Summary
Background
Chilblains (‘COVID toes’) are being seen with increasing frequency in children and young adults during the COVID‐19 pandemic. Detailed histopathological descriptions of COVID‐19 ...chilblains have not been reported, and causality of SARS‐CoV‐2 has not yet been established.
Objectives
To describe the histopathological features of COVID‐19 chilblains and to explore the presence of SARS‐CoV‐2 in the tissue.
Methods
We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID‐19 pandemic. Immunohistochemistry for SARS‐CoV‐2 was performed in all cases and electron microscopy in one.
Results
Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS‐CoV‐2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy.
Conclusions
Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS‐CoV‐2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID‐19 chilblains and perhaps also in a group of patients severely affected by COVID‐19 presenting with features of microangiopathic damage.
What is already known about this topic?
Despite the high number of cases of chilblains seen during the COVID‐19 pandemic, a definite causative role for SARS‐CoV‐2 has not yet been proven.
Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors.
What does this study add?
The demonstration of SARS‐CoV‐2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID‐19.
Virus‐induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID‐19 chilblains.
Our findings support the hypothesis that widespread endothelial infection by SARS‐CoV‐2 could have a pathogenetic role in the severe forms of COVID‐19.
Linked Comment: Wetter. Br J Dermatol 2020; 183:611.
Linked Comment: Wetter. Br J Dermatol 2020; 183:611.
Plain language summary available online
Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis ...with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.
Soil pollution by lead, zinc, cadmium and copper was characterized in the mine tailings and surrounding soils (arable and pasture lands) of an old Spanish Pb–Zn mine. Sixty soil samples were ...analyzed, determining the total metal concentration by acid digestion and the chemical fractionation of Pb and Zn by the modified BCR sequential extraction method. Samples belonging to mine waste areas showed the highest values, with mean concentrations of 28,453.50
mg
kg
−1 for Pb, 7000.44
mg
kg
−1 for Zn, 20.57
mg
kg
−1 for Cd and 308.48
mg
kg
−1 for Cu. High concentrations of Pb, Zn and Cd were found in many of the samples taken from surrounding arable and pasture lands, indicating a certain extent of spreading of heavy metal pollution. Acidic drainage and wind transport of dust were proposed as the main effects causing the dispersion of pollution. Sequential extraction showed that most of the Pb was associated with non-residual fractions, mainly in reducible form, in all the collected samples. Zn appeared mainly associated with the acid-extractable form in mine tailing samples, while the residual form was the predominant one in samples belonging to surrounding areas. Comparison of our results with several criteria reported in the literature for risk assessment in soils polluted by heavy metals showed the need to treat the mine tailings dumped in the mine area.
The current technology of air‐filtration materials for protection against highly toxic chemicals, that is, chemical‐warfare agents, is mainly based on the broad and effective adsorptive properties of ...hydrophobic activated carbons. However, adsorption does not prevent these materials from behaving as secondary emitters once they are contaminated. Thus, the development of efficient self‐cleaning filters is of high interest. Herein, we report how we can take advantage of the improved phosphotriesterase catalytic activity of lithium alkoxide doped zirconium(IV) metal–organic framework (MOF) materials to develop advanced self‐detoxifying adsorbents of chemical‐warfare agents containing hydrolysable PF, PO, and CCl bonds. Moreover, we also show that it is possible to integrate these materials onto textiles, thereby combining air‐permeation properties of the textiles with the self‐detoxifying properties of the MOF material.
The silk of human kindness: Insertion of lithium alkoxides in zirconium metal–organic frameworks (MOF) which are then deposited on silk fibers gives rise to protective fabrics capable of self‐detoxifying chemical‐warfare agents. The fabrics combine the air‐permeation properties of the textiles with the highly active phosphotriesterase catalytic activity of the MOF for the hydrolysis of PF, PO, and CCl bonds.
Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2‐arachidonoylglycerol (2‐AG). MAGL inhibitors show analgesic and tissue‐protecting effects in ...several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18 μM) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1‐mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.
Reversibility is the key: The development of a potent, reversible, selective and in vivo active inhibitor of monoacylglycerol lipase (MAGL), the enzyme responsible for the inactivation of the endocannabinoid 2‐arachidonoylglycerol (2‐AG), validates, for the first time, the therapeutic potential of MAGL for the treatment of multiple sclerosis.
Mesenchymal stromal cells (MSCs) have shown to be a promising tool in cell therapies to treat different conditions. Several pre-clinical and clinical studies have proved that the transplantation of ...MSCs improves wound healing. Here, we compare the beneficial effects of mouse bone marrow-derived allogeneic MSCs (allo-mBM-MSCs) and their acelullar derivatives (allo-acd-mMSCs) on skin wound healing in Non-Obese Diabetic (NOD) mice. One dose of allo-mBM-MSCs (1×106 cells) or one dose of allo-acd-mMSCs (1X) were intradermally injected around wounds in 8-10 week old female NOD mice. Wound healing was evaluated macroscopically (wound closure) every two days, and microscopically (reepithelialization, dermoepidermal junction, skin appendage regeneration, leukocyte infiltration, vascularization, granulation tissue formation, and density of collagen fibers in the dermis) after 16 days of MSC injection. In addition, we measured growth factors and specific proteins that were present in the allo-acd-mMSCs. Results showed significant differences in the wound healing kinetics of lesions that received allo-acd-mMSCs compared to lesions that received vehicle or allo-mBM-MSCs. In particular, mice treated with allo-acd-mMSCs reached significantly higher percentages of wound closure at day 4, 6 and 8, relative to the allo-mBM-MSCs and vehicle groups (p < 0.05), while wound closure percentages could not be statistically distinguished between the allo-mBM-MSCs and vehicle groups. Also, allo-acd-mMSCs had a greater influence in the skin would healing process. Specifically, they caused a less pronounced inflammatory severe response (p < 0.0001), more granulation tissue formation at an advanced stage (p < 0.0001), and higher density of collagen fibers (p < 0.05) compared to the other groups. Nevertheless, at day 16, both allo-mBM-MSCs and allo-acd-mMSCs revealed a higher effect on the recovery of the quality skin (continuous epidermis; regular dermoepidermal junction and skin appendages) relative to untreated lesions (p < 0.0001), but not between them. On the other hand, ELISA analyses indicated that the allo-acd-mMSCs contained growth factors and proteins relevant to wound healing such as IGF-1, KGF, HGF, VEGF, ANG-2, MMP-1, CoL-1 and PGE2. Compared to allo-acd-mMSCs, the administration of allo-mBM-MSCs is insufficient for wound healing in diabetic mice and delays the therapeutic effect, which maybe explained by the fact that trophic factors secreted by MSCs are critical for skin regeneration, and not the cells per se, suggesting that MSCs may require some time to secrete these factors after their administration.
