Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients.

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRß in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.

Setting the stage for the review of the international estimate of short-term intake (IESTI) equation.

In the framework of setting Maximum Residue Limits (MRLs) for pesticides, both chronic and acute health risks to consumers arising from the long-term and short-term dietary exposure to pesticide residues have to be assessed. The current internationally harmonized approach for assessing the acute dietary exposure is based on deterministic methods for calculating the IESTI (International Estimate of Short-Term Intake). Recently, it became apparent that the IESTI approach needs a revision in the light of new scientific and political aspects. The main reasons that require this review were the lack of an international harmonization of the methodology which implies trade barriers as well as difficulties in risk communication concerning the public trust in regulatory systems. The most recent milestone in the scientific debate on a possible revision of the IESTI equation was an international scientific workshop held in Geneva in September 2015. The main objectives of this meeting were the re-evaluation, and where possible, the international harmonization of the input parameters for the IESTI equations as well as the equations themselves. The main recommendations from the workshop were (i) to replace the highest residue and supervised trials median residue with the maximum residue limit (MRL), (ii) to use a standard variability factor of three, (iii) to derive the P97.5 large portion value from the distribution of consumption values of dietary surveys expressed as kg food/kg bw/d, and (iv) to remove the commodity unit weight from the equations. In addition, the application of conversion factors and processing factors was addressed. On the initiative of the (World Health Organization) WHO Collaborating Centre on Chemical Food Safety at the National Institute for Public Health and the Environment (RIVM), the Netherlands, an international working group with members from the French Agency for Food, Environmental and Occupational Health and Safety, France (ANSES), Australian Pesticides and Veterinary Medicines Authority, Australia (APVMA), German Federal Institute for Risk Assessment, Germany (BfR), Chemical Regulation Division, the United Kingdom (CRD), European Food Safety Authority (EFSA), and RIVM, the Netherlands was formed after the IESTI workshop to conduct a comprehensive impact assessment of the proposed changes of the IESTI equations.

Impact of a proposed revision of the IESTI equation on the acute risk assessment conducted when setting maximum residue levels (MRLs) in the European Union (EU): A case study.

Proposals to update the methodology for the international estimated short-term intake (IESTI) equations were made during an international workshop held in Geneva in 2015. Changes to several parameters of the current four IESTI equations (cases 1, 2a, 2b, and 3) were proposed. In this study, the overall impact of these proposed changes on estimates of short-term exposure was studied using the large portion data available in the European Food Safety Authority PRIMo model and the residue data submitted in the framework of the European Maximum Residue Levels (MRL) review under Article 12 of Regulation (EC) No 396/2005. Evaluation of consumer exposure using the current and proposed equations resulted in substantial differences in the exposure estimates; however, there were no significant changes regarding the number of accepted MRLs. For the different IESTI cases, the median ratio of the new versus the current equation is 1.1 for case 1, 1.4 for case 2a, 0.75 for case 2b, and 1 for case 3. The impact, expressed as a shift in the IESTI distribution profile, indicated that the 95th percentile IESTI shifted from 50% of the acute reference dose (ARfD) with the current equations to 65% of the ARfD with the proposed equations. This IESTI increase resulted in the loss of 1.2% of the MRLs (37 out of 3110) tested within this study. At the same time, the proposed equations would have allowed 0.4% of the MRLs (14 out of 3110) that were rejected with the current equations to be accepted. The commodity groups that were most impacted by these modifications are solanacea (e.g., potato, eggplant), lettuces, pulses (dry), leafy brassica (e.g., kale, Chinese cabbage), and pome fruits. The active substances that were most affected were fluazifop-p-butyl, deltamethrin, and lambda-cyhalothrin.

Impact of proposed changes in IESTI equations for short-term dietary exposure to pesticides from Australian and Codex perspective.

