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BACKGROUND: Ascending aorta dilation and aortic valve degeneration are common complications in patients with bicuspid aortic valve. Several retrospective studies have suggested the benefit of statins in reducing these complications. This study aimed to determine whether atorvastatin treatment is effective in reducing the growth of aortic diameters in bicuspid aortic valve and if it slows the progression of valve calcification. METHODS: In a randomized clinical trial, 220 patients with bicuspid aortic valve (43 women; 46±13 years of age) were included and treated with either 20 mg of atorvastatin per day or placebo for 3 years. Inclusion criteria were ≥18 years of age, nonsevere valvular dysfunction, nonsevere valve calcification, and ascending aorta diameter ≤50 mm. Computed tomography and echocardiography studies were performed at baseline and after 3 years of treatment. RESULTS: During follow-up, 28 patients (12.7%) discontinued medical treatment (15 on atorvastatin and 13 taking placebo). Thus, 192 patients completed the 36 months of treatment. Low-density lipoprotein cholesterol levels decreased significantly in the atorvastatin group (median [interquartile range], -30 mg/dL [-51.65 to -1.75 mg/dL] versus 6 mg/dL [-4, 22.5 mg/dL]; P<0.001). The maximum ascending aorta diameter increased with no differences between groups: 0.65 mm (95% CI, 0.45-0.85) in the atorvastatin group and 0.74 mm (95% CI, 0.45-1.04) in the placebo group (P=0.613). Similarly, no significant differences were found for the progression of the aortic valve calcium score (P=0.167) or valvular dysfunction. CONCLUSIONS: Among patients with bicuspid aortic valve without severe valvular dysfunction, atorvastatin treatment was not effective in reducing the progression of ascending aorta dilation and aortic valve calcification during 3 years of treatment despite a significant reduction in low-density lipoprotein cholesterol levels. REGISTRATION: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001808-57. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02679261.
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Válvula Aórtica , Atorvastatina , Enfermedad de la Válvula Aórtica Bicúspide , Calcinosis , Progresión de la Enfermedad , Enfermedades de las Válvulas Cardíacas , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Atorvastatina/uso terapéutico , Femenino , Masculino , Persona de Mediana Edad , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Válvula Aórtica/anomalías , Válvula Aórtica/efectos de los fármacos , Calcinosis/tratamiento farmacológico , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Enfermedad de la Válvula Aórtica Bicúspide/diagnóstico por imagen , Enfermedad de la Válvula Aórtica Bicúspide/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/tratamiento farmacológico , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Enfermedades de las Válvulas Cardíacas/patología , Adulto , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Dilatación Patológica/tratamiento farmacológico , Estudios de Seguimiento , Método Doble Ciego , Resultado del Tratamiento , Aorta/diagnóstico por imagen , Aorta/patología , Aorta/efectos de los fármacos , Enfermedad de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula AórticaRESUMEN
The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.
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Anticuerpos Antivirales/sangre , Vacuna BNT162/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Vacunación , Adulto , Anciano , Anticuerpos Neutralizantes/sangre , Femenino , Humanos , Inmunoglobulina G/sangre , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
INTRODUCTION: Levofloxacin and rifampicin are the preferred treatment for prosthetic joint infection (PJI) caused by Staphylococcus aureus, especially when managed with implant retention (DAIR). However, a significant variability of success has been reported, which could be related to intrinsic characteristics of the microorganism. Our aim was to evaluate the variability in the anti-biofilm response to levofloxacin and rifampicin in a clinical collection of S. aureus. MATERIAL AND METHODS: Eleven levofloxacin- and rifampicin-susceptible S. aureus isolates causing PJI managed with DAIR were included. Levofloxacin, rifampicin and levofloxacinâ+ârifampicin were tested in an in vitro static biofilm model in microtitre plates, where 48â h biofilms were challenged with antimicrobials during 24â h. Additionally, two genetically similar strains were tested in the CDC Biofilm Reactor, where 48â h biofilms were treated during 56â h. Antimicrobial activity was assessed by viable biofilm-embedded cells recount, and by crystal violet staining. RESULTS: All antimicrobial regimens showed significant anti-biofilm activity, but a notable scattering in the response was observed across all strains (inter-strain coefficient of variation for levofloxacin, rifampicin and levofloxacinâ+ârifampicin of 22.8%, 35.8% and 34.5%, respectively). This variability was tempered with the combination regimen when tested in the biofilm reactor. No correlation was observed between the minimal biofilm eradicative concentration and the antimicrobial activity. Recurrent S. aureus isolates exhibited higher biofilm-forming ability compared with strains from resolved infections (7.6â log10â cfu/cm2±0.50 versus 9.0â log10â cfu±0.07). CONCLUSIONS: Significant variability may be expected in response to levofloxacin and rifampicin among biofilm-embedded S. aureus. A response in the lower range, together with other factors of bad prognosis, could be responsible of treatment failure.
