociada a los Lisosomas/metabolismo , Lisosomas/ultraestructura , Mitocondrias/ultraestructura , Mutación , Tetraspanina 30/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
There are few and partially discordant data regarding nasopharyngeal rhinovirus (RV) load and viremia, and none of the published studies evaluated the two variables together. The aim of this study was to provide new information concerning the clinical relevance of determining nasopharyngeal viral load and viremia when characterising RV infection. Nasopharyngeal swabs were obtained from 251 children upon their admission to hospital because of fever and signs and symptoms of acute respiratory infection in order to identify the virus and determine its nasopharyngeal load, and a venous blood sample was taken in order to evaluate viremia. Fifty children (19.9 %) had RV-positive nasopharyngeal swabs, six (12 %) of whom also had RV viremia: RV-C in four cases (66.6 %), and RV-A and RV-B in one case each. The RV nasopharyngeal load was significantly higher in the children with RV viremia (p < 0.001), who also had a higher respiratory rate (p = 0.02), white blood cell counts (p = 0.008) and C-reactive protein levels (p = 0.006), lower blood O2 saturation levels (P = 0.005), and more often required O2 therapy (p = 0.009). The presence of RV viremia is associated with a significantly higher nasopharyngeal viral load and more severe disease, which suggests that a high nasopharyngeal viral load is a prerequisite for viremia, and that viremia is associated with considerable clinical involvement.
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Nasofaringe/virología , Infecciones por Picornaviridae/patología , Infecciones del Sistema Respiratorio/patología , Rhinovirus/aislamiento & purificación , Carga Viral , Viremia/patología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Infecciones por Picornaviridae/virología , Infecciones del Sistema Respiratorio/virología , Índice de Severidad de la Enfermedad , Viremia/virologíaRESUMEN
BACKGROUND: Topical therapies represent the first-line treatment for mild-to-moderate psoriasis. Among various topical options, the fixed-dose combination of calcipotriene (Cal) and betamethasone dipropionate (BD) foam (Enstilar®, LEO Pharma, Ballerup, Denmark) showed superior efficacy to Cal and BD monotherapy and ointment and gel formulations. In addition, the Cal/BD foam is the only topical treatment allowed for either reactive treatment of relapse or twice-weekly maintenance use. Since treatment acceptability is crucial to optimize adherence, this paper presents a case series from a multicenter experience using the Cal/BD foam, to further characterize the use of this therapeutic approach. In addition, a narrative review of studies evaluating the acceptability of the Cal/BD foam, even compared with other formulations, is provided. CASE SERIES: The case series involved adult patients with mild-to-moderate psoriasis treated with the Cal/BD foam from October 2021 to June 2022. A clinical and dermoscopic evaluation of plaques was provided for all patients. Data from the clinical practice report complete clinical resolution of plaques in most patients after 4 weeks of active treatment with the Cal/BD foam, and the dermoscopic clearance after a maximum of 8 weeks. Full adherence to treatment was also reported. Literature evidence suggests that the Cal/BD foam is easy to apply and presents high cosmetic acceptance, rapid onset of action, high efficacy, optimal safety, and a high patient preference. The high satisfaction obtained with Cal/BD foam suggests that this formulation is better accepted than others. CONCLUSIONS: The Cal/BD foam represents a valuable approach for managing mild-to-moderate psoriasis, both in short and long-term treatment.
Asunto(s)
Fármacos Dermatológicos , Psoriasis , Adulto , Humanos , Fármacos Dermatológicos/uso terapéutico , Resultado del Tratamiento , Aerosoles/uso terapéutico , Psoriasis/tratamiento farmacológico , Betametasona/uso terapéutico , Administración Tópica , Combinación de Medicamentos , Estudios Multicéntricos como AsuntoRESUMEN
In the present study, trace metals contents (V, Cr, Mn, Fe, Ni, Cu, Zn, Cd and Pb) and physico-chemical parameters (nitrogen, organic and inorganic carbon, pH and particle size) in sediments samples along the Calore river were analyzed in two seasons. Sediment samples were collected in ten sites upstream and downstream of the city of Benevento and its industrial area, the confluence of Sabato and Tammaro tributaries, and the confluence of Calore and Volturno rivers. The highest contents of trace metals were found, generally, in the sites immediately downstream of industrial area and of Benevento city. The sites on the Tammaro and Sabato also showed relatively high contents of Ni and, only for Sabato sites, of Cr, and Fe. With the exception of Cd, the heavy metal contents were highest in the last site of Calore river, which therefore is a source of pollution to the Volturno river. Besides the sites downstream of Benevento city showed the higher pH values and also the highest contents of fine particles size and organic matter. Positive correlations among trace metals, organic substance, particle size sediments were found. The data obtained in this study were analyzed with reference to Interim Sediment Quality Guidelines and indicated moderate-to-high pollution by some trace metals (V, Cr, Mn, Fe, Ni, Cu).
