Stability testing of iomeprol and iopamidol formulations subjected to X-ray radiation.

INTRODUCTION: Exposure of iodinated contrast media (ICM) to X-rays is not uncommon, as contrast media are often stored in close proximity to radiological equipment. However, the interaction between X-rays and ICM is not widely investigated in literature. The present study aims to investigate the chemical stability of iomeprol and iopamidol, two commercial iodinated ICM commonly used in diagnostic imaging, under X-rays exposure. METHODS: Different formulations of iopamidol and iomeprol (iodine concentration 9 to 400 mgI/mL, volume 50-500 mL) were exposed to three different conditions of X-ray irradiation: i) 1 month storage in CT room (≈5-15 mGy); (ii) low-dose protocol (≈10 mGy); (ii) stressed protocol (≈100 mGy). Unexposed and exposed solutions were characterized by high-performance liquid chromatography in terms of concentration of active pharmaceutical ingredient (API), iodine species and by products. In addition, appearance and colour of the solutions were inspected and pH measured. RESULTS: API concentrations, appearance, colour and pH of the exposed formulations remained unaffected by X-rays. Measured concentrations of iodine species and by products were observed well within the acceptability criteria, i.e. values turned out to be lower than specifications limits established by the manufacturer, considering both release and shelf-life values. CONCLUSIONS: Up to 100 mGy X-ray exposure did not induce any alteration of iomeprol and iopamidol formulation, nor a detectable increase in the concentration of iodine species or by-products. IMPLICATIONS FOR PRACTICE: Our study strengthens the hypothesis that ICM are stable under X-rays exposure up to 100 mGy.

Cerebral sinovenous thrombosis as a cause of subdural hemorrhage in the pediatric population: Is there a correlation?

PURPOSE: Cerebral sinovenous thrombosis is an increasingly recognized cause of stroke in children and neonates. Its true incidence appears to be underestimated. Despite being a rare event, certain studies have found a correlation between subdural hemorrhage and cerebral sinus thrombosis. The literature suggests that spontaneous cerebral sinovenous thrombosis in the pediatric population may lead to the occurrence of a subdural hemorrhage. In this report, we present a case of cerebral venous thrombosis associated with chronic subdural hematoma and review the literature to highlight the importance of these conditions. CASE REPORT: An 11-year-old boy was admitted in the neurosurgery department with headache and a neurological examination without changes. The imaging studies identified a heterogeneous subdural collection in the fronto-temporo-parietal region. The patient underwent surgical drainage of the subdural hematoma, and the procedure was performed without complications. The magnetic resonance and angiography showed an extensive thrombosis of the superior sagittal sinus, extending downward to the occipital sinus and partially to the right transverse sinus. CONCLUSIONS: Appropriate management in the diagnosis and an early treatment of dural sinus thrombosis associated with subdural hemorrhage can reduce the risk of recurrence and improve the clinical outcome.

Tissue-engineered collagenous fibrous cap models to systematically elucidate atherosclerotic plaque rupture.

A significant amount of vascular thrombotic events are associated with rupture of the fibrous cap that overlie atherosclerotic plaques. Cap rupture is however difficult to predict due to the heterogenous composition of the plaque, unknown material properties, and the stochastic nature of the event. Here, we aim to create tissue engineered human fibrous cap models with a variable but controllable collagen composition, suitable for mechanical testing, to scrutinize the reciprocal relationships between composition and mechanical properties. Myofibroblasts were cultured in 1 × 1.5 cm-sized fibrin-based constrained gels for 21 days according to established (dynamic) culture protocols (i.e. static, intermittent or continuous loading) to vary collagen composition (e.g. amount, type and organization). At day 7, a soft 2 mm ∅ fibrin inclusion was introduced in the centre of each tissue to mimic the soft lipid core, simulating the heterogeneity of a plaque. Results demonstrate reproducible collagenous tissues, that mimic the bulk mechanical properties of human caps and vary in collagen composition due to the presence of a successfully integrated soft inclusion and the culture protocol applied. The models can be deployed to assess tissue mechanics, evolution and failure of fibrous caps or complex heterogeneous tissues in general.