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Artritis Infecciosa , Infecciones Estafilocócicas , Humanos , Staphylococcus aureus/fisiología , Levofloxacino/farmacología , Levofloxacino/uso terapéutico , Rifampin/farmacología , Rifampin/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , BiopelículasRESUMEN
Remote ischemic conditioning (RIC) and the GLP-1 analog exenatide activate different cardioprotective pathways and may have additive effects on infarct size (IS). Here, we aimed to assess the efficacy of RIC as compared with sham procedure, and of exenatide, as compared with placebo, and the interaction between both, to reduce IS in humans. We designed a two-by-two factorial, randomized controlled, blinded, multicenter, clinical trial. Patients with ST-segment elevation myocardial infarction receiving primary percutaneous coronary intervention (PPCI) within 6 h of symptoms were randomized to RIC or sham procedure and exenatide or matching placebo. The primary outcome was IS measured by late gadolinium enhancement in cardiac magnetic resonance performed 3-7 days after PPCI. The secondary outcomes were myocardial salvage index, transmurality index, left ventricular ejection fraction and relative microvascular obstruction volume. A total of 378 patients were randomly allocated, and after applying exclusion criteria, 222 patients were available for analysis. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. IS was similar between groups for the RIC (24 ± 11.8% in the RIC group vs 23.7 ± 10.9% in the sham group, P = 0.827) and the exenatide hypotheses (25.1 ± 11.5% in the exenatide group vs 22.5 ± 10.9% in the placebo group, P = 0.092). There were no effects with either RIC or exenatide on the secondary outcomes. Unexpected adverse events or side effects of RIC and exenatide were not observed. In conclusion, neither RIC nor exenatide, or its combination, were able to reduce IS in STEMI patients when administered as an adjunct to PPCI.
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Brazo/irrigación sanguínea , Exenatida/uso terapéutico , Incretinas/uso terapéutico , Precondicionamiento Isquémico , Miocardio/patología , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/terapia , Anciano , Terapia Combinada , Método Doble Ciego , Exenatida/efectos adversos , Femenino , Humanos , Incretinas/efectos adversos , Imagen por Resonancia Cinemagnética , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Estudios Prospectivos , Flujo Sanguíneo Regional , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/patología , Infarto del Miocardio con Elevación del ST/fisiopatología , España , Factores de Tiempo , Resultado del Tratamiento , Función Ventricular IzquierdaRESUMEN
Multidrug-resistant (MDR) Pseudomonas aeruginosa represents a major clinical concern. The interplay between antimicrobial resistance and virulence of P. aeruginosa was investigated in in vitro and in vivo studies. Thirty-eight well-characterized (21 MDR and 17 non-MDR) P. aeruginosa strains from patients with bacteraemia were analysed. Resistance phenotype, carbapenemase production, clonal relatedness, type III secretion system genotype, O-antigen serotype, cytotoxicity (ability to lyse cells) on A549 cells, and virulence (lethality in nematodes) in a Caenorhabditis elegans model were investigated. MDR strains showed lower cytotoxicity (35.4 ± 21.30% vs. 45.0 ± 18.78 %; P = 0.044) and virulence (66.7% vs. 100%; P = 0.011) than non-MDR strains. However, the pathogenicity of MDR high-risk clones varied broadly, with ST235 and ST175 clones being the most and least cytotoxic (51.8 ± 10.59% vs. 11.0 ± 1.25%; P < 0.0001) and virulent ([100% vs. 73.1; P = 0.075] and [0% vs. 93.9%; P < 0.0001], respectively). The pathogenicity of the ST235 clone was similar to that of non-MDR strains, and its ability to lyse cells and high virulence were related with the exoU-positive genotype. Furthermore, the O11 serotype was more frequent among the ST235 clone and exoU-positive genotype strains and was also essential for the pathogenicity of P. aeruginosa. Our data suggest that the pathogenicity of MDR high-risk clones is the result not only of the resistance phenotype but also of the virulence genotype. These findings have implications for the clinical management of patients and infection control programmes.
