72 research outputs found
Implementation of a nurse-led alternate care site for the management of the surge of patients with COVID-19 in an Italian emergency department
No full textBackground To accommodate and separate the large numbers of patients going to hospital with COVID-19, many EDs had to create new pathways for patients. We describe the outcomes of patients treated in a nurse-led alternate care site (ACS) at our hospital. Methods This was a retrospective study of outcomes of patients managed at the ACS of 'San Bassiano' Hospital ED, Bassano del Grappa, Italy between 9 March and 16 April 2020. Self-presenting patients aged 5 years and older, suspected of having COVID-19, were initially diverted to the ACS. Patients with a National Early Warning Score >= 5 or with a desaturation >= 4% after the walking test were sent back to the main ED COVID-19 path for further evaluation and medical attention and were not further followed up. In the ACS, patients received a CXR, blood samples and a nasopharyngeal swab to test for SARS-CoV-2, and were sent home. An emergency physician reviewed the results later and called the patient back 5-6 hours later with instructions to return for medical evaluation of abnormal findings, or to seek their general practitioner's attention. Patients received a follow-up phone call 15 days later to learn of their course. Results A total of 487 patients were fully managed in the ACS and discharged home. Of the 392 (80.5%) patients with no abnormalities after the workup and instructed to stay at home, 29 reattended the ED in the next 15 days, and 13 were admitted. Among the 95 patients asked to return and receive medical attention, 20 were admitted and of those discharged, 3 reattended the ED within 15 days. At 15 days, no patient was deceased or received invasive ventilation; one admitted patient received non-invasive ventilation. Conclusions A nurse-led ACS diverted a substantial proportion of patients from main ED resources without associated negative clinical outcomes
From \u27\u27secret cell\u27\u27 to compostella: Medieval itineararies of \u27Theosis\u27
No full textThe medieval author who sought to faithfully represent spiritual experience was aware that his task was hampered by the very medium in which he worked: language, like the world which it mediated, had been alienated from God through the Fall. As a solution to this problem, he sought to create a sacred space within his text where historical experience could intersect with a sacred intertext, thereby permitting the encounter with God, theosis. By elaborating such textual reliquaries, the author could then claim transcendent authority despite being forced to articulate those claims in fallen language. This dissertation studies these ideas as demonstrated in Augustine\u27s Confessions and two early medieval pilgrimage guides, the Itinerarium Egeriae and the Guide du pelerin de Compostelle, and is divided into 6 chapters. The introduction provides a general overview of medieval strategies for making God accessible, along with a discussion of Scripture as the paradigmatic authority for such an attempt. Chapter 1 discusses Augustine\u27s elaboration of the secret cell , an internal textual reliquary to which man, like the Prodigal Son, returns from exile in the fallen world through the authority of Scripture. Chapter 2 identifies the Itinerarium as a text which seeks to project the experience of the secret cell onto the landscape of the Holy Land, substituting the pilgrim for the exile as the figure authorized by Scripture. Chapter 3 examines the first chapters of the Guide in the light of the Itinerarium and then focuses on the role of Roland and Roncevaux in the pilgrim\u27s search for authority. Chapter 4 demonstrates how the Guide rewrites the material of the first part so as to frame it in terms of the community of saints and, more specifically, in terms of the confessor; it ends by suggesting that the chasse of St. Gilles merits so much attention from the pilgrim because it serves to guarantee his whole project. The conclusion discusses why arriving at Compostella is not necessary for the success of the pilgrimage, and suggests ways in which the itinerary from sacred cell to Compostella might be extended into the later medieval period
Of cancer and other things : conversations with the Royal Philosopher on pilgrimage to Santiago de Compostella
No full textThis dissertation presents an outline, and one interpretation of, the life of its author, The Reverend Doctor Melvyn John Macarthur. It seeks to do this through both its methodology, which is textual and experiential, and through dialogue with the provocateur, Qoheleth, author of the book of Ecclesiastes. The dialogue component (the ‘Conversations’) reflects the author’s passion to engage with people in conversation and also his love of theatre.
