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Composites based on poly(ε-caprolactone) (PCL) were prepared by melt blending the polymer with natural and modified bentonite. Soy lecithin (SL), a natural and nontoxic biosurfactant, was used as modifier agent. Three organoclays with different SL contents were employed as fillers and composites containing 1 and 2 wt% of each clay, were prepared. Thermal (by thermogravimetric analysis, and differential scanning calorimetry), morphological (by X-ray diffraction (XRD) and melt rheology), mechanical (by tensile tests) and barrier properties (by means of water vapor permeability tests) of matrix and composites were studied as a function of clay type and content. Morphological analysis by XRD showed nanocomposites with intercalated-exfoliated structures while melt rheology suggests thermal degradation of PCL matrix catalyzed by SL bentonite modifier. Thermal and mechanical properties were consistent with this assumption, due to the slight increment in crystallinity percentage and detriment in the Young’s modulus of the nanocomposites in comparison with the neat matrix. On the other hand, water vapor permeability of PCL significantly decreased in composites, as is expected for polymer/clay nanocomposites, favoring its potential application as food packaging. Thus, dissimilar tendencies were found in the final properties of the nanocomposites that were attributed to the matrix molecular weight degradation catalyzed by the novel green clay organo-modifier. [ABSTRACT FROM AUTHOR]

The purpose of this investigation was to evaluate the impact of liver stiffness (LS) on the response to direct-acting antiviral (DAA)-based therapy against hepatitis C virus (HCV) infection in cirrhotic patients. Those patients included in two Spanish prospective cohorts of patients receiving therapy based on at least one DAA, who showed a baseline LS ≥ 12.5 kPa and who had reached the scheduled time point for sustained virological response evaluation 12 weeks after completing therapy (SVR12) were analysed. Pegylated interferon/ribavirin-based therapy plus an HCV NS3/4A protease inhibitor (PR-PI group) was administered to 198 subjects, while 146 received interferon-free regimens (IFN-free group). The numbers of patients with SVR12 according to an LS < 21 kPa versus ≥21 kPa were 59/99 (59.6%) versus 46/99 (46.5%) in the PR-PI group ( p = 0.064) and 41/43 (95.3%) versus 90/103 (87.4%) in the IFN-free group ( p = 0.232). Corresponding figures for the relapse rates in those who presented end-of-treatment response (ETR) were 3/62 (4.8%) versus 10/56 (17.9%, p = 0.024) and 1/42 (2.4%) versus 8/98 (8.2%, p = 0.278), respectively. In a multivariate analysis adjusted for age, sex and use of interferon, a baseline LS ≥ 21 kPa was identified as an independent predictor of relapse [adjusted odds ratio, AOR (95% confidence interval, CI): 4.228 (1.344-13.306); p = 0.014] in those patients with ETR. LS above 21 kPa is associated with higher rates of relapse to DAA-based therapy in HCV-infected patients with cirrhosis in clinical practice. LS could help us to tailor the duration and composition of DAA-based combinations in cirrhotic subjects, in order to minimise the likelihood of relapse. [ABSTRACT FROM AUTHOR]

In April 2015, the Spanish National Health System (SNHS) developed a national strategic plan for the diagnosis, treatment, and management of hepatitis C virus (HCV). Our aim was to analyze the impact of this on human immunodeficiency virus (HIV)-infected patients included in the HERACLES cohort during the first 6 months of its implementation. The HERACLES cohort (NCT02511496) was set up in March 2015 to evaluate the status and follow-up of chronic HCV infection in patients co-infected with HIV in the south of Spain. In September 2015, the data were analyzed to identify clinical events (death, liver decompensation, and liver fibrosis progression) and rate of treatment implementation in this population. The study population comprised a total of 3474 HIV/HCV co-infected patients. The distribution according to liver fibrosis stage was: 1152 F0-F1 (33.2 %); 513 F2 (14.4 %); 641 F3 (18.2 %); 761 F4 (21.9 %); and 407 whose liver fibrosis was not measured (12.3 %). During follow-up, 248 patients progressed by at least one fibrosis stage [7.1 %; 95 % confidence interval (CI): 6.3-8 %]. Among cirrhotic patients, 52 (6.8 %; 95 % CI: 5.2-8.9 %) developed hepatic decompensation. In the overall population, 50 patients died (1.4 %; 95 % CI: 1.1-1.9 %). Eight hundred and nineteen patients (23.56 %) initiated interferon (IFN)-free treatment during follow-up, of which 47.8 % were cirrhotic. In our study, during 6 months of follow-up, 23.56 % of HIV/HCV co-infected patients included in our cohort received HCV treatment. However, we observed a high incidence of negative short-term outcomes in our population. [ABSTRACT FROM AUTHOR]