Equianalgesia, opioid switch and opioid association in different clinical settings: a narrative review.

Emergency or postoperative pain often represents an authentic challenge in patients who were already on opioid treatment for chronic pain. Thus, their management requires not only the physician's ability to treat acute pain, but also competence in switching the opioid that lost efficacy. Different aspects should be considered, such as opioids titration, switching, association and equianalgesia. The objective of this paper is to provide a narrative review, which has been elaborated and discussed among clinicians through an iterative process involving development and review of the draft during two web-based meetings and via email. This expert opinion aims to facilitate the correct opioid use through appropriate practices with a focus on pain treatment in emergency and postoperative pain. Equianalgesia tables were reviewed and integrated by clinicians and researchers with expertise in anesthesia, postoperative medicine, intensive care, emergency medicine pharmacology and addiction medicine. Special populations (liver/kidney failure, elder, pediatric, pregnancy/lactation) are discussed in detail along with other critical scenarios, such as: (i) rapid pain worsening in chronic pain (aggravating pain due to disease progression or tolerance development to analgesic therapy); (ii) acute pain on maintenance treatment; and (iii) pain management of complicated patients in emergency care. Extended and updated equianalgesia tables and conversion rates for 17 different opioid formulations (of 9 different molecules) are presented as follows. Opioids remain the class that best suits clinical needs of emergency and post-operative medicine. However, it should be stressed that equianalgesia can be affected by drug-to-drug interactions and pharmacological imprecision, in a complex field where clinical experience may be the main guiding principle.

Parenting stress and family resilience affect the association of adverse childhood experiences with children's mental health and attention-deficit/hyperactivity disorder.

INTRODUCTION: Exposure to adverse childhood experience (ACE) has harmful consequences for children's health and well-being. However, it is less clear how different social processes may amplify or mitigate the effects of ACE on children's mental health. We examined how parenting stress mediates and family resilience moderates the associations of ACE with children's mental health and attention-deficit/hyperactivity disorder (ADHD) outcomes. METHODS: This secondary data analysis included 44,684 children aged 6-17 years from the 2016-17 National Survey of Children's Health (NSCH). Logistic regression with survey weights was used to account for the complex survey design and obtain odds ratios (OR) and 95% CI adjusted for sociodemographics. RESULTS: Overall, 7.3% of children had any mental health condition and 10.4% had ADHD. A higher ACE score (per 1-unit increase) was associated with a higher prevalence of any mental health condition (OR = 1.33, 95% CI: 1.27-1.40) and ADHD (OR = 1.21; 95% CI: 1.15-1.27) after adjustment for sociodemographics. Parenting stress mediated 57% of the total effect of ACE on any mental health condition and 60% of the total effect of ACE on ADHD diagnosis. The effect of ACE on mental health and ADHD outcomes was stronger among children with low levels of family resilience and connection index (FRCI) than among those with higher levels of FRCI. CONCLUSIONS: Parenting stress may be a potential mechanism through which ACE impacts a child's mental health and behavioral outcomes. Family resilience can lessen the impact of ACE on children's mental health and behavioral disorders.

Seed traits and germination behaviour of four Sardinian populations of Helichrysum microphyllum subsp. tyrrhenicum (Asteraceae) along an altitudinal gradient.

Helichrysum microphyllum subsp. tyrrhenicum (Asteraceae) is an endemic taxon of Sardinia and Corsica, where it grows at different altitudes. The objective of this study was to investigate the seed traits and germination behaviour of four Sardinian populations of this taxon located at different altitudes. Seed traits were evaluated, and germination tests were carried out by incubating seeds at a range of constant (5-30 °C) and alternating (25/10 °C) temperatures. The dry after-ripening (DAR) pre-treatment was also applied by storing seed in dry conditions for 3 months at 25 °C. Seed traits and germination behaviour data were statistically analysed to identify if there was a correlation with altitude. Differences in seed size, area and mass among populations were recorded, however, no relationship was found with altitude. High germination percentages were obtained in all populations, both in untreated and DAR seeds, and were positively affected by alternating temperatures. The final germination percentage and time required to reach 50% final germination (T50 ) showed no relationship with altitude. The differences in seed traits and germination detected among the studied populations of H. microphyllum subsp. tyrrhenicum were not correlated with altitude. This study provides new and important knowledge for this taxon. H. microphyllum subsp. tyrrhenicum is characterised by high germination percentages and low T50 values and does not seem to require any dormancy-breaking treatment. This species represents a high-potential native plant species that should be considered within environmental management plans.

