Analyzing the Effect of Zr, W, and V Isomorph Framework Substitution on ZSM-5 and Beta Zeolites for Their Use as Hydrocarbon Trap.

This work evaluates the effect on the adsorption and desorption kinetics of propene and toluene (used as probe molecules for vehicle cold-start emissions) of the isomorph framework substitution of Zr, W, and V on commercial ZSM-5 and beta zeolites. TG-DTA and XRD characterization data indicated that: (i) Zr does not modify the crystalline structure of the parent zeolites, (ii) W develops a new crystalline phase, and (iii) V causes the breakdown of the zeolite structure during the aging step. The CO2 and N2 adsorption data revealed that the substituted zeolites present a narrower microporosity than pristine zeolites. As a consequence of all these modifications, the modified zeolites feature different adsorption capacity and kinetics of HCs, so, different hydrocarbon trapping ability than pristine zeolites. However, a clear correlation is not observed between the changes in the porosity/acidity of zeolites and the adsorption capacity and kinetics, which depends on: (i) the zeolite (ZSM-5 or BEA), (ii) the hydrocarbon (toluene or propene), and (iii) the cation to be inserted (Zr, W, or V).

Monitoring of SARS-CoV-2 seroprevalence among primary healthcare patients in the Barcelona Metropolitan Area: the SeroCAP sentinel network protocol.

INTRODUCTION: SARS-CoV-2 seroprevalence studies are currently being recommended and implemented in many countries. Forming part of the COVID-19 monitoring and evaluation plan of the Catalan Government Health Department, our network aims to initiate a primary healthcare sentinel monitoring system as a surrogate of SARS-CoV-2 exposure in the Barcelona Metropolitan Area. METHODS AND ANALYSIS: The seroCAP is a serial cross-sectional study, which will be performed in the Barcelona Metropolitan Area to estimate antibodies against SARS-CoV-2. From February 2021 to March 2022, the detection of serum IgG antibodies against SARS-CoV-2 trimeric spike protein will be performed on a monthly basis in blood samples collected for diverse clinical purposes in three reference hospitals from the three Barcelona healthcare areas (BCN areas). The samples (n=2588/month) will be from patients attended by 30 primary healthcare teams at 30 basic healthcare areas (BHA). A lab software algorithm will systematically select the samples by age and sex. Seroprevalence will be estimated and monitored by age, sex, BCN area and BHA. Descriptive and cluster analysis of the characteristics and distribution of SARS-CoV-2 infections will be performed. Sociodemographic, socioeconomic and morbidity-associated factors will be determined using logistic regression. We will explore the association between seroprevalence, SARS-CoV-2 confirmed cases and the implemented measures using interrupted time series analysis. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University Institute Foundation for Primary Health Care Research Jordi Gol i Gurina ethics committee. An informed consent is not required regarding the approval of the secondary use of biological samples within the framework of the COVID-19 pandemic. A report will be generated quarterly. The final analysis, conclusions and recommendations will be shared with the stakeholders and communicated to the general public. Manuscripts resulting from the network will be submitted for publication in peer-reviewed journals.

Trend from 2001 to 2015 in the prevalence of bronchiectasis among patients hospitalized for asthma and effect of bronchiectasis on the in-hospital mortality.

OBJECTIVE: We aimed to analyze the prevalence of bronchiectasis among patients hospitalized with asthma and to assess the effect of suffering bronchiectasis on in-hospital mortality (IHM). METHODS: We used the Spanish National Hospital Discharge Database from 2000 to 2015 to evaluate all admissions for asthma exacerbation as the main diagnosis, dividing them according to the presence or absence of associated bronchiectasis. We assessed time trends in the prevalence, clinical characteristics, length of hospital stay, costs, and IHM. RESULTS: Of 342,644 admissions for asthma, 10,377 (3.02%) had bronchiectasis. The prevalence of bronchiectasis increased from 2.16% in 2001 to 4.47% in 2015 (p < 0.001). Compared to patients without bronchiectasis, those with bronchiectasis were more frequently women (77.06% vs. 22.94%, p < 0.001), were older (68.87 ± 15.16 vs. 47.05 ± 30.66 years, p < 0.001) and had more comorbid conditions (Charlson comorbidity index ≥ 2: 9.45% vs. 6.58%, p < 0.001). Pseudomonas (8% vs. 0.66%, p < 0.001), Aspergillus (0.93% vs. 0.15%, p < 0.001), eosinophilia (0.29% vs. 0.17%, p = 0.005) and IHM (2.07% vs. 1.2%, p < 0.001) were more frequent in patients with bronchiectasis. After multivariable adjustments, IHM was not associated with bronchiectasis. The presence of bronchiectasis was associated with a longer length of hospital stay and higher costs. CONCLUSIONS: Admissions for asthma with bronchiectasis have increased over time in Spain. In our investigation, the presence of bronchiectasis was not associated with higher IHM, but it increased the length of hospital stay and costs.

