Ab Initio Phase Diagram of Gold in Extreme Conditions.

A phase diagram of gold is proposed in the [0; 1000] GPa and [0; 10 000] K ranges of pressure and temperature, respectively, topologically modified with respect to previous predictions. Using finite-temperature ab initio simulations and nonequilibirum thermodynamic integration, both accelerated by machine learning, we evaluate the Gibbs free energies of three solid phases previously proposed. At room temperature, the face-centered cubic (fcc) phase is stable up to ∼500 GPa whereas the body-centered cubic (bcc) phase only appears above 1 TPa. At higher temperature, we do not highlight any fcc-bcc transition line between 200 and 400 GPa, in agreement with ramp-compressed experiments. The present results only disclose a bcc domain around 140-235 GPa and 6000-8000 K, consistent with the triple point recently found in shock experiments. We demonstrate that this re-stabilization of the bcc phase at high temperature is due to anharmonic effects.

Uncovering new indicators to predict stability, maturity and biodiversity of compost on an industrial scale.

Currently, the metagenomic study of the composting process has gained great importance since it has allowed the identification of the existence of microorganisms that, until now, had not been isolated during the process by traditional techniques. However, it is still complex to determine which bioindicators could reveal the degree of maturity and stability of a particular compost. Thereby, the main objective of this work was to demonstrate the possible correlation between traditional parameters of maturity and stability of compost, with other indicators of biodiversity in products highly heterogeneous from composting processes on an industrial scale. The results demonstrated the enormous influence of the raw materials in characterizing the products obtained. Even so, important relationships were established between the Chao1 and Shannon indexes, and certain parameters related to the maturity, stability and toxicity of the samples, such as nitrification index, humification rate, phenolic content, germination index or oxygen consumption.

Evaluating the influence of raw materials on the behavior of nitrogen fractions in composting processes on an industrial scale.

Success of composting as an ecological technology for organic waste management has allowed its implementation in the current circular economy models. However, composting on an industrial scale often shows drawbacks and peculiarities. In this work, a comparative analysis of 15 industrial composting facilities was carried out in which different anthropogenic organic waste were processed. Results showed that composting process on an industrial scale did not always evolve in a standard way. Monitoring parameters as well as enzymatic activity depended largely on the raw materials and were strongly linked to the transformation of nitrogen fractions. Despite the heterogeneity of the processes and raw materials, microbial activity managed to the optimal biotransformation, obtaining products that comply with the agronomic quality standards. This work represents a breakthrough in composting and provides new knowledge for better management of this process on an industrial scale.

[Screening for Chagas disease in pregnancy and newborns in Andalusia (Spain)]. / Cribado de Chagas en embarazo y neonato en Andalucía (España).

BACKGROUND: To determine the current state of the implementation of Chagas screening in pregnancy and newborns at risk in the eight Andalusian provinces. METHODS: An observational, cross-sectional and descriptive study was carried out through a survey reviewed and validated by experts from the Andalusian Group of Pediatric Infectious Diseases and Immunology. Eighteen pediatric infectious disease specialists from Andalusian referral hospitals (fourteen public and four private) participated. RESULTS: The Chagas screening during pregnancy was known by seventeen specialists (94%), and systema-tically applied in seven hospitals (38.9%) by gynecologists or midwives. The protocol for following-up newborns at risk was known by sixteen specialists (88.9%) and applied in ten hospitals (55.5%), two of which did not study siblings and relatives of these newborns. Only two cases of vertical transmission of Chagas (11.1%) were detected; it happened in two hospitals applying systematically the Chagas screening to pregnant woman at risk, the same ones that also diagnosed two cases in siblings of newborns at risk. CONCLUSION: In Andalusia screening of Chagas disease in pregnant women and newborns at risk is not carried out in a systematic and uniform way in all the reference hospitals, so an underdiagnosis of congenital Chagas disease is highly probable. The training of professionals involved in assisting pregnant women and their offspring, and the unification of the follow-up criteria for newborns at risk would be essential for carrying out both a correct diagnosis and an early treatment of these cases.

