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Perturbations to the global climate system changed from net cooling to net heating during the first month after the 2022 Hunga Tonga-Hunga Ha-apai eruption, according to radiative forcing estimates based on satellite, ground-based, in situ and radiosonde observations.

ABSTRACT: The purpose of this study was to evaluate the effect of 6 different feeding systems (based on corn silage as the main ingredient) on the chemical composition of milk and to highlight the potential of untargeted metabolomics to find discriminant marker compounds of different nutritional strategies. Interestingly, the multivariate statistical analysis discriminated milk samples mainly according to the high-moisture ear corn (HMC) included in the diet formulation. Overall, the most discriminant compounds, identified as a function of the HMC, belonged to AA (10 compounds), peptides (71 compounds), pyrimidines (38 compounds), purines (15 compounds), and pyridines (14 compounds). The discriminant milk metabolites were found to significantly explain the metabolic pathways of pyrimidines and vitamin B6. Interestingly, pathway analyses revealed that the inclusion of HMC in the diet formulation strongly affected the pyrimidine metabolism in milk, determining a significant up-accumulation of pyrimidine degradation products, such as 3-ureidopropionic acid, 3-ureidoisobutyric acid, and 3-aminoisobutyric acid. Also, some pyrimidine intermediates (such as l-aspartic acid, N-carbamoyl-l-aspartic acid, and orotic acid) were found to possess a high discrimination degree. Additionally, our findings suggested that the inclusion of alfalfa silage in the diet formulation was potentially correlated with the vitamin B6 metabolism in milk, being 4-pyridoxic acid (a pyridoxal phosphate degradation product) the most significant and up-accumulated compound. Taken together, the accumulation trends of different marker compounds revealed that both pyrimidine intermediates and degradation products are potential marker compounds of HMC-based diets, likely involving a complex metabolism of microbial nitrogen based on total splanchnic fluxes from the rumen to mammary gland in dairy cows. Also, our findings highlight the potential of untargeted metabolomics in both foodomics and foodomics-based studies involving dairy products.

We use a combination of spaceborne instruments to study the unprecedented stratospheric plume after the Tonga eruption of 15 January 2022. The aerosol plume was initially formed of two clouds at 30 and 28 km, mostly composed of submicron-sized sulfate particles, without ash, which is washed out within the first day following the eruption. The large amount of injected water vapour led to a fast conversion of SO2 to sulfate aerosols and induced a descent of the plume to 24–26 km over the first 3 weeks by radiative cooling. Whereas SO2 returned to background levels by the end of January, volcanic sulfates and water still persisted after 6 months, mainly confined between 35∘ S and 20∘ N until June due to the zonal symmetry of the summer stratospheric circulation at 22–26 km. Sulfate particles, undergoing hygroscopic growth and coagulation, sediment and gradually separate from the moisture anomaly entrained in the ascending branch Brewer–Dobson circulation. Sulfate aerosol optical depths derived from the IASI (Infrared Atmospheric Sounding Interferometer) infrared sounder show that during the first 2 months, the aerosol plume was not simply diluted and dispersed passively but rather organized in concentrated patches. Space-borne lidar winds suggest that those structures, generated by shear-induced instabilities, are associated with vorticity anomalies that may have enhanced the duration and impact of the plume.

Excessive numerical diffusion is one of the major limitations in the representation of long-range transport by chemistry transport models. In the present study, we focus on excessive diffusion in the vertical direction, which has been shown to be a major issue, and we explore three possible ways of addressing this problem: increasing the vertical resolution, using an advection scheme with anti-diffusive properties and more accurately representing the vertical wind. This study was carried out using the CHIMERE chemistry transport model for the 18 March 2012 eruption of Mount Etna, which released about 3 kt of sulfur dioxide into the atmosphere in a plume that was observed by satellite instruments (the Infrared Atmospheric Sounding Interferometer instrument, IASI, and the Ozone Monitoring Instrument, OMI) for several days. The change from the classical Van Leer (1977) scheme to the Després and Lagoutière (1999) anti-diffusive scheme in the vertical direction was shown to provide the largest improvement to model outputs in terms of preserving the thin plume emitted by the volcano. To a lesser extent, the improved representation of the vertical wind field was also shown to reduce plume dispersion. Both of these changes helped to reduce vertical diffusion in the model as much as a brute-force approach (increasing vertical resolution).

We present version 3 (V3) of the Cloud_cci Along-Track Scanning Radiometer (ATSR) and Advanced ATSR (AATSR) data set. The data set was created for the European Space Agency (ESA) Cloud_cci (Climate Change Initiative) programme. The cloud properties were retrieved from the second ATSR (ATSR-2) on board the second European Remote Sensing Satellite (ERS-2) spanning 1995–2003 and the AATSR on board Envisat, which spanned 2002–2012. The data are comprised of a comprehensive set of cloud properties: cloud top height, temperature, pressure, spectral albedo, cloud effective emissivity, effective radius, and optical thickness, alongside derived liquid and ice water path. Each retrieval is provided with its associated uncertainty. The cloud property retrievals are accompanied by high-resolution top- and bottom-of-atmosphere shortwave and longwave fluxes that have been derived from the retrieved cloud properties using a radiative transfer model. The fluxes were generated for all-sky and clear-sky conditions. V3 differs from the previous version 2 (V2) through development of the retrieval algorithm and attention to the consistency between the ATSR-2 and AATSR instruments. The cloud properties show improved accuracy in validation and better consistency between the two instruments, as demonstrated by a comparison of cloud mask and cloud height with co-located CALIPSO data. The cloud masking has improved significantly, particularly in its ability to detect clear pixels. The Kuiper Skill score has increased from 0.49 to 0.66. The cloud top height accuracy is relatively unchanged. The AATSR liquid water path was compared with the Multisensor Advanced Climatology of Liquid Water Path (MAC-LWP) in regions of stratocumulus cloud and shown to have very good agreement and improved consistency between ATSR-2 and AATSR instruments. The correlation with MAC-LWP increased from 0.4 to over 0.8 for these cloud regions. The flux products are compared with NASA Clouds and the Earth's Radiant Energy System (CERES) data, showing good agreement within the uncertainty. The new data set is well suited to a wide range of climate applications, such as comparison with climate models, investigation of trends in cloud properties, understanding aerosol–cloud interactions, and providing contextual information for co-located ATSR-2/AATSR surface temperature and aerosol products. The following new digital identifier has been issued for the Cloud_cci ATSR-2/AATSRv3 data set: https://doi.org/10.5676/DWD/ESA_Cloud_cci/ATSR2-AATSR/V003 (Poulsen et al., 2019).