The effect of hypoxia and flow decrease in macroinvertebrate functional responses: A trait-based approach to multiple-stressors in mesocosms.

River ecosystems are most often subject to multiple co-occurring anthropogenic stressors. Mediterranean streams are particularly affected by water scarcity and organic loads that commonly lead to a simultaneous reduction in flow and increasing depletion of dissolved oxygen. In the present study, the single and combined effects of water scarcity (flow velocity reduction) and dissolved oxygen depletion were used to evaluate alterations of drifting macroinvertebrates on a channel mesocosm system, by employing a multiple trait-based approach. Our main findings confirmed that the impact of the two combined stressors can be implicated in alterations of ecosystem functions as result of the changes in proportions of biological traits. Overall, our results showed that, individually, flow velocity reduction and a severe oxygen depletion promoted a shift in community traits. In more detail, biological traits describing the dispersal of organisms and their respiration showed the strongest responses. The respiration mode responded to low flow with drift increase of gill breathers and decrease of individuals with tegument, whereas dispersal was clearly affected by the combination of stressors. Resistance through eggs was higher with the single effect of flow reduction, while swimmers´ relative abundance increased in individuals that drift after exposure to the combination of stressors. Thus, while flow reduction alone is expected to specifically filter out the gill breathers and the egg producers, the combination of stressors will impact more drastically organism's dispersal and swimmers. Such changes in biological traits can result in variations in ecosystem functioning through, for example, local changes in biomass, secondary production, stream metabolism as well as resulting in biodiversity losses or alterations of its distribution patterns.

Vanadyl dithiolate single molecule transistors: the next spintronic frontier?

On the road towards quantum devices, chemistry can offer elementary pieces with a built-in function, like [TbPc2]- which functions as a molecular transistor for nuclear spin detection. We argue that a large class of molecules have similar potential. In particular, we review the recent progress regarding highly coherent spin qubits based on vanadium dithiolate complexes. We propose their use as single molecule transistors to read and control a triple nuclear spin qubit, which could enable a low-current nuclear spin detection scheme by means of a spin valve effect.

New insights on the baker's yeast-mediated hydration of oleic acid: the bacterial contaminants of yeast are responsible for the stereoselective formation of (R)-10-hydroxystearic acid.

AIMS: The preparation of the high-value flavour γ-dodecalactone is based on the biotransformation of natural 10-HSA, which is in turn obtained by microbial hydration of oleic acid. We want to establish a reliable baker's yeast-mediated procedure for 10-HSA preparation. METHODS AND RESULTS: The previously reported yeast-mediated hydration procedures are unreliable because bacteria-free baker's yeast is not able to hydrate oleic acid. The actual responsible for performing this reaction are the bacterial contaminants present in baker's yeast. Moreover, we demonstrated that the enantioselectivity in the production of (R)-10-HSA is affected mainly by the temperature used in the biotransformation. CONCLUSIONS: We demonstrated that Saccharomyces cerevisiae is not able to hydrate oleic acid, whereas different bacterial strains present in baker's yeast transform oleic acid into (R)-10-HSA. We reported a general procedure for the preparation of (R)-10-HSA starting from oleic acid and using commercially available baker's yeast. SIGNIFICANCE AND IMPACT OF THE STUDY: This study holds both scientific and industrial interest. It unambiguously establishes that the eukaryote micro-organisms present in baker's yeast are not able to hydrate oleic acid. The isolation of oleic acid hydrating bacterial strains from commercial baker's yeast points to their prospective use for the industrial synthesis of 10-HSA.