Role of Functional Imaging Techniques to Assess Motor and Language Cortical Plasticity in Glioma Patients: A Systematic Review.

Cerebral plasticity is the ability of the central nervous system to reorganize itself in response to different injuries. The reshaping of functional areas is a crucial mechanism to compensate for damaged function. It is acknowledged that functional remodeling of cortical areas may occur also in glioma patients. Principal limits of previous investigations on cortical plasticity of motor and language functions included scarce reports of longitudinal evaluations and limited sample sizes. This systematic review is aimed at elucidating cortical brain plasticity for motor and language functions, in adult glioma patients, by means of preoperative and intraoperative mapping techniques. We systematically reviewed the literature for prospective studies, assessing cortical plasticity of motor and language functions in low-grade and high-grade gliomas. Eight longitudinal studies investigated cortical plasticity, evaluated by motor and language task-based functional MRI (fMRI), motor navigated transcranial magnetic stimulation (n-TMS), and intraoperative mapping with cortical direct electrocortical stimulation (DES) of language and motor function. Motor function reorganization appeared relatively limited and mostly characterized by intrahemispheric functional changes, including secondary motor cortices. On the other hand, a high level of functional reshaping was found for language function in DES studies. Occurrence of cortical functional reorganization of language function was described focusing on the intrahemispheric recruitment of perilesional areas. However, the association between these functional patterns and recovery of motor and language deficits still remains partially clear. A number of relevant methodological issues possibly affecting the finding generalization emerged, such as the complexity of plasticity outcome measures and the lack of large longitudinal studies. Future studies are required to further confirm these evidences on cortical plasticity in larger samples, combining both functional imaging and intraoperative mapping techniques in longitudinally evaluations.

Enzymatic profiles associated with the evolution of the lignocellulosic fraction during industrial-scale composting of anthropogenic waste: Comparative analysis.

In the new European Waste Law, composting is proposed as one of the best options to properly manage organic waste of anthropogenic origin. Currently, the massive generation of this type of waste, as well as its heterogeneity, makes difficult in many cases control this process of degradation on an industrial scale. In this work, 15 facilities were selected based on 5 types of organic waste: Urban Solid Waste, Vegetable Waste, Sewage Sludges, Agrifood Waste and "Alpeorujo". The samples were collected in different thermal phases. The results revealed very different physicochemical and enzymatic profiles, as well as different degrees of humification depending on the process and the raw materials. However, parameters such as ß-glucosidase, amylase, lignin/holocellulose ratio and humification rate showed similar trends in all cases. All of them could act as important indicators to evaluate the quality of a composting process, despite the heterogeneity of the starting materials.

Comparison of T1 mapping and fixed T1 method for dynamic contrast-enhanced MRI perfusion in brain gliomas.

OBJECTIVES: To compare dynamic contrast-enhanced MRI (DCE-MRI) data obtained using different prebolus T1 values in glioma grading and molecular profiling. METHODS: We retrospectively reviewed 83 cases of gliomas: 46 lower-grade gliomas (LGG; grades II and III) and 37 high-grade gliomas (HGG; grade IV). DCE-MRI maps of plasma volume fraction (Vp), extravascular-extracellular volume fraction (Ve), and tracer transfer constant from plasma to tissue (Ktrans) were obtained using a fixed T1 value of 1400 ms and a measured T1 obtained with variable flip angle (VFA). Tumour segmentations were performed and first-order histogram parameters were extracted from volumes of interest (VOIs) after co-registration with the perfusion maps. The two methods were compared using Wilcoxon matched-pairs signed-rank test and Bland-Altman analysis. Diagnostic accuracy was obtained and compared using ROC curve analysis and DeLong's test. RESULTS: Perfusion parameters obtained with the fixed T1 value were significantly higher than those obtained with the VFA. As regards diagnostic accuracy, there were no significant differences between the two methods both for glioma grading and molecular classification, except for few parameters of both methods. CONCLUSIONS: DCE-MRI data obtained with different prebolus T1 are not comparable and the definition of a prebolus T1 by T1 mapping is not mandatory since it does not improve the diagnostic accuracy of DCE-MRI. KEY POINTS: • DCE-MRI data obtained with different prebolus T1 are significantly different, thus not comparable. • The definition of a prebolus T1 by T1 mapping is not mandatory since it does not improve the diagnostic accuracy of DCE-MRI for glioma grading. • The use of a fixed T1 value represents a valid alternative to T1 mapping for DCE-MRI analysis.