We developed an optimal-estimation algorithm to simultaneously retrieve, for the first time, coexisting volcanic gaseous SO2 and sulfate aerosols (SA) from ground-based Fourier transform infrared (FTIR) observations. These effluents, both linked to magmatic degassing process and subsequent atmospheric evolution processes, have overlapping spectral signatures leading to mutual potential interferences when retrieving one species without considering the other. We show that significant overestimations may be introduced in SO2 retrievals if the radiative impact of coexistent SA is not accounted for, which may have impacted existing SO2 long-term series, e.g. from satellite platforms. The method was applied to proximal observations at Masaya volcano, where SO2 and SA concentrations, and SA acidity, were retrieved. A gas-to-particle sulfur partitioning of 400 and a strong SA acidity (sulfuric acid concentration: 65 %) were found, consistent with past in situ observations at this volcano. This method is easily exportable to other volcanoes to monitor magma extraction processes and the atmospheric sulfur cycle in the case of ash-free plumes.

Ash clouds are a geographically far-reaching hazard associated with volcanic eruptions. To minimise the risk that these pose to aircraft and to limit disruption to the aviation industry, it is important to closely monitor the emission and atmospheric dispersion of these plumes. The altitude of the plume is an important consideration and is an essential input into many models of ash cloud propagation. CO2 slicing is an established technique for obtaining the top height of aqueous clouds, and previous studies have demonstrated that there is potential for this method to be used for volcanic ash. In this study, the CO2 slicing technique has been adapted for volcanic ash and applied to spectra obtained from the Infrared Atmospheric Sounding Interferometer (IASI). Simulated ash spectra are first used to select the most appropriate channels and then demonstrate that the technique has merit for determining the altitude of the ash. These results indicate a strong match between the true heights and CO2 slicing output with a root mean square error (RMSE) of less than 800 m. Following this, the technique was applied to spectra obtained with IASI during the Eyjafjallajökull and Grímsvötn eruptions in 2010 and 2011 respectively, both of which emitted ash clouds into the troposphere, and which have been extensively studied with satellite imagery. The CO2 slicing results were compared against those from an optimal estimation scheme, also developed for IASI, and a satellite-borne lidar is used for validation. The CO2 slicing heights returned an RMSE value of 2.2 km when compared against the lidar. This is lower than the RMSE for the optimal estimation scheme (2.8 km). The CO2 slicing technique is a relatively fast tool and the results suggest that this method could be used to get a first approximation of the ash cloud height, potentially for use for hazard mitigation, or as an input for other retrieval techniques or models of ash cloud propagation.

The 6-month-long 2014–2015 Holuhraun eruption was the largest in Iceland for 200 years, emitting huge quantities of sulfur dioxide (SO2) into the troposphere, at times overwhelming European anthropogenic emissions. Weather, terrain and latitude made continuous ground-based or UV satellite sensor measurements challenging. Infrared Atmospheric Sounding Interferometer (IASI) data are used to derive the first time series of daily SO2 mass present in the atmosphere and its vertical distribution over the entire eruption period. A new optimal estimation scheme is used to calculate daily SO2 fluxes and average e-folding time every 12 h. For the 6 months studied, the SO2 flux was observed to be up to 200 kt day−1 and the minimum total SO2 erupted mass was 4.4±0.8 Tg. The average SO2 e-folding time was 2.4±0.6 days. Where comparisons are possible, these results broadly agree with ground-based near-source measurements, independent remote-sensing data and values obtained from model simulations from a previous paper. The results highlight the importance of using high-resolution time series data to accurately estimate volcanic SO2 emissions. The SO2 mass missed due to thermal contrast is estimated to be of the order of 3 % of the total emission when compared to measurements by the Ozone Monitoring Instrument. A statistical correction for cloud based on the AVHRR cloud-CCI data set suggested that the SO2 mass missed due to cloud cover could be significant, up to a factor of 2 for the plume within the first kilometre from the vent. Applying this correction results in a total erupted mass of 6.7±0.4 Tg and little change in average e-folding time. The data set derived can be used for comparisons to other ground- and satellite-based measurements and to petrological estimates of the SO2 flux. It could also be used to initialise climate model simulations, helping to better quantify the environmental and climatic impacts of future Icelandic fissure eruptions and simulations of past large-scale flood lava eruptions.

This study focuses on two new aspects of inverse modelling of volcanic emissions. First, we derive an observation operator for satellite retrievals of plume height, and second, we solve the inverse problem using an algorithm based on the 4D-Var data assimilation method. The approach is first tested in a twin experiment with simulated observations and further evaluated by assimilating IASI SO2 plume height and total column retrievals in a source term inversion for the 2010 eruption of Eyjafjallajökull. The inversion resulted in temporal and vertical reconstruction of the SO2 emissions during 1–20 May 2010 with formal vertical and temporal resolutions of 500 m and 12 h.The plume height observation operator is based on simultaneous assimilation of the plume height and total column retrievals. The plume height is taken to represent the vertical centre of mass, which is transformed into the first moment of mass (centre of mass times total mass). This makes the observation operator linear and simple to implement. The necessary modifications to the observation error covariance matrix are derived.Regularization by truncated iteration is investigated as a simple and efficient regularization method for the 4D-Var-based inversion. In the twin experiments, the truncated iteration was found to perform similarly to the commonly used Tikhonov regularization, which in turn is equivalent to a Gaussian a priori source term. However, the truncated iteration allows the level of regularization to be determined a posteriori without repeating the inversion.In the twin experiments, assimilating the plume height retrievals resulted in a 5–20 % improvement in root mean squared error but simultaneously introduced a 10–20 % low bias on the total emission depending on assumed emission profile. The results are consistent with those obtained with real data. For Eyjafjallajökull, comparisons with observations showed that assimilating the plume height retrievals reduced the overestimation of injection height during individual periods of 1–3 days, but for most of the simulated 20 days, the injection height was constrained by meteorological conditions, and assimilation of the plume height retrievals had only small impact. The a posteriori source term for Eyjafjallajökull consisted of 0.29 Tg (with total column and plume height retrievals) or 0.33 Tg (with total column retrievals only) erupted SO2 of which 95 % was injected below 11 or 12 km, respectively.