In 2015 a scientific workshop was held in Geneva, where updating the four equations for estimating the short-term dietary exposure (International Estimated Short Term Intake, IESTI) to pesticides was suggested. The impact of these proposed changes on the exposure was studied by using residue data and large portion consumption data from Codex and Australia. For the Codex data, the exposure increased by a median factor of 2.5 per commodity when changing to the proposed IESTI equations. The increase in exposure was highest for bulked and blended food commodities (case 3 equations), followed by medium-sized food commodities (case 2a equations) and small- and large-sized food commodities (case 1 and case 2b equations). For the Australian data, out of 184 maximum residue limit (MRL) large portion combinations showing acute exposures below the acute reference dose (ARfD) with the current IESTI equations, 23 exceeded the ARfD with the proposed IESTI equations (12%). The percentage exceeding the ARfD was higher for the Australian MRL large portion combinations (12% of 184) than for those of Codex (1.3% of 8,366). However, the percentage MRL loss in the Australian dataset may not be representative of all pesticide MRLs since it concerns six pesticides only, specifically selected to elucidate the potential effects of the use of the proposed IESTI equations. For the Codex data, the increase in exposure using the proposed equations resulted in a small increased loss of 2.6% of the 1,110 MRLs estimated by the Joint FAO/WHO Meeting on Pesticide Residues (JMPR): 1.4% of the MRLs were already not acceptable with the current equations, 4.0% of the MRLs were not acceptable with the newly proposed equations. Our study revealed that case 3 commodities may be impacted more by the proposed changes than other commodities. This substantiates one of the conclusions of the Geneva workshop to gather information on bulking and blending practices in order to refine MRL setting and dietary risk assessment for case 3 commodities where possible.

Effect of individual parameter changes on the outcome of the estimated short-term dietary exposure to pesticides.

In 2015 a scientific workshop was held in Geneva, where updating the International Estimate of Short-Term Intake (IESTI) equations was suggested. This paper studies the effects of the proposed changes in residue inputs, large portions, variability factors and unit weights on the overall short-term dietary exposure estimate. Depending on the IESTI case equation, a median increase in estimated overall exposure by a factor of 1.0-6.8 was observed when the current IESTI equations are replaced by the proposed IESTI equations. The highest increase in the estimated exposure arises from the replacement of the median residue (STMR) by the maximum residue limit (MRL) for bulked and blended commodities (case 3 equations). The change in large portion parameter does not have a significant impact on the estimated exposure. The use of large portions derived from the general population covering all age groups and bodyweights should be avoided when large portions are not expressed on an individual bodyweight basis. Replacement of the highest residue (HR) by the MRL and removal of the unit weight each increase the estimated exposure for small-, medium- and large-sized commodities (case 1, case 2a or case 2b equations). However, within the EU framework lowering of the variability factor from 7 or 5 to 3 counterbalances the effect of changes in other parameters, resulting in an estimated overall exposure change for the EU situation of a factor of 0.87-1.7 and 0.6-1.4 for IESTI case 2a and case 2b equations, respectively.

Cumulative risk assessment with pesticides in the framework of MRL setting.

This abstract presents a report on the proposed work programme, focus on cumulative risk assessment (CRA) for chemical risks, specifically pesticide residues in food. While not a scientific publication, this technical report aims to provide insights without including the fellow's data to avoid publication restrictions. This report focuses on addressing the question concerning the trigger value to perform a prospective CRA in case of a new maximum residue level (MRL) setting. The 1,000 margin of exposure (MOE) threshold value was tested and compared to preliminary ANSES results. Alternative thresholds were calculated and explored. The EU-FORA fellow selected two cumulative assessment groups (CAGs) related to acute craniofacial alterations and chronic thyroid effects. The fellow performed exposure assessments, integrating effects data, French monitoring data, processing factors, agricultural uses, MRLs and extrapolations into Monte Carlo risk assessment (MCRA). Retrospective cumulative exposures using MCRA were conducted for children, adults and a vulnerable group of childbearing women based on the French survey INCA3, identifying background levels at P99.9. The fellow also performed prospective assessments with MCRA, analysing results at P99.9 to evaluate the adequacy of the 1,000 MOE threshold. Alternative thresholds are discussed and proposed.

Towards comprehensive identification of pesticide degradation products following thermal processing below and above 120 °C: A review.

Characterising pesticide residues from a qualitative and quantitative point of view is key to both risk assessment in the framework of pesticide approval and risk management. In the European Union (EU), these concerns are addressed during the evaluation of active substances at the European level prior to marketing authorisation. In the framework of this review, we will focus on one specific item of the residue section, namely the effect of process (industrial or domestic transformation of the raw commodities) on the nature of the residue in food. A limited number of hydrolysis conditions defined by three parameters (temperature, pH and time) are set to be "representative of the most widely used industrial and domestic food processing technologies". These hydrolysis conditions, however, do not cover processes at temperatures higher than 120 °C, such as cooking with a conventional oven or in a pan, frying or using a microwave oven.

