Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey

Background and purpose: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. Methods: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. Results: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. Conclusions: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities

Trombo atrapado en foramen oval permeable causante de infarto agudo de miocardio

A 57 year-old male was derived to our institution because of an acute myocardial infarction due to paradoxical embolism caused by thrombus passing through a patent ovale foramen. We present the main clinical and imaging findings of the case, along diagnostic and management options for this condition.Se presenta el caso de un varón de 57 años derivado al centro de los autores por infarto agudo de miocardio secundario a una embolia paradójica causada por un trombo atrapado en un foramen oval permeable. Se describen los principales hallazgos de las técnicas de imagen, características clínicas, diagnósticas y opciones terapéuticas

A Novel Pathway of TEF Regulation Mediated by MicroRNA-125b Contributes to the Control of Actin Distribution and Cell Shape in Fibroblasts

BACKGROUND: Thyrotroph embryonic factor (TEF), a member of the PAR bZIP family of transcriptional regulators, has been involved in neurotransmitter homeostasis, amino acid metabolism, and regulation of apoptotic proteins. In spite of its relevance, nothing is known about the regulation of TEF. PRINCIPAL FINDINGS: p53-dependent genotoxic agents have been shown to be much more harmful for PAR bZIP-deficient mice as compared to wild type animals. Here we demonstrate that TEF expression is controlled by p53 through upregulation of microRNA-125b, as determined by both regulating the activity of p53 and transfecting cells with microRNA-125b precursors. We also describe a novel role for TEF in controlling actin distribution and cell shape in mouse fibroblasts. Lack of TEF is accompanied by dramatic increase of cell area and decrease of elongation (bipolarity) and dispersion (multipolarity). Staining of actin cytoskeleton also showed that TEF (-/-) cells are characterized by appearance of circumferential actin bundles and disappearance of straight fibers. Interestingly, transfection of TEF (-/-) fibroblasts with TEF induced a wild type-like phenotype. Consistent with our previous findings, transfection of wild type fibroblasts with miR-125b promoted a TEF (-/-)-like phenotype, and a similar but weaker effect was observed following exogenous expression of p53. CONCLUSIONS/SIGNIFICANCE: These findings provide the first evidence of TEF regulation, through a miR-125b-mediated pathway, and describes a novel role of TEF in the maintenance of cell shape in fibroblasts

High energy variability of 3C 273 during the AGILE multiwavelength campaign of December 2007-January 2008

55We report the results of a 3-week multi-wavelength campaign targeting the flat spectrum radio quasar 3C 273 carried out with the AGILE gamma-ray mission, covering the 30 MeV-50 GeV and 18-60 keV, the REM observatory (covering the near-IR and optical), Swift (nearUV/Optical, 0.2-10 keV and 15-50 keV), INTEGRAL (3-200 keV) and Rossi XTE (2-12 keV). This is the first observational campaign including gamma-ray data, after the last EGRET observations, more than 8 years ago. Aims. This campaign has been organized by the AGILE team with the aim of observing, studying and modelling the broad band energy spectrum of the source, and its variability on a week timescale, testing the emission models describing the spectral energy distribution of this source. Methods. Our study was carried out using simultaneous light curves of the source flux from all the involved instruments, in the different energy ranges, to search for correlated variability. Then a time-resolved spectral energy distribution was used for a detailed physical modelling of the emission mechanisms. Results. The source was detected in gamma-rays only in the second week of our campaign, with a flux comparable to the level detected by EGRET in June 1991. We found an indication of a possible anti-correlation between the emission at gamma-rays and at soft and hard X-rays, supported by the complete set of instruments. Instead, optical data do not show short term variability, as expected for this source. Only in two preceding EGRET observations (in 1993 and 1997) 3C 273 showed intra-observation variability in gamma-rays. In the 1997 observation, flux variation in gamma-rays was associated with a synchrotron flare. The energy-density spectrum with almost simultaneous data partially covers the regions of synchrotron emission, the big blue bump, and the inverse-Compton. We adopted a leptonic model to explain the hard X/gamma-ray emissions, although from our analysis hadronic models cannot be ruled out. In the adopted model, the soft X-ray emission is consistent with combined synchrotron-self Compton and external Compton mechanisms, while hard X and gamma-ray emissions are compatible with external Compton from thermal photons of the disk. Under this model, the time evolution of the spectral energy distribution is well interpreted and modelled in terms of an acceleration episode of the electron population, leading to a shift in the inverse Compton peak towards higher energies.openPacciani Luigi; Donnarumma I; Vittorini V; D'Ammando F; Fiocchi MT; Impiombato Domenico; Stratta G; Verrecchia F; Bulgarelli A; Chen Rongchang; Giuliani Andrea; Longo Francesco; Pucella Gianluca; Vercellone S; Tavani Marco; Argan A; Barbiellini Amidei Guido; Boffelli Fabrizio; Caraveo Patrizia; Cattaneo Paolo Walter; Cocco Veronica; Costa E; Del Monte Ettore; Di Cocco G; Evangelista Yuri; Feroci Marco; Froysland Tom Vidar; Fuschino F; Galli M; Gianotti F; Labanti C; Lapshov I; Lazzarotto F; Lipari Paolo; Marisaldi M; Mereghetti S; Morselli Aldo; Pellizzoni A; Perotti F; Picozza Piergiorgio; Prest Michela; Rapisarda Massimo; Soffitta P; Trifoglio M; Tosti Gino; Trois A; Vallazza Erik Silvio; Zanello Dino; Antonelli Lucio Angelo; Colafrancesco Sergio; Cutini Sara; Gasparrini Dario; Giommi P; Pittori Carlotta; Salotti LPacciani, Luigi; Donnarumma, I; Vittorini, V; D'Ammando, F; Fiocchi, Mt; Impiombato, Domenico; Stratta, G; Verrecchia, F; Bulgarelli, A; Chen, Rongchang; Giuliani, Andrea; Longo, Francesco; Pucella, Gianluca; Vercellone, S; Tavani, Marco; Argan, A; Barbiellini Amidei, Guido; Boffelli, Fabrizio; Caraveo, Patrizia; Cattaneo Paolo, Walter; Cocco, Veronica; Costa, E; Del Monte, Ettore; Di Cocco, G; Evangelista, Yuri; Feroci, Marco; Froysland Tom, Vidar; Fuschino, F; Galli, M; Gianotti, F; Labanti, C; Lapshov, I; Lazzarotto, F; Lipari, Paolo; Marisaldi, M; Mereghetti, S; Morselli, Aldo; Pellizzoni, A; Perotti, F; Picozza, Piergiorgio; Prest, Michela; Rapisarda, Massimo; Soffitta, P; Trifoglio, M; Tosti, Gino; Trois, A; Vallazza Erik, Silvio; Zanello, Dino; Antonelli Lucio, Angelo; Colafrancesco, Sergio; Cutini, Sara; Gasparrini, Dario; Giommi, P; Pittori, Carlotta; Salotti, L