A new optimal estimation algorithm for the retrieval of volcanic ash properties has been developed for use with the Infrared Atmospheric Sounding Interferometer (IASI). The retrieval method uses the wave number range 680–1200 cm−1, which contains window channels, the CO2 ν2 band (used for the height retrieval), and the O3 ν3 band.Assuming a single infinitely (geometrically) thin ash plume and combining this with the output from the radiative transfer model RTTOV, the retrieval algorithm produces the most probable values for the ash optical depth (AOD), particle effective radius, plume top height, and effective radiating temperature. A comprehensive uncertainty budget is obtained for each pixel. Improvements to the algorithm through the use of different measurement error covariance matrices are explored, comparing the results from a sensitivity study of the retrieval process using covariance matrices trained on either clear-sky or cloudy scenes. The result showed that, due to the smaller variance contained within it, the clear-sky covariance matrix is preferable. However, if the retrieval fails to pass the quality control tests, the cloudy covariance matrix is implemented.The retrieval algorithm is applied to scenes from the Eyjafjallajökull eruption in 2010, and the retrieved parameters are compared to ancillary data sources. The ash optical depth gives a root mean square error (RMSE) difference of 0.46 when compared to retrievals from the MODerate-resolution Imaging Spectroradiometer (MODIS) instrument for all pixels and an improved RMSE of 0.2 for low optical depths (AOD

The vulnerability of the European airspace to volcanic eruptions was brought to the attention of the public and the scientific community by the 2010 eruptions of the Icelandic volcano Eyjafjallajökull. As a consequence of this event, ash concentration thresholds replaced the “zero tolerance to ash” rule, drastically changing the requirements on satellite ash retrievals. In response to that, the ESA funded several projects aiming at creating an optimal end-to-end system for volcanic ash plume monitoring and prediction. Two of them, namely the SACS-2 and SMASH projects, developed and improved dedicated satellite-derived ash plume and sulfur dioxide level assessments. The validation of volcanic ash levels and height extracted from the GOME-2 and IASI instruments on board the MetOp-A satellite is presented in this work. EARLINET lidar measurements are compared to different satellite retrievals for two eruptive episodes in April and May 2010. Comparisons were also made between satellite retrievals and aircraft lidar data obtained with the UK's BAe-146-301 Atmospheric Research Aircraft (managed by the Facility for Airborne Atmospheric Measurements, FAAM) over the United Kingdom and the surrounding regions. The validation results are promising for most satellite products and are within the estimated uncertainties of each of the comparative data sets, but more collocation scenes would be desirable to perform a comprehensive statistical analysis. The satellite estimates and the validation data sets are better correlated for high ash optical depth values, with correlation coefficients greater than 0.8. The IASI retrievals show a better agreement concerning the ash optical depth and ash layer height when compared with the ground-based and airborne lidar data.

Sulfur dioxide (SO2) is an important atmospheric constituent that plays a crucial role in many atmospheric processes. Volcanic eruptions are a significant source of atmospheric SO2 and its effects and lifetime depend on the SO2 injection altitude. The Infrared Atmospheric Sounding Interferometer (IASI) on the METOP satellite can be used to study volcanic emission of SO2 using high-spectral resolution measurements from 1000 to 1200 and from 1300 to 1410 cm−1 (the 7.3 and 8.7 µm SO2 bands) returning both SO2 amount and altitude data. The scheme described in Carboni et al. (2012) has been applied to measure volcanic SO2 amount and altitude for 14 explosive eruptions from 2008 to 2012. The work includes a comparison with the following independent measurements: (i) the SO2 column amounts from the 2010 Eyjafjallajökull plumes have been compared with Brewer ground measurements over Europe; (ii) the SO2 plumes heights, for the 2010 Eyjafjallajökull and 2011 Grimsvötn eruptions, have been compared with CALIPSO backscatter profiles. The results of the comparisons show that IASI SO2 measurements are not affected by underlying cloud and are consistent (within the retrieved errors) with the other measurements. The series of analysed eruptions (2008 to 2012) show that the biggest emitter of volcanic SO2 was Nabro, followed by Kasatochi and Grímsvötn. Our observations also show a tendency for volcanic SO2 to reach the level of the tropopause during many of the moderately explosive eruptions observed. For the eruptions observed, this tendency was independent of the maximum amount of SO2 (e.g. 0.2 Tg for Dalafilla compared with 1.6 Tg for Nabro) and of the volcanic explosive index (between 3 and 5).

The impact of volcanic emissions, especially from passive degassing and minor explosions, is a source of uncertainty in estimations of aerosol indirect effects. Observations of the impact of volcanic aerosol on clouds contribute to our understanding of both present-day atmospheric properties and of the pre-industrial baseline necessary to assess aerosol radiative forcing. We present systematic measurements over several years at multiple active and inactive volcanic islands in regions of low present-day aerosol burden. The time-averaged indirect aerosol effects within 200 km downwind of island volcanoes are observed using Moderate Resolution Imaging Spectroradiometer (MODIS, 2002–2013) and Advanced Along-Track Scanning Radiometer (AATSR, 2002–2008) data. Retrievals of aerosol and cloud properties at Kīlauea (Hawai'i), Yasur (Vanuatu) and Piton de la Fournaise (la Réunion) are rotated about the volcanic vent to be parallel to wind direction, so that upwind and downwind retrievals can be compared. The emissions from all three volcanoes – including those from passive degassing, Strombolian activity and minor explosions – lead to measurably increased aerosol optical depth downwind of the active vent. Average cloud droplet effective radius is lower downwind of the volcano in all cases, with the peak difference ranging from 2–8 μm at the different volcanoes in different seasons. Estimations of the difference in Top of Atmosphere upward Short Wave flux upwind and downwind of the active volcanoes from NASA's Clouds and the Earth's Radiant Energy System (CERES) suggest a downwind elevation of between 10 and 45 Wm−2 at distances of 150–400 km from the volcano, with much greater local (< 80 km) effects. Comparison of these observations with cloud properties at isolated islands without degassing or erupting volcanoes suggests that these patterns are not purely orographic in origin. Our observations of unpolluted, isolated marine settings may capture processes similar to those in the pre-industrial marine atmosphere.

A new optimal estimation algorithm for the retrieval of sulphur dioxide (SO2) has been developed for the Infrared Atmospheric Sounding Interferometer (IASI) using the channels between 1000–1200 and 1300–1410 cm−1. These regions include the two SO2 absorption bands centred at about 8.7 and 7.3 μm (the ν1 and ν3 bands respectively). The retrieval assumes a Gaussian SO2 profile and returns the SO2 column amount in Dobson units and the altitude of the plume in millibars (mb). Forward modelled spectra (against which the measurements are compared) are based on the Radiative Transfer for TOVS (RTTOV) code. In our implementation RTTOV uses atmospheric profiles from European Centre for Medium-Range Weather Forecasts (ECMWF) meteorological data. The retrieval includes a comprehensive error budget for every pixel derived from an error covariance matrix that is based on the SO2-free climatology of the differences between the IASI and forward modelled spectra. The IASI forward model includes the ability to simulate a cloud or ash layer in the atmosphere. This feature is used to illustrate that: (1) the SO2 retrieval is not affected by underlying cloud but is affected if the SO2 is within or below a cloud layer; (2) it is possible to discern if ash (or other atmospheric constituents not considered in the error covariance matrix) affects the retrieval using quality control based on the fit of the measured spectrum by the forward modelled spectrum. In this work, the algorithm is applied to follow the behaviour of SO2 plumes from the Eyjafjallajökull eruption during April and May 2010. From 14 April to 4 May (during Phase I and II of the eruption) the total amount of SO2 present in the atmosphere, estimated by IASI measurements, is generally below 0.02 Tg. During the last part of the eruption (Phase III) the values are an order of magnitude higher, with a maximum of 0.18 Tg measured on the afternoon of 7 May.