The ‘Conversations’ in the dissertation take place on the Camino Santiago de Compostella (French Way), a long distance, ancient pilgrim route from St Jean Pied de Port in France to Santiago de Compostella in Spain. The dialogue partners are the author of the dissertation and Qoheleth. Qoheleth, the self-proclaimed Royal Philosopher, is a mysterious figure about whom much is conjectured, but little known. Qoheleth has been, and remains, a controversial figure in the Judeo-Christian traditions: considerable numbers of people, whether lay, ordained or scholar, hold that Ecclesiastes should not have been included in the canons. This author holds the view that the work of Qoheleth is among the most thoughtful and unique of the canonical writings. One hope held for this dissertation is that it would be a vehicle whereby I could ‘lean toward’ (Pelias, 2016; 9-11) the person Qoheleth. The motivation for doing this is that his remarkable honesty and depth of thought commends Qoheleth as an ideal provocateur, one who is able to offer a searching critique of the wide and varied life experience of the author, one who it is enticing to lean toward. Ronald Pelias (2016; 12) writes of his use of multiple qualitative methods in the writing of personal narratives. The methodology of this dissertation is, likewise, eclectic, and I would argue, ’necessarily’ so. A human life is complex and mine is no exception. A human life does not readily lend itself, convincingly at least, to understandings from a single discipline. This dissertation draws on material and methods from a variety of disciplines in an endeavour to convey and clarify aspects of the life of the author. The influences in the life of this author are, as mentioned, wide and varied: his professional life in social work, particularly in child protection; his vocational life in ordained ministry and pilgrimage; his more than four decades of participation as a student and researcher in a wide variety of pursuits in the academy; his experience of wilderness for significant periods during his adult lifetime and his last ten years of living with a life threatening cancer (non Hodgkins lymphoma) have all significantly impacted his life. The methodology of the dissertation is built upon these foundations that are termed ‘abiding interests’.
For anyone wishing to have more detail of the author’s life prior to the reading of this dissertation, a brief curriculum vitae is attached as Appendix One.
An appraisal of the author’s account is presented at the conclusion of the ‘Conversations’ with Qoheleth. The appraisal takes the form of commentaries written from the widely differing theological, philosophical and social perspectives of the Reverend Brand, the central character of Henrik Ibsen’s play Brand and the Grand Inquisitor, a prominent figure in Fyodor Dostoevsky’s novel, The Karamazov Brothers. The author’s personal reflections about the pilgrimage to Santiago follow on from and take a full account of, the appraisals of The Reverend Brand and the Grand Inquisitor, in addition to the conversations with Qoheleth
The Concerted Impact of Galaxies and QSOs on the Ionization and Thermal State of the Intergalactic Medium
No full textWe present a detailed analysis of the ionization and thermal structure of the intergalactic medium (IGM) around a high-redshift QSO using a large suite of cosmological, multi-frequency radiative transfer (RT) simulations, exploring the contribution from galaxies as well as the QSO, and the effect of X-rays and secondary ionization. We show that in high-z QSO environments both the central QSO and the surrounding galaxies concertedly control the reionization morphology of hydrogen and helium and have a non-linear impact on the thermal structure of the IGM. A QSO imprints a distinctive morphology on H II regions if its total ionizing photon budget exceeds that of the surrounding galaxies since the onset of hydrogen reionization; otherwise, the morphology shows little difference from that of H II regions produced only by galaxies. In addition, the spectral shape of the collective radiation field from galaxies and QSOs controls the thickness of the I-fronts. While a UV-obscured QSO can broaden the I-front, the contribution from other UV sources, either galaxies or unobscured QSO, is sufficient to maintain a sharp I-front. X-rays photons from the QSO are responsible for a prominent extended tail of partial ionization ahead of the I-front. QSOs leave a unique imprint on the morphology of He II / He III regions. We suggest that, while the physical state of the IGM is modified by QSOs, the most direct test to understand the role of galaxies and QSOs during reionization is to perform galaxy surveys in a region of sky imaged by 21 cm tomography
Ceramide Is Involved in Temozolomide Resistance in Human Glioblastoma U87MG Overexpressing EGFR
No full textGlioblastoma multiforme (GBM) is the most frequent and deadly brain tumor. Many
sphingolipids are crucial players in the regulation of glioma cell growth as well as in the response
to different chemotherapeutic drugs. In particular, ceramide (Cer) is a tumor suppressor lipid, able
to induce antiproliferative and apoptotic responses in different types of tumors including GBM,
most of which overexpress the epidermal growth factor receptor variant III (EGFRvIII). In this
paper, we investigated whether Cer metabolism is altered in the U87MG human glioma cell line
overexpressing EGFRvIII (EGFR+ cells) to elucidate their possible interplay in the mechanisms
regulating GBM survival properties and the response to the alkylating agent temozolomide (TMZ).