Comparative Live-Cell Imaging Analyses of SPA-2, BUD-6 and BNI-1 in Neurospora crassa Reveal Novel Features of the Filamentous Fungal Polarisome

A key multiprotein complex involved in regulating the actin cytoskeleton and secretory machinery required for polarized growth in fungi, is the polarisome. Recognized core constituents in budding yeast are the proteins Spa2, Pea2, Aip3/Bud6, and the key effector Bni1. Multicellular fungi display a more complex polarized morphogenesis than yeasts, suggesting that the filamentous fungal polarisome might fulfill additional functions. In this study, we compared the subcellular organization and dynamics of the putative polarisome components BUD-6 and BNI-1 with those of the bona fide polarisome marker SPA-2 at various developmental stages of Neurospora crassa. All three proteins exhibited a yeast-like polarisome configuration during polarized germ tube growth, cell fusion, septal pore plugging and tip repolarization. However, the localization patterns of all three proteins showed spatiotemporally distinct characteristics during the establishment of new polar axes, septum formation and cytokinesis, and maintained hyphal tip growth. Most notably, in vegetative hyphal tips BUD-6 accumulated as a subapical cloud excluded from the Spitzenkörper (Spk), whereas BNI-1 and SPA-2 partially colocalized with the Spk and the tip apex. Novel roles during septal plugging and cytokinesis, connected to the reinitiation of tip growth upon physical injury and conidial maturation, were identified for BUD-6 and BNI-1, respectively. Phenotypic analyses of gene deletion mutants revealed additional functions for BUD-6 and BNI-1 in cell fusion regulation, and the maintenance of Spk integrity. Considered together, our findings reveal novel polarisome-independent functions of BUD-6 and BNI-1 in Neurospora, but also suggest that all three proteins cooperate at plugged septal pores, and their complex arrangement within the apical dome of mature hypha might represent a novel aspect of filamentous fungal polarisome architecture

Understanding the clinical spectrum of complicated Plasmodium vivax malaria: a systematic review on the contributions of the Brazilian literature

The resurgence of the malaria eradication agenda and the increasing number of severe manifestation reports has contributed to a renewed interested in the Plasmodium vivax infection. It is the most geographically widespread parasite causing human malaria, with around 2.85 billion people living under risk of infection. The Brazilian Amazon region reports more than 50% of the malaria cases in Latin America and since 1990 there is a marked predominance of this species, responsible for 85% of cases in 2009. However, only a few complicated cases of P. vivax have been reported from this region. A systematic review of the Brazilian indexed and non-indexed literature on complicated cases of vivax malaria was performed including published articles, masters' dissertations, doctoral theses and national congresses' abstracts. The following information was retrieved: patient characteristics (demographic, presence of co-morbidities and, whenever possible, associated genetic disorders); description of each major clinical manifestation. As a result, 27 articles, 28 abstracts from scientific events' annals and 13 theses/dissertations were found, only after 1987. Most of the reported information was described in small case series and case reports of patients from all the Amazonian states, and also in travellers from Brazilian non-endemic areas. The more relevant clinical complications were anaemia, thrombocytopaenia, jaundice and acute respiratory distress syndrome, present in all age groups, in addition to other more rare clinical pictures. Complications in pregnant women were also reported. Acute and chronic co-morbidities were frequent, however death was occasional. Clinical atypical cases of malaria are more frequent than published in the indexed literature, probably due to a publication bias. In the Brazilian Amazon (considered to be a low to moderate intensity area of transmission), clinical data are in accordance with the recent findings of severity described in diverse P. vivax endemic areas (especially anaemia in Southeast Asia), however in this region both children and adults are affected. Finally, gaps of knowledge and areas for future research are opportunely pointed out

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta