Intranasal dexmedetomidine and intranasal ketamine association allows shorter induction time for pediatric sedation compared to intranasal dexmedetomidine and oral midazolam

Background: Non-painful diagnostic procedures require an inactive state for a prolonged time, so that sedation is often needed in younger children to perform the procedures. Our standard of care in this setting consists of the association between oral midazolam (0.5 mg/kg) and intranasal dexmedetomidine (4 mcg/kg). One of the limits of this approach is that the onset of action is quite delayed (up to 55 min) and poorly predictable. We chose to compare this association with intranasal-ketamine and intranasal-dexmedetomidine.Methods: This is a "pre-post" study. The study population included the first forty children receiving sedation with the "new" combination intranasal ketamine (3 mg/kg) and intranasal dexmedetomidine (4 mcg/kg) compared to a historical cohort including the last forty children receiving sedation with our standard of care combination of intranasal dexmedetomidine (4mcg/kg) and oral midazolam (0,5 mg/kg).Results: The association intranasal dexmedetomidine and intranasal ketamine allowed for a significantly shorter sedation induction time than the combination intranasal dexmedetomidine and oral midazolam (13,5 min versus 35 min). Both group's cumulative data showed a correlation between age and sedation effectiveness, with younger children presenting a higher success rate and shorter induction time (p 0,001).Conclusions: This study suggests that the ketamine and dexmedetomidine intranasal association may have a shorter onset of action when compared to intranasal dexmedetomidine and oral midazolam