The influence of the anodization voltage ramp on the morphology and thickness homogeneity of porous anodic alumina films was studied. The samples were prepared in the oxalic acid at 120 V during the hard anodization process. As a nondestructive characterization method, the smallangle Xray scattering technique was used. The analysis of diffraction patterns allows determining the mean value and dispersion of interpore distance and the channel tortuosity with high accuracy. The increase of voltage ramp at the initial stage of hard anodization process was shown to lead to reduction of mechanical deformation (tortuosity) of anodic alumina film during crystallization. [ABSTRACT FROM AUTHOR]

The implementation of hepatitis C (HCV) direct-acting antiviral drugs is prioritized in several populations in which its application provides the most immediate and impactful benefit. In this scenario, a precise knowledge of the situation of human immunodeficiency virus (HIV)/HCV chronic co-infection is required to adequately address this disease. This cross-sectional study was performed in 21 hospitals in Andalusia (Spain). The study population consisted of HIV-infected patients with an active HCV chronic infection who were not receiving HCV treatment at the time of inclusion. A total of 13,506 HIV-infected patients were included in the study. Of them, 2561 (18.9 %) presented chronic HCV infection. The majority of the patients included were on highly active antiretroviral therapy (HAART; 96.2 %), showed plasma levels with an undetectable HIV viral load (92.5 %), and had a good immunological status (median CD4+ cell count of 486 cells/mL). The HCV genotype distribution was as follows: 58.1 % were genotype 1, 1.1 % were genotype 2, 16.1 % were genotype 3, and 22.1 % were genotype 4 (2.6 % were missing data). In total, 24.8 % of the patients showed liver fibrosis stage F0-F1, 27.9 % showed stage F2, 16.7 % showed stage F3, and 21 % showed stage F4 (9.6 % were missing data). With regards to previous HCV treatment experiences, 68.05 % of the patients were naïve and 31.95 % had failed to respond to a previous treatment. The burden of HCV/HIV co-infected patients in our population was reported as one in five HIV-infected patients requiring HCV treatment. The implementation of extra resources to face this important health challenge is mandatory. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the efficacy of and the risk of major bleeding during pegylated interferon (peg-IFN)/ribavirin (RBV) treatment among human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients according to the pretreatment platelet count. Two hundred and seventy-four HCV/HIV-coinfected, previously naïve individuals with compensated cirrhosis enrolled in one Spanish prospective cohort who received peg-IFN/RBV were included in this study. The frequency of severe bleeding and sustained virological response (SVR) rate were compared between patients with a pretreatment platelet count ≤70,000/mm and >70,000/mm, respectively. Sixty-one (22 %) patients had a baseline platelet count ≤70,000/mm. The median (Q1-Q3) pretreatment platelet count was 58,000 (49,000-65,000) cells/mm in the platelet ≤70,000 group and 129,000 (102,500-166,000) cells/mm in the platelet >70,000 group ( p < 0.0001). Seventeen (28 %) subjects of the platelet ≤70,000 group and 71 (33 %) patients of the platelet >70,000 group achieved SVR ( p = 0.4). Only 2 (3.2 %) patients in the platelet ≤70,000 group developed a severe hemorrhagic event, specifically esophageal variceal bleeding. The efficacy of therapy with peg-IFN/RBV in HIV/HCV-coinfected patients with low pretreatment platelet counts is comparable to that found in the overall subset of subjects with compensated cirrhosis. The frequency of severe hemorrhagic events related with this therapy is low in this population. [ABSTRACT FROM AUTHOR]

Evasion of cell death is fundamental to the development of cancer and its metastasis. The role of the BCL-2-mediated (intrinsic) apoptotic program in these processes remains poorly understood. Here we have investigated the relevance of the pro-apoptotic protein BIM to breast cancer progression using the MMTV-Polyoma middle-T (PyMT) transgenic model. BIM deficiency in PyMT females did not affect primary tumor growth, but substantially increased the survival of metastatic cells within the lung. These data reveal a role for BIM in the suppression of breast cancer metastasis. Intriguingly, we observed a striking correlation between the expression of BIM and the epithelial to mesenchymal transition transcription factor SNAI2 at the proliferative edge of the tumors. Overexpression and knockdown studies confirmed that these two genes were coordinately expressed, and chromatin immunoprecipitation analysis further revealed that Bim is a target of SNAI2. Taken together, our findings suggest that SNAI2-driven BIM-induced apoptosis may temper metastasis by governing the survival of disseminating breast tumor cells. [ABSTRACT FROM AUTHOR]

A number of risk scores already exist to predict cardiovascular (CV) events. However, scores developed with data collected some time ago might not accurately predict the CV risk of contemporary hypertensive patients that benefit from more modern treatments and management. Using data from the randomised clinical trial Anglo-Scandinavian Cardiac Outcomes Trial-BPLA, with 15 955 hypertensive patients without previous CV disease receiving contemporary preventive CV management, we developed a new risk score predicting the 5-year risk of a first CV event (CV death, myocardial infarction or stroke). Cox proportional hazard models were used to develop a risk equation from baseline predictors. The final risk model (ASCORE) included age, sex, smoking, diabetes, previous blood pressure (BP) treatment, systolic BP, total cholesterol, high-density lipoprotein-cholesterol, fasting glucose and creatinine baseline variables. A simplified model (ASCORE-S) excluding laboratory variables was also derived. Both models showed very good internal validity. User-friendly integer score tables are reported for both models. Applying the latest Framingham risk score to our data significantly overpredicted the observed 5-year risk of the composite CV outcome. We conclude that risk scores derived using older databases (such as Framingham) may overestimate the CV risk of patients receiving current BP treatments; therefore, 'updated' risk scores are needed for current patients. [ABSTRACT FROM AUTHOR]

The pro-apoptotic BH3-only protein Bim has a major role in hematopoietic homeostasis, particularly in the lymphocyte compartment, where it strongly affects immune function. The three major Bim isoforms (BimEL, BimL and BimS) are generated by alternative splicing. BimEL, the most abundant isoform, contains a unique sequence that has been reported to be the target of phosphorylation by several MAP kinases. In particular, Erk1/2 has been shown to interact with BimEL through the DEF2 domain of BimEL and specifically phosphorylate this isoform, thereby targeting it for ubiquitination and proteasomal degradation. To examine the physiological importance of this mechanism of regulation and of the alternative splicing of Bim, we have generated several Bim knock-in mouse strains and analyzed their hematopoietic system. Although mutation in the DEF2 domain reduces BimEL degradation in some circumstances, this mutation did not significantly increase Bim's pro-apoptotic activity in vivo nor impact on the homeostasis of the hematopoietic system. We also show that BimEL and BimL are interchangeable, and that BimS is dispensable for the function of Bim. Hence, we conclude that physiological regulation of Bim relies on mechanisms independent of its alternative splicing or the Erk-dependent phosphorylation of BimEL. [ABSTRACT FROM AUTHOR]