Longitudinal quantitative magnetic resonance imaging in adrenomyeloneuropathy.

BACKGROUND AND PURPOSE: Adrenomyeloneuropathy (AMN) is the most frequent metabolic hereditary spastic paraplegia. Accordingly, its main site of pathological changes is the spinal cord. It is difficult to quantify AMN progression because commonly used clinical scales have limitations and reliable biomarkers are lacking. The goal was to investigate whether spinal cord and brain quantitative magnetic resonance imaging may assess structural changes in AMN over a relatively short time period. METHODS: In this longitudinal observational study, the total cord areas (TCAs) from the C2-C3 to T2-T3 level and diffusion tensor imaging (DTI) metrics of the cervical spinal cord and brain portion of the corticospinal tracts in six AMN and six age-matched control subjects at baseline and at a mean follow-up of 22.6 months were assessed. RESULTS: A significant reduction of the mean TCA at the T1-T2 level (-3.79%) and a trend of reduction at the lowest cervical levels were observed only in AMN patients. Additionally, DTI metrics revealed significant changes in fractional anisotropy (-8.84%), mean diffusivity (+12.62%) and radial diffusivity (+25.91%) at the C2-C3 level. DISCUSSION: The study encourages the assessment of TCAs and spinal cord DTI metrics as surrogate outcome measures in AMN, by focusing on the cervical-thoracic junction and the uppermost part of the cervical spinal cord. Despite the limitation of the results due to the small number of investigated subjects, these observations are useful for forthcoming clinical trials in AMN and possibly other hereditary diseases with predominant spinal cord involvement.

Application of fluorescence spectroscopy and chemometric models for the detection of vegetable oil adulterants in Maltese virgin olive oils.

Fluorescence spectrometry, combined with principle component analysis, partial least-squares regression (PLSR) and artificial neural network (ANN), was applied for the analysis of Maltese extra virgin olive oil (EVOO) adulterated by blending with vegetable oil (corn oil, soybean oil, linseed oil, or sunflower oil). The novel results showed that adjusted PLSR models based on synchronised spectra for detecting the % amount of EVOO in vegetable oil blends had a lower root mean square error (0.02-6.27%) and higher R2 (0.983-1.000) value than those observed when using PLSR on the whole spectrum. This study also highlights the use of ANN as an alternative chemometric tool for the detection of olive oil adulteration. The performance of the model generated by the ANN is highly dependent both on the type of data input and the mode of cross validation; for spectral data which had a variable importance plot value > 0.8 the excluded row cross validation was more appropriate while for complete spectral analysis k-fold or CV-10 was more appropriate.

Dexamethasone-induced upregulation of CaV3.2 T-type Ca2+ channels in rat cardiac myocytes.