[All Roads Lead to Rome: Results of Non-Invasive Respiratory Therapies Applied in a Tertiary-Care Hospital Without an Intermediate Care Unit During the COVID-19 Pandemic]. / Todos los caminos llevan a Roma: resultados de las terapias respiratorias no invasivas aplicadas en un centro terciario sin Unidad de Cuidados Intermedios durante la pandemia de COVID-19.

Introduction: Non-invasive respiratory therapies (NRT) were widely used in the first wave of the COVID-19 pandemic in different settings, depending on availability. The objective of our study was to present 90-day survival and associated factors in patients treated with NRT in a tertiary hospital without an Intermediate Respiratory Care Unit. The secondary objective was to compare the outcomes of the different therapies. Methods: Observational study of patients treated with NRT outside of an intensive care or intermediate respiratory care unit setting, diagnosed with COVID-19 and acute respiratory distress syndrome by radiological criteria and SpO2/FiO2 ratio. A multivariate logistic regression model was developed to determine independently associated variables, and the outcomes of high flow nasal cannula and continuous positive airway pressure were compared. Results: In total, 107 patients were treated and 85 (79.4%) survived at 90 days. Before starting NRT, the mean SpO2/FiO2 ratio was 119.8 ± 59.4. A higher SOFA score was significantly associated with mortality (OR 2,09; 95% CI 1.34-3.27), while self-pronation was a protective factor (OR 0.23; 95% CI 0.06-0.91). High flow nasal cannula was used in 63 subjects (58.9%), and continuous positive airway pressure in 41 (38.3%), with no differences between them. Conclusion: Approximately 4 out of 5 patients treated with NRT survived to 90 days, and no significant differences were found between high flow nasal cannula and continuous positive airway pressure.

Hospitalizations for Community-Acquired and Non-Ventilator-Associated Hospital-Acquired Pneumonia in Spain: Influence of the Presence of Bronchiectasis. A Retrospective Database Study.

To examine and compare in-hospital mortality (IHM) of community-acquired pneumonia (CAP) and non-ventilator hospital-acquired pneumonia (NV-HAP) among patients with or without bronchiectasis (BQ) using propensity score matching. A retrospective observational epidemiological study using the Spanish Hospital Discharge Records, 2016-17. We identified 257,455 admissions with CAP (3.97% with BQ) and 17,069 with NV-HAP (2.07% with BQ). Patients with CAP and BQ had less comorbidity, lower IHM, and a longer mean length of hospital stay (p < 0.001) than non-BQ patients. They had a higher number of isolated microorganisms, including Pseudomonas aeruginosa. In patients with BQ and NV-HAP, no differences were observed with respect to comorbidity, in-hospital mortality (IHM), or mean length of stay. P. aeruginosa was more frequent (p = 0.028). IHM for CAP and NV-HAP with BQ was 7.89% and 20.06%, respectively. The factors associated with IHM in CAP with BQ were age, comorbidity, pressure ulcers, surgery, dialysis, and invasive ventilation, whereas in NV-HAP with BQ, the determinants were age, metastatic cancer, need for dialysis, and invasive ventilation. Patients with CAP and BQ have less comorbidity, lower IHM and a longer mean length of hospital stay than non-BQ patients. However, they had a higher number of isolated microorganisms, including Pseudomonas aeruginosa. In patients with BQ and NV-HAP, no differences were observed with respect to comorbidity, in-hospital mortality, or mean length of stay, but they had a greater frequency of infection by P. aeruginosa than non-BQ patients. Predictors of IHM for both types of pneumonia among BQ patients included dialysis and invasive ventilation.

