Innovative Post-Processing for Complex Geometries and Inner Parts of 3D-Printed AlSi10Mg Devices.

A new technology consisting of new and sustainable chemical polishing treatment for aluminum components with complex shapes, such as heat exchangers, manifolds, busbars, aerospace devices, etc., manufactured by Additive Manufacturing (AM) technologies is described in this paper. This technology will contribute to the development of a more efficient manufacturing process driven by AM, reinforcing the main idea of AM, which is based on reducing the amount of material and achieving cost savings through smart and improved designs. The present study shows a significant reduction in the surface roughness of consolidated AlSi10Mg metal parts manufactured by the SLM technique after carrying out the new chemical polishing post-process investigated in this work. Roughness values have been measured by mechanical and optical profilometry. The results obtained demonstrate the effectiveness of the chemical polishing, decreasing the roughness by up to 40%, being a reproducible and repeatable post-process. The presence of smut as solid residues on such types of chemical treatments has been also analyzed with XRF and ICP-MS techniques. The results obtained show that Si and Mg precipitates are removed from the metal surface at the last step of the investigated post-process. The percentages of the elements decrease from 25.0% to 8.09% Si and from 0.86% to 0.42% Mg, achieving the alloy smut-free composition on the metal surface. Tensile strength measurements have shown that the post-process described not only maintains the mechanical properties of the bulk material but, in comparison with non-post-processed parts, a slight improvement is observed with respect to the initial values, Young modulus (61.1 GPa to final 62.2 GPa), yield strength (from 236.8 to 246.7 MPa), and tensile strength (from 371.9 to 382.5 MPa) is observed, suggesting that the post-process has positive impact on the printed metal part.

Feasibility and outcomes of transjugular intrahepatic portosystemic shunts in infants.

BACKGROUND: Experience with transjugular intrahepatic portosystemic shunts (TIPS) in the pediatric population, especially in infants, is limited. OBJECTIVE: To evaluate the feasibility, efficacy and safety of TIPS placement in infants. MATERIALS AND METHODS: This retrospective non-comparative observational cohort study analyzed all pediatric patients < 12 months of age treated with TIPS while waiting for liver transplant between October 2018 and April 2021. The sample consisted of 10 infants with chronic liver disease. All had refractory ascites and decreased portal vein size. Their mean age ± standard deviation was 5 ± 1 months and their mean weight was 5.4 ± 1.0 kg. We calculated the pediatric end-stage liver disease score and portosystemic gradients before and after TIPS placement. We used ultrasound to check for complications and to assess the presence of ascites. We used paired-sample t-test for the mean comparison of paired variables. RESULTS: Ten TIPS procedures were performed that were technically and hemodynamically successful except for one, in which an extrahepatic portal puncture required surgical repair. Ascites resolved in three infants and was reduced in six. The portal vein size remained stable after TIPS placement. Four infants had early stent thrombosis and two had late stent thrombosis treated with angioplasty or covered stents. CONCLUSION: TIPS placement in infants is a feasible, safe and effective procedure.

Long-term impact of COVID-19 associated acute respiratory distress syndrome.

OBJECTIVES: To determine the health status, exercise capacity, and health related quality of life (HRQoL) of COVID-19 associated acute respiratory distress syndrome (ARDS) survivors, 8 months after diagnosis. METHODS: All eligible patients were interviewed and underwent a physical examination, chest X-ray, and 6 min walk test (6MWT). Scales to evaluate post-traumatic stress disorder, depression, anxiety, and HRQoL were applied. RESULTS: Of 1295 patients, 365 suffered ARDS and 166 survived to hospital discharge. Five died after discharge and 48 were lost to follow-up. Of the 113 remaining patients, 81% had persistent symptoms. More than 50% of patients completed less than 80% of the theoretical distance on the 6MWT, 50% had an abnormal X-ray and 93% of patients developed psychiatric disorders. Mean SF-36 scores were worse than in the general population. After multivariate regression analysis, female sex, non-Caucasian race, and Charlson index>2 were independent risk factors for a worse mental health component summary score on the SF-36, and age was associated with a better prognosis. Female sex and chronic obstructive pulmonary disease were independently associated with a worse physical component summary score. CONCLUSION: COVID-19 associated ARDS survivors have long-term consequences in health status, exercise capacity, and HRQoL. Strategies addressed to prevent these sequelae are needed.