Glucocorticoids are widely used to treat acute and chronic diseases. Unfortunately, their therapeutic use is associated with severe side effects. Glucocorticoids are known to regulate several ion channels in cardiac myocytes, including voltage-dependent Ca2+ channels. Low-voltage-activated T-type Ca2+ channels are expressed in ventricular myocytes during the fetal and perinatal period, but are practically absent in the adult. However, these channels can be re-expressed in adult cardiomyocytes under some pathological conditions. We have investigated the glucocorticoid regulation of T-type Ca2+ channels in rat cardiomyocytes. Molecular studies revealed that dexamethasone induces the upregulation of CaV3.2 mRNA in neonatal rat ventricular myocytes, whereas CaV3.1 mRNA is only slightly affected. Patch-clamp recordings confirmed that T-type Ca2+ channel currents were upregulated in dexamethasone treated cardiomyocytes, and the addition of 50 µmol/L NiCl2 demonstrated that the CaV3.2 channel is responsible for this upregulation. The effect of dexamethasone on CaV3.2 is mediated by the activation and translocation to the cell nucleus of the glucocorticoid receptor (GR). We have isolated the upstream promoter of the Cacna1h gene and tested its activity in transfected ventricular myocytes. The initial in silico analysis of Cacna1h promoter revealed putative glucocorticoid response elements (GREs). Transcriptional activity assays combined with deletion analyses and chromatin immunoprecipitation assays demonstrated that GR binds to a region a GRE located in -1006/-985 bp of Cacna1h promoter. Importantly, upregulation of the CaV3.2 channel is also observed in vitro in adult rat ventricular myocytes, and in vivo in a rat model of excess of glucocorticoids.

Metastatic neuroblastoma in infants: are survival rates excellent only within the stringent framework of clinical trials?

INTRODUCTION: SIOPEN INES protocol yielded excellent 5-year survival rates for MYCN-non-amplified metastatic neuroblastoma. Patients deemed ineligible due to lack or delay of MYCN status or late registration were treated, but not included in the study. Our goal was to analyse survival at 10 years among the whole population. MATERIALS AND METHODS: Italian and Spanish metastatic INES patients' data are reported. SPSS 20.0 was used for statistical analysis. RESULTS: Among 98 infants, 27 had events and 19 died, while 79 were disease free. Five- and 10-year event-free survival (EFS) were 73 and 70 %, and overall survival (OS) was 81 and 74 %, respectively. MYCN status was significant for EFS, but not for OS in multivariate analysis. CONCLUSIONS: The survival rates of patients who complied with all the inclusion criteria for INES trials are higher compared to those that included also not registered patients. Five-year EFS and OS for INES 99.2 were 87.8 and 95.7 %, while our stage 4s population obtained 78 and 87 %. Concerning 99.3, 5-year EFS and OS were 86.7 and 95.6 %, while for stage 4 we registered 61 and 68 %. MYCN amplification had a strong impact on prognosis and therefore we consider it unacceptable that many patients were not studied for MYCN and probably inadequately treated. Ten-year survival rates were shown to decrease: EFS from 73 to 70 % and OS from 81 to 74 %, indicating a risk of late events, particularly in stage 4s. Population-based registries like European ENCCA WP 11-task 11 will possibly clarify these data.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81µgcm-2h-1 whereas the highest iontophoretic transport was 46.4±3.6µgcm-2h-1. These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations.

Detection of interleukin-2 is not useful for distinguishing between latent and active tuberculosis in clinical practice: a prospective cohort study.