Hydroponics versus field lysimeter studies of urea, ammonium and nitrate uptake by oilseed rape (Brassica napus L.).

N-fertilizer use efficiencies are affected by their chemical composition and suffer from potential N-losses by volatilization. In a field lysimeter experiment, (15)N-labelled fertilizers were used to follow N uptake by Brassica napus L. and assess N-losses by volatilization. Use of urea with NBPT (urease inhibitor) showed the best efficiency with the lowest N losses (8% of N applied compared with 25% with urea alone). Plants receiving ammonium sulphate, had similar yield achieved through a better N mobilization from vegetative tissues to the seeds, despite a lower N uptake resulting from a higher volatilization (43% of applied N). Amounts of (15)N in the plant were also higher when plants were fertilized with ammonium nitrate but N-losses reached 23% of applied N. In parallel, hydroponic experiments showed a deleterious effect of ammonium and urea on the growth of oilseed rape. This was alleviated by the nitrate supply, which was preferentially taken up. B. napus was also characterized by a very low potential for urea uptake. BnDUR3 and BnAMT1, encoding urea and ammonium transporters, were up-regulated by urea, suggesting that urea-grown plants suffered from nitrogen deficiency. The results also suggested a role for nitrate as a signal for the expression of BnDUR3, in addition to its role as a major nutrient. Overall, the results of the hydroponic study showed that urea itself does not contribute significantly to the N nutrition of oilseed rape. Moreover, it may contribute indirectly since a better use efficiency for urea fertilizer, which was further increased by the application of a urease inhibitor, was observed in the lysimeter study.

Locus Coeruleus Degeneration Differs Between Frontotemporal Lobar Degeneration Subtypes.

BACKGROUND: There are few studies on the locus coeruleus (LC) in frontotemporal lobar degeneration (FTLD) and the potential differences in the LC related to the underlying proteinopathy. OBJECTIVE: The aim of this study was to investigate the LC in FTLD subgroups. METHODS: Neuropathological cases diagnosed with FTLD were included. The subgroups consisted of FTLD with tau, transactive response DNA-binding protein 43 (TDP) and fused in sarcoma (FUS). Micro- and macroscopical degeneration of the LC were assessed with respect to the number of neurons and the degree of depigmentation. A group of cognitively healthy subjects and a group with vascular cognitive impairment (VCI) served as comparison groups. RESULTS: A total of 85 FTLD cases were included, of which 44 had FTLD-TDP, 38 had FTLD-tau, and three had FTLD-FUS. The groups were compared with 25 VCI cases and 41 cognitively healthy control cases (N = 151 for the entire study). All FTLD groups had a statistically higher microscopical degeneration of the LC compared to the controls, but the FTLD-tau group had greater micro- and macroscopical degeneration than the FTLD-TDP group. Age correlated positively with the LC score in the FTLD-tau group, but not in the FTLD-TDP group. CONCLUSION: A greater microscopical degeneration of the LC was observed in all FTLD cases compared to healthy controls and those with VCI. The LC degeneration was more severe in FTLD-tau than in FTLD-TDP. The macroscopically differential degeneration of the LC in FTLD subgroups may facilitate differential diagnostics, potentially with imaging.

Overexpression of the epidermis-specific homeodomain-leucine zipper IV transcription factor Outer Cell Layer1 in maize identifies target genes involved in lipid metabolism and cuticle biosynthesis.

Transcription factors of the homeodomain-leucine zipper IV (HD-ZIP IV) family play crucial roles in epidermis-related processes. To gain further insight into the molecular function of OUTER CELL LAYER1 (OCL1), 14 target genes up- or down-regulated in transgenic maize (Zea mays) plants overexpressing OCL1 were identified. The 14 genes all showed partial coexpression with OCL1 in maize organs, and several of them shared preferential expression in the epidermis with OCL1. They encoded proteins involved in lipid metabolism, defense, envelope-related functions, or cuticle biosynthesis and include ZmWBC11a (for white brown complex 11a), an ortholog of AtWBC11 involved in the transport of wax and cutin molecules. In support of the annotations, OCL1-overexpressing plants showed quantitative and qualitative changes of cuticular wax compounds in comparison with wild-type plants. An increase in C24 to C28 alcohols was correlated with the transcriptional up-regulation of ZmFAR1, coding for a fatty acyl-coenzyme A reductase. Transcriptional activation of ZmWBC11a by OCL1 was likely direct, since transactivation in transiently transformed maize kernels was abolished by a deletion of the activation domain in OCL1 or mutations in the L1 box, a cis-element bound by HD-ZIP IV transcription factors. Our data demonstrate that, in addition to AP2/EREBP and MYB-type transcription factors, members of the HD-ZIP IV family contribute to the transcriptional regulation of genes involved in cuticle biosynthesis.