Correction to: Superior performance of 18F-fluorocholine digital PET/CT in the detection of parathyroid adenomas.

The correct administered activity of 18F-FCH is 0.1-0.14 mCi/Kg, which is equivalent to 3.7-5.2 MBq/kg.

Improved in vivo efficacy of clinical-grade cryopreserved human hepatocytes in mice with acute liver failure.

Clinical hepatocyte transplantation short-term efficacy has been demonstrated; however, some major limitations, mainly due to the shortage of organs, the lack of quality of isolated cells and the low cell engraftment after transplantation, should be solved for increasing its efficacy in clinical applications. Cellular stress during isolation causes an unpredictable loss of attachment ability of the cells, which can be aggravated by cryopreservation and thawing. In this work, we focused on the use of a Good Manufacturing Practice (GMP) solution compared with the standard cryopreservation medium, the University of Wisconsin medium, for the purpose of improving the functional quality of cells and their ability to engraft in vivo, with the idea of establishing a biobank of cryopreserved human hepatocytes available for their clinical use. We evaluated not only cell viability but also specific hepatic function indicators of the functional performance of the cells such as attachment efficiency, ureogenic capability, phase I and II enzymes activities and the expression of specific adhesion molecules in vitro. Additionally, we also assessed and compared the in vivo efficacy of human hepatocytes cryopreserved in different media in an animal model of acute liver failure. Human hepatocytes cryopreserved in the new GMP solution offered better in vitro and in vivo functionality compared with those cryopreserved in the standard medium. Overall, the results indicate that the new tested GMP solution maintains better hepatic functions and, most importantly, shows better results in vivo, which could imply an increase in long-term efficacy when used in patients.

Superior performance of 18F-fluorocholine digital PET/CT in the detection of parathyroid adenomas.

OBJECTIVE: To compare detectability of hyperfunctioning parathyroid tissue (HPT) by digital and analog 18F-fluorocholine PET/CT in patients with primary hyperparathyroidism and negative/inconclusive 99mTc-MIBI scintigraphy-SPECT/CT. MATERIALS AND METHODS: Thirty-three patients with primary hyperparathyroidism and negative/inconclusive 99mTc-MIBI scintigraphy-SPECT/CT were prospectively included. All patients accepted to be scanned by digital and analog PET/CT in the same imaging session after a single injection of 18F-fluorocholine. Three nuclear medicine physicians evaluated the digital and analog PET/CT datasets to assess the detection rate of HPT. Maximum standard uptake values (SUVmax) of HPT and locoregional lymph nodes were measured in both systems. RESULTS: HPT was detected in 30/33 patients by the digital system, whereas it was detected in 22/33 patients by the analog system (p < 0.01). Moreover, in 21 of these 33 patients, both systems detected one focal 18F-fluorocholine uptake, and in one patient the digital system detected two foci. Histopathology demonstrated HPT in 32 patients and it was inconclusive in one patient. The digital PET/CT detected HPT in 29 of the 32 patients, and the analog system in 22 of the 32 (p < 0.01). All HPT suspected lesions resected and detected only by the digital system (n = 8) were < 10 mm (7.5 ± 1.3 mm), while those detected by both systems (n = 22) were > 10 mm (13 ± 3.8 mm). SUVmax of HPT lesions was significantly higher than SUVmax of locoregional lymph node independently of the PET/CT system used (4.5 ± 1.9 vs. 2.9 ± 1.3, p < 0.0001). CONCLUSIONS: Digital PET/CT offers superior performance over analog system in patients with suspected HPT and previous negative/inconclusive imaging examinations, particularly in sub-centimeter lesions. SUVmax can help in the differentiation between HTP and locoregional lymph nodes.