This work provides a comparison of satellite retrievals of Saharan desert dust aerosol optical depth (AOD) during a strong dust event through March 2006. In this event, a large dust plume was transported over desert, vegetated, and ocean surfaces. The aim is to identify the differences between current datasets. The satellite instruments considered are AATSR, AIRS, MERIS, MISR, MODIS, OMI, POLDER, and SEVIRI. An interesting aspect is that the different algorithms make use of different instrument characteristics to obtain retrievals over bright surfaces. These include multi-angle approaches (MISR, AATSR), polarisation measurements (POLDER), single-view approaches using solar wavelengths (OMI, MODIS), and the thermal infrared spectral region (SEVIRI, AIRS). Differences between instruments, together with the comparison of different retrieval algorithms applied to measurements from the same instrument, provide a unique insight into the performance and characteristics of the various techniques employed. As well as the intercomparison between different satellite products, the AODs have also been compared to co-located AERONET data. Despite the fact that the agreement between satellite and AERONET AODs is reasonably good for all of the datasets, there are significant differences between them when compared to each other, especially over land. These differences are partially due to differences in the algorithms, such as assumptions about aerosol model and surface properties. However, in this comparison of spatially and temporally averaged data, it is important to note that differences in sampling, related to the actual footprint of each instrument on the heterogeneous aerosol field, cloud identification and the quality control flags of each dataset can be an important issue.

Fast and reliable methods for the detection of atmospheric trace species are needed for near-real-time applications including volcanic hazard avoidance. One common approach using hyperspectral instruments is to measure the difference in brightness temperature between a small number of target sensitive and background channels to determine the presence of the target species. Although fast and robust, current brightness temperature difference methods do not fully exploit the spectral range and resolution of hyperspectral instruments, and the noise associated with the measurements remains high. In this paper, we describe a way to make full use of the spectral information from hyperspectral sounders allowing the presence of the target species to be determined with much better sensitivity in near-real-time if required. The technique is demonstrated using the MetOp Infrared Atmospheric Sounding Interferometer considering two case studies: (a) the detection of sulphur dioxide from the eruption of the Kasatochi volcano in Alaska in August 2008, and (b) the detection of ammonia emissions related to agriculture over Southern Asia in May 2008. The performance of this method is compared against that of existing brightness temperature difference methods. It is found that the sensitivity of the detection of these trace species is improved by up to an order of magnitude.

The Global Retrieval of ATSR Cloud Parameters and Evaluation (GRAPE) project has produced a global data-set of cloud and aerosol properties from the Along Track Scanning Radiometer-2 (ATSR-2) instrument, covering the time period 1995–2001. This paper presents the validation of aerosol optical depths (AODs) over the ocean from this product against AERONET sun-photometer measurements, as well as a comparison to the Advanced Very High Resolution Radiometer (AVHRR) optical depth product produced by the Global Aerosol Climatology Project (GACP). The GRAPE AOD over ocean is found to be in good agreement with AERONET measurements, with a Pearson's correlation coefficient of 0.79 and a best-fit slope of 1.0±0.1, but with a positive bias of 0.08±0.04. Although the GRAPE and GACP datasets show reasonable agreement, there are significant differences. These discrepancies are explored, and suggest that the downward trend in AOD reported by GACP may arise from changes in sampling due to the orbital drift of the AVHRR instruments.

The aerosol component of the Oxford-Rutherford Aerosol and Cloud (ORAC) combined cloud and aerosol retrieval scheme is described and the theoretical performance of the algorithm is analysed. ORAC is an optimal estimation retrieval scheme for deriving cloud and aerosol properties from measurements made by imaging satellite radiometers and, when applied to cloud free radiances, provides estimates of aerosol optical depth at a wavelength of 550 nm, aerosol effective radius and surface reflectance at 550 nm. The aerosol retrieval component of ORAC has several incarnations – this paper addresses the version which operates in conjunction with the cloud retrieval component of ORAC (described by Watts et al., 1998), as applied in producing the Global Retrieval of ATSR Cloud Parameters and Evaluation (GRAPE) data-set. The algorithm is described in detail and its performance examined. This includes a discussion of errors resulting from the formulation of the forward model, sensitivity of the retrieval to the measurements and a priori constraints, and errors resulting from assumptions made about the atmospheric/surface state.

Abstract Sulforaphane (SFN) is an isothiocyanate‐type phytomolecule present in crucifers, which is mainly synthesized in response to biotic stress. In animals, SFN incorporated in the diet has anticancer properties among others. The mechanism of action and signaling are well described in animals; however, little is known in plants. The goal in the present study is to elucidate components of the SFN signaling pathway, particularly the production of reactive oxygen species (ROS), and its effect on the transcriptome. Our results showed that in Arabidopsis, SFN causes ROS production exclusively through the action of the NADPH oxidase RBOH isoform D that requires calcium as a signaling component for the ROS production. To add to this, we also analyzed the effect of SFN on the transcriptome by RNAseq. We observed the highest expression increase for heat shock proteins (HSP) genes and also for genes associated with the response to oxidative stress. The upregulation of several genes linked to the biotic stress response confirms the interplay between SFN and this stress. In addition, SFN increases the levels of transcripts related to the response to abiotic stress, as well as phytohormones. Taken together, these results indicate that SFN induces an oxidative burst leading to signaling events. This oxidative burst may cause the increase of the expression of genes such as heat shock proteins to restore cellular homeostasis and genes that codify possible components of the signaling pathway and putative effectors.

Background: The aim of this extended review of multicenter case series is to describe the prenatal ultrasound features and pathogenetic mechanisms underlying placental and umbilical cord anomalies and their relationship with adverse perinatal outcome. From an educational point of view, the case series has been divided in three parts; Part 1 is dedicated to placental abnormalities., Methods: Multicenter case series of women undergoing routine and extended prenatal ultrasound and perinatal obstetric care., Results: Prenatal ultrasound findings, perinatal care, and pathology documentation in cases of placental pathology are presented., Conclusions: Our case series review and that of the medical literature confirms the ethiopathogenetic role and involvement of placenta abnormalities in a wide variety of obstetrics diseases that may jeopardize the fetal well-being. Some of these specific pathologies are strongly associated with a high risk of poor perinatal outcome., (© 2024 Wiley Periodicals LLC.)