Asunto(s)
Sedimentos Geológicos/análisis , Metales Pesados/análisis , Contaminantes Químicos del Agua/análisis , Carbono/análisis , Ciudades , Sedimentos Geológicos/química , Concentración de Iones de Hidrógeno , Industrias , Italia , Tamaño de la Partícula , Ríos , Contaminación Química del AguaRESUMEN
Trace metals and polycyclic aromatic hydrocarbons, severely affecting human, animal and plants health, highly contribute to the air pollution in urban areas mainly due to car traffic. In this study the air biomonitoring of the city of Caserta (South Italy) has been performed by using Quercus ilex L., a widespread ornamental plant in parks, gardens and avenues. The plant leaves from different sites within the urban area were collected and used to determine the concentrations of V, Cd, Cr, Pb, Ni, Cu, and PAHs as well as the free amino acid content and peroxidase enzyme activity as indices of the leaf physiological conditions. All the tested trace metals showed concentrations higher than the control site. Lead was positively correlated to Cd and Cr and showed, also, a positive trend with Ni and Cu that, in their turn, were highly correlated between them. Positive and significant correlations were evidenced between total PAHs and carcinogenic PAHs and negative correlations between those and all trace metals assayed except V. Cu and Cd contents evidence negative correlations with peroxidase activity, and the free amino acid contents. The PAHs, in particular Carc-PAHs, were negatively correlated to the tested heavy metals. POD was positively correlated only with V and negatively correlated with Cu and Cd.
Asunto(s)
Peroxidasa/metabolismo , Hojas de la Planta/metabolismo , Hidrocarburos Policíclicos Aromáticos/metabolismo , Quercus/metabolismo , Oligoelementos/metabolismo , ItaliaRESUMEN
Pulmonary arterial hypertension (PAH) is a heart failure syndrome characterized by right ventricular (RV) to pulmonary circulation uncoupling, counteracted by the sympathetic nervous system activation leading to ß1-receptors and α-myosin heavy chain downregulation, downregulation of the sarcoplasmic reticulum Ca2+ATPase, and ß-myosin heavy chain upregulation. Increased ventilation (VE) associated with VE inefficiency further characterizes PAH, as shown by an elevated VE versus carbon dioxide relationship slope during exercise, reflecting a specific behavior with progressive increase of dead space (VD) VE. The sympathetic system interacts with chemoreceptor-mediated VE control with increased VD leading to VE/perfusion mismatch. Growing evidence in the experimental models shows beneficial effects of different adrenoreceptor blockers on both right heart and pulmonary artery morphology and function. These effects can significantly change among ß-blockers according to their different pharmacokinetic and pharmacodynamic profiles. Since the first observation in the clinical setting, showing improvement associated with ß-blocker withdraw in PAH patients, recent studies suggest that the effects of ß-blockers in PAH might be related to the ß1-adrenergic receptors selectivity and α1- and ß3-related ancillary properties. While in the advanced stages of PAH ß-blockers may result deleterious as counteract the compensatory adrenergic-mediated effects of low cardiac output, in the early stages the modulation of the adrenergic system could ultimately improve VE efficiency and promote beneficial effects on heart failure gene expression and RV remodeling, particularly ß1-selective blockers and those associated with α- or ß3-activities. At present, all the above are physiologically sound but clinically unproven suggestions, and need to be tested in future randomized controlled trials.