Characteristics and outcomes of patients hospitalized with interstitial lung diseases in Spain, 2014 to 2015.

To assess characteristics and outcomes of patients hospitalized with interstitial lung diseases (ILD) and to analyze patient's comorbidities, procedures, and in-hospital outcomes.We identified patients hospitalized with idiopathic pulmonary fibrosis and others ILD such as hypersensitivity pneumonitis, cryptogenic organizing pneumonia, lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, and sarcoidosis in Spain during 2014 and 2015.We identified 14,565 discharges among patients admitted for ILD in Spain during the study period: idiopathic pulmonary fibrosis (IPF) in 42.32% (n = 6164), sarcoidosis in 37.65% (n = 5484), hypersensitivity pneumonitis in 10.55% (n = 1538), cryptogenic organizing pneumonia in 7.06% (n = 1028), pulmonary Langerhans cell histiocytosis in 1.48% (n = 215), and lymphangioleiomyomatosis in 0.94% (n = 136). The most common associated comorbidities according to those included in the Charlson Comorbidity Index (CCI) were COPD, diabetes, and congestive heart disease. The presence of pulmonary hypertension increased the probability of dying in patients with idiopathic pulmonary fibrosis (OR 1.36; 95%CI 1.06-1.73). Patients with cryptogenic organizing pneumonia had the longest length of hospital stay and the highest percentage of hospital readmissions (23.64%). The highest IHM corresponded to the idiopathic pulmonary fibrosis (14.94%). Computed tomography of the chest was the procedure more used during admissions for ILD.IPF was responsible for larger percentage of hospital admission among ILD in our study. In addition, the IHM were higher in IPF patients in comparison with those with other ILD. The most common associated comorbidity in ILD according to those included in the CCI was COPD. Computed tomography of the chest was the procedure more frequently used.

Bronchiectasis in patients hospitalized with acute exacerbation of COPD in Spain: Influence on mortality, hospital stay, and hospital costs (2006-2014) according to gender.

PURPOSE: The objectives of this study were to analyze the characteristics of male and female patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) during 2006-2014 according to the presence or absence of bronchiectasis and to study the factors associated with in-hospital mortality (IHM) in patients hospitalized with AE-COPD and concomitant bronchiectasis. METHODS: We used the Spanish National Hospital Database to analyze patients admitted with AE-COPD as their primary diagnosis. Patients included in the study were stratified according to the presence or absence of bronchiectasis as their secondary diagnosis. RESULTS: We identified 386,646 admissions for AE-COPD, of which 19,679 (5.09%) involved patients with concomitant bronchiectasis. When patients with and without bronchiectasis were compared, we observed that the incidence of infection by Pseudomonas aeruginosa was substantially higher in the former, as were the mean stay, cost, and percentage of readmissions, although IHM and comorbidity were lower. The course of patients with AE-COPD and bronchiectasis was characterized by a gradual increase in prevalence and mean age among men and no differences in prevalence or lower mean age in women. Mortality was 4.24% and 5.02% in patients with and without bronchiectasis, respectively, although significance was lost after a multivariate adjustment (OR 0.94; 95% CI, 0.88-1.01). The factors associated with IHM were older age, higher comorbidity, isolation of P. aeruginosa, mechanical ventilation and readmission. CONCLUSIONS: The prevalence of admission with AE-COPD and bronchiectasis increased in men but not in women during the study period. In patients hospitalized with AE-COPD, we did not find differences in mortality when comparing the presence and absence of bronchiectasis. The analysis of temporal trends revealed a significant reduction in mortality from 2006 to 2014 in male patients with COPD and concomitant bronchiectasis, but not among women. It is important to consider the factors associated with IHM such as age, comorbidity, isolation of P. aeruginosa, mechanical ventilation and readmission to better identify those patients who are at greater risk of dying during hospitalization.