Adolescent stress (AS) has been associated with higher vulnerability to psychiatric disorders such as schizophrenia, depression, or drug dependence. Moreover, the alteration of brain catecholamine (CAT) transmission in the medial prefrontal cortex (mPFC) has been found to play a major role in the etiology of psychiatric disturbances. We investigated the effect of adolescent stress on CAT transmission in the mPFC of freely moving adult rats because of the importance of this area in the etiology of psychiatric disorders, and because CAT transmission is the target of a relevant group of drugs used in the therapy of depression and psychosis. We assessed basal dopamine (DA) and norepinephrine (NE) extracellular concentrations (output) by brain microdialysis in in the mPFC of adult rats that were exposed to chronic mild stress in adolescence. To ascertain the role of an altered release or reuptake, we stimulated DA and NE output by administering either different doses of amphetamine (0.5 and 1.0 mg / kg s.c.), which by a complex mechanism determines a dose dependent increase in the CAT output, or reboxetine (10 mg/kg i.p.), a selective NE reuptake inhibitor. The results showed the following: (i) basal DA output in AS rats was lower than in controls, while no difference in basal NE output was observed; (ii) amphetamine, dose dependently, stimulated DA and NE output to a greater extent in AS rats than in controls; (iii) reboxetine stimulated NE output to a greater extent in AS rats than in controls, while no difference in stimulated DA output was observed between the two groups. These results show that AS determines enduring effects on DA and NE transmission in the mPFC and might lead to the occurrence of psychiatric disorders or increase the vulnerability to drug addiction., Competing Interests: Declaration of competing interest On the behave of all authors I declare that all authors have no conflict of interest or any financial and personal relationships with other people or organizations that could inappropriately influence (bias) our work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, which weakens the development and administration of proper therapies. In an α-synuclein (αSyn)-based model of PD featuring early motor and cognitive impairments, we investigated the transcriptome profile of brain regions involved in PD with cognitive deficits, via a transcriptomic analysis based on RNA sequencing (RNA-seq) technology. Rats infused in the substantia nigra with human α-synuclein oligomers (H-SynOs) developed mild cognitive deficits after three months, as measured by the two-trial recognition test in a Y-maze and the novel object recognition test. RNA-seq analysis showed that 17,436 genes were expressed in the anterior cingulate cortex (ACC) and 17,216 genes in the hippocampus (HC). In the ACC, 51 genes were differentially expressed between vehicle and H-αSynOs treated samples, which showed N= 21 upregulated and N = 30 downregulated genes. In the HC, 104 genes were differentially expressed, the majority of them not overlapping with DEGs in the ACC, with N = 41 upregulated and N = 63 downregulated in H-αSynOs-treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related with immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Immunofluorescence analysis confirmed the decreased expression of CD68 within microglial cells. In contrast, the most significantly enriched terms in the HC were mainly involved in mitochondrial homeostasis, potassium voltage-gated channel, cytoskeleton and fiber organisation, suggesting that the gene expression in the neuronal population was mostly affected in this region in early disease stages. Altogether results show that H-αSynOs trigger a region-specific dysregulation of gene expression in ACC and HC, providing a pathological substrate for MCI associated with early PD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abnormal metal distribution in vulnerable brain regions is involved in the pathogenesis of most neurodegenerative diseases, suggesting common molecular mechanisms of metal dyshomeostasis. This study aimed to compare the intra- and extra-neuronal metal content and the expression of proteins related to metal homeostasis in the substantia nigra (SN) from patients with Parkinson's disease (PD), multiple sclerosis (MS), and control subjects. Metal quantification was performed via ion-beam micro-analysis in neuromelanin-positive neurons and the surrounding tissue. For proteomic analysis, SN tissue lysates were analyzed on a nanoflow chromatography system hyphenated to a hybrid triple-quadrupole time-of-flight mass spectrometer. We found increased amounts of iron in neuromelanin-positive neurons and surrounding tissue in patients with PD and MS compared to controls (4- to 5-fold higher) that, however, also showed large inter-individual variations. Copper content was systematically lower (-2.4-fold) in neuromelanin-positive neurons of PD patients compared with controls, whereas it remained unchanged in MS. Protein-protein interaction (PPI) network analyses revealed clusters related to Fe and Cu homeostasis among PD-deregulated proteins. An enrichment for the term "metal homeostasis" was observed for MS-deregulated proteins. Important deregulated hub proteins included hemopexin and transferrin in PD, and calreticulin and ferredoxin reductase in MS. Our findings show that PD and MS share commonalities in terms of iron accumulation in the SN. Concomitant proteomics experiments revealed PPI networks related to metal homeostasis, substantiating the results of metal quantification., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: (1) The aim of this article is to describe the physiopathology underlying umbilical cord diseases and their relationship with obstetric and perinatal outcomes. (2) Methods: Multicenter case series of umbilical cord diseases with illustrations from contributing institutions are presented. (3) Results: Clinical presentations of prenatal ultrasound findings, clinical prenatal features and postnatal outcomes are described. (4) Conclusions: Analysis of our series presents and discusses how umbilical cord diseases are associated with a wide variety of obstetric complications leading to a higher risk of poor perinatal outcomes in pregnancies. Knowing the physiopathology, prenatal clinical presentations and outcomes related to umbilical diseases allow for better prenatal counseling and management to potentially avoid severe obstetric and perinatal complications.

Parkinson's disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease's motor and non-motor aspects. Here, we show that the bilateral intracerebral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc) offers a valid model for studying the cognitive symptoms of PD, which adds to the classical motor aspects previously described in the same model. Indeed, H-αSynOs-infused rats displayed memory deficits in the two-trial recognition task in a Y maze and the novel object recognition (NOR) test performed three months after the oligomer infusion. In the anterior cingulate cortex (ACC) of H-αSynOs-infused rats the in vivo electrophysiological activity was altered and the expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) and the AMPA receptor subunit GluR1 were decreased. The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in cognition-related regions such as the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. We found an increased GFAP reactivity and the acquisition of a proinflammatory phenotype by microglia, as indicated by the increased levels of microglial Tumor Necrosis Factor alpha (TNF-α) as compared to vehicle-infused rats. Moreover, diffused deposits of phospho-alpha synuclein (p-αSyn) and Lewy neurite-like aggregates were found in the SNpc and striatum, suggesting the spreading of toxic protein within anatomically interconnected areas. Altogether, we present a neuropathological rat model of PD that is relevant for the study of cognitive dysfunction featuring the disease. The intranigral infusion of toxic oligomeric species of alpha-synuclein (α-Syn) induced spreading and neuroinflammation in distant cognition-relevant regions, which may drive the altered neuronal activity underlying cognitive deficits.