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Insuficiencia Cardíaca , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Antagonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Cadenas Pesadas de Miosina , Hipertensión Arterial Pulmonar/tratamiento farmacológicoRESUMEN
Periodic repetition of right heart catheterization (RHC) in pulmonary arterial hypertension (PAH) can be challenging. We evaluated the correlation between RHC and cardiopulmonary exercise test (CPET) aiming at CPET use as a potential noninvasive tool for hemodynamic burden evaluation. One hundred and forty-four retrospective PAH patients who had performed CPET and RHC within 2 months were enrolled. The following analyses were performed: (a) CPET parameters in hemodynamic variables tertiles; (b) position of hemodynamic parameters in the peak end-tidal carbon dioxide pressure (PETCO2) versus ventilation/carbon dioxide output (VE/VCO2) slope scatterplot, which is a specific hallmark of exercise respiratory abnormalities in PAH; (c) association between CPET and a hemodynamic burden score developed including mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index, and right atrial pressure. VE/VCO2 slope and peak PETCO2 significantly varied in mPAP and PVR tertiles, while peak oxygen uptake (peak VO2) and O2 pulse varied in the tertiles of all hemodynamic parameters. PETCO2 versus VE/VCO2 slope showed a strong hyperbolic relationship (R 2 = 0.7627). Patients with peak PETCO2 > median (26 mmHg) and VE/VCO2 slope < median (44) presented lower mPAP and PVR (p < 0.005) than patients with peak PETCO2 < median and VE/VCO2 slope > median. Multivariate analysis individuated peak VO2 (p = 0.0158) and peak PETCO2 (p = 0.0089) as hemodynamic score independent predictors; the formula 11.584 - 0.0925 × peak VO2 - 0.0811 × peak PETCO2 best predicts the hemodynamic score value from CPET data. A significant correlation was found between estimated and calculated scores (p < 0.0001), with a precise match for patients with mild-to-moderate hemodynamic burden (76% of cases). The results of the present study suggest that CPET could allow to estimate the hemodynamic burden in PAH patients.
RESUMEN
Considered as some of the most devastating complications, Cutibacterium acnes (C. acnes)-related osteomyelitis are among the hardest infections to diagnose and treat. Mesenchymal stem cells (MSCs) secrete number of immunomodulatory and antimicrobial soluble factors, making them an attractive treatment for bacterial infection. In this study, we examined MSCs/C. acnes interaction and analyzed the subsequent MSCs and bacteria's behaviors. Human bone marrow-derived MSCs were infected by C. acnes clinical strain harvested from non-infected bone site. Following 3 h of interaction, around 4% of bacteria were found in the intracellular compartment. Infected MSCs increased the secretion of prostaglandin E2 and indolamine 2,3 dioxygenase immunomodulatory mediators. Viable intracellular bacteria analyzed by infrared spectroscopy and atomic force microscopy revealed deep modifications in the wall features. In comparison with unchallenged bacteria, the viable intracellular bacteria showed (i) an increase in biofilm formation on orthopaedical-based materials, (ii) an increase in the invasiveness of osteoblasts and (iii) persistence in macrophage, suggesting the acquisition of virulence factors. Overall, these results showed a direct impact of C. acnes on bone marrow-derived MSCs, suggesting that blocking the C. acnes/MSCs interactions may represent an important new approach to manage chronic osteomyelitis infections. STATEMENT OF SIGNIFICANCE: The interaction of bone commensal C. acnes with bone marrow mesenchymal stem cells induces modifications in C. acnes wall characteristics. These bacteria increased (i) the biofilm formation on orthopaedical-based materials, (ii) the invasiveness of bone forming cells and (iii) the resistance to macrophage clearance through the modification of the wall nano-features and/or the increase in catalase production.
Asunto(s)
Células Madre Mesenquimatosas , Osteomielitis , Biopelículas , Células de la Médula Ósea , Humanos , Propionibacterium acnes , Prótesis e ImplantesRESUMEN
BACKGROUND: Although a dramatic decrease in AIDS progression has been observed after Highly Active Anti Retroviral Therapy (HAART) in both low- and high-resource settings, few data support that fact in low-resource settings.This study describes the incidence of AIDS-defining illnesses (ADI) after HAART initiation and analyzes their risk factors in a low-resource setting. A focus was put on CD4 cell counts and viral load measurements. METHODS: 404 HIV-1-infected Senegalese adult patients were enrolled in a prospective observational cohort and data censored as of April 2008. A Poisson regression was used to model the incidence of ADIs over two periods and to assess its association with baseline variables, current CD4, current viral load, CD4 response, and virological response. RESULTS: ADI incidence declined from 20.5 ADIs per 100 person-years, 95% CI = [16.3;25.8] during the first year to 4.3, 95% CI = [2.3;8.1] during the fourth year but increased afterwards. Before 42 months, the decrease was greater in patients with clinical stage CDC-C at baseline and with a viral load remaining below 1000 cp/mL but was uniform across CD4 strata (p = 0.1). After 42 months, 293 patients were still at risk. The current CD4 and viral load were associated with ADI incidence (decrease of 21% per 50 CD4/mm3 and of 61% for patients with a viral load < 1000 cp/mL). CONCLUSIONS: During the first four years, a uniform decline of ADI incidence was observed even in patients with low CD4-cell counts at HAART initiation as long as the viral load remained undetectable. An increase was noted later in patients with immunologic and virological failures but also in patients with only virological failure.