Notably, we demonstrated that a low dose of TMZ significantly increases Cer levels in U87MG cells
but slightly in EGFR+ cells (sensitive and resistant to TMZ, respectively). Moreover, the inhibition
of the synthesis of complex sphingolipids made EGFR+ cells sensitive to TMZ, thus involving Cer
accumulation/removal in TMZ resistance of GBM cells. This suggests that the enhanced resistance of
EGFR+ cells to TMZ is dependent on Cer metabolism. Altogether, our results indicate that EGFRvIII
expression confers a TMZ-resistance phenotype to U87MG glioma cells by counteracting Cer increase
La serva-pellegrina. Storia di «monna Margherita [che] andò al Sipolchro e a San Iachopo e [a] Ascesi» (Firenze, 1426-1427)
No full textITALIANO: Nella sua dichiarazione fiscale al catasto fiorentino presentata il 12 luglio 1427, una serva di
nome Margherita D’Antonio raccontò come, sei mesi prima, aveva indirizzato ai «Collegi» del Comune di Firenze una petizione contro il suo ex padrone, il notaio ser Stefano di Michele Martelli, nella quale rivendicava quattordici anni di salario per altrettanti anni in cui era stata a
servizio in casa sua senza mai esser stata pagata. Convocati entrambi a gennaio 1427, per un’audizione, ser Stefano riconobbe che Margherita era stata la sua serva in casa per 15 anni, dal 1411 al 1426, mentre Margherita ribadì la sua richiesta di essere pagata per tutto quel tempo, salvo l’anno in cui «andò al Sipolchro e a San Iacopo e Ascesi», in pellegrinaggio. L’esito deliberativo della petizione fu favorevole a Margherita, ma nell’estate 1427 il notaio non aveva ancora pagato il suo debito. Mettendo insieme alcuni indizi rintracciati anche nella dichiarazione fiscale del
notaio, l’articolo cerca di tratteggiare i lineamenti di questa umile donna, serva audace nonché intrepida pellegrina, capace di appropriarsi di un nuovo spazio pubblico di scrittura come il catasto per ribadire la sua vicenda giudiziaria e i suoi diritti e così facendo svelare un po’ della sua storia. L’edizione della portata di Margherita d’Antonio è presentata nell’appendice documentaria. / ENGLISH: In her portata (tax declaration) to the Florentine catasto submited on 12 July 1427, a
maidservant named Margherita d’Antonio told how, six months earlier, she had addressed a petition to the ‘Collegi’ of the Commune of Florence against her former master, the notary ser Stefano di Michele Martelli, in which she claimed fourteen years’ wages for as many years that she had served in his house without ever having been paid. Both were called upon in January 1427 for a hearing: ser Stefano acknowledged that Margherita had been his servant in the house for 15 years, from 1411 to 1426, while Margherita reiterated her request to be paid for all that time, except for the year in which she ‘went to Jerusalem and San Iacopo [Santiago
di Compostella] di Compostella and Assisi’ on pilgrimage. The outcome of the petition was favorable to Margherita, but by the summer of 1427 the notary had still not paid his debt. By assembling some evidence also found in the notary's tax declaration, the article attempts to sketch the features of this humble and illiterate woman, a daring servant as well as an intrepid pilgrim, who was able to appropriate a new public space of writing such as the catasto to reassert her legal case and her rights and thus reveal a little of her story. The edition of the Margherita d'Antonio's portata is presented in a documentary appendix
Cortical Inhibitory Imbalance in functional paralysis
No full textBackground: Functional neurological disorders are characterized by neurological symptoms that have no identifiable pathology and little is known about their underlying pathophysiology. Objectives: To analyze motor cortex excitability and intracortical inhibitory and excitatory circuits' imbalance in patients with flaccid functional weakness. Methods: Twenty-one consecutive patients with acute onset of flaccid functional weakness were recruited. Single and paired-pulse transcranial magnetic stimulation (TMS) protocols were used to analyze resting motor thresholds (RMT) and intracortical inhibitory (short interval intracortical inhibition - SICI) and excitatory (intracortical facilitation - ICF) circuits' imbalance between the affected and non-affected motor cortices. Results: We observed a significant increase in RMT and SICI in the affected motor cortex (p < 0.001), but not for ICF, compared to the contralateral unaffected side. Conclusion: This study extends current knowledge of functional weakness, arguing for a specific central nervous system abnormality which may be involved in the symptoms' pathophysiology
Quasars at the Cosmic Dawn: effects on Reionization properties in cosmological simulations