EVOLUTIONARY ADAPTATIONS IN ANTARCTIC FISH: THE OXYGEN-TRANSPORT SYSTEM

Understanding molecular adaptations evolved in response to environmental temperature changes is essential, because temperature affects the kinetic energy of molecules and modifies molecular interactions, macromolecular stability/functioning and membrane features. Environmental oxygen availability may also play an important role in the evolution of polar marine organisms, as suggested by the physiological and biochemical strategies adopted by these organisms to acquire, deliver and scavenge oxygen.This review summarises the current knowledge on the structure and function of hemoglobins of fish living in Antarctic habitats. The variety of adaptations underlying the ability of Antarctic fish to survive at temperatures permanently close to freezing is unique among teleosts. The dominant perciform suborder Notothenioidei affords an excellent study group for elaborating the evolution of biochemical adaptation to temperature. The availability of notothenioid taxa living in a wide range of latitudes (Antarctic, sub-Antarctic, and temperate regions) offers a remarkable opportunity to study the physiological and biochemical characters gained and, conversely, lost in response to cold and to reconstruct the likely evolutionary events modulating the ability to carry oxygen in freezing habitats. Although oxygen can be transported in freely dissolved form most animals rely on one or more protein carriers to deliver it to the respiring tissues. Compared to temperate and tropical species, high-Antarctic notothenioids have evolved reduced hemoglobin concentration/multiplicity. The Antarctic family Channichthyidae (the notothenioid crown group) is devoid of hemoglobin. All extant icefish species lack hemoglobin and many have lost myoglobin expression. In these species, oxygen delivery to tissues occurs by transport of the gas physically dissolved in the plasma.ADAPTACIONES EVOLUTIVAS EN PECES ANTÁRTICOS: EL SISTEMA DE TRANSPORTE DE OXÍGENO. Comprender las adaptaciones moleculares que han evolucionado en respuesta a los cambios de temperatura del medio ambiente es esencial, porque la temperatura afecta la energía cinética de las moléculas y  modiica  las  interacciones  moleculares,  la  estabilidad  de  las  macromoleculares,  sus  características  y  el funcionamiento de la membrana. La disponibilidad de oxígeno ambiental desempeña un papel importante en la evolución de los organismos marinos polares, como se evidencia en las estrategias isiológicas y bioquímicas adoptadas  por  estos  organismos  para  adquirir,  gastar  y  usar  oxígeno.  Esta  revisión  resume  el  conocimiento actual sobre la estructura y función de la hemoglobina de los peces que viven en hábitats antárticos. La amplia variedad de adaptaciones que permiten que los peces antárticos tengan la capacidad para sobrevivir de forma permanente en temperaturas cerca de la congelación es única entre los teleósteos. El suborden Notothenioidei, perteneciente a los Perciformes, es un excelente grupo para el estudio de la evolución y adaptación bioquímica a la temperatura. La gran variedad de taxones de nototénidos que viven en una amplia variedad de latitudes (Antártida, sub-antárticas, y las regiones templadas) ofrece una oportunidad extraordinaria para estudiar las características  isiológicas  y  bioquímicas  adquiridas  y  perdidas  por  este  grupo  en  respuesta  al  frío,  además de la posibilidad de reconstruir  los eventos más probables que direccionaron la evolución de la capacidad de transportar oxígeno en hábitats polares. Aunque el oxígeno puede ser transportado en su forma libre disuelta, la mayoría de los animales dependen de una o más proteínas para entregarlo a los tejidos para la respiración. En comparación con especies de zonas templadas y tropicales, los nototenoideos de la alta Antártida han evolucionado reduciendo la concentración y multiplicidad de hemoglobina. La familia antártica Channichthyidae (el grupo con corona de los Nototénidos) carece de la hemoglobina. Todas las especies de peces existentes que viven en el hielo carecen de hemoglobina y muchas han perdido la expresión de la mioglobina. En estas especies, el aporte de oxígeno a los tejidos se produce por el transporte del gas físicamente disuelto en el plasma. Palabras clave: Antártida; adaptaciones al frio; evolución; hemoglobina.ADAPTAÇÕES EVOLUTIVAS EM PEIXES ANTÁTRTICOS: O SISTEMA DE TRANSPORTE DE OXIGÊNIO.  Compreender as adaptações moleculares envolvidas na resposta às mudanças na temperatura  ambiental  é  essencial,  pois  a  temperatura  afeta  a  energia  cinética  das  moléculas  e  modiica  as interações moleculares, a estabilidade/funcionamento das macromoléculas e as características da membrana. A disponibilidade de oxigênio no ambiente pode também ter um importante papel na evolução dos organismos marinhos polares, como indicado pelas estratégias isiológicas e bioquímicas adotadas por estes organismos para adquirir, transportar e trocar oxigênio.   Esta revisão resume o conhecimento atual da estrutura e funcionamento das hemoglobinas de peixes que ocorrem em ambientes Antárticos. A diversidade de adaptações que sustentam a habilidade de peixes antárticos sobreviverem em temperaturas permanentemente próximas do congelamento é  única  entre  os  teleósteos.  A  dominante  sub-ordem  Perciforme  Notothenioidei  apresenta-se  como  um excelente  grupo  de  estudo  para  melhorar  o  conhecimento  sobre  a  evolução  das  adaptações  bioquímicas  à temperatura. A ocorrência de nototenióides em uma ampla variedade de latitudes (Antártica, sub-Antártica e regiões temperadas) oferece uma oportunidade notável para estudar as características isiológicas e bioquímicas obtidas  e,  por  outro  lado,  perdidas  em  resposta  ao  frio,  além  de  tornar  possível  a  reconstrução  dos  eventos evolutivos  que  provavelmente  modularam  a  habilidade  desses  peixes  de  transportar  oxigênio  em  ambientes extremamente frios. Embora  o  oxigênio  possa  ser  transportado  livremente  na  sua  forma  dissolvida,  a  maioria  dos  animais depende de um ou mais tipos de proteínas carreadoras para entregar o oxigênio aos tecidos. Quando comparadas às  espécies  temperadas  e  tropicais,  os  nototenióides  da  região Antártica,  propriamente  dita,  desenvolveram reduzida  concentração/multiplicidade  de  hemoglobinas.  A  família  de  peixes  Antárticos  Channichthyidae (crown group  nototenióide)  não  apresenta  hemoglobina.  Todas  as  espécies  de iceish  (peixes-do-gelo)  não possuem hemoglobinas e muitas também não produzem mioglobinas. Nessas espécies, o transporte de oxigênio aos tecidos ocorre através do gás isicamente dissolvido no plasma. Palavras-chave: Antártica; adaptações ao frio; evolução; hemoglobina