Poder pronóstico de mortalidad a corto plazo de los biomarcadores en los ancianos atendidos en Urgencias por infección / Prognostic power of biomarkers for short-term mortality in the elderly patients seen in Emergency Departments due to infections

Objetivos: Analizar y comparar el poder predictivo de mortalidad a 30 días de varios biomarcadores (proteína C reactiva, procalcitonina, lactato, suPAR y proadrenomedulina) en los pacientes ancianos que acuden al servicio de Urgencias (SU) por un episodio de infección. Y, secundariamente, comprobar si estos mejoran la capacidad pronóstica de los criterios de sepsis (síndrome de respuesta inflamatoria sistémica y quick Sepsis-related Organ Failure Assessment [qSOFA]). Métodos: Estudio observacional, prospectivo, multicéntrico y analítico. Se incluyó consecutivamente a pacientes de 75 o más años atendidos en 8 SU por un proceso infeccioso. Se analizaron 25 variables independientes (epidemiológicas, de comorbilidad, funcionales, clínicas y analíticas) que pudieran influir en la mortalidad a corto plazo (30 días). Resultados: Se incluyó a 136 pacientes, de los que 13 (9,5%) habían fallecido a los 30 días tras su consulta en el SU. La MRproADM es el biomarcador que consigue la mayor área bajo la curva ROC para predecir mortalidad a los 30 días (0,864; IC 95% 0,775-0,997; p < 0,001), con un punto de corte de mayor capacidad predictiva de 2,07 nmol/l, que ofrece una sensibilidad del 77% y una especificidad del 96%. La escala qSOFA ≥ 2 consigue un área bajo la curva ROC de 0,763 (IC 95% 0,623-0,903; p = 0,002), con una sensibilidad del 76% y una especificidad del 75%. El modelo combinado (MRproADM con qSOFA ≥2 ) mejora el área bajo la curva ROC a 0,878 (IC 95% 0,749-1; p < 0,001) y ofrece el mejor rendimiento pronóstico, con una sensibilidad del 69% y una especificidad del 97%. Conclusiones: En los pacientes ancianos que acuden al SU por un episodio de infección, la MRproADM presenta una capacidad pronóstica de mortalidad a los 30 días superior al resto de los biomarcadores, la qSOFA obtiene mayor rendimiento que los criterios de síndrome de respuesta inflamatoria sistémica, y el modelo combinado qSOFA ≥ 2 con MRproADM > 2,07nmol/l mejora el poder predictivo de qSOFA

Objectives: To analyse and compare 30-day mortality prognostic power of several biomarkers (C-reactive protein, procalcitonin, lactate, suPAR and pro-adremomedullin) in elderly patients seen in Emergency Departments (ED) due to infections. Secondly, if these could improve the prognostic accuracy of sepsis criteria (systemic inflammatory response syndrome and quick Sepsis-related Organ Failure Assessment [qSOFA]). Methods: A prospective, observational, multicentre and analytical study. Patients aged 75 years and older who were treated for infection in the ED of 8 participating hospitals were enrolled consecutively. An assessment was made of 25 independent variables (epidemiological, comorbidity, functional, clinical and analytical variables) that could influence short-term mortality (at 30 days). Results: The study included 136 patients, 13 (9.5%) of whom died within 30 days of visiting the ED. MR-proADM is the biomarker with the best area under the curve ROC to predict 30-day mortality (0.864; 95% CI 0.775-0.997; P <.001) with a prognostic cut-off > 2.07nmol/l, sensitivity of 77% and specificity of 96%. The qSOFA score ≥ 2 had an area under the curve ROC of 0.763 (95% CI 0.623-0.903; P=.002), sensitivity of 76% and specificity of 75%. The mixed model (MR-proADM plus qSOFA ≥ 2) improved the area under the curve ROC to 0.878 (95% CI 0.749-1; P < .001) with the best prognostic performance with sensitivity of 69% and specificity of 97%. Conclusions: MR-proADM showed the best performance for 30-day mortality prognostic power compared to other biomarkers in elderly patients seen in EDs due to infections. qSOFA score achieves better results than systemic inflammatory response syndrome, and the mixed model (qSOFA ≥ 2 plus MR-proADM > 2.07nmol/l) increased the predictive power of qSOFA

Prognostic power of biomarkers for short-term mortality in the elderly patients seen in Emergency Departments due to infections. / Poder pronóstico de mortalidad a corto plazo de los biomarcadores en los ancianos atendidos en Urgencias por infección.

