Investigation into the Hydration Behavior of K₂CO₃ Packed Beds:An NMR Study

K2CO3 is seen as a promising heat storage material, available for applications in the domestic sector. For practical purposes, the material is hereby often employed in a packed bed containing millimeter-sized particles. To gain more insight into the hydration behavior of these packed beds, quantitative NMR measurements, capable of following the in-situ hydration behavior, are presented for the first time. It is found that hydration behavior varies significantly, depending on the specific hydration conditions that are chosen. At low airflows hydration is found to proceed via a hydration front, while higher airflows cause the hydration front to widen. Since an increase in flow rate coincided with an increase in the supplied water vapor, hydration is eventually found to proceed in a uniform manner. A comparison between TGA and NMR measurements shows that the overall packed bed hydration kinetics hereby transition to the reaction kinetics of single K2CO3 particles. Graphical Abstract: [Figure not available: see fulltext.]</p

Enhancing the effectiveness of medical device incident reporting: final report of the EU pilot on the manufacturer incident reporting form (MIR form)

Aim of the report This report provides a final assessment by DG JRC of the 'EU MIR form pilot' project, concerning the use of nomenclature for manufacturer incident reporting. The purpose of this analysis is to exploit the submitted data in view of addressing the following key questions: 1. Is reporting of adverse events using nomenclature feasible and helpful? 2. Are existing nomenclatures relating to device problems and evaluations of causes adequate? 3. Is there a need for introducing new terms, e.g. to cover novel technologies? 4. What are the lessons learned from the pilot study in terms of international harmonisation of nomenclatures (IMDRF) and development of future reporting tools (e.g. EUDAMED)? Key findings This report focuses on the use of adverse 'event-type' and 'evaluation' terms which relate to problems with the medical device. The device-related terms were used in a 'Manufacturer Incident Report' form, which was designed for the pilot study, and was called the MIR pilot form. 786 forms, which were submitted by 13 manufacturers reporting from 15 European countries, were analysed. Concerning nomenclature usage, the report analyses whether incidents were reported adequately using (1) existing nomenclature (ISO/TS 19218), (2) newly introduced nomenclature (EDMA's IVD-related terms), and (3) newly proposed terms (by the participating manufacturers of the pilot study). The analysis has shown a number of important issues which concern five main topics: 1. Pilot data relate to approx. 50% of device categories on the market Due to voluntary participation, the submitted MIR pilot forms reflect only a certain proportion of medical devices on the market. This needs to be considered when interpreting and using the pilot data. 2. No participation of SMEs in the pilot project Additional bias may be due to (1) the absence of SME participation; and (2) a single manufacturer submitting >60% of the total number of forms (bias towards a particular device category). 3. Adequacy of term selection by manufacturers We assessed the adequacy of term use by comparing textual incident descriptions with the categorised terms chosen by reporters. It was based on a set of 100 randomly selected pilot forms representative of the pilot's overall device portfolio. Both, the event-type and evaluation terms chosen by manufacturers for reporting incidents were largely adequate. Moreover, the analysis shows that three choices per level to describe the incident (event-type terms) or final investigation (evaluation terms) appear sufficient. 4. Available terminology (ISO/TS 19218) is not fully adequate On the basis of the frequency of some proposed terms it appears that the existing ISO/TS 19218 terms are overall not sufficient. This is not surprising given the fact that the terms were derived from FDA's terminology in 2005 and have, since then, not been updated. To resolve the most frequently encountered issues in the analysis, the JRC has proposed several changes to terms used (cf. Fig. 18-24). 5. Proposals for new terms by manufacturers ISO/TS 19218 uses a 2-level hierarchical coding structure for reporting adverse events. Though the pilot study allowed for new proposals at these levels (level 1, 2), it was particularly designed for new proposals at an additional more granular third level. In line with this is the observation that the majority of new terms proposed concern level three terms. The analysis also showed that, although selection of existing terms was overall adequate, many of the new terms proposed by manufacturers are either redundant or do not reflect device problems but are, in fact, patient outcome terms. This clearly shows a need for reporters to have a better understanding of the terms and the reporting form used. Some of the confusion may stem from the simple fact that ISO's medical device problem terminology is called "Adverse Event Terms", i.e. seemingly suggesting that this nomenclature should be used to report adversity, i.e. clinical phenomena at patient / user level. In cases where level one event-type terms have been proposed, these related mainly (>80%) to the orthopaedic device category (cf. Fig. 13). It therefore appears that there is a need for a more elaborate nomenclature in this device category. Proposed terms that were deemed valid when compared with ISO/TS 19218 were subsequently compared with FDA's terms for device problems. This led to the identification of a number of proposed terms that could be proposed for incorporation into ongoing efforts in the development of a globally used nomenclature in the context of the work of the Adverse Event Terminology Working Group of IMDRF. EDMA has proposed new terms to cover specific needs of reporting incidents with in vitro diagnostic medical devices (IVDs). These were meant to complement the ISO/TS 19218 terms, and several of them have been used in the submissions. A closer look at the definitions of some of EDMA's terms does, however, show that they would need to be revised, for example four terms (corresponding to level 2) have identical definitions adding unnecessary ambiguity to their use. The report also provides in Annex I a summary of agreements reached during the workshop and topics that remain to be addressed when developing future tools for incident reporting including concerns voiced by stakeholders. Annex I also considers additional reflections made after the workshop and provides, as a synthesis, key recommendations for a way forward. In summary, this report shows that the outcome of the 'EU MIR form pilot' project has proven to be extremely useful for three reasons. 1. It confirmed the general feasibility of categorised reporting of incidents by manufacturers. 2. It identified inadequacies of the existing ISO/TS 19218 nomenclature suggesting the need for increased efforts into the development of freely available, scientifically and technically satisfying and, from a regulatory and end-user point of view, adequate nomenclature for adverse event reporting of incidents and events also in the pre-market space. 3. It led to the proposal of several potentially useful terms in view of future developments of nomenclature for incident / adverse event reporting.JRC.F.2-Consumer Products Safet