Local site effects estimation at Amatrice (Central Italy) through seismological methods

We present the results of seismological and geophysical investigations performed by the “Istituto Nazionale di Geofisica e Vulcanologia” team operating in Amatrice village (Central Italy), in the emergency phases following the Mw 6.0 event of August 24th 2016, that caused severe damage in downtown and surrounding areas. Data from seven seismic stations equipped with both weak and strong motion sensors are analyzed in terms of standard spectral ratio to empirically define amplification function using a bedrock reference site. Ambient vibration spectral ratios between horizontal and vertical component of motion are also evaluated in a large number of sites, spread out in the investigated area, to recover the resonance frequency of the soft soil outcropping layers and to generalize the results obtained by earthquake data. Ambient noise vibration are also used for applying a 2D array approach based on surface waves techniques in order to define the near-surface velocity model and to verify its lateral variation. The results allows to better understand the amplification factors in the investigated area, showing spatial variation of site effects despite of the homogeneous shallow geological condition indicated by the microzonation studies available at moment of the described field campaign. The analysis reveals a diffuse amplification effect which reaches its maximum values in downtown area with a resonant frequency of about 2 Hz. The obtained results were used to integrate the microzonation studies and they can be used for urban planning and reconstruction activities.Published5713–57394T. Sismicità dell'ItaliaJCR Journa

Site effects estimation and their effects on strong ground motion at Amatrice village (Central Italy)

We present a summary of seismological and geophysical investigations at Amatrice (Central Italy), a village seated on an alluvial terrace and severely stroke by the Mw 6.0 event of August 24th 2016. The high vulnerability alone could not explain the heavy damage (X-XI MCS), whereas the vicinity of the seismic source and the peculiar site effects should be claimed to understand the ground motion variability. After the first mainshock, we investigated the Amatrice terrace for microzonation purposes together with several Italian institutions (Priolo et al., Bull. Earthquake Eng. 2019). In particular: (i) we installed 7 seismic stations as a part of the 3A network (DOI: 10.13127/SD/ku7Xm12Yy9; Cara et al., Sci. Data 2019); we performed (ii) an extensive campaign of 60 single-station ambient noise measurements (downtown stations recorded also few earthquakes), and (iii) several 2D passive seismic arrays aimed at obtaining Vs profiles down to a depth of few tens of meters (Milana et al., Bull. Earthquake Eng. 2019). Earthquake recordings were used to empirically evaluate ground motion amplification effects through spectral ratio approaches, and noise data were collected for defining the spatial distribution of the resonance frequencies. Data analysis reveals a diffuse amplification effect that reaches its maximum values in downtown area with a resonant frequency (f0) of about 2 Hz. Seismic amplification is also characterized by spatial variation and directional amplification, mainly in downtown to the west side of the alluvial terrace, and related to both stratigraphic and topographic effects. This effect tends to decrease and almost vanishes in the central part of the terrace, and it increases again moving towards its eastern edge with a clear shift of f0 towards higher frequencies. Empirical transfer functions were then used to recover the ground motion that could have hit the historical center of Amatrice during the August 24th mainshock, through the convolution with the only record in the vicinity (IT.AMT station experienced a PGA of 0.87 g). The reconstructed peak values are much greater than expected from ground motion models, showing that detailed studies on local site response can largely modify the seismic hazard assessment.PublishedSan Francisco, California (USA)4T. Sismicità dell'Italia5T. Sismologia, geofisica e geologia per l'ingegneria sismic

Site effect studies following the 2016 Mw 6.0 Amatrice Earthquake (Italy): the Emersito Task Force activities