Major depressive disorder is one of the primary causes of disability and disease worldwide. The therapy of depression is prevalently based on monoamine reuptake blockers; consequently, investigations aimed to clarify the aetiology of depression have mostly looked at brain areas innervated by monamines and brain circuitry involved in inputs and outputs of these areas. The recent approval of esketamine as a rapid-acting antidepressant drug in treatment-resistant depression, has definitively projected glutamatergic transmission as a key constituent in the use of new drugs in antidepressant therapy. In this review we have examined the role of several brain areas: namely, the hippocampus, the medial Prefrontal Cortex (mPFC), the nucleus accumbens (NAc), the Lateral Habenula (LHb), the amygdala and the Bed Nucleus of Stria Terminalis (BNST). The reason for undertaking an in-depth review is due to their significant role in animal models of depression, which highlight their inter-connections as well as their inputs and outputs. In particular, we examined the modification of the expression and release of the brain derived neurotrophic factor (BDNF) and associated changes in dendritic density induced by chronic stress in the above areas of animal models of depression (AnMD). We also examined the effectiveness of ketamine and standard antidepressants in reversing these alterations, with the aim of identifying a brain circuit where pathological alteration might trigger the appearance of depression symptoms. Based on the role that these brain areas play in the generation of the symptoms of depression, we assumed that the mPFC, the NAc/Ventral Tegmental Area (VTA) and the hippocampus form a primary circuit of depression, where regular performance can endure resilience to stress. We have also examined how this circuit is affected by environmental challenges and how the activation of one or more areas, including amygdala, LHb or BNST can produce local detrimental effects that spread over specific circuits and generate depression symptoms. Furthermore, we also examined how, through their outputs, these three areas can negatively influence the NAc/VTA-PFC circuit directly or through the BNST, to generate anhedonia, one of the most devastating symptoms of depression., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Currently, there are a few detailed guidelines on the overall management of children and adolescents with moderate-severe atopic dermatitis. AD ​​is a complex disease presenting with different clinical phenotypes, which require an individualized and multidisciplinary approach. Therefore, appropriate interaction between primary care pediatricians, pediatric allergists, and pediatric dermatologists is crucial to finding the best management strategy. In this manuscript, members of the Italian Society of Pediatric Allergology and Immunology (SIAIP), the Italian Society of Pediatric Dermatology (SIDerP), and the Italian Society of Pediatrics (SIP) with expertise in the management of moderate-severe atopic dermatitis have reviewed the latest scientific evidence in the field. This narrative review aims to define a pathway to appropriately managing children and adolescents with moderate-severe atopic dermatitis., (© 2022. The Author(s).)

Competing Interests: The authors declare that they have no conflict of interest.

Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients., (© 2022. The Author(s).)

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder whose prevalence is rapidly increasing worldwide. The molecular mechanisms underpinning the pathophysiology of sporadic PD remain incompletely understood. Therefore, causative therapies are still elusive. To obtain a more integrative view of disease-mediated alterations, we investigated the molecular landscape of PD in human post-mortem midbrains, a region that is highly affected during the disease process., Methods: Tissue from 19 PD patients and 12 controls were obtained from the Parkinson's UK Brain Bank and subjected to multi-omic analyses: small and total RNA sequencing was performed on an Illumina's HiSeq4000, while proteomics experiments were performed in a hybrid triple quadrupole-time of flight mass spectrometer (TripleTOF5600+) following quantitative sequential window acquisition of all theoretical mass spectra. Differential expression analyses were performed with customized frameworks based on DESeq2 (for RNA sequencing) and with Perseus v.1.5.6.0 (for proteomics). Custom pipelines in R were used for integrative studies., Results: Our analyses revealed multiple deregulated molecular targets linked to known disease mechanisms in PD as well as to novel processes. We have identified and experimentally validated (quantitative real-time polymerase chain reaction/western blotting) several PD-deregulated molecular candidates, including miR-539-3p, miR-376a-5p, miR-218-5p and miR-369-3p, the valid miRNA-mRNA interacting pairs miR-218-5p/RAB6C and miR-369-3p/GTF2H3, as well as multiple proteins, such as CHI3L1, HSPA1B, FNIP2 and TH. Vertical integration of multi-omic analyses allowed validating disease-mediated alterations across different molecular layers. Next to the identification of individual molecular targets in all explored omics layers, functional annotation of differentially expressed molecules showed an enrichment of pathways related to neuroinflammation, mitochondrial dysfunction and defects in synaptic function., Conclusions: This comprehensive assessment of PD-affected and control human midbrains revealed multiple molecular targets and networks that are relevant to the disease mechanism of advanced PD. The integrative analyses of multiple omics layers underscore the importance of neuroinflammation, immune response activation, mitochondrial and synaptic dysfunction as putative therapeutic targets for advanced PD., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Regional iron accumulation and α-synuclein (α-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α-syn, facilitating its aggregation and regulating α-syn expression, it remains unclear if and how iron also modulates α-syn spreading. To elucidate the influence of iron on the propagation of α-syn pathology, we investigated α-syn spreading after stereotactic injection of α-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5-µg PFFs were performed to induce seeding of α-syn aggregates. At 90 days post-injection, PFFs-injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of α-syn phosphorylated at S129 showed reduced α-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans-synaptic α-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that α-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome., (© 2021 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

During the initial phase of the national lockdown, we found that there were sharp decreases in admissions to two pediatric emergency departments (EDs) in northern Italy (Cremona and Novara). Here we present a detailed analysis of these admission patterns and types of admissions over a longer timeframe. ED admissions data were anonymously extracted from the departmental management software. Admissions data from 2019 and 2020 were analyzed and compared separately for each ED and combined. There was a 73.2% decrease in total admissions compared with the same period in 2019. With respect to admission diagnoses, there was a significant ( p < 0.001) drop in infectious (-51%), respiratory (-25.5%), and nervous systems diseases (-50%) and injuries and poisoning (-17%) but not endocrine, metabolic, neoplastic, circulatory, or musculoskeletal diseases. White codes (patients with minor injuries for whom ED medical care is not required) significantly decreased by 56.3% ( p < 0.001). Even if the COVID-19 pandemic represented an enormous healthcare burden in Italy, especially during the first months of the pandemic (late February to May), the workload of pediatric EDs was significantly reduced, especially for unnecessary accesses (white codes).

In order to automate the counting of ovarian follicles required in multigeneration reproductive studies performed in the rat according to Organization for Economic Co-operation and Development guidelines 443 and 416, the application of deep neural networks was tested. The manual evaluation of the differential ovarian follicle count is a tedious and time-consuming task that requires highly trained personnel. In this regard, deep learning outputs provide overlay pictures for a more detailed documentation, together with an increased reproducibility of the counts. To facilitate the planned good laboratory practice (GLP) validation a workflow was set up using MLFlow to make all steps from generating of scans, training of the neural network, uploading of study images to the neural network, generation and storage of the results in a compliant manner controllable and reproducible. PyTorch was used as main framework to build the Faster region-based convolutional neural network for the training. We compared the performances of different depths of ResNet models with specific regard to the sensitivity, specificity, accuracy of the models. In this paper, we describe all steps from data labeling, training of networks, and the performance metrics chosen to evaluate different network architectures. We also make recommendation on steps, which should be taken into consideration when GLP validation is aimed for.

Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine's use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carboni, Carta, Carboni and Novelli.)

The bed nucleus of stria terminalis (BNST) is a complex limbic area involved in neuroendocrine and behavioural responses and, in particular, in the modulation of the stress response. BNST is innervated by dopamine and norepinephrine, which are known to be involved in drug addiction. It is also known that several drugs of abuse increase dopamine transmission in the BNST, but there has been less research regarding the effect on norepinephrine transmission. Here, we have used the microdialysis technique to investigate the effect of several drugs of abuse on norepinephrine transmission in the BNST of freely moving rats. We observed that nicotine (0.2-0.4 mg/kg), cocaine (2.5-5 mg/kg), amphetamine (0.25-0.5 mg/kg), and ethanol (0.5-1.0 g/kg), dose-dependently increased norepinephrine output while the effect of morphine at 3.0 was lower than that of 1.0 mg/kg. These results suggest that many drugs of abuse, though possessing diverse mechanisms of action, share the property of increasing norepinephrine transmission in the BNST. Furthermore, we suggest that the recurring activation of NE transmission in the BNST, due to drug administration, contributes to the alteration of the function that BNST assumes in how the behavioural response to stress manifests, favouring the establishment of the stress-induced drug seeking., (© 2019 Society for the Study of Addiction.)

The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson's disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.

Parkinson's disease (PD) is considered a synucleinopathy because of the intraneuronal accumulation of aggregated α-synuclein (αSyn). Recent evidence points to soluble αSyn-oligomers (αSynO) as the main cytotoxic species responsible for cell death. Given the pivotal role of αSyn in PD, αSyn-based models are crucial for the investigation of toxic mechanisms and the identification of new therapeutic targets in PD. By using a metabolomics approach, we evaluated the metabolic profile of brain and serum samples of rats infused unilaterally with preformed human αSynOs (HαSynOs), or vehicle, into the substantia nigra pars compacta (SNpc). Three months postinfusion, the striatum was dissected for striatal dopamine (DA) measurements via High Pressure Liquid Chromatography (HPLC) analysis and mesencephalon and serum samples were collected for the evaluation of metabolite content via gas chromatography mass spectrometry analysis. Multivariate, univariate and correlation statistics were applied. A 40% decrease of DA content was measured in the HαSynO-infused striatum as compared to the contralateral and the vehicle-infused striata. Decreased levels of dehydroascorbic acid, myo-inositol, and glycine, and increased levels of threonine, were found in the mesencephalon, while increased contents of fructose and mannose, and a decrease in glycine and urea, were found in the serum of HαSynO-infused rats. The significant correlation between DA and metabolite content indicated that metabolic variations reflected the nigrostriatal degeneration. Collectively, the metabolomic fingerprint of HαSynO-infused rats points to an increase of oxidative stress markers, in line with PD neuropathology, and provides hints for potential biomarkers of PD.

Mucolipidosis II and III are lysosomal storage diseases caused by pathogenetic mutations in GNPTAB and GNPTG genes which cause an impaired activity of the lysosomal hydrolase N-acetylglucosamine- 1-phosphotransferase, a key enzyme in the synthesis of the mannose-6-phosphate targeting signals on lysosomal enzymes. Patients with MLII alpha/beta present coarse facial features, cessation of statural growth, important skeletal manifestations, impaired neuromotor development and cardiorespiratory involvement. All children appear to have cardiac involvement, but severe dilated cardiomyopathy is uncommon. In this report we describe the case of an 11-month-old girl who is affected by a MLII. Analysis of the GNPTAB gene identified at a heterozygous level the previously described gene variants c. 2693delA p(Lys898Serfs*13) and c. 2956C>T p(Arg986Cys). Her main clinical features were coarse face with gingival hypertrophy, dysostosis multiplex, recurrent respiratory infection and an early onset of dilated cardiomyopathy, an uncommon feature for MLII. To our knowledge, dilated cardiomyopathy has been previously described in literature in only two cases of MLII and in one patient affected by MLIII., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic disease (COVID-19) that has spread globally causing more than 30,000 deaths. Despite the immense and ongoing global effort, no efficacious drugs to fight this plague have been identified and patients admitted to the intensive care units (ICU), for respiratory distress, are managed mostly by means of supportive care based on oxygen maintenance. Several authors have reported that the prevalence of hypertension, diabetes, cardiovascular and cerebrovascular diseases comorbidities were indeed frequent among patients with COVID-19, which suggests that these conditions are likely to aggravate and complicate the prognosis. What the aforementioned diseases have in common is a latent chronic inflammatory state that may be associated with the alteration of laboratory parameters that are typical of the metabolic syndrome and insulin resistance. In severe COVID-19 patients laboratory markers of inflammation such as C-reactive protein, IL-6, D-dimer, serum ferritin and lactate dehydrogenase are elevated in many patients; assessed since the 4th-6th day of illness onset, such increases seem to be predictive of an adverse prognosis. Our hypothesis is that drugs belonging to the family of thiazolidinediones (TZD) such as pioglitazone or rosiglitazone, approved for treating the condition of insulin resistance and the accompanying inflammation, could ameliorate the prognosis of those COVID-19 patients with diabetes, hypertension and cardiovascular disorders comorbidities. TZD are PPARγ agonists that act on nuclear receptors, thereby triggering certain transcription factors. TZD were widely used for type-2 diabetes in the first decade of this century and although concerns have been raised for possible side effects associated with long-term treatment, their use has been recently revaluated for their anti-inflammatory properties in numerous medical conditions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Elsevier Ltd. All rights reserved.)