Structure and expression analysis of rice paleo duplications.

Having a well-known history of genome duplication, rice is a good model for studying structural and functional evolution of paleo duplications. Improved sequence alignment criteria were used to characterize 10 major chromosome-to-chromosome duplication relationships associated with 1440 paralogous pairs, covering 47.8% of the rice genome, with 12.6% of genes that are conserved within sister blocks. Using a micro-array experiment, a genome-wide expression map has been produced, in which 2382 genes show significant differences of expression in root, leaf and grain. By integrating both structural (1440 paralogous pairs) and functional information (2382 differentially expressed genes), we identified 115 paralogous gene pairs for which at least one copy is differentially expressed in one of the three tissues. A vast majority of the 115 paralogous gene pairs have been neofunctionalized or subfunctionalized as 88%, 89% and 96% of duplicates, respectively, expressed in grain, leaf and root show distinct expression patterns. On the basis of a Gene Ontology analysis, we have identified and characterized the gene families that have been structurally and functionally preferentially retained in the duplication showing that the vast majority (>85%) of duplicated have been either lost or have been subfunctionalized or neofunctionalized during 50-70 million years of evolution.

Comparative phenotypic, genotypic and genomic analyses of Bacillus thuringiensis associated with foodborne outbreaks in France.

Bacillus thuringiensis (Bt) belongs to the Bacillus cereus (Bc) group, well known as an etiological agent of foodborne outbreaks (FBOs). Bt distinguishes itself from other Bc by its ability to synthesize insecticidal crystals. However, the search for these crystals is not routinely performed in food safety or clinical investigation, and the actual involvement of Bt in the occurrence of FBOs is not known. In the present study, we reveal that Bt was detected in the context of 49 FBOs declared in France between 2007 and 2017. In 19 of these FBOs, Bt was the only microorganism detected, making it the most likely causal agent. Searching for its putative origin of contamination, we noticed that more than 50% of Bt isolates were collected from dishes containing raw vegetables, in particular tomatoes (48%). Moreover, the genomic characterization of isolates showed that most FBO-associated Bt isolates exhibited a quantified genomic proximity to Bt strains, used as biopesticides, especially those from subspecies aizawai and kurstaki. Taken together, these results strengthen the hypothesis of an agricultural origin for the Bt contamination and call for further investigations on Bt pesticides.

Dietary exposure to pesticide residues and associated health risks in infants and young children - Results of the French infant total diet study.

A total diet study (TDS) was undertaken to estimate the chronic dietary exposure to pesticide residues and health risks for the French infants and young children below 3 years old. As a whole, 516 pesticides and metabolites were analysed in 309 food composite samples including 219 manufactured baby foods and 90 common foods, which cover 97% of infants and young children's diet. These composite samples were prepared using 5,484 food products purchased during all seasons from 2011 to 2012 and processed as consumed. Pesticide residues were detected in 67% of the samples and quantified in 27% of the baby food samples and in 60% of the common foods. Seventy-eight different pesticides were detected and 37 of these quantified at levels ranging from 0.02 to 594 µg/kg. The most frequently detected pesticides (greater than 5% samples) were (1) the fungicides 2-phenylphenol, azoxystrobin, boscalid, captan and its metabolite tetrahydrophthalimide, carbendazim, cyprodinil, difenoconazole, dodine, imazalil, metalaxyl, tebuconazole, thiabendazole, (2) the insecticides acetamiprid, pirimiphos-methyl and thiacloprid, (3) the herbicide metribuzin and (4) the synergist piperonyl butoxide. Dietary intakes were estimated for each of the 705 individuals studied and for 431 pesticides incl. 281 with a toxicological reference value (TRV). In the lower-bound scenario, which tends to underestimate the exposure, the TRV were never exceeded. In the upper-bound scenario that overestimates exposure, the estimated intakes exceeded the TRV for dieldrin and lindane (two persistent organic pollutants) and propylene thiourea, a metabolite of propineb. For these three substances, more sensitive analyses are needed to refine the assessment. For 17 other detected and/or prioritised pesticides, the risk could not be characterised due to the lack of a valid TRV, of certain food analyses or the absence of analytical standards for their metabolites.