Advanced cell-based modeling of the royal disease: characterization of the mutated F9 mRNA.

Essentials The Royal disease (RD) is a form of hemophilia B predicted to be caused by a splicing mutation. We generated an iPSC-based model of the disease allowing mechanistic studies at the RNA level. F9 mRNA analysis in iPSC-derived hepatocyte-like cells showed the predicted abnormal splicing. Mutated F9 mRNA level was very low but we also found traces of wild type transcripts. SUMMARY: Background The royal disease is a form of hemophilia B (HB) that affected many descendants of Queen Victoria in the 19th and 20th centuries. It was found to be caused by the mutation F9 c.278-3A>G. Objective To generate a physiological cell model of the disease and to study F9 expression at the RNA level. Methods Using fibroblasts from skin biopsies of a previously identified hemophilic patient bearing the F9 c.278-3A>G mutation and his mother, we generated induced pluripotent stem cells (iPSCs). Both the patient's and mother's iPSCs were differentiated into hepatocyte-like cells (HLCs) and their F9 mRNA was analyzed using next-generation sequencing (NGS). Results and Conclusion We demonstrated the previously predicted aberrant splicing of the F9 transcript as a result of an intronic nucleotide substitution leading to a frameshift and the generation of a premature termination codon (PTC). The F9 mRNA level in the patient's HLCs was significantly reduced compared with that of his mother, suggesting that mutated transcripts undergo nonsense-mediated decay (NMD), a cellular mechanism that degrades PTC-containing mRNAs. We also detected small proportions of correctly spliced transcripts in the patient's HLCs, which, combined with genetic variability in splicing and NMD machineries, could partially explain some clinical variability among affected members of the European royal families who had lifespans above the average. This work allowed the demonstration of the pathologic consequences of an intronic mutation in the F9 gene and represents the first bona fide cellular model of HB allowing the study of rare mutations at the RNA level.

Theoretical Evaluation of [VIV(α-C3S5)3]2- as Nuclear-Spin-Sensitive Single-Molecule Spin Transistor.

In a straightforward application of molecular nanospintronics to quantum computing, single-molecule spin transistors can be used to measure nuclear spin qubits. Conductance jumps accompany electronic spin flips at the so-called anticrossings between energy levels, which take place only at specific magnetic fields determined by the nuclear spin state. To date, the only molecular hardware employed for this technique has been the terbium(III) bis(phthalocyaninato) complex. Here we explore theoretically whether a similar behavior is expected for a highly stable molecular spin qubit, the vanadium tris-dithiolate complex [VIV(α-C3S5)3]2-. We consider such a molecule between two gold electrodes and determine the spin-dependent conductance. We verify that the transport channel in experimental conditions does not overlap with the occupied spin orbitals, indicating that the spin states may survive in the conduction regime. We validate the robustness of the theoretical methodology by studying two chemically related vanadium complexes and offer some criteria to guide the experiments.

Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22.

Even if NOTCH1 is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1 mutations in CLL.

Nuclear magnetic resonance studies of DNP-ready trehalose obtained by solid state mechanochemical amorphization.

(1)H nuclear spin-lattice relaxation and Dynamic Nuclear Polarization (DNP) have been studied in amorphous samples of trehalose sugar doped with TEMPO radicals by means of mechanical milling, in the 1.6-4.2 K temperature range. The radical concentration was varied between 0.34 and 0.81%. The highest polarization of 15% at 1.6 K, observed in the sample with concentration 0.50%, is of the same order of magnitude of that reported in standard frozen solutions with TEMPO. The temperature and concentration dependence of the spin-lattice relaxation rate 1/T1, dominated by the coupling with the electron spins, were found to follow power laws with an exponent close to 3 in all samples. The observed proportionality between 1/T1 and the polarization rate 1/Tpol, with a coefficient related to the electron polarization, is consistent with the presence of Thermal Mixing (TM) and a good contact between the nuclear and the electron spins. At high electron concentration additional relaxation channels causing a decrease in the nuclear polarization must be considered. These results provide further support for a more extensive use of amorphous DNP-ready samples, obtained by means of comilling, in dissolution DNP experiments and possibly for in vivo metabolic imaging.