OBJECTIVES: To analyse and compare 30-day mortality prognostic power of several biomarkers (C-reactive protein, procalcitonin, lactate, suPAR and pro-adremomedullin) in elderly patients seen in Emergency Departments (ED) due to infections. Secondly, if these could improve the prognostic accuracy of sepsis criteria (systemic inflammatory response syndrome and quick Sepsis-related Organ Failure Assessment [qSOFA]). METHODS: A prospective, observational, multicentre and analytical study. Patients aged 75 years and older who were treated for infection in the ED of 8 participating hospitals were enrolled consecutively. An assessment was made of 25 independent variables (epidemiological, comorbidity, functional, clinical and analytical variables) that could influence short-term mortality (at 30 days). RESULTS: The study included 136 patients, 13 (9.5%) of whom died within 30 days of visiting the ED. MR-proADM is the biomarker with the best area under the curve ROC to predict 30-day mortality (0.864; 95% CI 0.775-0.997; P<.001) with a prognostic cut-off>2.07nmol/l, sensitivity of 77% and specificity of 96%. The qSOFA score≥2 had an area under the curve ROC of 0.763 (95% CI 0.623-0.903; P=.002), sensitivity of 76% and specificity of 75%. The mixed model (MR-proADM plus qSOFA≥2) improved the area under the curve ROC to 0.878 (95% CI 0.749-1; P<.001) with the best prognostic performance with sensitivity of 69% and specificity of 97% CONCLUSIONS: MR-proADM showed the best performance for 30-day mortality prognostic power compared to other biomarkers in elderly patients seen in EDs due to infections. qSOFA score achieves better results than systemic inflammatory response syndrome, and the mixed model (qSOFA≥2 plus MR-proADM>2.07nmol/l) increased the predictive power of qSOFA.

Comorbidities and risk of mortality among hospitalized patients with idiopathic pulmonary fibrosis in Spain from 2002 to 2014.

BACKGROUND: To describe and compare the comorbid conditions, the in-hospital mortality (IHM) and the length of hospital stay (LOHS) among idiopathic pulmonary fibrosis (IPF) patients and non-IPF-matched patients hospitalized in Spain. We assess the performance of the Charlson Comorbidity Index[CCI] and the Elixhauser Comorbidity Index[ECI] to predict IHM in IPF and we identify the specific predictive factors of IHM in patients suffering IPF. METHODS: We identified patients with IPF hospitalized in years 2002, 2006, 2010 and 2014. Cases of IPF were matched with non-IPF controls by sex, age, province of residence and year. Data were collected from the Spanish National Hospital Discharge Database. RESULTS: We identified 10,285 hospitalizations with IPF, evidencing an increase in the number of IPF patients from 2002 to 2014. Overtime the prevalence of comorbidities included in the CCI significantly increased in patients with IPF, exception made of myocardial infarction and dementia. The prevalence of comorbidities included in the ECI, except paralysis and peptic ulcer disease excluding bleeding, increased significantly overtime. LOHS was longer among IPF patients than non-IPF controls and decreased significantly from 2002 to 2014. IHM was significantly higher in patients with IPF (adjustedOR 1.97; 95%CI 1.77-2.19). Area under the ROC curves showed that ECI model had a better performance to predict IHM than CCI. CONCLUSIONS: The incidence of hospitalizations for IPF increased significantly from 2002 to 2014. We observed an increase overtime of most of the comorbidities included in CCI and ECI. LOHS and IHM were higher in patients with IPF than in non-IPF controls.

Retrospective observational study of trends in hospital admissions for idiopathic pulmonary fibrosis in Spain (2004-2013) using administrative data.

OBJECTIVE: To assess changes in incidence, diagnostic procedures, comorbidity profiles, length of hospital stay (LOHS), economic costs and in-hospital mortality (IHM) associated with idiopathic pulmonary fibrosis (IPF). METHODS: We identified patients hospitalised with IPF in Spain from 2004 to 2013. Data were collected from the National Hospital Discharge Database. RESULTS: The study population comprised 22 214 patients. Overall crude incidence increased from 3.82 to 6.98 admissions per 100 000 inhabitants from 2004 to 2013 (p<0.05). The percentage of lung biopsies decreased significantly from 10.68% in 2004 to 9.04% in 2013 (p<0.05). The percentage of patients with a Charlson comorbidity index ≥2 was 15.14% in 2004, increasing to 26.95% in 2013 (p<0.05). IHM decreased from 14.77% in 2004 to 13.72% in 2013 (adjusted OR 0.98; 95% CI 0.97 to 0.99). Mean LOHS was 11.87±11.18 days in 2004, decreasing to 10.20±11.12 days in 2013 (p<0.05). The mean cost per patient increased from €4838.51 in 2004 to €5410.90 in 2013 (p<0.05). CONCLUSIONS: The frequency of hospital admissions for IPF increased during the study period, as did healthcare costs. However, IHM and LOHS decreased.