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Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Síndrome de Inmunodeficiencia Adquirida/patología , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Femenino , VIH-1/aislamiento & purificación , Humanos , Incidencia , Masculino , Estudios Prospectivos , Factores de Riesgo , Senegal/epidemiología , Carga ViralRESUMEN
Soil biological properties are influenced by trace metals. The main sources of these pollutants in the urban areas are industrial plants, power stations, domestic heating systems and motor vehicles. The aim of this work was to evaluate, in relation to distance from urban roads, soil trace metal concentrations (Pb, Cu, Cr, Cd and V) and their influence on C-microbial biomass as well as on soil respiration and enzyme activities (phosphatase glucosidase, galactosidase, xylanase, cellulase, trealase, protease and invertase). The samplings were carried out at four sites, along a route that goes from Giannone Street to Passionisti Street, two heavily travelled roads at two different times of the year (spring and autumn). Heavy metal contents and microbial activities were highest at the sites near the roads. The highest values of microbial activities were found in the inner site; here, on the contrary, the lowest concentrations of heavy metals were measured. Significant and negative correlations were found between microbial activity and heavy metal contents.
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Metales/análisis , Microbiología del Suelo , Población Urbana , Monitoreo del Ambiente/métodos , Italia , Contaminantes del Suelo/análisisRESUMEN
Crosstalk between mesenchymal stem cells (MSCs) and bacteria plays an important role in regulating the regenerative capacities of MSCs, fighting infections, modulating immune responses and maintaining tissue homeostasis. Commensal Cutibacterium acnes (C. acnes) bacterium becomes an opportunistic pathogen causing implant-associated infections. Herein, we examined MSCs/C. acnes interaction and analysed the subsequent bacteria and MSCs behaviours following infection. Human bone marrow derived MSCs were infected by two clinical and one laboratory C. acnes strains. Following 3h of interaction, all bacterial strains were able to invade MSCs. Viable intracellular bacteria acquired virulence factors by increasing biofilm formation and/or by affecting macrophage phagocytosis. Although the direct and indirect (through neutrophil stimulation) antibacterial effects of the MSCs secretome were not enhanced following C. acnes infection, ELISA analysis revealed that C. acnes clinical strains are able to license MSCs to become immunosuppressive cell-like by increasing the secretion of IL-6, IL-8, PGE-2, VEGF, TGF-ß and HGF. Overall, these results showed a direct impact of C. acnes on bone marrow derived MSCs, providing new insights into the development of C. acnes during implant-associated infections. STATEMENT OF SIGNIFICANCE: The originality of this work relies on the study of relationship between human bone marrow derived mesenchymal stem cells (MSCs) phenotype and C. acnes clinical strains virulence following cell infection. Our major results showed that C. acnes are able to invade MSCs, inducing a transition of commensal to an opportunistic pathogen behaviour. Although the direct and indirect antibacterial effects were not enhanced following C. acnes infection, secretome analysis revealed that C. acnes clinical strains were able to license MSCs to become immunosuppressive and anti-fibrotic cell-like. These results showed a direct impact of C. acnes on bone marrow derived MSCs, providing new insights into the development of C. acnes during associated implant infections.
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Células de la Médula Ósea/microbiología , Huesos/patología , Células Madre Mesenquimatosas/microbiología , Propionibacteriaceae/fisiología , Infecciones Relacionadas con Prótesis/microbiología , Adulto , Anciano , Antibacterianos/farmacología , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Células de la Médula Ósea/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Humanos , Inmunomodulación/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Persona de Mediana Edad , Neutrófilos/efectos de los fármacos , Propionibacteriaceae/efectos de los fármacos , Propionibacteriaceae/patogenicidad , Virulencia/efectos de los fármacosRESUMEN
AIMS AND BACKGROUND: Various genes have been identified for monogenic disorders resembling Parkinson's disease. The products of some of these genes are associated with mitochondria and have been implicated in cellular protection against oxidative damage. In the present study we analysed fibroblasts from a patient carrying the homozygous mutation p.W437X in the PTEN-induced kinase 1 (PINK1), which manifested a very early onset parkinsonism. RESULTS: Patient's fibroblasts did not show variation in the mtDNA copy number or in the expression of the oxidative phosphorylation complexes. Sequence analysis of the patient's mtDNA presented two new missense mutations in the ND5 (m.12397A>G, p.T21A) and ND6 (m. 14319T>C, p.N119D) genes coding for two subunits of complex I. The two mutations were homoplasmic in both the patient and the patient's mother. Patient's fibroblasts resulted in enhanced constitutive production of the superoxide anion radical that was abrogated by inhibitor of the complex I. Moreover enzyme kinetic analysis of the NADH:ubiquinone oxidoreductase showed changes in the substrates affinity. CONCLUSION: To our knowledge, this is the first report showing co-segregation of a Parkinson's disease related nuclear gene mutation with mtDNA mutation(s). Our observation might shed light on the clinical heterogeneity of the hereditary cases of Parkinson's disease, highlighting the hitherto unappreciated impact of coexisting mtDNA mutations in determining the development and the clinical course of the disease.