On August 24, 2016, at 01:36 UTC a MW 6.0 earthquake struck an extensive area of the Central Apennines (Italy) be-tween the towns of Norcia and Amatrice. Due to the mainshock magnitude and the widespread damaging level of build-ings in the epicentral area, the Emersito task force has been mobilized by the Istituto Nazionale di Geofisica e Vulcanologia (INGV). The aim of Emersito is to carry out and coordinate the monitoring of local site effects, caused by geological and geomorphological settings. During the first days of the seismic emergency, Emersito installed a tempo-rary seismic network for site effect studies at 4 municipalities close to the epicentral area (Amandola, Civitella del Tronto, Montereale and Capitignano), using 22 stations equipped with both velocimetric and accelerometric sensors. The selection of the sites where stations have been installed was mainly driven by the proximity to the epicentral area (without interfere with the rescue operations) and by peculiar geologic and geomorphologic settings (topographic irregu-larities, fault zones, alluvial plains). Preliminary analyses performed on ambient noise and aftershocks signals show that directional amplification effects may have occurred at stations installed on the top of topographic irregularities. We also observed the lengthening and amplification of the seismograms and a variability of the peaked frequency across the sedi-mentary basin between Montereale and Capitignano, probably related to a different thickness of the deposits. Further analyses are necessary to assess the correlation with surface geology.Published4T. Sismologia, geofisica e geologia per l'ingegneria sismica1SR. TERREMOTI - Servizi e ricerca per la Società1IT. Reti di monitoraggioJCR Journa

Tollip Is a Mediator of Protein Sumoylation

Tollip is an interactor of the interleukin-1 receptor involved in its activation. The endosomal turnover of ubiquitylated IL-1RI is also controlled by Tollip. Furthermore, together with Tom1, Tollip has a general role in endosomal protein traffic. This work shows that Tollip is involved in the sumoylation process. Using the yeast two-hybrid technique, we have isolated new Tollip partners including two sumoylation enzymes, SUMO-1 and the transcriptional repressor Daxx. The interactions were confirmed by GST-pull down experiments and immunoprecipitation of the co-expressed recombinants. More specifically, we show that the TIR domain of the cytoplasmic region of IL-1RI is a sumoylation target of Tollip. The sumoylated and unsumoylated RanGAP-1 protein also interacts with Tollip, suggesting a possible role in RanGAP-1 modification and nuclear-cytoplasmic protein translocation. In fact, Tollip is found in the nuclear bodies of SAOS-2/IL-1RI cells where it colocalizes with SUMO-1 and the Daxx repressor. We conclude that Tollip is involved in the control of both nuclear and cytoplasmic protein traffic, through two different and often contrasting processes: ubiquitylation and sumoylation

Temporary dense seismic network during the 2016 Central Italy seismic emergency for microzonation studies

In August 2016, a magnitude 6.0 earthquake struck Central Italy, starting a devastating seismic sequence, aggravated by other two events of magnitude 5.9 and 6.5, respectively. After the first mainshock, four Italian institutions installed a dense temporary network of 50 seismic stations in an area of 260 km2. The network was registered in the International Federation of Digital Seismograph Networks with the code 3A and quoted with a Digital Object Identifier ( https://doi.org/10.13127/SD/ku7Xm12Yy9 ). Raw data were converted into the standard binary miniSEED format, and organized in a structured archive. Then, data quality and completeness were checked, and all the relevant information was used for creating the metadata volumes. Finally, the 99 Gb of continuous seismic data and metadata were uploaded into the INGV node of the European Integrated Data Archive repository. Their use was regulated by a Memorandum of Understanding between the institutions. After an embargo period, the data are now available for many different seismological studies.Publishedid 1825T. Sismologia, geofisica e geologia per l'ingegneria sismicaJCR Journa