Time Trends in Hospital Admissions for Bronchiectasis: Analysis of the Spanish National Hospital Discharge Data (2004 to 2013).

OBJECTIVE: To analyze changes in the incidence, diagnostic procedures, comorbidity, length of hospital stay (LOHS), costs and in-hospital mortality (IHM) for patients with bronchiectasis who were hospitalized in Spain over a 10-year period. METHODS: We included all admissions for patients diagnosed with bronchiectasis as primary or secondary diagnosis during 2004-2013. RESULTS: 282,207 patients were admitted to the study. After controlling for possible confounders, we observed a significant increase in the incidence of hospitalizations over the study period when bronchiectasis was a secondary diagnosis. When bronchiectasis was the primary diagnosis we observed a significant decline in the incidence. In all cases, this pathology was more frequent in males, and the average age and comorbidity increased significantly during the study period (p<0.001). When bronchiectasis was the primary diagnosis, the most frequent secondary diagnosis was Pseudomonas aeruginosa infection. When bronchiectasis was the secondary diagnosis, the most frequent primary diagnosis was COPD. IHM was low, tending to decrease from 2004 to 2013 (p<0.05). The average LOHS decreased significantly during the study period in both cases (p<0.001). The mean cost per patient decreased in patients with bronchiectasis as primary diagnosis, but it increased for cases of bronchiectasis as secondary diagnosis (p<0.001). CONCLUSIONS: Our results reveal an increase in the incidence of hospital admissions for patients with bronchiectasis as a secondary diagnosis from 2004 to 2013, as opposed to cases of bronchiectasis as the primary diagnosis. Although the average age and comorbidity significantly increased over time, both IHM and average LOHS significantly decreased.

ITH12410/SC058: a new neuroprotective compound with potential in the treatment of Alzheimer's disease.

The neuroprotective profile of the dibenzothiadiazepine ITH12410/SC058 (2-chloro-5,6-dihydro-5,6-diacetyldibenzo[b,f][1,4,5]thiadiazepine) against several neurotoxicity models related to neurodegenerative diseases is herein described. ITH12410/SC058 protected SH-SY5Y cells against the loss of cell viability elicited by amyloid beta peptide and okadaic acid, a selective inhibitor of phosphoprotein phosphatase 2A that induces neurofibrillary tangle formation. Furthermore, ITH12410/SC058 is neuroprotective against several in vitro models of oxidative stress, that is, H2O2 exposure or incubation with rotenone plus oligomycin A in SH-SY5Y cells, and oxygen and glucose deprivation followed by reoxygenation in rat hippocampal slices. By contrast, ITH12410/SC058 was unable to significantly protect SH-SY5Y neuroblastoma cells against the toxicity elicited by Ca(2+) overload. Our results confirm the hypothesis that the dibenzothiadiazepine ITH12410/SC058 features its neuroprotective actions in a multitarget fashion, and is a promising drug for the treatment of neurodegenerative diseases.

Dibenzo[1,4,5]thiadiazepine: a hardly-known heterocyclic system with neuroprotective properties of potential usefulness in the treatment of neurodegenerative diseases.

In this work we describe a new family of dibenzo[1,4,5]thiadiazepines (2-12) that showed an interesting in vitro biological profile, namely neuroprotective and antioxidant properties, as well as blockade of cytosolic calcium entry. They showed no cytotoxic effects and the majority were predicted as CNS-permeable compounds. In human neuroblastoma cells they displayed good neuroprotective properties against mitochondrial oxidative stress which, in many cases, almost reached the full protection (>90%) when compounds were incubated with cells 24 h before the addition of toxic stressors. In co-incubation conditions these figures were smaller, although some compounds maintained an interesting level of neuroprotection, higher than 50%. Four selected compounds (2, 5, 8, and 11) were found to be effective antioxidant agents by sequestering mitochondrial radical oxygen species (ROS). Moreover, compound 2 showed a remarkable calcium-channel modulating activity. The interest of these compounds is increased by the fact that dibenzo[1,4,5]thiadiazepine is a barely known structure that is not difficult to synthesize and presents very few described derivatives, opening a new and broad line of research in Medicinal Chemistry.