Minimally invasive diagnosis of a pericardial mass by CT-guided fine-needle aspiration.

The preferred management of a cardiac mass remains controversial, but it often includes open-chest surgical excision to obtain an adequate tissue sample for histological workup. We herein report a less invasive approach in which an accurate and timely cytological diagnosis of pericardial angiosarcoma was reached by studying a CT-guided fine-needle aspiration cell block. The cell block showed proliferation of atypical cells with occasional mitotic figures, vasoformative features, and immunoreactivity to WT1, vimentin, CD31, CD34, ERG, and Ki67. Recourse to fine-needle aspiration and cell block study is a valuable diagnostic approach to be considered when a cardiac mass is percutaneously accessible.

[Amyloidosis complicating spondyloarthropathies: Study of 15 cases]. / Amiloidosis secundaria a espondiloartritis: estudio de 15 casos.

BACKGROUND AND OBJECTIVE: Secondary amyloidosis (AA) is a rare complication of rheumatic diseases. OBJECTIVE: The aim of this study was to determine the frequency of symptomatic amyloidosis AA in patients with spondyloarthropathy. PATIENTS AND METHOD: Retrospective study (1984-2013). We reviewed the medical records of patients with spondyloarthropathy who had a histological diagnosis of amyloidosis AA (15 patients). RESULTS: We identified 1.125 patients with spondyloarthropathies. Fifteen (1.3%) patients with amyloidosis AA were recruited. It was suspected in 14 patients (93.3%) because of nephrotic syndrome in most of them: 14 were symptomatic (93.3%): 5 (33.3%) ankylosing spondylitis (AS), 5 (33.3%) spondylitis associated with inflammatory bowel diseases (IBD), 4 (26.7%) psoriatic arthritis, and one (6.7%) reactive arthritis. The mean disease duration was 23.9 years. Mortality after one and 5 years of follow-up was 30 and 50% respectively. CONCLUSIONS: The frequency of clinical amyloidosis AA in our patients was 1.3%. There was a marked male predominance, with AS or IBD. Clinical amyloidosis was diagnosed at a relatively late stage in spondyloarthropathy.

Fibroelastoma en válvula pulmonar. Valoración multimodal por imagen / Multimodality imaging for pulmonary valve papillary fibroelastoma

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A joint transcriptomic, proteomic and metabolic analysis of maize endosperm development and starch filling.

The maize endosperm transcriptome was investigated through cDNA libraries developed at three characteristic stages: (i) lag phase [10 days after pollination (DAP)]; (ii) beginning of storage (14 DAP); and (iii) maximum starch accumulation rate (21 DAP). Expressed sequence tags for 711, 757 and 384 relevant clones, respectively, were obtained and checked manually. The proportion of sequences with no clear function decreased from 35% to 20%, and a large increase in storage protein sequences (i.e. 5% to 38%) was observed from stages (i) to (iii). The remaining major categories included metabolism (11%-13%), transcription-RNA processing-protein synthesis (13%-20%), protein destination (5%-9%), cellular communication (3%-9%) and cell rescue-defence (4%). Good agreement was generally found between category rank in the 10-DAP transcriptome and the recently reported 14-DAP proteome, except that kinases and proteins for RNA processing were not detected in the latter. In the metabolism category, the respiratory pathway transcripts represented the largest proportion (25%-37%), and showed a shift in favour of glycolysis at 21 DAP. At this stage, amino acid metabolism increased to 17%, whereas starch metabolism surprisingly decreased to 7%. A second experiment focused on carbohydrate metabolism by comparing gene expression at three levels (transcripts, proteins and enzyme activities) in relation to substrate or product from 10 to 40 DAP. Here, two distinct patterns were observed: invertases and hexoses were predominant at the beginning, whereas enzyme patterns in the starch pathway, at the three levels, anticipated and paralleled starch accumulation, suggesting that, in most cases, transcriptional control is responsible for the regulation of starch biosynthesis.