Background: The detection of adverse events following immunization (AEFI) fundamentally depends on how these events are classified. Standard methods impose a choice between either grouping similar events together to gain power or splitting them into more specific definitions. We demonstrate a method of medically guided Bayesian information sharing that avoids grouping or splitting the data, and we further combine this with the standard epidemiological tools of stratification and multivariate regression.Objective: The aim of this study was to assess the ability of a Bayesian hierarchical model to identify gastrointestinal AEFI in children, and then combine this with testing for effect modification and adjustments for confounding.Study Design: Reporting odds ratios were calculated for each gastrointestinal AEFI and vaccine combination. After testing for effect modification, these were then re-estimated using multivariable logistic regression adjusting for age, sex, year and country of report. A medically guided hierarchy of AEFI terms was then derived to allow information sharing in a Bayesian model.Setting: All spontaneous reports of AEFI in children under 18 years of age in the WHO VigiBase™ (Uppsala Monitoring Centre, Uppsala, Sweden) before June 2010. Reports with missing age were included in the main analysis in a separate category and excluded in a subsequent sensitivity analysis.Exposures: The 15 most commonly prescribed childhood vaccinations, excluding influenza vaccines.Main Outcome Measures: All gastrointestinal AEFI coded by WHO Adverse Reaction Terminology.Results: A crude analysis identified 132 signals from 655 reported combinations of gastrointestinal AEFI. Adjusting for confounding by age, sex, year of report and country of report, where appropriate, reduced the number of signals identified to 88. The addition of a Bayesian hierarchical model identified four further signals and removed three. Effect modification by age and sex was identified for six vaccines for the outcomes of vomiting, nausea, diarrhoea and salivary gland enlargement.Conclusion: This study demonstrated a sequence of methods for routinely analysing spontaneous report databases that was easily understandable and reproducible. The combination of classical and Bayesian methods in this study help to focus the limited resources for hypothesis testing studies towards adverse events with the strongest support from the data. [ABSTRACT FROM AUTHOR]

This investigation examined the impact of a multistressor situation on salivary immunoglobulin A (sIgA) levels, and incidence of upper respiratory tract infection (URTI) during the French commando training (3 weeks of training followed by a 5-day combat course). For the URTI, the types of symptoms were classified according to the anatomical location of the infection. Saliva samples were collected (8 a.m.) from 21 males [21 (2) years] before entry into the commando training, the morning following the 3 weeks of training, after the 5-day combat course, and after 1 week of recovery. sIgA, protein and cortisol concentrations were measured. Symptoms of URTI were recorded during the study from health logs and medical examinations. After the 3 weeks of training, the sIgA concentration was not changed, although it was reduced after the 5-day course [from 120 (14) mg l(-1) to 71 (9) mg l(-1), P<0.01]. It returned to pre-training levels within a week of recovery. The incidence of URTI increased during the trial (chi(2)=53.48; P<0.01), but was not related to sIgA. Among the 30 episodes of URTI reported, there were 12 rhino-pharyngitis, 6 bronchitis, 5 tonsillitis, 4 sinusitis and 3 otitis. Cortisol levels were raised after the 3-week training (P<0.01), dropping below baseline after the combat course (P<0.01). Stressful situations have an adverse effect on mucosal immunity and incidence of URTI. However, the relationship between sIgA and illness remained unclear. The large proportion of rhino-pharyngitis indicated that the nasopharyngeal cavity is at a higher risk of infection. [ABSTRACT FROM AUTHOR]

We examined the extent of morphological alterations and the myosin heavy chain (MHC) distribution in the rat soleus muscle after a 4-week period of spontaneous recovery or retraining after hindlimb suspension (HS). Moreover, we tested the hypothesis that dantrolene sodium, which affects the flux of calcium over the sarcoplasmic reticulum membrane, was able to attenuate muscle damage. Three groups of rats were submitted to 3 weeks of HS, followed by either 4 weeks of unrestricted cage activity (HC, n = 7), or running training for the same period and were compared to age-matched animals (C, n = 8). Trained rats were treated with either placebo or dantrolene sodium (HTP, HTD, n = 8 each, respectively). Four weeks after HS recovery, the percentage of myofibres with internal nuclei (%in) was determined by histological staining with hematoxylin and eosin. %in was affected by the individual rat ( P < 0.001), and was higher in the mid-belly region of the muscle ( P < 0.05). Muscle damage, as estimated by %in, was more extensive in trained rats (i.e. HTP and HTD) than in HC animals (23% and 12%, respectively). Moreover, dantrolene sodium tended to exert a protective effect on training-induced muscle injury. A 12% increase in type I MHC was observed in both HTP and HTD rats, in comparison with group C animals ( P < 0.001). The relative proportion of type-I MHC was inversely correlated with %in ( r = −0.65, P < 0.001). Running recovery led to an increased citrate synthase activity in comparison with that of C or HC rats. In conclusion, the present findings demonstrate that running recovery from HS increases the incidence of muscle damage, and that dantrolene sodium administration has only limited protective effects against exercise-induced muscle injury. [ABSTRACT FROM AUTHOR]