Aggregates of alpha-synuclein (αSyn) have been described in Parkinson's disease (PD) patients, and recent evidence has suggested that the most toxic αSyn species in PD are small soluble aggregates including oligomers, prefibrils, protofibrils. The physiological function of αSyn is still highly debated, with a possible role in synaptic vesicle trafficking and release at the presynaptic compartment, and in the regulation of gene expression in the nucleus. Emerging evidence indicate that most of αSyn functions are related with the crucial ability to bind biological membranes, which is associated with structural conversion from a disordered monomer to an α-helical enriched structure. Conformational properties of αSyn can be modulated by a number of factors including post-translational modifications, gene duplication and triplication-driven overexpression, single point mutations, environmental changes, which affect membrane binding and the protein propensity to aggregate in toxic species. The recognized toxic role of αSyn in PD has laid the rational for purposing of αSyn-based, neuropathologically relevant preclinical models of PD. Different approaches have led to the establishment of transgenic models, viral vector-based models, and more recently models based on the intracerebral inoculation of exogenous αSyn preformed fibrils/oligomers. Here, we overview and compare viral vector-based models of αSyn overexpression and models obtained by direct intracerebral infusion of in vitro preformed αSyn species. The advantages and pitfalls associated with these different approaches are discussed., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose of Review: In allergy, personalized medicine passes through the assessment of molecular allergens sensitization profiles. Such technique may help to better diagnose and treat patients suffering from allergic respiratory diseases., Recent Findings: Different laboratory tests are available today to assess sensitization to molecular allergens, from singleplex assays, to unspecific, screening multiplex assays, mainly performed through microarrays or macroarrays. It is important to collect both results from specific IgE toward allergen extracts and toward molecular allergens, to collect the most complete information on the patient's profile, and therefore to highlight genuine sensitization, and exclude cross-reaction and sensitization because of pan-allergens. Being able to know the exact molecular sensitization profile of the patient, also helps predicting the possible evolution of the disease, and targeting the most appropriate allergen immunotherapy treatment to prescribe., Summary: Even though a cost-effective analysis of running multiple assays in allergic patients has not been performed yet, such technique proved to be more efficient in detecting the appropriate treatment in each patient and in analyzing the true sensitization profile in patients suffering from allergic rhinitis, conjunctivitis, and asthma.

Yolk sac tumor (YST) is a rare tumor that usually occurs in the first two decades of life. It is considered the second most common malignant germ cell tumor of the ovary, characterized by a rapid growth and a bad prognosis due to the frequent metastasis. We report the case of a 12-year-old girl who came to our observation for an acute abdominal pain. Clinical examination evidenced a vague mass in the suprapubic region and a lower abdomen tenderness, the US imaging revealed a complex lesion of the left ovary (19 x 13 cm) and the alpha-fetoprotein (AFP) resulted high (5858 ng/mL). Computed tomography (CT) revealed a large pelvic mass. The treatment consisted of debulking surgery of yolk sac tumor followed by 4 cycles of BEP protocol (Bleomycin, Etoposide, Cisplatin). After 3 years of follow-up there was no evidence of disease recurrence. (www.actabiomedica.it).

Background: Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model., Methods: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control., Results: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels., Conclusions: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates., Competing Interests: The authors declare no conflict of interest.

We present a case of an 11-month-old girl who was referred to our unit for an erythematous rash that appeared on the face and extremities. Personal and family history was not relevant. Laboratory tests were normal. During recovery, diameter and colour intensity of the cutaneous lesions increased, but after some weeks, lesions had a self-limited resolution without any treatment. Based on clinical and laboratory findings, a diagnosis of acute hemorrhagic edema of infancy (AHEI) was made.  AHEI is a rare cutaneous leukocytoclastic vasculitis that usually affects children aged between 4 and 24 months. Etiology is unknown but almost of 75% of cases are preceded by infectious episodes, vaccinations or use of medications. In contrast to the dramatic cutaneous eruption, clinical conditions are usually optimal. Classically, AHEI is characterized by a triad of symptoms: fever, edema and purpura. Skin lesions are erythematous, annular, medallion-like, purpuric plaques that have a rapid onset and appear on the face and extremities, sparing trunk and mucosal membranes. Initially interpreted as a variant of Henoch-Schönlein purpura, now it is considered a distinct disease. In the majority of cases the disease is benign and self-limited without a visceral involvement, so a conservative approach is most often chosen., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Carboni E et al.)

Down Syndrome (DS) is an essential genetic disease that involves many other body systems along with cerebral functions. The postnatal approach to treat this genetic disease includes intervention on various related disorders (e.g., heart failure, respiratory, oral, ear, and hearing disorders). However, different proposed treatments do not significantly improve the quality of life of these subjects. Another approach to the treatment of DS considering the possibility to intervene on the embryo was recently introduced. As of this, the current study has reviewed different outcomes regarding DS treatment in an animal model, namely the Ts65Dn mouse. The obtained results encouraged spending more time, efforts, and resources in this field. Besides, various treatment strategies were tried to include genetic modification, treatment with vasoactive intestinal peptide derivatives or fluoxetine. However, the main obstacle to the use of these possible treatments is the ethical issues it raises. The progression of the pregnancy in spite of awareness that DS affects the unborn and prenatal treatment of DS injured embryo are relevant dilemmas. Thus, talented researchers should spend more efforts to improve the quality of life for people affected by DS, which will allow probably a better approach to the ethical issues., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To identify factors that discriminate between transient and permanent congenital hypothyroidism., Methods: Retrospective evaluation of 58 children with congenital hypothyroidism and eutopic thyroid gland. Gender, gestational age, birth weight, TSH and serum thyroxine levels at diagnosis and L-thyroxine dose at 12 and 24 months of age were analyzed., Results: Median (IQR) initial TSH levels were 73.3 (276.5) µIU/mL in permanent hypothyroidism and 24.24 (52.7) µU/mL in transient hypothyroidism (P =0.0132). The optimum cut-off value of initial TSH to predict transient hypothyroidism was 90 µIU/mL. Mean (SD) L-thyroxine doses at 24 months of age were 2.64 (0.98) µg/kg/day in permanent hypothyroidism and 1.91 (0.65) µg/kg/day in transient hypothyroidism. Requirement of L-thyroxine dose at 24 months of ≤0.94 µg/kg/day had the highest sensitivity (100%) to predict transient hypothyroidism., Conclusions: L-thyroxine doses at 24 months can predict transient hypothyroidism in patients with eutopic thyroid gland earlier than at 36 months.

We have used scanning X-ray diffraction (XRD) and X-ray fluorescence (XRF) with micro-focused synchrotron radiation to study histological sections from human substantia nigra (SN). Both XRF and XRD mappings visualize tissue properties, which are inaccessible by conventional microscopy and histology. We propose to use these advanced tools to characterize neuronal tissue in neurodegeneration, in particular in Parkinson's disease (PD). To this end, we take advantage of the recent experimental progress in x-ray focusing, detection, and use automated data analysis scripts to enable quantitative analysis of large field of views. XRD signals are recorded and analyzed both in the regime of small-angle (SAXS) and wide-angle x-ray scattering (WAXS). The SAXS signal was analyzed in view of the local myelin structure, while WAXS was used to identify crystalline deposits. PD tissue scans exhibited increased amounts of crystallized cholesterol. The XRF analysis showed increased amounts of iron and decreased amounts of copper in the PD tissue compared to the control., Competing Interests: The authors declare that there are no conflicts of interest related to this article.