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues

Functional and comparative studies of haemoproteins from polar fishes

Proteins, such as the members of the globin superfamily, are sensitive to temperature and their properties are the result of a long process of adaptation to the conditions encountered during the species evolution. The globin superfamily comprises globular proteins that reversibly bind gaseous ligands such as O2, CO and NO to a haem prosthetic group, Fe-protoporphyrin IX. The globins of this family are the components of classical haemoglobin (Hb) and myoglobin (Mb), but also of neuroglobin, cytoglobin (Cygb), globin X, globin Y and eye-globin. In this study, particular attention has been given to biochemical and physico-chemical characterisation of two proteins. On one hand, the O2 transport systems from two Arctic fish species (Lycodes reticulatus and the cod Gadus morhua) have been investigated. On the other, Cygb has been studied from two Antarctic fish species, one belonging to the family Channichthyidae (icefish) lacking Hb and Mb (Chaenocephalus aceratus) and one red-blooded species belonging to the family Nototheniidae (Dissosticus mawsoni). The Arctic and Antarctic regions have the low temperature in common but differ in geographic position and history. The Antarctic is a continent isolated by the Polar Front, a circular oceanic system, and the temperatures are constantly close to -1.87°C. In contrast, the Arctic is essentially an ocean that lies between North America, Greenland, Europe and Asia. There are strong currents with high temperature variations. The Arctic and Antarctic icthyofaunas are very different. In the Antarctic, a single group of teleost fishes is dominant, the suborder Notothenioidei, that includes eight families. The modern family Channichtyidae is particularly interesting because its species have coulorless blood, lacking Hb and in some cases Mb. In contrast, in the Arctic there are six marin groups, nobody being dominant. Given a shorter evolutionary time at polar temperatures, than the Antarctic ichthyofauna, Arctic fish may provide valuable information on the effects of environmental temperature on specific physiological and biochemical traits. It is note that fish Hbs offer the possibility to investigate functional differentiation and molecular adaptations in species living in a large variety of environmental conditions. In this study, the structural and functional characterisation of the hemolysate of L. reticulatus (family Zoarcidae), living on the sea floor near the coasts of northern Europe and North America is reported. The hemolysate shows only a single α chain, whereas polymorphism of two β chains, which differ by only four residues corresponding to two Hbs. For such a high identity, complete purification of the two Hbs was not achieved and the functional studies were carried out on the hemolysate. The latter showed a low Bohr effect and no Root effect. The Hbs tend to form high-molecular mass polymers at physiological pH and low temperature (4°C), as shown by gel-filtration chromatography and dynamic light scattering. The elucidation of the primary structure has allowed to establish correlation between functional behaviour (no Root effect) and structural properties (polymerisation). In fact, it was demonstrated that Cys residues are present in high number and tend to form intermolecular disulphide bridges as shown by mass spectrometry. Recently, an unusual process of Hb polymerisation (sickling), which occurs in vivo in red blood cells of several Arctic species of the family Gadidae, was discovered and reported in the literature. The G. morhua Hb polymerisation showed pH- and concentration-dependence in the deoxygenate state in vitro, suggesting that polymerisation may be an adaptive response to extreme and stressful environmental conditions. Therefore, Arctic fish Hbs appear to be very useful models for studying sickling disorders and Hb-polymerisation processes. The second topic of the thesis were two Cygbs from Antarctic fish. Cygb is a cytoplasmatic protein found in almost all tissues and characterized by endogenous hexacoordination of the haem. The function is not clear. Involvement in protection from oxidative stress, in NO metabolism, in collagen synthesis and in defence mechanisms of cancer cells was hypothesised. Cygb was found in both: in red-blood D. mawsoni and in the icefish C. aceratus. The Cygbs were cloned, expressed and purified and a preliminary characterisation was carried out. It was demonstrated that they are hexacoordinated independently of pH- and temperature, similar to human Cygb. Understanding the role of the Cygb genes in species lacking Hb and Mb is a very important task necessary to elucidate of the function of this protein