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Bacteriemia/microbiología , Farmacorresistencia Bacteriana Múltiple , Enfermedades Endémicas , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/patogenicidad , Células A549 , Animales , Antibacterianos/farmacología , Proteínas Bacterianas , Caenorhabditis elegans , Genotipo , Humanos , Pruebas de Sensibilidad Microbiana , Fenotipo , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/genética , Virulencia , beta-LactamasasRESUMEN
Immune checkpoint inhibition suggests promising progress for the treatment of advanced hepatocellular carcinoma (HCC). However, the underlying cellular mechanisms remain unclear because liver cancer cells apparently do not upregulate inhibitory checkpoint molecules. Here, we analysed whether regulatory T cells (Tregs) can alternatively trigger checkpoint inhibition pathways in HCC. Using flow cytometry we analysed expression of checkpoint molecules (PD-1, PD-L1, CTLA-4, GITR, Tim-3) on peripheral CD4+CD25+Foxp3+ Tregs and their secretion of inhibitory mediators (IL-10, IL-35, TGF-beta, galectin-9) in 116 individuals (50 patients with HCC, 41 non-tumour bearing liver disease controls, 25 healthy controls). Functional activity of Tregs on T effector cells (IFN-gamma production, cytotoxicity) was characterized in vitro using a lectin-dependent cellular cytotoxicity (LDCC) assay against checkpoint inhibitor-negative P815 target cells. Unlike liver patients without malignancy and healthy controls, the frequency of checkpoint inhibitor-positive Tregs inversely correlated to age of patients with HCC (PD-L1, p = 0.0080; CTLA-4, p = 0.0029) and corresponded to enhanced numbers of Tregs producing IL-10 and IL-35 (p < 0.05 each). Tregs inhibited IFN-gamma secretion and cytotoxicity of CD8+ T cells when added to LDCC against P815 cells. Treg-induced inhibition of IFN-gamma secretion could be partially blocked by neutralizing PD-1 and PD-L1 antibodies specifically in HCC patients. In HCC peripheral Tregs upregulate checkpoint inhibitors and contribute to systemic immune dysfunction and antitumoural activity by several inhibitory pathways, presumably facilitating tumour development at young age. Blocking PD-L1/PD-1 interactions in vitro selectively interfered with inhibitory Treg -T effector cell interactions in the patients with HCC and resulted in improved antitumoural activity also against checkpoint inhibitor-negative tumour cells.
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Anticuerpos Monoclonales/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Carcinoma Hepatocelular/inmunología , Inmunoterapia/métodos , Neoplasias Hepáticas/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Citotoxicidad Inmunológica , Femenino , Humanos , Tolerancia Inmunológica , Interferón gamma/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Adulto JovenRESUMEN
Prosthetic joint infections are considered difficult to treat they needing aggressive surgery and long antimicrobial treatments. However, the exact duration of these therapies has been established empirically. In the last years, several studies have explored the possibility of reducing the length of treatment in this setting, with conflicting results. In this narrative review, we critically appraise the published evidence, considering the different surgical approaches (implant retention [DAIR] and one-step and two-step exchange procedures) separately. In patients managed with DAIR, usually treated for at least 12 weeks, a large, randomized trial failed to show that 6 weeks were non-inferior. However, another randomized clinical trial supports the use of 8 weeks, as long as the surgical conditions are favorable and antibiotics with good antibiofilm activity can be administered. In patients managed with a two-step exchange procedure, usually treated during 6 weeks, a randomized clinical trial showed the efficacy of a 4-week course of antimicrobials. Also, the use of local antibiotics may allow the use of even shorter treatments. Finally, in the case of one-step exchange procedures, there is a trend towards reducing the length of therapy, and the largest randomized clinical trial supports the use of 6 weeks of therapy.