The only glaciers existing today in the Iberian Peninsula are small features located in the Pyrenees, though their number and extension has undergone significant changes over the Late Quaternary. The ...wide range of glacial landforms and deposits distributed across different Iberian ranges suggests the occurrence of several past periods with larger glacial systems. The objective of this research is to summarize the current knowledge on the spatial and temporal patterns of glacial activity in the Iberian mountains during the Late Quaternary. To this purpose, the chronological framework was divided in six periods: glaciations prior to the Last Glacial Cycle (Middle Pleistocene), Last Glacial Cycle (Late Pleistocene), Termination-1, Holocene, Little Ice Age (LIA) and present-day. The data were geographically divided considering the mountain systems where glacial evidence exists: Pyrenees, Cantabrian Range, NW ranges, Central Range, Iberian Range and Sierra Nevada. During Quaternary cold stages, ice accumulated in the head valleys of these mountain ranges and glaciers flowed down-valleys. In all cases, glaciers remained confined within the mountain systems and did not reach the surrounding lowlands. Depending on the combination of temperatures and moisture conditions, more or less ice was stored. In some ranges, there is evidence of Middle Pleistocene glaciations, one potentially correlating with marine isotope stage (MIS) 12 and another correlating with MIS 6 with glaciation dated to ca. 130-170 ka. However, most of the glacial records correspond to the Last Glacial Cycle and subsequent Termination. The maximum glacial expansion of this last Pleistocene glaciation stage occurred well before the global Last Glacial Maximum (LGM) between 30 and 60 ka in the Cantabrian Mountains and Pyrenees, at ca. 30 ka in Sierra Nevada and NW ranges, and (almost) synchronously to the LGM in the Central Range and Iberian Range. A massive glacial retreat occurred in all ranges at 19-20 ka, but the long-term deglaciation process was interrupted by cold intervals, such as the Oldest and Younger Dryas, which favoured glacial expansion in the highest mountains. Temperature increase recorded during the Holocene conditioned the melting of glaciers, which only reappeared in the highest massifs during the coldest periods, such as the LIA. However, post-LIA warming led to glacier disappearance in the Cantabrian Mountains, Sierra Nevada and most massifs of the Pyrenees, together with an accelerated shrinkage of the small glaciers still existing in this range at elevations near 3000 m.
•Maize responses to heat were monitored over three years under a wide range of temperatures.•Maize phenology was well captured with the simplified beta function.•Heat stress did not cause silking ...delay in relation to anthesis in the range of temperatures considered.•Maize yield is reduced under heat stress mainly via pollen viability and via a smaller effect of the female component.•Additional field experiments with a range of temperatures that assure optimum temperature being overpassed are needed.
Heat stress is a main threat to current and future global maize production. Adaptation of maize to future warmer conditions requires improving our understanding of crop responses to elevated temperatures. For this purpose, the same short-season (FAO 300) maize hybrid PR37N01 was grown over three years of field experiments on three contrasting Spanish locations in terms of temperature regime. The information complemented three years of greenhouse experiments with the same hybrid, applying heat treatments at various critical moments of the crop cycle. Crop phenology, growth, grain yield, and yield components were monitored. An optimized beta function improved the calculation of thermal time compared to the linear-cutoff estimator with base and optimum temperatures of 8 and 34°C, respectively. Our results showed that warmer temperatures accelerate development rate resulting in shorter vegetative and reproductive phases (ca. 30days for the whole cycle). Heat stress did not cause silking delay in relation to anthesis (extended anthesis-silking interval), at least in the range of temperatures (maximum temperature up to 42.9°C in the field and up to 52.5°C in the greenhouse) considered in this study. Our results indicated that maize grain yield is reduced under heat stress mainly via pollen viability that in turn determines kernel number, although a smaller but significant effect of the female component has been also detected.
The duration and intensity of future heat waves are analyzed for 53 cities in the Middle East and the North Africa (MENA) region for the 21st century under two different scenarios (RCP4.5 and ...RCP8.5). A consistent approach is carried out using data from 13 Regional models within the framework of the Coordinated Regional Climate Downscaling Experiment (CORDEX). By the end of the century, 80% of the most populated MENA cities are expected to be at least 50% of the days under heat wave conditions during the warm season. In addition, the mean and maximum intensity of the heat waves will also increase. Changes in the duration and intensity of heat waves have shown to be negatively correlated. Therefore, the vulnerability of the MENA cities to future heat waves was determined using a cumulative index (CI) that takes into account both duration and intensity. This CI indicates that Middle East and the eastern part of Africa will suffer the most unfavorable temperature conditions in the future. Assuming no intervention trough adaptation/mitigation strategies, these results, together with the particular properties of the MENA region, such as aridity or lack of precipitation, make it likely that the area will be affected by disease or famine.
PDF