No full textAbstractWe study a model of cosmic reionization where quasars (QSOs) are the dominant source of ionizing photons at all relevant epochs. We employ a suite of adaptive hydrodynamical simulations post-processed with a multi-wavelength Monte Carlo radiative-transfer code and calibrate them in order to accurately reproduce the observed quasar luminosity function and emissivity evolution. Our results show that the QSO-only model fails in reproducing key observables linked to the Helium reionization, as the temperature evolution of the inter-galactic medium (IGM) and the HeII effective optical depth in synthetic Lyα spectra. Nevertheless, we find hints that an increased quasar contribution can explain recent measurements of a large inhomogeneity in the IGM at redshift z ≈ 5. Finally, we devise a method capable of constraining the QSOs contribution to the reionization from the properties of the HeII Lyα forest at z ≈ 3.5.</jats:p
Antigen-presentation of non-peptidic antigens lipid trafficking and loading
No full textT cells recognize a broad variety of antigens, including peptides, lipids and non-peptidic phosphorylated metabolites. Clarification of the rules rendering non-peptidic molecules immunogenic is essential to understand and to influence the reactions of the immune system to this class of substances in health and disease. Despite recent advances in research about immune responses to non-peptidic compounds, important issues remain unanswered. Molecular mechanisms governing the immunogenicity of non-peptidic ligands such as their cell internalization, trafficking within intracellular organelles, association with dedicated antigen-presenting molecules, induction of central and peripheral tolerance, and finally their role in autoimmune diseases as well as in protection during infections are unknown to date.
The aims of this thesis were to assess some of the immunological functions and cell biological rules governing the immunogenicity of non-peptidic antigens, with particular emphasis on cell trafficking of non-peptidic antigens and antigen-presenting molecules. It focused on (i) the antigen reactivity and presence of human invariant natural killer T (iNKT) cells in diseases, (ii) the role of CD1a trafficking in lipid antigen presentation by this protein, and (iii) the requirements of membrane translocation of phosphorylated mevalonate metabolites that stimulate human T cell receptor (TCR) gamma-delta cells.
With the development of alpha-galactosylceramide (alpha-GC)-loaded soluble CD1d dimers, which specifically interact with the TCR of iNKT cells, we have the perfect tool in our hands to perform detailed studies on iNKT cells. Analysis of the iNKT cells in blood unveiled large differences in their fluorescence intensity suggesting the presence of semi-invariant iNKT TCR with large disparities in the affinity for the alpha-GC-CD1d complex. Unexpectedly, established iNKT cell clones showed no correlation between CD1d dimer-staining levels and alpha-GC reactivity, indicating that additional mechanisms control responsiveness of iNKT cells, at least to this lipid antigen.
The identification of lipid antigens stimulating exclusively some desired functions in human iNKT cells might lead to new medical therapies or vaccines. To screen a variety of synthetic lipids for their capacity to activate iNKT cells, we devised an in vitro model based on plastic-bound CD1d. Piperidinones, molecules with a ceramide- or sphingosine-like structure, revealed that a single lipid tail is sufficient to form stimulatory complexes with CD1d. Interestingly, piperidinones preferentially induce TH1-like cytokines, predicting a possible role as novel leader molecules to functionally direct iNKT cell responses deployable in clinical therapies.
The balance of proinflammatory TH1 to regulatory TH2 cytokines is well-known to be decisive for the outcome of many diseases. Atherosclerosis (ATH) is a chronic inflammatory disease characterized by lipid accumulation in plaques. The disease is complicated by cardiovascular events provoked by plaque rupture or erosion. Because inflammation participates in lesion progression and rupture of plaques, the identification of its causes and of the culprit leukocyte populations involved in plaque destabilization is crucial for effective prevention of cardiovascular events. We used CD1d dimers to detect and characterize iNKT cells in ATH patients. We found that, in human atherosclerotic lesions, the abundance of CD1d-positive antigen-presenting cells (APC) and of iNKT cells correlates with disease severity and activity. CD1d-positive cells colonize advanced plaques in symptomatic patients and are most abundant in plaques with concomitant signs of ectopic neovascularization. In plaques, the frequency of iNKT cells among total T cells exceeds the one in blood. After having successfully isolated iNKT cell lines from plaque tissue, we showed that they promptly release proinflammatory cytokines upon lipid antigen stimulation and promote endothelial cell migration and microvascular sprout formation in vitro. This functional proangiogenic activity is ascribed to interleukin-8 released by iNKT cells after lipid recognition. These findings introduce iNKT cells as novel candidates to induce plaque neovascularization and destabilization in human ATH. Targeting iNKT cells could lead to late stage ATH treatment.