Eficacia académica percibida, crianza, uso de internet y comportamiento en la adolescencia / Achievement perceived, parenting, internet use and adolescent behavior

Resumen El uso intensivo de internet puede contribuir a desarrollar disfunciones psicosociales graves en la adolescencia. El objetivo de esta investigación es analizar las relaciones de la percepción de eficacia académica con el uso de internet para ocio, los estilos de crianza y los problemas exteriorizados e interiorizados en la adolescencia (agresividad proactiva, reactiva, física y verbal, afiliación a pares rebeldes e inestabilidad emocional). Han participado 762 adolescentes de 12 a 17 años (M = 13.69; DT = 1.40; varones 52.8%). Utilizan internet en tiempo de ocio entre cero y 98 horas semanales, de ahí que la población se haya distribuido en cuartiles. Las variables se han obtenido a través de pruebas estandarizadas. Los análisis estadísticos se basan en metodología descriptiva y predictiva. Los resultados han permitido obtener tres conclusiones. Primera, el número de horas de internet para fines recreativos se relaciona con una peor eficacia académica percibida. Segunda, los adolescentes que usan Internet intensamente perciben más permisividad de los padres y menos apoyo y comunicación por parte de los padres. Estos adolescentes presentan más riesgo de conectarse con pares rebeldes y tienen índices más altos de inestabilidad emocional y agresividad (reactiva, proactiva, física y verbal). Tercera, la paternidad más punitiva, la agresividad y la afiliación a pares rebeldes aumentan el uso intensivo de Internet. Esta investigación corrobora la necesidad de una formación adecuada, dirigida a fomentar el apoyo y la comunicación paterno-filial para educar el uso racional y responsable de internet de ambos, padres y adolescentes.

Abstract The intensive use of the Internet can contribute to the development of serious psychosocial dysfunctions in adolescents. The purpose of this research is to analyze the relationships between achievement perceived with the leisure use of the internet, parenting, and externalized and internalized problems during adolescence (aggressiveness reactive, proactive, physical and verbal, affiliation with deviant peers and emotional instability). The sample is made of 762 adolescents from 12 to 17 years old (M = 13.69, SD = 1.40), with 52.8% of males and 47.2% of females. The use of internet in leisure time is between 0-98 hours per week. Hence the population has been distributed in quartiles. The variables have been obtained through standardized tests. Statistical analyzes are descriptive and predictive methodology. The analyses carried out have allowed us to obtain three conclusions. First, the number of hours of internet for recreational purposes is related to worse achievement perceived of the adolescent. Second, it has been found that adolescents who use Internet intensively greater perceived permissiveness of the parents and a lower support and communication with them. These adolescents present an increased risk of joining deviant peers and have higher rates of emotional instability and aggressiveness (reactive, proactive, and physical and verbal). Third, more punitive parenting, aggressiveness and affiliation with deviant peers boost the intensive use of the internet. This empirical research corroborates the need for adequate training aimed at fostering parental-child support and communication to educate the rational and responsible use of the Internet by both parents and adolescents.

Correction to: Digital vs. analog PET/CT: intra-subject comparison of the SUVmax in target lesions and reference regions.

The article Digital vs. analog PET/CT: intra-subject comparison of the SUVmax in target lesions and reference regions, written by Francisco Fuentes-Ocampo, Diego Alfonso López-Mora, Albert Flotats, Gabriela Paillahueque.

Comparison of image quality and lesion detection between digital and analog PET/CT.

OBJECTIVE: The purpose of this study was to compare image quality and lesion detection capability between a digital and an analog PET/CT system in oncological patients. MATERIALS AND METHODS: One hundred oncological patients (62 men, 38 women; mean age of 65 ± 12 years) were prospectively included from January-June 2018. All patients, who accepted to be scanned by two systems, consecutively underwent a single day, dual imaging protocol (digital and analog PET/CT). Three nuclear medicine physicians evaluated image quality using a 4-point scale (-1, poor; 0, fair; 1, good; 2, excellent) and detection capability by counting the number of lesions with increased radiotracer uptake. Differences were considered significant for a p value <0.05. RESULTS: Improved image quality in the digital over the analog system was observed in 54% of the patients (p = 0.05, 95% CI, 44.2-63.5). The percentage of interrater concordance in lesion detection capability between the digital and analog systems was 97%, with an interrater measure agreement of κ = 0.901 (p < 0.0001). Although there was no significant difference in the total number of lesions detected by the two systems (digital: 5.03 ± 10.6 vs. analog: 4.53 ± 10.29; p = 0.7), the digital system detected more lesions in 22 of 83 of PET+ patients (26.5%) (p = 0.05, 95% CI, 17.9-36.7). In these 22 patients, all lesions detected by the digital PET/CT (and not by the analog PET/CT) were < 10 mm. CONCLUSION: Digital PET/CT offers improved image quality and lesion detection capability over the analog PET/CT in oncological patients, and even better for sub-centimeter lesions.

Digital vs. analog PET/CT: intra-subject comparison of the SUVmax in target lesions and reference regions.

PURPOSE: The purpose of this study was to assess whether digital photon counting technology in digital PET/CT influences the quantification of SUVmax in target lesions and regions of reference compared to analog PET/CT before an interchangeable use of either system in follow up studies. METHODS: From January to June of 2018, 100 oncological patients underwent successive PET/CT imaging with digital and analog systems in the same day. Fifty-eight patients underwent analog imaging first and digital imaging thereafter, and 42 patients the other way round. SUVmax was measured in reference regions (liver and mediastinal blood pool) and in the most metabolically active target lesion in each patient. According to the sequence order of PET/CT acquisition, two groups of SUVmax values were obtained, i.e. group 1: analog PET/CT performed first; group 2: digital PET/CT performed first. RESULTS: Mean SUVmax in the total sample (regardless of the order of PET/CT acquisition) in the target lesions with the analog PET/CT was 8.14 ± 6.39 and the digital 9.97 ± 6.14 (P = 0.000). Total mean SUVmax in the liver with the analog was 4.39 ± 2.59 and the digital 4.46 ± 3.18 (P = 0.477). Total mean SUVmax in the mediastinal blood pool with the analog was 2.30 ± 0.67 and the digital 2.54 ± 0.74 (P = 0.000). Group 1: mean SUVmax in the target lesions with the analog system was 6.64 ± 4.71 and the digital 9.48 ± 5.60 (P = 0.000). Mean liver SUVmax with the analog was 4.70 ± 2.90 and the digital 4.80 ± 3.72 (P = 0.088). Mediastinal blood pool SUVmax with the analog was 2.33 ± 0.66 and the digital 2.45 ± 0.73 (P = 0.041). Group 2: mean SUVmax in target lesions with the digital system was 10.63 ± 6.88 and the analog 10.16 ± 7.76 (P = 0.046). Mean liver SUVmax with the digital was 3.99 ± 2.20 and the analog 3.96 ± 2.04 (P = 0.218). Mediastinal blood pool SUVmax with the digital was 2.66 ± 0.75 and the analog 2.27 ± 0.68 (P = 0.000). No significant differences between both time delays were found. CONCLUSIONS: Improved photon counting technology in the digital PET/CT, and the effect of delayed increased uptake and retention significantly increases SUVmax values. This has to be taken into account before interchangeable use of either system in follow up studies.

Selection of Reference Regions to Model Neurodegeneration in Huntington Disease by 18F-FDG PET/CT Using Imaging and Clinical Parameters.