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The utility of reverse transcription-polymerase chain reaction (RT-PCR) in analysis SARS-COV-2 variants was evaluated. RT-PCR tests were used to analyse the majority of new SARS-CoV-2 cases (n = 9315) in a tertiary hospital (Madrid, Spain) throughout 2021. Subsequently, whole genome sequencing (WGS) was conducted on 10.8% of these samples (n = 1002). Notably, the Delta and Omicron variants emerged rapidly. There were no discrepancies between RT-PCR and WGS results. Continuous surveillance of SARS-CoV-2 variants is essential, and RT-PCR is a highly useful method, specially during periods of high COVID-19 incidence. This feasible technique can be implemented in all SARS-CoV-2 laboratories. However, WGS remains the gold standard method for comprehensive detection of all existing SARS-CoV-2 variants.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/epidemiología , Pandemias , LaboratoriosRESUMEN
Succinate is enhanced during initial reperfusion in blood from the coronary sinus in ST-segment elevation myocardial infarction (STEMI) patients and in pigs submitted to transient coronary occlusion. Succinate levels might have a prognostic value, as they may correlate with edema volume or myocardial infarct size. However, blood from the coronary sinus is not routinely obtained in the CathLab. As succinate might be also increased in peripheral blood, we aimed to investigate whether peripheral plasma concentrations of succinate and other metabolites obtained during coronary revascularization correlate with edema volume or infarct size in STEMI patients. Plasma samples were obtained from peripheral blood within the first 10 min of revascularization in 102 STEMI patients included in the COMBAT-MI trial (initial TIMI 1) and from 9 additional patients with restituted coronary blood flow (TIMI 2). Metabolite concentrations were analyzed by 1H-NMR. Succinate concentration averaged 0.069 ± 0.0073 mmol/L in patients with TIMI flow ≤ 1 and was significantly increased in those with TIMI 2 at admission (0.141 ± 0.058 mmol/L, p < 0.05). However, regression analysis did not detect any significant correlation between most metabolite concentrations and infarct size, extent of edema or other cardiac magnetic resonance (CMR) variables. In conclusion, spontaneous reperfusion in TIMI 2 patients associates with enhanced succinate levels in peripheral blood, suggesting that succinate release increases overtime following reperfusion. However, early plasma levels of succinate and other metabolites obtained from peripheral blood does not correlate with the degree of irreversible injury or area at risk in STEMI patients, and cannot be considered as predictors of CMR variables.Trial registration: Registered at www.clinicaltrials.gov (NCT02404376) on 31/03/2015. EudraCT number: 2015-001000-58.
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Insuficiencia Cardíaca , Infarto del Miocardio , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Animales , Imagen por Resonancia Magnética , Infarto del Miocardio/patología , Reperfusión , Ácido Succínico , Porcinos , Resultado del TratamientoRESUMEN
BACKGROUND: Persistent and relapsing prosthetic joint infection (PJI) due to Staphylococcus aureus presents a clinical challenge. This study aimed to provide an extensive description of phenotypic and genomic changes that could be related to persistence or relapse. METHODS: Initial and second S. aureus isolates from 6 cases of persistent and relapsing PJI, along with clinical isolates from 8 cases, with favorable outcome were included. All isolates were studied by phenotypic and genotypic approaches. RESULTS: Recurrent S. aureus isolates exhibited a significant increase in adhesive capacity, invasion and persistence compared to resolved isolates. No association was found for the presence or absence of certain genes with the persistence or relapse of PJI. All sequential isolates showed identical sequence type (ST). Resistance gene loss during the infection and a great diversity of variants in different virulence genes between the pair of strains, mainly in genes encoding adhesins such as fnbA, were observed. CONCLUSIONS: S. aureus-caused relapse and persistence PJI is associated with bacterial phenotypical and genotypical adaptation. The main paths of adaptation were persistence in the intracellular compartment, and the loss of antibiotic resistance genes and variant acquisition, especially in genes encoding adhesins.
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AIM: Gallium-68-labelled inhibitors of the fibroblast activation protein (FAPi) enable positron emission tomography/computed tomography (PET/CT) imaging of fibroblast activation. We evaluated if [68Ga]Ga-DATA5m.SA.FAPi PET/CT is related to Ki-67 as a marker of tumour aggressiveness in patients with liver metastases of NET. METHODS: Thirteen patients with liver metastases of a histologically confirmed NET who underwent PET/CT with [68Ga]Ga-DATA5m.SA.FAPi, [18F]FDG and [68Ga]Ga-DOTA-TOC were retrospectively analyzed. PET-positive liver tumour volumes were segmented for calculation of volume, SUVmax and PET-positive tumour fraction (TF). PET parameters were correlated with Ki-67. RESULTS: FDGSUVmax correlated positively (rho = 0.543, p < 0.05) and DOTATOCSUVmax correlated negatively (rho = -0.618, p < 0.05) with Ki-67, the correlation coefficients were in the moderate range. There was no significant correlation between FAPiSUVmax and Ki-67 (rho = 0.382, p > 0.05). FAPiTF correlated positively (rho = 0.770, p < 0.01) and DOTATOCTF correlated negatively (rho = -0.828, p < 0.01) with Ki-67, both significantly with high correlation coefficients. FDGTF also correlated significantly with Ki-67, with a moderate correlation coefficient (rho = 0.524, p < 0.05). The ratio FAPiVOL:DOTATOCVOL showed a significant and strong correlation with Ki-67 (rho = 0.808, p < 0.01). CONCLUSION: The ratio FAPiVOL:DOTATOCVOL might serve as a clinical parameter for the assessment of dedifferentiation and aggressiveness of liver metastases in patients with NET. [68Ga]Ga-DATA5m.SA.FAPi might hold potential for identification of high-risk patients. Further studies are warranted to evaluate its prognostic significance in comparison to [18F]FDG in patients with NET.