Tips on How to Collect and Administer the Mesenchymal Stem Cell Secretome for Central Nervous System Applications.

Human mesenchymal stem cells (hMSCs) have been proposed as possible therapeutic agents for central nervous system (CNS) disorders. Recently, it has been suggested that their effects are mostly mediated through their secretome, which contains a number of neuroregulatory molecules capable of increasing cell proliferation, differentiation, and survival in different physiological conditions. Here, we present an overview of the hMSC secretome as a possible candidate in the creation of new cell-free therapies, demonstrating the process of its collection and route of administration, focusing our attention on their effects in CNS regenerative medicine.

Polymerization shrinkage and spherical glass mega fillers: effects on cuspal deflection.

PURPOSE: The Authors analyzed the effect of spherical glass mega fillers (SGMF) on reducing contraction stress in dental composite resins, by means of a cavity model simulating the cuspal deflection which occurs on filled tooth cavity walls in clinical condition. MATERIALS AND METHODS: 20 stylized MOD cavities (C-factor = 0.83) were performed in acrylic resin. The inner surface of each cavity was sand blasted and adhesively treated in order to ensure a valid bond with the composite resin. Three different diameter of SGMF were used (i.e. 1, 1,5, 2 mm). The samples were divided in 4 groups of 5 each: Group 1 samples filled with the composite only; Group 2 samples filled with composite added with SGMFs, Ø1mm (16 spheres for each sample); Group 3 samples filled with composite added with SGMFs, Ø1,5 mm (5 spheres for each sample); Group 4 samples filled with composite added with SGMFs, Ø2 mm (2 spheres for each sample). Digital pictures were taken, in standardized settings, before and immediately after the polymerization of the composite material, placed into the cavities. With a digital image analysis software the distances from the coronal reference points of the cavity walls were measured. Then the difference between the first and second measurement was calculated. The data were analyzed by means of the ANOVA test. RESULTS: A significative reduction on cavity walls deflection, when the composite resin is used in addiction with the SGMFs was observed. The SGMFs of smallest diameter (1mm) showed the better outcome. CONCLUSION: The SGMFs are reliable in reducing contraction stress in dental composite resins.

Specific Changes of Exocarp and Mesocarp Occurring during Softening Differently Affect Firmness in Melting (MF) and Non Melting Flesh (NMF) Fruits.

Melting (MF) and non melting flesh (NMF) peaches differ in their final texture and firmness. Their specific characteristics are achieved by softening process and directly dictate fruit shelf life and quality. Softening is influenced by various mechanisms including cell wall reorganization and water loss. In this work, the biomechanical properties of MF Spring Crest's and NMF Oro A's exocarp and mesocarp along with the amount and localization of hydroxycinnamic acids and flavonoids were investigated during fruit ripening and post-harvest. The objective was to better understand the role played by water loss and cell wall reorganization in peach softening. Results showed that in ripe Spring Crest, where both cell turgor loss and cell wall dismantling occurred, mesocarp had a little role in the fruit reaction to compression and probe penetration response was almost exclusively ascribed to the epidermis which functioned as a mechanical support to the pulp. In ripe Oro A's fruit, where cell wall disassembly did not occur and the loss of cell turgor was observed only in mesocarp, the contribution of exocarp to fruit firmness was consistent but relatively lower than that of mesocarp, suggesting that in addition to cell turgor, the integrity of cell wall played a key role in maintaining NMF fruit firmness. The analysis of phenols suggested that permeability and firmness of epidermis were associated with the presence of flavonoids and hydroxycinnamic acids.

Analysis of the intra- and intertumoral heterogeneity of hypoxia in pancreatic cancer patients receiving the nitroimidazole tracer pimonidazole.