OBJECTIVE: Previous reports have identified interleukin-2 (IL-2), quantified in the supernatants of QuantiFERON®-TB Gold In-tube (QFT) after 72 h of incubation, as a potential biomarker for distinguishing between latent and active tuberculosis (TB). However, its validity has not been tested in an appropriate clinical cohort. METHODS: A multicentre study of 161 consecutive adult patients undergoing evaluation for active TB at eight TB Units in Spain. Interferon-γ (IFN-γ) and IL-2 were assessed in the supernatant of QFT after 16-24 h and 72 h of incubation. The accuracy of IL-2 for indicating latent TB infection (LTBI) was assessed by receiving operating characteristic curves. . RESULTS: Twenty-eight participants were not infected, 43 had LTBI, 69 had TB, and 21 were not classifiable. Median (interquartile range) IL-2 concentrations after 72 h of incubation were 0.0 pg/mL (0.0-0.0) in uninfected individuals, 261.0 pg/mL (81.0-853.0) in LTBI individuals, 166.5 pg/mL (33.5-551.5) in patients with extrapulmonary TB, 95.0 pg/mL (26.0-283.0) in patients with smear-negative pulmonary TB, and 38.5 pg/mL (7.5-178.0) in patients with smear-positive pulmonary TB (p <0.0001). The area under the curve of the receiving operating characteristic curve (95% CI) of IL-2 after 72 h of incubation for the diagnosis of LTBI was 0.63 (0.53-0.74) when all TB cases were considered as a single group, ranging from 0.59 (0.47-0.71) to 0.72 (0.58-0.85) when only extrapulmonary and smear-positive pulmonary TB cases respectively were considered. CONCLUSIONS: Quantification of IL-2 in the supernatant of QFT after a prolonged incubation is not useful to distinguish between LTBI and active disease in clinical practice.

Attract them anyway: benefits of large, showy flowers in a highly autogamous, carnivorous plant species.

Reproductive biology of carnivorous plants has largely been studied on species that rely on insects as pollinators and prey, creating potential conflicts. Autogamous pollination, although present in some carnivorous species, has received less attention. In angiosperms, autogamous self-fertilization is expected to lead to a reduction in flower size, thereby reducing resource allocation to structures that attract pollinators. A notable exception is the carnivorous pyrophyteDrosophyllum lusitanicum(Drosophyllaceae), which has been described as an autogamous selfing species but produces large, yellow flowers. Using a flower removal and a pollination experiment, we assessed, respectively, whether large flowers in this species may serve as an attracting device to prey insects or whether previously reported high selfing rates for this species in peripheral populations may be lower in more central, less isolated populations. We found no differences between flower-removed plants and intact, flowering plants in numbers of prey insects trapped. We also found no indication of reduced potential for autogamous reproduction, in terms of either seed set or seed size. However, our results showed significant increases in seed set of bagged, hand-pollinated flowers and unbagged flowers exposed to insect visitation compared with bagged, non-manipulated flowers that could only self-pollinate autonomously. Considering that the key life-history strategy of this pyrophytic species is to maintain a viable seed bank, any increase in seed set through insect pollinator activity would increase plant fitness. This in turn would explain the maintenance of large, conspicuous flowers in a highly autogamous, carnivorous plant.

Hypoxic induction of T-type Ca(2+) channels in rat cardiac myocytes: role of HIF-1α and RhoA/ROCK signalling.

T-type Ca(2+) channels are expressed in the ventricular myocytes of the fetal and perinatal heart, but are normally downregulated as development progresses. Interestingly, however, these channels are re-expressed in adult cardiomyocytes under pathological conditions. We investigated low voltage-activated T-type Ca(2+) channel regulation in hypoxia in rat cardiomyocytes. Molecular studies revealed that hypoxia induces the upregulation of Cav 3.2 mRNA, whereas Cav 3.1 mRNA is not significantly altered. The effect of hypoxia on Cav 3.2 mRNA was time- and dose-dependent, and required hypoxia inducible factor-1α (HIF-1α) stabilization. Patch-clamp recordings confirmed that T-type Ca(2+) channel currents were upregulated in hypoxic conditions, and the addition of 50 µm NiCl2 (a T-type channel blocker) demonstrated that the Cav 3.2 channel is responsible for this upregulation. This increase in current density was not accompanied by significant changes in the Cav 3.2 channel electrophysiological properties. The small monomeric G-protein RhoA and its effector Rho-associated kinase I (ROCKI), which are known to play important roles in cardiovascular physiology, were also upregulated in neonatal rat ventricular myocytes subjected to hypoxia. Pharmacological experiments indicated that both proteins were involved in the observed upregulation of the Cav 3.2 channel and the stabilization of HIF-1α that occurred in response to hypoxia. These results suggest a possible role for Cav 3.2 channels in the increased probability of developing arrhythmias observed in ischaemic situations, and in the pathogenesis of diseases associated with hypoxic Ca(2+) overload.