Tuberculosis in pediatric solid organ and hematopoietic stem cell transplant recipients.

The burden of tuberculosis after pediatric solid organ transplant or hematopoietic stem cell transplantation has not been well characterized. We report 7 pediatric cases with disseminated (4/7) or pulmonary (3/7) tuberculosis after solid organ transplant (n=6) or hematopoietic stem cell transplantation (n=1) during 26 years. The outcome was favorable in 6 patients. Isoniazid-induced hepatitis and rifampin interactions were common.

Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases.

A family of huprine-tacrine heterodimers has been developed to simultaneously block the active and peripheral sites of acetylcholinesterase (AChE). Their dual site binding for AChE, supported by kinetic and molecular modeling studies, results in a highly potent inhibition of the catalytic activity of human AChE and, more importantly, in the in vitro neutralization of the pathological chaperoning effect of AChE toward the aggregation of both the ß-amyloid peptide (Aß) and a prion peptide with a key role in the aggregation of the prion protein. Huprine-tacrine heterodimers take on added value in that they display a potent in vitro inhibitory activity toward human butyrylcholinesterase, self-induced Aß aggregation, and ß-secretase. Finally, they are able to cross the blood-brain barrier, as predicted in an artificial membrane model assay and demonstrated in ex vivo experiments with OF1 mice, reaching their multiple biological targets in the central nervous system. Overall, these compounds are promising lead compounds for the treatment of Alzheimer's and prion diseases.

N-acylaminophenothiazines: neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer's disease.

We have previously reported the multifunctional profile of N-(3-chloro-10H-phenothiazin-10-yl)-3-(dimethylamino)propanamide (1) as an effective neuroprotectant and selective butyrylcholinesterase inhibitor. In this paper, we have developed a series of N-acylaminophenothiazines obtained from our compound library or newly synthesised. At micro- and sub-micromolar concentrations, these compounds selectively inhibited butyrylcholinesterase (BuChE), protected neurons against damage caused by both exogenous and mitochondrial free radicals, showed low toxicity, and could penetrate into the CNS. In addition, N-(3-chloro-10H-phenothiazin-10-yl)-2-(pyrrolidin-1-yl)acetamide (11) modulated the cytosolic calcium concentration and protected human neuroblastoma cells against several toxics, such as calcium overload induced by an L-type Ca2+-channel agonist, tau-hyperphosphorylation induced by okadaic acid and Aß peptide.

Old phenothiazine and dibenzothiadiazepine derivatives for tomorrow's neuroprotective therapies against neurodegenerative diseases.

From an in-house library of compounds, five phenothiazines and one dibenzothiadiazepine were selected to be tested in neuroprotective and cholinergic assays. Three of them, derived from the N-alkylphenothiazine, the N-acylaminophenothiazine, and the 1,4,5-dibenzo[b,f]thiadiazepine system, protected human neuroblastoma cells against oxidative stress generated by both exogenous and mitochondrial free radicals. They could also penetrate the CNS, according to an in vitro blood-brain barrier model, and an N-acylaminophenothiazine derivative behaved as a selective inhibitor of butyrylcholinesterase. Free radical capture and/or promotion of antioxidant protein biosynthesis are mechanisms that can be implicated in their neuroprotective actions. Due to their excellent pharmacological properties and the fact that they were not biologically explored in the past, one N-acylaminophenothiazine and one 1,4,5-dibenzo[b,f]thiadiazepine have been selected to develop two new series that are currently in progress.

Novel tacrine-8-hydroxyquinoline hybrids as multifunctional agents for the treatment of Alzheimer's disease, with neuroprotective, cholinergic, antioxidant, and copper-complexing properties.

Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease beta-amyloid (Abeta) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer's disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Abeta aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier model.