Safety of tattoos and permanent make-up State of play and trends in tattoo practices

The European Commission launched the 18-month project "Tattoos and Permanent Make-up" with the aim of collecting data about the use, the ingredients, the EU market and possible health problems associated to tattoo and permanent make-up (PMU) inks. The report on work package 1 (2015, Piccinini P. et al.) is available at http://bookshop.europa.eu/en/safety-of-tattoos-and-permanent-make-up-compilation-of-information-on-legislative-framework-and-analytical-methods-pbLBNA27394/ The present report is the outcome of the work package 2 which aims to describe the status of tattoo and PMU practices like tattoo prevalence in the population, including the removal processes, details on service providers and ink manufacturers, tattoo and PMU market, inks' chemical composition, RAPEX notifications and national market surveillance. The information was gathered through questionnaires sent to 32 national authorities (all EU MS and EFTA countries), plus OECD Secretariat, 38 ink manufacturers/distributors/private labels and 23 tattooists/PMU professionals' associations. Replies were collected from 24 EU/EFTA national authorities, 4 non-EU/EFTA countries, 7 ink manufacturers/ distributors/private labels and 10 associations. In addition, we reviewed thoroughly data available from other sources like scientific literature, RAPEX (Rapid Alert System for dangerous non-food products) notifications and national surveillance reports, as of May 2015. The main findings show that: Tattoo and PMU inks are complex chemical mixtures containing several ingredients. The main ingredients are the colorants, pigments in particular; more than 100 of them have been identified in tattoo and PMU inks. These pigments are not produced specifically for such application and a risk assessment taking into account their injection and permanence into the human body is not carried out. An additional identified risk is the presence of impurities; in fact tattoo and PMU inks' purity is on average around 70-90 %. Azo pigments, group to which most of the organic colorants in use belong, are proved to release potentially carcinogenic aromatic amines when exposed to solar, UV or laser irradiation. It is estimated that around 12 % of the whole European population, all ages comprised, are tattooed (estimation based on available data from 14 Member States) and more than 20 % in the United States. Higher tattoo prevalence was reported in young population, including adolescents. While traditionally men were more tattooed than women, figures show that this trend in Europe, Australia and North America is changing. Nowadays in a number of cases the tattoo prevalence in women is higher than in men, particularly in young generations. Most of the tattoo inks used in Europe are imported from the United States, while PMU inks are mostly produced in Europe. The European manufacturers are mainly based in the United Kingdom, Germany, Italy and Spain. With regards to the tattoo artists performing the tattoos, the number of "non-professional tattooists" might represent up to 10 times the number of "registered/professionals" ones. Around 95 % of the 126 RAPEX alerts notified for tattoo/PMU during the last decade related to chemical risks: hazardous chemicals and/or impurities (such as carcinogenic aromatic amines, polycyclic aromatic hydrocarbons, sensitizers, preservatives and heavy metals). The remaining 5% concerned microbiological risks, which are mainly due to the lack of sterility of the inks before opening and from the use of tap water for their dilution. Two thirds of the RAPEX notifications pertain to products imported, with the highest percentages from the United States.JRC.I.1-Chemical Assessment and Testin

A Role for NuSAP in Linking Microtubules to Mitotic Chromosomes

SummaryThe spindle apparatus is a microtubule (MT)-based machinery that attaches to and segregates the chromosomes during mitosis and meiosis. Self-organization of the spindle around chromatin involves the assembly of MTs, their attachment to the chromosomes, and their organization into a bipolar array. One regulator of spindle self-organization is RanGTP. RanGTP is generated at chromatin and activates a set of soluble, Ran-regulated spindle factors such as TPX2, NuMA, and NuSAP [1]. How the spindle factors direct and attach MTs to the chromosomes are key open questions. Nucleolar and Spindle-Associated Protein (NuSAP) was recently identified as an essential MT-stabilizing and bundling protein that is enriched at the central part of the spindle [2, 3]. Here, we show by biochemical reconstitution that NuSAP efficiently adsorbs to isolated chromatin and DNA and that it can directly produce and retain high concentrations of MTs in the immediate vicinity of chromatin or DNA. Moreover, our data reveal that NuSAP-chromatin interaction is subject to Ran regulation and can be suppressed by Importin α (Impα) and Imp7. We propose that the presence of MT binding agents such as NuSAP, which can be directly immobilized on chromatin, are critical for targeting MT production to vertebrate chromosomes during spindle self-organization

