1,720,961 research outputs found
Further Insights into the Hematological Disorders Observed in Shwachman-Diamond Syndrome: mTOR and STAT3 Hyper-Phosphorylation in CD4+ and CD8+ T Cells and Efficacy of Rapamycin Treatment
Full text linkShwachman-Diamond syndrome (SDS) is a rare autosomal recessive disease which affects 1/168,000 newborns in Italy with a mean of 3.0 new cases/year. SDS is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene, which encodes for the homonymous protein SBDS, whose exact function is still unknown. SBDS protein has been reported to play a role in eukaryotic ribosome biogenesis. Thus, SDS is considered a ribosomopathy. The pathology is characterized by multiple-organ impairment involving bone marrow failure, exocrine pancreatic insufficiency, skeletal malformations, hepatic and cognitive disorders. Neutropenia and impaired neutrophil chemotaxis, which in turn cause recurrent infections, are reported in young children. Furthermore, 15-20% of SDS patients develop myelodysplastic syndrome (MDS), with increased risk of acute myeloid leukemia (AML) progression, which represent the main cause of mortality. However, the exact pathologic mechanism whereby loss of SDBS function could lead to the specific SDS hematological issues remains unclear. We recently reported, for the first time to the best of our knowledge, that the mammalian Target of Rapamycin (mTOR) and Signal Transducer and Activator of Transcription (STAT)-3 pathways are hyper-activated in B cells, PMNs and, mostly, in monocytes obtained from SDS patients (Bezzerri V et al, Sci Rep 2016, in press). Since mTOR and STAT3 activation are associated with neutrophil development and AML, this finding could at least partially explain the onset of the hematological issues. Here we show a further Phospho flow analysis of mTOR and STAT3 pathways activation in otherlymphocytes subsets,in particular in CD8+/CD4+ T cells and NK cells obtained from five SDS patients. We found that STAT3 S727 is the most phosphorylated site in CD8+ and CD4+ T cells (more than twice than the healthy control cells, each). Furthermore, mTOR (S2448) is hyper-phosphorylated in CD8+ and CD4+ T cells derived from SDS patients. Median fluorescence intensity shifted from 220 ± 25 (healthy controls) to 405 ± 29 (SDS patients) in CD8+ T cells and from 350 ± 132 (healthy controls) to 590 ± 150 (SDS patients) in CD4+ T cells, similarly to results obtained from Monocytes and B cells. NK seems to be less responsive to mTOR/STAT3 activation than B and T cells. Importantly, mTOR inhibitor rapamycin is able to reduce both mTOR and STAT3 activation, with different efficacy, in a cell type-dependent manner. In particular, rapamycin strongly reduces both mTOR and STAT3 S727 phosphorylation in CD8+ and CD4+ T cells. Thus, these results suggest a role of mTOR/STAT3 pathways in both myeloid and lymphoid lineages of SDS blood cells. Since several drugs approved by FDA and EMA targeting the JAK-STAT and mTOR pathways have been currently evaluated for the treatment of different forms of hematological malignancies, this work could open a wider scenario into the current SDS therapeutic approaches
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Drug-related deaths: analysis of an Italian spontaneous reporting database.
No full textBACKGROUND: Adverse drug reactions (ADRs) represent a major public health concern, with death as the ultimate adverse drug outcome. Despite the relevance of this, the frequency of fatal ADRs (FADRs) is to a large extent unknown. Although spontaneous reporting data cannot give an exact estimate of the magnitude of drug-related mortality, it may highlight the importance and large dimensions of this public health problem.
OBJECTIVE:
To describe the types and pattern of reported FADRs by analysing data from the national spontaneous reporting system in Italy.
METHODS:
The Italian Medicines Agency (AIFA) runs a pharmacovigilance database where all the individual case safety reports (since January 2001) are stored. We selected and then analysed in detail all the case reports (to the end of December 2006) in which death was reported as the outcome. We included in the study only FADR case reports with a probable or possible causality assessment, according to the criteria established by the WHO. In line with the Italian reporting form, we divided FADR reports into two groups: (i) suspected ADRs that caused death; and (ii) suspected ADRs that contributed to death.
RESULTS:
In the AIFA database 38 507 suspected ADR case reports were collected, of which 641 (1.66%) had a fatal outcome. We analysed 450 case reports (1.17% of total reports), 159 (35.33%) of them causing the patient's death and 291 (64.67%) contributing to death. The annual percentage of FADR reports followed a constant trend during the 6-year period. The majority of fatal reports (79%) were sent by hospital doctors. In total, 222 different drugs were suspected as causes of FADRs. 'Systemic anti-infective drugs' was the drug category associated with the highest percentage of FADRs (21.9%), followed by antineoplastic and immunomodulating agents (18.8%), and then by nervous system drugs (14.8%). Other drug categories involved in the fatal case reports were antithrombotic agents, NSAIDs and contrast media.
CONCLUSIONS:
The drugs most frequently involved in FADRs were drugs of wide usage with a narrow therapeutic range or those that caused serious skin or systemic allergic reactions. Ceftriaxone, ticlopidine and nimesulide were associated with the highest number of fatal case reports; the related FADRs were already known and recognized for each of these drugs. We highlight some cases reflecting probable inappropriate drug use by Italian physicians. This suggests a need for continued clinical pharmacology training and that many FADRs might be preventable through better medical and prescribing practice
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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