OBJECTIVE: Normalization to an appropriate reference region in F-FDG PET imaging may enhance diagnostic performance in Huntington disease (HD). We aimed to identify stable brain areas that could be used to model neurometabolic degeneration in HD correlating imaging (SUVrvalues at the basal ganglia [BBGG]) and clinical parameters (disease burden score [DBS]). MATERIALS AND METHODS: We performed brain F-FDG PET/CT in 38 manifest HD patients (meanage ± SD, 54 ± 14.3 years; CAGrepeats ± SD, 44.2 ± 3.1), 20 premanifest HD patients (meanage ± SD, 42.7 ± 11.7 years; CAGrepeats ± SD, 40 ± 3.8), and 18 healthy controls (NC; meanage ± SD, 45 ± 13.2 years). For quantitative analysis, we selected (a) defined reference regions from the Montreal Neurological Institute space atlas (pons, whole cerebellum, cerebral white matter, thalamus, and a pons-cerebellar vermis region of interest), and (b) reference clusters obtained by voxelwise statistical comparison across groups (P < 0.05 FWE; extent voxel threshold k = 200). Each candidate reference region and reference cluster was quantitatively assessed using imaging and clinical parameters. RESULTS: Comparing HD and NC groups, we obtained a reference cluster in the cerebellum, and in temporal and frontal lobes. Comparing manifest HD and premanifest HD patients, we observed reference clusters in the cerebellum, pons, thalamus, parietal lobe, and cuneus. The set of reference regions showed a significant correlation between SUVrvalues at the BBGG and DBS in all HD patients. In premanifest HD patients, the correlation between SUVrvalues at the BBGG and DBS was significant using the pons-cerebellar vermis region of interest, the thalamus as defined reference regions, and the pons and thalamus as reference clusters. In manifest HD patients, the correlation was significant using the temporal and white matter frontal lobe clusters. Variance between SUVrvalues in the set of reference regions and reference clusters was minimal within NC. CONCLUSIONS: The pons may be a stable and reliable region to calculate SUVrvalues to model the neurometabolic degeneration in quantitative F-FDG PET imaging in HD.

PI3K, p38 and JAK/STAT signalling in bronchial tissue from patients with asthma following allergen challenge.

BACKGROUND: Inhaled allergen challenges are often used to evaluate novel asthma treatments in early phase clinical trials. Current novel therapeutic targets in asthma include phosphoinositide 3-kinases (PI3K) delta and gamma, p38 mitogen-activated protein kinase (p38) and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling pathways. The activation of these pathways following allergen exposure in atopic asthma patients it is not known. METHODS: We collected bronchial biopsies from 11 atopic asthma patients at baseline and after allergen challenge to investigate biomarkers of PI3K, p38 MAPK and JAK/STAT activation by immunohistochemistry. Cell counts and levels of eosinophil cationic protein and interleukin-5 were also assessed in sputum and bronchoalvelar lavage. RESULTS: Biopsies collected post-allergen had an increased percentage of epithelial cells expressing phospho-p38 (17.5 vs 25.6%, p = 0.04), and increased numbers of sub-epithelial cells expressing phospho-STAT5 (122.2 vs 540.6 cells/mm2, p = 0.01) and the PI3K marker phospho-ribosomal protein S6 (180.7 vs 777.3 cells/mm2,p = 0.005). Type 2 inflammation was increased in the airways post allergen, with elevated levels of eosinophils, interleukin-5 and eosinophil cationic protein. CONCLUSIONS: Future clinical trials of novel kinase inhibitors could use the allergen challenge model in proof of concept studies, while employing these biomarkers to investigate pharmacological inhibition in the lungs.

Influence of antrum size on gastric emptying and weight-loss outcomes after laparoscopic sleeve gastrectomy (preliminary analysis of a randomized trial).