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Neoplasias Hepáticas , Tumores Neuroendocrinos , Fibroblastos , Humanos , Antígeno Ki-67 , Neoplasias Hepáticas/diagnóstico por imagen , Tumores Neuroendocrinos/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios RetrospectivosRESUMEN
AIM: Previous studies have suggested a more frequent and severe course of novel coronavirus SARS-CoV-2 infection in cancer patients undergoing active oncologic treatment. Our aim was to describe the characteristics of the disease in this population and to determine predictive factors for poor outcome in terms of severe respiratory distress (acute respiratory distress syndrome [ARDS]) or death. PATIENTS AND METHODS: Patients consecutively admitted for SARS-CoV-2 infection were prospectively collected, and retrospective statistical analysis was performed. Univariate and multivariate analyses were performed to assess potential factors for poor outcomes defined as ARDS or death. RESULTS: Sixty-three patients were analysed, and 34 of them developed respiratory failure (70% as ARDS). Lymphocytes/mm3 (412 versus 686; p = 0.001), serum albumin (2.84 versus 3.1); lactate dehydrogenase (LDH) (670 versus 359; p < 0.001) and C-reactive protein (CRP) levels (25.8 versus 9.9; p < 0.001) discriminate those that developed respiratory failure. Mortality rate was 25%, significantly higher among ARDS, neutropenic patients (p = 0.01) and in those with bilateral infiltrates (44% versus 0%; p < 0.001). Multivariate logistic analyses model confirmed the predictive value of severe neutropenia (odds ratio [OR] 16.54; 95% confidence interval [CI] 1.43-190.9, p 0.025), bilateral infiltrates (OR 32.83, CI 95% 3.51-307, p 0.002) and tumour lung involvement (OR 4.34, CI 95% 1.2-14.95, p 0.02). CONCLUSION: Cancer patients under active treatment admitted for SARS-CoV-2 infection have worse outcomes in terms of mortality and respiratory failure rates compared with COVID-19 global population. Lymphopenia, LDH, CRP and albumin discriminate illness severity, whereas neutropenia, bilateral infiltrates and tumour pulmonary involvement are predictive of higher mortality.
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Betacoronavirus/patogenicidad , Infecciones por Coronavirus/mortalidad , Neoplasias/complicaciones , Neumonía Viral/mortalidad , Insuficiencia Respiratoria/mortalidad , Anciano , Antineoplásicos/efectos adversos , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Femenino , Humanos , Inmunoterapia/efectos adversos , Masculino , Persona de Mediana Edad , Mortalidad , Neoplasias/terapia , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico , Neumonía Viral/virología , Pronóstico , Estudios Prospectivos , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/virología , Estudios Retrospectivos , Medición de Riesgo , SARS-CoV-2RESUMEN
BACKGROUND: Staphylococcus aureus may invade and persist intracellularly in prosthetic joint infections (PJIs). Despite optimized treatments with levofloxacin plus rifampin, the intracellular reservoir may lead to infection relapse. This study assessed the intracellular activity of levofloxacin and rifampin in an in-vitro model of human osteoblastic infection. METHODS: Ten meticillin-susceptible S. aureus strains were used to infect osteoblastic MG63 cells. Osteoblasts were challenged with rifampin and levofloxacin at cortical and cancellous bone concentrations. Efficacy was measured as the intracellular counts of colony-forming units (log10CFU) compared with untreated controls. The emergence of small colony variants (SCVs) was determined, and the results were stratified according to the patient's prognosis (six cured and four with persistence/relapse). RESULTS: All regimes led to a significant decrease in CFU count compared with controls (1-2 log10CFU). Levofloxacin was the most effective treatment at both cortical and cancellous bone concentrations (-2.4 to -1.9 log10CFU, respectively). The addition of rifampin to levofloxacin did not improve performance (-1.9 log10CFU for cortical concentration and -1.8 log10 CFU for cancellous concentration). An increase in SCVs was observed in the presence of rifampin. The efficacy of antimicrobials was higher and the formation of SCVs was lower against strains belonging to PJIs with a favourable outcome. CONCLUSIONS: Levofloxacin plus rifampin had good intracellular activity against S. aureus. However, from the intracellular perspective, the addition of rifampin to levofloxacin showed no benefit but could account for an increased number of SCVs.