Rer1p competes with APH-1 for binding to nicastrin and regulates γ-secretase complex assembly in the early secretory pathway

The γ-secretase complex, consisting of presenilin, nicastrin, presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1) cleaves type I integral membrane proteins like amyloid precursor protein and Notch in a process of regulated intramembrane proteolysis. The regulatory mechanisms governing the multistep assembly of this “proteasome of the membrane” are unknown. We characterize a new interaction partner of nicastrin, the retrieval receptor Rer1p. Rer1p binds preferentially immature nicastrin via polar residues within its transmembrane domain that are also critical for interaction with APH-1. Absence of APH-1 substantially increased binding of nicastrin to Rer1p, demonstrating the competitive nature of these interactions. Moreover, Rer1p expression levels control the formation of γ-secretase subcomplexes and, concomitantly, total cellular γ-secretase activity. We identify Rer1p as a novel limiting factor that negatively regulates γ-secretase complex assembly by competing with APH-1 during active recycling between the endoplasmic reticulum (ER) and Golgi. We conclude that total cellular γ-secretase activity is restrained by a secondary ER control system that provides a potential therapeutic value

NuSAP, a novel microtubule-associated protein involved in mitotic spindle organization

Here, we report on the identification of nucleolar spindle–associated protein (NuSAP), a novel 55-kD vertebrate protein with selective expression in proliferating cells. Its mRNA and protein levels peak at the transition of G2 to mitosis and abruptly decline after cell division. Microscopic analysis of both fixed and live mammalian cells showed that NuSAP is primarily nucleolar in interphase, and localizes prominently to central spindle microtubules during mitosis. Direct interaction of NuSAP with microtubules was demonstrated in vitro. Overexpression of NuSAP caused profound bundling of cytoplasmic microtubules in interphase cells, and this relied on a COOH-terminal microtubule-binding domain. In contrast, depletion of NuSAP by RNA interference resulted in aberrant mitotic spindles, defective chromosome segregation, and cytokinesis. In addition, many NuSAP-depleted interphase cells had deformed nuclei. Both overexpression and knockdown of NuSAP impaired cell proliferation. These results suggest a crucial role for NuSAP in spindle microtubule organization

Presenilin 1 mediates the turnover of telencephalin in hippocampal neurons via an autophagic degradative pathway

Presenilin 1 (PS1) interacts with telencephalin (TLN) and the amyloid precursor protein via their transmembrane domain (Annaert, W.G., C. Esselens, V. Baert, C. Boeve, G. Snellings, P. Cupers, K. Craessaerts, and B. De Strooper. 2001. Neuron. 32:579–589). Here, we demonstrate that TLN is not a substrate for γ-secretase cleavage, but displays a prolonged half-life in PS1−/− hippocampal neurons. TLN accumulates in intracellular structures bearing characteristics of autophagic vacuoles including the presence of Apg12p and LC3. Importantly, the TLN accumulations are suppressed by adenoviral expression of wild-type, FAD-linked and D257A mutant PS1, indicating that this phenotype is independent from γ-secretase activity. Cathepsin D deficiency also results in the localization of TLN to autophagic vacuoles. TLN mediates the uptake of microbeads concomitant with actin and PIP2 recruitment, indicating a phagocytic origin of TLN accumulations. Absence of endosomal/lysosomal proteins suggests that the TLN-positive vacuoles fail to fuse with endosomes/lysosomes, preventing their acidification and further degradation. Collectively, PS1 deficiency affects in a γ-secretase–independent fashion the turnover of TLN through autophagic vacuoles, most likely by an impaired capability to fuse with lysosomes

A role for NuSAP in linking microtubules to mitotic chromosomes

The spindle apparatus is a microtubule (MT)-based machinery that attaches to and segregates the chromosomes during mitosis and meiosis. Self-organization of the spindle around chromatin involves the assembly of MTs, their attachment to the chromosomes, and their organization into a bipolar array. One regulator of spindle self-organization is RanGTP. RanGTP is generated at chromatin and activates a set of soluble, Ran-regulated spindle factors such as TPX2, NuMA, and NuSAP [1]. How the spindle factors direct and attach MTs to the chromosomes are key open questions. Nucleolar and Spindle-Associated Protein (NuSAP) was recently identified as an essential MT-stabilizing and bundling protein that is enriched at the central part of the spindle [2, 3]. Here, we show by biochemical reconstitution that NuSAP efficiently adsorbs to isolated chromatin and DNA and that it can directly produce and retain high concentrations of MTs in the immediate vicinity of chromatin or DNA. Moreover, our data reveal that NuSAP-chromatin interaction is subject to Ran regulation and can be suppressed by Importin alpha (Imp alpha) and Imp7. We propose that the presence of MT binding agents such as NuSAP, which can be directly immobilized on chromatin, are critical for targeting MT production to vertebrate chromosomes during spindle self-organization.status: publishe