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has increased in popularity in recent years as a definitive bariatric procedure. Despite its growing popularity worldwide, the surgical technique is not well standardized. There is a lack of evidence on the matter of the antrum size and its relation to gastric emptying and weight-loss outcomes. The aim of the study is to evaluate the influence of antrum size over gastric emptying and weight-loss outcomes. METHODS: Twenty-five patients were prospectively randomized according to the distance between the first firing and the pylorus: AR group (antrum resection-2 cm from the pylorus) and AP group (antrum preservation-5 cm from the pylorus). Gastric emptying (%GE) was evaluated by a gastric emptying scintigraphy before surgery, 2 months and 1 year after LSG. Antrum volume was measured using a MultiSlice CT Scan performed 2 months and 1 year after surgery. The percent of excess weight loss (%EWL) was calculated after 1 year follow-up. RESULTS: At 2 months after LSG the mean %GE was 69.7 ± 18 in the AR group and 72.8 ± 20 in the AP group (p = 0.69). At 1 year it was 66.5 ± 21 and 74.2 ± 16 in the AR and AP groups, respectively (p = 0.30). A significant accelerated gastric emptying was observed at 2 months (p = 0.025) and at 1 year (p = 0.013) in the AP group. Meanwhile in the AR group this increase was not significant (p = 0.12 at 2 months and p = 0.21 at 1 year). Differences regarding the %EWL between groups were no statistically significant (p = 0.74). CONCLUSIONS: After LSG there is a global tendency to an accelerated gastric emptying, although only significant in the antrum preservation group; however, no differences were observed regarding the %EWL between groups after 1 year follow-up.

Tofacitinib ameliorates inflammation in a rat model of airway neutrophilia induced by inhaled LPS.

BACKGROUND AND PURPOSE: The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model. EXPERIMENTAL APPROACH: Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o. KEY RESULTS: Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue. CONCLUSIONS AND IMPLICATIONS: In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases.

Recomendaciones sobre la prevención de aspiraciones de cuerpos extraños / Recommendations for the prevention of foreign body aspiration

La aspiración de un cuerpo extraño sigue siendo un problema pediátrico frecuente, con graves consecuencias, pudiendo producir tanto patología aguda como crónica. Suele afectar a niños por debajo de los 5 años, normalmente en su domicilio, que aspiran por lo común alimentos o frutos secos. Esta circunstancia puede provocar una crisis de asfixia aguda, constituyendo una urgencia médica que requiere de un diagnóstico precoz y una actitud terapéutica urgente, ya que puede producir la muerte en unos minutos. En el presente artículo, el Comité de Seguridad y Prevención de Lesiones No Intencionadas en la Infancia de la Asociación Española de Pediatría proporciona una serie de recomendaciones, tanto educativas (en la alimentación y en el juego) como legales para prevenir este tipo de lesiones

The aspiration of a foreign body remains a common paediatric problem, with serious consequences that can produce both acute and chronic disease. Aspiration usually causes a medical emergency that requires a prompt diagnosis and an urgent therapeutic approach as it may result in the death of the child or severe brain injury. It typically involves organic foreign bodies (mainly food or nuts) aspirated by children under 5 years old, and usually at home. In this statement, the Committee on Safety and Prevention of Non-Intentional Injury in Childhood of the Spanish Paediatrics Association provides a series of recommendations, both educational (while eating and playing), as well as legal, to prevent such episodes)

[Recommendations for the prevention of foreign body aspiration]. / Recomendaciones sobre la prevención de aspiraciones de cuerpos extraños.

The aspiration of a foreign body remains a common paediatric problem, with serious consequences that can produce both acute and chronic disease. Aspiration usually causes a medical emergency that requires a prompt diagnosis and an urgent therapeutic approach as it may result in the death of the child or severe brain injury. It typically involves organic foreign bodies (mainly food or nuts) aspirated by children under 5 years old, and usually at home. In this statement, the Committee on Safety and Prevention of Non-Intentional Injury in Childhood of the Spanish Paediatrics Association provides a series of recommendations, both educational (while eating and playing), as well as legal, to prevent such episodes.

Liver Cholesterol Overload Aggravates Obstructive Cholestasis by Inducing Oxidative Stress and Premature Death in Mice.