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ADN Mitocondrial/química , Complejo I de Transporte de Electrón/genética , Mutación Missense , Trastornos Parkinsonianos/genética , Proteínas Quinasas/genética , Adulto , Células Cultivadas , Análisis Mutacional de ADN , ADN Mitocondrial/análisis , Complejo I de Transporte de Electrón/metabolismo , Femenino , Fibroblastos/enzimología , Fibroblastos/metabolismo , Genotipo , Humanos , Fosforilación Oxidativa , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/metabolismo , Fenotipo , Superóxidos/metabolismoRESUMEN
OBJECTIVE: Data about the distribution of stroke severity and its correlates are sparse. In a population-based approach, we determined the NIH Stroke Scale Score (NIHSSS) and studied associations with demographic variables, stroke unit care, etiology, the onset assessment interval (OAI), and the rate of thrombolysis. METHODS: We performed a databank-based post-hoc analysis of data ascertained during the prospective, population-based stroke study among the 188,015 permanent residents of Basel City, Switzerland. RESULTS: In 246/269 (91.4%) patients, NIHSSS was available. The median NIHSSS was 5.0 +/- 6.0. NIHSSS 0-6, 7-15, and >15 were present in 156 (63%), 56 (23%), and 34 (14%) patients. Higher NIHSSS were associated with advancing age (p = 0.038), female gender (p = 0.04), stroke unit treatment (p = 0.003), cardioembolism (p < 0.001), shorter OAI (p = 0.009), and thrombolytic therapy (p < 0.001). In multivariate regression analyses, age, OAI, and thrombolysis correlated independently with higher NIHSSS. Stroke unit patients differed from non-stroke unit patients in shorter OAI, younger age, and higher NIHSSS. CONCLUSION: In a geographically defined stroke population, 1/3 patients had moderate-to-severe stroke. Patients with less severe strokes were younger, sought medical attention later and were less likely to receive thrombolysis. Thus, public stroke awareness programs might consider targeting also younger individuals and stress that also mild-to-moderate strokes benefit from emergency medical care.
Asunto(s)
Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Terapia Trombolítica , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Sistema de Registros , Análisis de Regresión , Factores de Riesgo , Factores Sexuales , Suiza/epidemiologíaRESUMEN
OBJECTIVES: Autophagy is a physiological and highly regulated mechanism, crucial for cell homeostasis maintenance. Its impairment seems to be involved in the onset of several diseases, including muscular dystrophies, myopathies and sarcopenia. According to few papers, chemotherapeutic drug treatment is able to trigger side effects on skeletal muscle tissue and, among these, a defective autophagic activation, which leads to the persistence of abnormal organelles within cells and, finally, to myofiber degeneration. The aim of this work is to find a strategy, based on diet modulation, to prevent etoposide-induced damage, in a model of in vitro skeletal muscle cells. METHODS: Glutamine supplementation and nutrient deprivation have been chosen as pre-treatments to counteract etoposide effect, a chemotherapeutic drug known to induce oxidative stress and cell death. Cell response has been evaluated by means of morpho-functional, cytofluorimetric and molecular analyses. RESULTS: Etoposide treated cells, if compared to control, showed dysfunctional mitochondria presence, ER stress and lysosomal compartment damage, confirmed by molecular investigations. CONCLUSIONS: Interestingly, both dietary approaches were able to rescue myofiber from etoposide-induced damage. Glutamine supplementation, in particular, seemed to be a good strategy to preserve cell ultrastructure and functionality, by preventing the autophagic impairment and partially restoring the normal lysosomal activity, thus maintaining skeletal muscle homeostasis.