The aim of this study was to quantify the degenerative and regenerative changes in rat soleus muscle resulting from 3-week hindlimb suspension at 45° tilt (HS group, n = 8) and 4-week normal cage recovery (HS-R group, n = 7). Degenerative changes were quantified by microscope examination of muscle cross sections, and the myosin heavy chain (MHC) composition of soleus muscles was studied by sodium dodecyl sulphate polyacrylamide gel electrophoresis. At the end of 3-week hindlimb suspension, histological signs of muscle degenerative changes were detected in soleus muscles. There was a significant variability in the percentage of fibres referred to as degenerating (%dg) in individual animals in the HS group [%dg = 8.41 (SEM 0.5)%, range 4.66%–14.08%]. Moreover, %dg varied significantly along the length of the soleus muscle. The percentage of fibres with internal nuclei was less than %dg in HS-soleus muscles [4.12 (SEM 0.3)%, range 1.24%–8.86%]. In 4-week recovery rats, the greater part of the fibres that were not referred to as normal, retained central nuclei [15.8 (SEM 2.2)%, range 6.2%–21.1%]. A significant increase in the slow isoform of MHC was recorded in the HS-R rats, compared to muscles from age-matched rats ( P < 0.01). These results would suggest that a cycle of myofibre degeneration-regeneration occurred during HS and passive recovery, and that the increased accumulation of slow MHC observed in soleus muscles after recovery from HS could be related to the prevalence of newly formed fibres. [ABSTRACT FROM AUTHOR]

Fusaric acid (FA) administration to the rats promoted one hour later a large decrease in plasma total tryptophan (TRP), without affecting either plasma free TRP or lipolysis, as measured by plasma non esterified fatty acid concentration. The previous change was associated with hypoinsulinemia, hyperglycemia and increased plasma corticosterone level. Regression analysis revealed a significant correlation between brain TRP and the percentage of plasma TRP which was free ( i.e. unbound to albumin), both increased by FA injection. The increase in brain TRP promoted an increased brain serotonin synthesis, as measured by the enhanced brain and CSF 5-HIAA levels. Valine pretreatment, which blocks TRP entry into the brain, completely prevented FA-induced brain TRP and brain 5-HIAA increases. These results suggest that the increased brain serotonergic turnover following FA treatment was due to a peripheral action of the drug upon TRP disposition. The latter effect may be caused (i) by in vivo peripheral alterations in catecholaminergic metabolism and (ii) by FA chemical structure since in vitro experiments revealed that FA was able to displace TRP binding to albumin, thus increasing the plasma free TRP pool. [ABSTRACT FROM AUTHOR]

The original version of this Article contained an error in Fig. 4. In the left histogram of the right panel of Fig. 4d, several data points were inadvertently deleted from the histogram during the production process. This error has been corrected in both the PDF and HTML versions of the Article. The original, incorrect version of Fig. 4 is presented in the accompanying Publisher Correction. [ABSTRACT FROM AUTHOR]

Primary triple negative breast cancers (TNBC) are prone to dissemination but sub-clonal relationships between tumors and resulting metastases are poorly understood. Here we use cellular barcoding of two treatment-naïve TNBC patient-derived xenografts (PDXs) to track the spatio-temporal fate of thousands of barcoded clones in primary tumors, and their metastases. Tumor resection had a major impact on reducing clonal diversity in secondary sites, indicating that most disseminated tumor cells lacked the capacity to 'seed', hence originated from 'shedders' that did not persist. The few clones that continued to grow after resection i.e. 'seeders', did not correlate in frequency with their parental clones in primary tumors. Cisplatin treatment of one BRCA1-mutated PDX model to non-palpable levels had a surprisingly minor impact on clonal diversity in the relapsed tumor yet purged 50% of distal clones. Therefore, clonal features of shedding, seeding and drug resistance are important factors to consider for the design of therapeutic strategies. Triple negative breast cancers (TNBC) disseminate and metastasise, but the clonal relationship of metastases to primary tumours is poorly understood. Here, the authors use cellular barcoding of TNBC patient-derived xenografts and track the fate of barcoded clones in primary tumours and their metastases, including after resection or chemotherapy. [ABSTRACT FROM AUTHOR]