BACKGROUND: Hypoxia is thought to be an adverse feature of pancreatic cancer, but direct measurement in patients is technically challenging. To address this, we characterised the intra/interpatient heterogeneity of hypoxia in surgical specimens from patients who received the 2-nitroimidazole tracer pimonidazole pre-operatively. METHODS: Pimondazole was given intravenously 16-20 h before pancreatectomy, and the extent and intratumoral heterogeneity of hypoxia determined by image analysis applied to multiple tissue blocks stained by immunohistochemistry. Intra/interpatient heterogeneity was estimated by variance component analysis. RESULTS: Pimonidazole staining was analysed in 10 tumours. The extent of labelling varied amongst patients (0-26%), with a broader range of hypoxia in the epithelial (1-39%) compared with the stromal (1-13%) compartments. Variance component analysis demonstrated greater inter- than intrapatient variability of hypoxia, and that multiple (4-5) tumour sections are required to provide a consistent evaluation of its extent in individual tumours. CONCLUSIONS: There is significant intra- and intertumoral heterogeneity of hypoxia in pancreatic cancers, and these do not appear to be generally more hypoxic than other cancer types. This study establishes the feasibility to assess hypoxia in pancreatic cancer patients using pimonidazole, but questions the reliability of measurements made using a single tissue section.

Role of primary care in the follow-up of patients with obstructive sleep apnoea undergoing CPAP treatment: a randomised controlled trial.

OBJECTIVE: To evaluate whether follow-up of patients with obstructive sleep apnoea (OSA) undergoing CPAP treatment could be performed in primary care (PC) settings. DESIGN: Non-inferiority, randomised, prospective controlled study. SETTINGS: Sleep unit (SU) at the University Hospital and in 8 PC units in Lleida, Spain. PARTICIPANTS: Patients with OSA were randomised to be followed up at the SU or PC units over a 6-month period. MAIN OUTCOMES MEASURED: The primary outcome was CPAP compliance at 6 months. The secondary outcomes were Epworth Sleep Scale (ESS) score, EuroQoL, patient satisfaction, body mass index (BMI), blood pressure and cost-effectiveness. RESULTS: We included 101 patients in PC ((mean±SD) apnoea-hypopnoea index (AHI) 50.8±22.9/h, age 56.2±11 years, 74% male) and 109 in the SU (AHI 51.4±24.4/h, age 55.8±11 years, 77% male)). The CPAP compliance was (mean (95% CI) 4.94 (4.47 to 5.5) vs 5.23 (4.79 to 5.66) h, p=0.18) in PC and SU groups, respectively. In the SU group, there were greater improvements in ESS scores (mean change 1.79, 95% CI +0.05 to +3.53, p=0.04) and patient satisfaction (-1.49, 95% CI -2.22 to -0.76); there was a significant mean difference in BMI between the groups (0.57, 95% CI +0.01 to +1.13, p=0.04). In the PC setting, there was a cost saving of 60%, with similar effectiveness, as well as a decrease in systolic blood pressure (-5.32; 95% CI -10.91 to +0.28, p=0.06). CONCLUSIONS: For patients with OSA, treatment provided in a PC setting did not result in worse CPAP compliance compared with a specialist model and was shown to be a cost-effective alternative. TRIAL REGISTRATION NUMBER: Clinical Trials NCT01918449.

The breast cancer susceptibility FGFR2 provides an alternate mode of HER2 activation.

Fibroblast growth factor receptor 2 (FGFR2) has been shown reproducibly in genome-wide association studies to be associated with increased breast cancer risk. Here we show that mouse mammary tumor virus-neu mice develop breast carcinomas with FGFR2 immunoreactivity that parallels HER2 expression. FGFR2 signaling promotes HER2 shedding through the metalloprotease ADAM10 leading to intracellular accumulation of the truncated p95HER2 protein. This is accompanied by enhanced HER2 signaling and diminished sensitivity to trastuzumab. Functionally, FGFR2 facilitates HER2-mediated cell proliferation, acinar growth in three-dimensional morphogenesis assays and promotes tumor progression in mouse xenografts. These data implicate FGFR2 in a novel mechanism of ErbB activation and demonstrate an important interaction between FGFR2 and HER2 in promoting breast cancer progression.Oncogene advance online publication, 2 February 2015; doi:10.1038/onc.2014.440.