Another approach to understand the role of lipid-specific immune responses is to investigate the molecular rules of lipid-CD1 complex formation. Lipids distribute, due to their physicochemical properties or with the help of specific transporters and lipid transfer proteins, to different intracellular compartments and membrane domains. Thus, it is advantageous for the immune system to utilize multiple CD1 isoforms, each with a distinct trafficking pattern, to facilitate sampling of lipid antigens localized in various membranes. Several studies have addressed trafficking of CD1 isoforms. However, the molecular mechanisms are known in only a few cases.
We identified invariant chain (Ii) and lipid rafts as key regulators of CD1a organization on the surface of APC and of its immunological function as antigen-presenting molecule. Colocalization of CD1a with Ii is dependent on raft integrity and CD1a internalization is increased by Ii. The localization of CD1a in lipid rafts is functionally relevant as raft disruption inhibits CD1a-restricted antigen presentation.
Moreover, we found that CD1a is internalized independently of clathrin and dynamin and that it follows a Rab22a- and adenosine diphosphate ribosylation factor (ARF) 6-dependent recycling pathway, similar to other clathrin-independent cargo. Posttranslational S-acylation of the CD1a cytoplasmic tail may occur but neither determines the rate of internalization nor recycling nor its localization to detergent-resistant membrane microdomains. These findings place CD1a close to major histocompatibility complex (MHC) class I in its trafficking routes although CD1a loads lipids in recycling endosomes and not in the endoplasmic reticulum as MHC class I.
Strikingly, the glycolipid antigen sulfatide was found localized predominantly to early and recycling endosomes where CD1a is located. Swapping the cytoplasmic tail of CD1a for the one of CD1b and hence targeting the CD1a protein to the late endosomal and lysosomal compartments decreases its capacity to present sulfatide and shortens the half-life of stimulatory complexes. Thus, the physiological intracellular trafficking route of CD1a is critical for efficient presentation of lipid antigens that traffic through the early endocytic and recycling pathways.
Intracellular trafficking of another class of non-peptidic antigens, namely the phosphorylated metabolites which stimulate human TCR gamma-delta cells expressing the Vgamma9/Vdelta2 heterodimer, was examined. These T cells recognize a family of structurally related compounds produced in the eukaryotic mevalonate and prokaryotic methylerythritol phosphate (MEP) pathways. The endogenous self-ligands are generated within the cytoplasm and must cross the membrane in order to associate with dedicated antigen-presenting molecules, which remain unknown at present.
Using an in vitro transport assay, we demonstrated that the multidrug resistance-associated protein (MRP) 5 transporter is involved in membrane translocation of antigenic phosphorylated metabolites. Confocal microscopy illustrated that MRP5 is located in membranes of both endoplasmic reticulum and early endosomes. Both the intracellular localization and active role in antigen transport confer an immunological function to MRP5, resembling that of TAP (transporter associated with antigen processing) transporters involved in peptide antigen translocation. This indicates a similar strategy used for antigen presentation to TCR alpha-beta and gamma-delta T cells.
In conclusion, these studies have underlined the physiological relevance of T cells recognizing non-peptidic ligands and have revealed unanticipated molecular mechanisms controlling the efficient presentation of such antigens
Bernardus Compostellanus Antiquus: A Study in the Glossators of the Canon Law
No full textMaster Bernard, archdeacon of Compostella, and a member of the Canon Law School of Bologna in the early thirteenth century, is generally known as the author of a collection of decretals which he compiled in 1208 at the Roman Curia, with the aid of Pope Innocent III's registers, covering the first ten years (February 22, 1198–February 21, 1208) of that pontificate. Bernard's contemporary, the celebrated master Tancred, further tells us that the Spaniard's compilation was used by the school for some time as Collectio Romana, until in 1210 Pope Innocent promulgated an official collection of his decretals, arranged by his subdeacon and notary, Petrus Collivaccinus of Benevento. One of the Pope's reasons for issuing the authentic law book—the first of its kind in Church history—had been the fact that some of the decretals in Bernard's work, though genuine papal letters, were not considered by the Curia as universally binding. The new official collection, commonly known as Compilatio tertia, at once superseded Bernard's private collection, and for centuries the latter was known only from hearsay until rediscovered in modern times.</jats:p
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