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Antibacterianos/farmacología , Levofloxacino/farmacología , Osteoartritis/microbiología , Osteoblastos/microbiología , Infecciones Relacionadas con Prótesis/microbiología , Rifampin/farmacología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/efectos de los fármacos , Línea Celular , Recuento de Colonia Microbiana , Humanos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Modelos TeóricosRESUMEN
BACKGROUND: Chemotherapy with gemcitabine and cisplatin is the current standard for patients with unresectable cholangiocarcinoma. Local photodynamic therapy has also demonstrated benefit in patients with extrahepatic cholangiocarcinoma. AIM: To evaluate the benefit of photodynamic therapy in combination with systemic chemotherapy in advanced extrahepatic cholangiocarcinoma. METHODS: Three hundred and fifty-three patients diagnosed with cholangiocarcinoma between 2004 and 2016 were treated at the University Hospital of Bonn, Germany. Of these, 96 suffering from unresectable extrahepatic cholangiocarcinoma were included. Patients were stratified according to treatment: combination photodynamic therapy and chemotherapy (36 patients), photodynamic therapy alone (34 patients), and chemotherapy alone (26 patients). RESULTS: Combined photodynamic therapy with chemotherapy resulted in significantly longer overall survival than chemotherapy alone (P = 0.022). Median survival was 20 months in the combination group (95% CI: 16.38-23.62), 15 months in the photodynamic alone group (95% CI: 10.02-19.98) and 10 months in the chemotherapy alone group (95% CI: 8.45-11.55). In multivariate analysis, combination therapy and photodynamic therapy alone (HR: 0.41, 95% CI: 0.22-0.77, P = 0.006), metal stenting, and radiofrequency ablation were independent predictors of longer survival. CONCLUSIONS: Combination photodynamic therapy and chemotherapy was well tolerated and resulted in significantly longer survival than chemotherapy alone. Application of photodynamic therapy significantly correlated with longer survival, demonstrating benefit in advanced cholangiocarcinoma. Thus, photodynamic therapy should be considered during therapeutic decision making in advanced cholangiocarcinoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/terapia , Colangiocarcinoma/terapia , Fotoquimioterapia/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/diagnóstico , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/diagnóstico , Cisplatino/administración & dosificación , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , GemcitabinaRESUMEN
Recently, increasing evidence has been found demonstrating direct effects of angiostatin on tumor cells themselves. We have applied the plasminogen derivatives K1-4 and K1-5 to a lung cancer model to analyse indirect angiostatic effects against endothelial and direct effects against tumor cells. In accordance with preceding findings both derivatives inhibited endothelial cell functions in vitro. Additionally K1-4 and K1-5 have also shown substantial anti-proliferative and pro-apoptotic effects in tumor cells and have inhibited tumor growth. In addition our data supports the recent conclusion that plasminogen derivatives have a dual antitumor mechanism affecting both tumor angiogenesis and tumor cells.
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Inhibidores de la Angiogénesis/metabolismo , Angiostatinas/metabolismo , Antineoplásicos/metabolismo , Carcinoma Pulmonar de Lewis/terapia , Células Endoteliales/metabolismo , Terapia Genética/métodos , Kringles , Neovascularización Fisiológica , Plasminógeno/metabolismo , Adenoviridae/genética , Inhibidores de la Angiogénesis/genética , Angiostatinas/genética , Animales , Apoptosis , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Línea Celular Tumoral , Proliferación Celular , Células Endoteliales/patología , Regulación Neoplásica de la Expresión Génica , Vectores Genéticos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neovascularización Fisiológica/genética , Plasminógeno/genética , Proteínas Recombinantes/metabolismo , Factores de Tiempo , Transducción GenéticaRESUMEN
La pandemia provocada por la COVID-19 ha mostrado algunas carencias y riesgos asociados en la atención comunitaria de la salud mental a los pacientes más graves. El objetivo de este estudio es analizar las necesidades asistenciales en una muestra de personas con trastorno mental grave durante el pico de la pandemia por COVID-19 en España en la Comunidad de Madrid, la Comunidad Valenciana, Extremadura y el País Vasco. Se utilizó el instrumento Needs of Assesment (NCA) y la Escala de Restricción de Vida (ERVI). La muestra fue de 669 personas y 144 cuidadores familiares convivientes. Los problemas clínicos más frecuentemente encontrados fueron los de ansiedad, seguidos de lentitud, baja actividad y depresión. En el área de destrezas y habilidades, los problemas más frecuentes fueron la estructuración del sueño, la integración comunitaria, la ocupación del tiempo y la capacidad cognitiva. En el área de soportes de apoyo, el principal problema fue la falta de red de apoyo social. Respecto al grado de cobertura, el 71% de los problemas clínicos estuvieron cubiertos. En el área de habilidades, el porcentaje desciende hasta un 68% y en los soportes sociales hasta el 66%. Se concluye que es necesario reforzar los Programas de Rehabilitación Psicosocial para atender las necesidades de pacientes graves de salud mental. Además, los modelos de atención deberían ser adaptados para asegurar su continuidad y permanencia en periodos de distanciamiento de la comunidad. (AU)
The pandemic caused by COVID-19 has revealed some deficiencies and associated risks in Community Mental Health Care for the most severe patients. The objective of this study is to analyze the needs in a sample of people with Severe Mental Illness during the peak of the COVID-19 pandemic in the Communities of Madrid, Valencia, Extremadura, and the Basque Country (in Spain). The Needs of Assessment (NCA) instrument and the Life Restriction Scale (ERVI) were used. The sample consisted of 669 people and 144 cohabiting family caregivers. The clinical problems most frequently encountered were anxiety, followed by slowness, low activity, and depression. In the area of skills and abilities, the most frequent problems were sleep structuring, community integration, time occupation, and cognitive ability. In the area of support, the main problem was the lack of a social support network. Regarding the degree of coverage, 71% of the clinical problems were covered. In the skills area, the percentage drops to 68% and in social media to 66%. It is concluded that it is necessary to reinforce Psychosocial Rehabilitation Programs to meet the needs of serious mental health patients. In addition, the care models should be adapted to ensure their continuity and permanence in periods of distance from the community. (AU)
Asunto(s)
Humanos , Trastornos Mentales , Evaluación de Necesidades , España , Rehabilitación Psiquiátrica , Estudios Transversales , Salud MentalRESUMEN
OBJECTIVE: To prevent catheter occlusion, intermittently used central venous catheters are frequently sealed with vitamin C solution or heparin solution between use. The present study was designed to test the effectiveness of this approach and to compare the efficiency of sealing solutions. DESIGN AND SETTING: Prospective randomized study performed on a 9-bed medical ICU and on medical wards of an academic tertiary care center. PARTICIPANTS. Ninety-nine central venous line placements were prospectively included in the study and randomized into three treatment groups: sodium chloride 0.9%, vitamin C (200 mg/ml) and heparin (5000 IU/ml) sealing solutions. INTERVENTIONS AND MEASUREMENTS: Catheters were filled with the respective sealing solution and patency was tested once every 2 days using a standardized routine. Catheter patency was compared among the three groups using Kaplan-Meier statistics and log-rank testing. RESULTS: There was a significant difference in catheter patency between the three groups (p<0.03, log-rank test). A comparison of catheter survival between the catheters filled with heparin and those filled with sodium chloride, but not between those filled with vitamin C solution and with sodium chloride solution, exhibited significant differences in catheter patency (p<0.04, log-rank test). CONCLUSIONS: Local anticoagulation of intermittently used central venous catheters prolongs catheter patency. High-dose (5000 IU/ml) heparin solution is a useful anticoagulant for this purpose, while vitamin C solution does not prolong catheter patency.
Asunto(s)
Anticoagulantes/administración & dosificación , Ácido Ascórbico/administración & dosificación , Cateterismo Venoso Central/métodos , Catéteres de Permanencia , Heparina/administración & dosificación , Cloruro de Sodio/administración & dosificación , Centros Médicos Académicos , Adulto , Anciano , Falla de Equipo , Femenino , Alemania , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Irrigación TerapéuticaRESUMEN
Excessive ethanol consumption is one of the main causes of liver fibrosis. However, direct effects of ethanol exposure on endothelial cells and their contribution to fibrogenesis and metastasis were not investigated. Therefore we analysed whether ethanol directly affects endothelial cells and if this plays a role during fibrogenesis and metastasis in the liver. Murine and human endothelial cells were exposed to ethanol for up to 72 hours. In vitro, effects on VEGF, HIF-1alpha, PECAM-1, and endothelial cell functions were analysed. In vivo, effects of continuous liver damage on blood vessel formation and metastasis were analysed by PECAM-1 immunohistochemistry. Ethanol increased HIF-1alpha and VEGF levels in murine and human endothelial cells. This resulted in enhanced intracellular signal transduction, and PECAM-1 expression as well as tube formation and wound healing. In vivo, toxic liver damage increased angiogenesis during fibrogenesis. Metastasis was also enhanced in fibrotic livers and located to PECAM-1 positive blood vessels compared to nonfibrotic mice. In conclusion, ethanol had strong effects on endothelial cells, which--at least in part--led to a profibrotic and prometastatic environment mediated by PECAM-1. Blockade of increased PECAM-1 expression could be a promising tool to inhibit fibrogenesis and metastasis in the liver.