Development of antimigraine transdermal delivery systems of pizotifen malate.

The aim of this study was to develop and evaluate a transdermal delivery system of pizotifen malate. Pizotifen is frequently used in the preventive treatment of migraine, but is also indicated in eating disorders. In the course of the project, the effects of chemical enhancers such as ethanol, 1,8-cineole, limonene, azone and different fatty acids (decanoic, decenoic, dodecanoic, linoleic and oleic acids) were determined, first using a pizotifen solution. Steady state flux, diffusion and partition parameters were estimated by fitting the Scheuplein equation to the data obtained. Among the chemical enhancers studied, decenoic acid showed the highest enhancement activity, which seemed to be due to the length of its alkyl chain and unsaturation at the 9th carbon. The influence of iontophoresis and the involvement of electrotransport in said process was determined. The absorption profile obtained with iontophoresis was similar to that obtained with fatty acids and terpenes, though skin deposition of the drug was lower with the former. Transdermal delivery systems (TDS) of pizotifen were manufactured by including chemical enhancers, decenoic acid or oleic acid, and were subsequently characterized. When the results obtained with solutions were compared with those obtained with the TDS, a positive enhancement effect was observed with the latter with respect to the partitioning and diffusion of the drug across the skin. Our findings endorse the suitability of our TDS for delivering therapeutic amounts of pizotifen malate.

Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors.

Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a ß-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in most differentiated and less aggressive neuroblastic tumors, such as GN and ganglioneuroblastoma, as well as in a subset of NB cases. Gal-3 expression is associated with the INPC histopathological categorization (P<0.001) and Shimada favorable phenotype (P=0.001), but not with other prognostically relevant features. Importantly, Gal-3 expression was associated with a better 5-year overall survival (P=0.003), and with improved cumulative survival in patient subsets at worse prognosis, such as older age at diagnosis, advanced stages or NB histopathological classification. In vitro, Gal-3 expression and nuclear accumulation accompanied retinoic acid-induced cell differentiation in NB cell lines. Forced Gal-3 overexpression increased phenotypic differentiation and substrate adherence, while inhibiting proliferation. Altogether, these findings suggest that Gal-3 is a biologically relevant player for neuroblastic tumors, whose determination by conventional immunohistochemistry might be used for outcome assessment and patient's risk stratification in the clinical setting.

Non-alcoholic fatty liver disease and hepatocellular carcinoma in a 7-year-old obese boy: coincidence or comorbidity?

BACKGROUND: Hepatocellular carcinoma (HCC) may develop from non-alcoholic fatty liver disease (NAFLD) either in the presence or in the absence of established cirrhosis. Non-cirrhotic patients with NAFLD-related HCC are usually adult, male and obese. However, this association has not been reported yet in younger age groups. Objectives In the present study, the clinical case of a 7-yaer-old obese boy with steatosis and HCC is presented. METHODS: A 7-year-old boy, with no evidence of chronic liver disease, was admitted for assessment of a liver mass. Preliminary assessment was suggestive of a combined and severe liver steatosis together with a malignant disease. RESULTS: A biopsy confirmed the suspected diagnosis of HCC; interestingly, the non-neoplastic liver was surrounded and characterized by the presence of steatosis and ballooning, and being absent of lobular inflammation and fibrosis. Chemotherapy and diet changes were conducted successfully with ultrasound characteristics suggesting improvements on both aspects: conventional liver mass resection could take place. CONCLUSIONS: This case report suggests that HCC might develop in paediatric age patients with obesity-related NAFLD, even in the absence of fibrosis.