Nonalcoholic steatohepatitis is one of the leading causes of liver disease. Dietary factors determine the clinical presentation of steatohepatitis and can influence the progression of related diseases. Cholesterol has emerged as a critical player in the disease and hence consumption of cholesterol-enriched diets can lead to a progressive form of the disease. The aim was to investigate the impact of liver cholesterol overload on the progression of the obstructive cholestasis in mice subjected to bile duct ligation surgery. Mice were fed with a high cholesterol diet for two days and then were subjected to surgery procedure; histological, biochemical, and molecular analyses were conducted to address the effect of cholesterol in liver damage. Mice under the diet were more susceptible to damage. Results show that cholesterol fed mice exhibited increased apoptosis and oxidative stress as well as reduction in cell proliferation. Mortality following surgery was higher in HC fed mice. Liver cholesterol impairs the repair of liver during obstructive cholestasis and aggravates the disease with early fatal consequences; these effects were strongly associated with oxidative stress.

Double-stranded RNA evokes exacerbation in a mouse model of corticosteroid refractory asthma.

RNA viruses are a major cause of respiratory infections and are known to exacerbate asthma and other respiratory diseases. Our aim was to test the ability of poly(I:C) (polyinosinic:polycytidylic acid), a viral surrogate, to elicit exacerbation in a model of severe asthma driven by HDM (house dust mite) in FCA (Freund's complete adjuvant). Poly(I:C) was administered intranasally around the HDM challenge in FCA-HDM-sensitized animals. Changes in AHR (airway hyperresponsiveness), BALF (bronchoalveolar lavage fluid) inflammatory infiltrate, HDM-specific immunoglobulins and cytokine/chemokine release were evaluated at different points after the challenge. The effect of oral dexamethasone was also assessed. Exacerbation was achieved when poly(I:C) was administered 24 h before the HDM challenge and was characterized by enhanced AHR and an increase in the numbers of neutrophils, macrophages and lymphocytes in the BALF. Th1, Th2 and Th17 cytokines were also elevated at different time points after the challenge. Peribronchial and alveolar inflammation in lung tissue were also augmented. AHR and inflammatory infiltration showed reduced sensitivity to dexamethasone treatment. We have set up a model that mimics key aspects of viral exacerbation in a corticosteroid-refractory asthmatic phenotype which could be used to evaluate new therapies for this condition.

Enhanced cough reflex in a model of bleomycin-induced lung fibrosis in guinea pigs.

Fibrotic lung diseases, such as idiopathic pulmonary fibrosis, are associated with spontaneous dry cough and hypersensitivity to tussive agents. Understanding the pathophysiology driving enhanced cough may help us to define better therapies for patients. We hypothesized that lung fibrosis induced by intratracheal bleomycin would exacerbate the cough reflex induced by tussive agents in guinea pigs. Disease progression in the lungs was characterized at days 1, 7, 14, 21 and 28 after bleomycin administration. Inflammatory and fibrotic markers, as well as neurotrophin levels, were assessed in bronchoalveolar lavage fluid and/or lung tissue. Cough sensitivity to citric acid, capsaicin and allylisothiocyanate was evaluated in conscious animals at days 14 and 21 after bleomycin administration. Pulmonary lesions evolved from an early inflammatory phase (from day 1 to day 7) to a fibrotic stage (between days 14 and 28). Fibrosis was related to increased levels of matrix metalloproteinase-2 in bronchoalveolar lavage fluid (day 21: saline, 0.26 ng/ml; bleomycin, 0.49 ng/ml). At day 14, we also observed increased cough reflexes to citric acid (163%), capsaicin (125%) and allylisothiocyanate (178%). Cough exacerbation persisted, but at a lower extent, by day 21 for capsaicin (100%) and allylisothiocyanate (54%). Moreover, bronchoalveolar lavage fluid concentrations of brain-derived neurotrophic factor, suggested to induce nerve remodelling in chronic cough, were also enhanced (day 1: saline, 14.21 pg/ml; bleomycin, 30.09 pg/ml). In summary, our model of bleomycin-induced cough exacerbation may be a valuable tool to investigate cough hypersensitivity and develop antitussive therapies for fibrotic lung diseases.

A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response.

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.