Asunto(s)
Células Endoteliales/efectos de los fármacos , Etanol/toxicidad , Neoplasias Hepáticas/patología , Hígado/patología , Neovascularización Patológica , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Animales , Línea Celular , Supervivencia Celular , Células Endoteliales/citología , Fibrosis , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C3H , Metástasis de la Neoplasia , Fosforilación , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Control of VEGF signaling is an intense objective of pre-clinical and clinical studies in HCC disease with steadily increasing clinical application. Despite its emerging role, several aspects of anti-VEGF based treatments are poorly investigated, like the impact on tumor cells themselves, such as the effect on intracellular signaling and apoptosis induction in hepatoma cells. Effects of siRNA-VEGF on VEGF, VEGF-receptor expression and VEGF-A signaling such as AKT and JNK phosphorylation were determined under normoxic or hypoxic conditions in murine hepatoma cells. Apoptosis induction was analyzed by SubG1-fraction, JC1-staining and caspase-8 activation. VEGF receptor expression was analysed by semiquantitative real time PCR. Independent of oxygen status, siRNA-VEGF reduced VEGF levels resulting in decreased AKT and increased JNK phosphorylation in Hepa129 cells. The VEGF-receptors neuropilin-1 (Nrp1) and neuropilin-2 (Nrp2) were downregulated following siRNA-VEGF treatment or hypoxia induction respectively. Functionally, hypoxia significantly increased the apoptosis rate (as analyzed by SubG1-fraction, JC1-staining and JNKphosphorylation) which was further stimulated by siRNA-VEGF treatment. Our data indicate that antitumoral efficacy of an anti-VEGF based treatment with siRNA is partly based on negative autocrine feedback mechanisms which are even enhanced under hypoxic conditions. This observation helps to understand why antitumoral efficacy can be maintained despite of counteracting stimulation of tumoral VEGF secretion due to hypoxia. The direct impact on tumor cells further underscores the attractiveness of an anti-VEGF based siRNA treatment.
Asunto(s)
Apoptosis , Hipoxia/metabolismo , Interferencia de ARN , Factor A de Crecimiento Endotelial Vascular/fisiología , Animales , Antineoplásicos/farmacología , Bencenosulfonatos/farmacología , Carcinoma Hepatocelular , Línea Celular Tumoral , Retroalimentación Fisiológica , MAP Quinasa Quinasa 4/metabolismo , Ratones , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridinas/farmacología , ARN Interferente Pequeño/genética , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Transducción de Señal , SorafenibRESUMEN
BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, and new alternative treatments are needed. AIMS: To comparatively test the angiostatic and antitumour effects of adenoviral gene transfer of angiostatin (PlgK1-4, amino acids 1-440) and full kringles 1-5 (PlgK1-5, amino acids 1-546) in a model of subcutaneously transferred HCC in mice. METHODS: PlgK1-4 and PlgK1-5 were generated from human WtPlg cDNA and used for adenovirus construction. Vector function and angiostatic effects were confirmed in vitro and in vivo. Antitumoral efficacies of intratumoral vector injections were studied in a model of subcutaneously transferred HCC model. RESULTS: Cell supernatants containing PlgK1-4 and PlgK1-5 reduced endothelial tube formation in vitro by about 30%, whereas WtPlg exerted no inhibitory effect. Endothelial cell infiltration in vivo was decreased by about 60%, but not in AdWtPlg-treated animals. Intratumoral treatment of subcutaneous HCC tumours inhibited growth by 40% for AdPlgK1-4 and 63% for AdPlgK1-5 in surviving mice 12 days after initiation of treatment, whereas treatment with AdWtPlg even led to accelerated growth. Although PlgK1-4 and PlgK1-5 have similar inhibitory effects on intratumoral microvessels, PlgK1-5 markedly improved the survival time compared with PlgK1-4. CONCLUSION: PlgK1-5 and PlgK1-4 effectively inhibited HCC growth. As PlgK1-5 could also prolong the survival time, inducing complete tumour elimination in half of the AdPlgK1-5-treated mice, PlgK1-5 might be the most potential plasminogen fragment for treatment of experimental HCC.