1,721,147 research outputs found
Genetica delle forme familiari comuni e rare di diabete mellito
No full textBackground. L’esperienza clinica quotidiana c’insegna che alcuni pazienti adulti che vengono diagnosticati come affetti da diabete mellito tipo 2 (DMT2) presentano una forma multigenerazionale di diabete che manca ancora di una precisa definizione clinica e molecolare.
Obiettivo. L’obiettivo principale di questo studio è stato quello di identificare, all’interno di una coorte d’individui già diagnosticati come DMT2, quei pazienti che erano in realtà affetti da una forma di diabete multigenerazionale, indipendente da mutazioni responsabili del Diabete giovanile dell’adulto (Maturity Onset Diabetes of the Young: MODY) o del Diabete Mitocondriale associato a sordità (Maternally Inherited Diabetes and Deafness: MIDD). Grazie a strategie di sequenziamento di nuova generazione, abbiamo analizzato il DNA di tali pazienti per determinare l’architettura genetica che sottende tale forma di diabete. Infine, ci siamo concentrati sulla determinazione delle caratteristiche cliniche di tali pazienti, per poi confrontarle con quelle di pazienti affetti da MODY o dal tradizionale DMT2.
Materiali e metodi. All'interno di un campione di 2,583 pazienti precedentemente diagnosticati come affetti da DMT2, sono stati selezionati quei pazienti che appartenevano a famiglie affette da diabete in almeno tre generazioni consecutive. I DNA dei soggetti identificati sono stati raccolti e sequenziati inizialmente con il metodo di Sanger, e successivamente attraverso le moderne tecniche del Targeted Resequencing, con lo scopo di individuare mutazioni in geni associati a forme di diabete monogenico come il MODY o il Diabete Neonatale (DN), e del Whole Exome Sequencing (WES), per identificare mutazioni in geni mai associati al diabete.
Risultati. Abbiamo osservato che il 2.6% di un campione di 2,583 pazienti precedentemente diagnosticati per il DMT2 era rappresentato da famiglie affette da una forma di diabete multigenerazionale che abbiamo proposto di definire FDA (Familial Diabetes of the Adulthood). In seguito all’analisi genetica compiuta attraverso il sequenziamento di Sanger ed il Targeted Resequencing su tali famiglie, è risultato che 6,7 e 1 famiglia riportavano mutazioni rispettivamente in geni MODY, DN e MODY + DN, mentre il sequenziamento degli esomi, compiuto tramite WES, ci ha premesso di identificare due mutazioni nel gene APPL1 che causano iperglicemia in due di tali famiglie. In seguito al confronto tra le caratteristiche cliniche di questi pazienti con quelle di 1,028 pazienti affetti dal DMT2, è risultato che l’FDA si caratterizza per un’età alla diagnosi più precoce (p<0.001). In 118 pazienti FDA e 838 pazienti DMT2 il tasso d’incidenza della mortalità generale è risultato simile: 1.93 contro 1.89 eventi/100 anni-persona.
Conclusioni. Con questo studio abbiamo caratterizzato un gruppo di pazienti affetti da una forma di diabete familiare multigenerazionale che abbiamo proposto di definire FDA. Tali pazienti si distinguevano da quelli affetti dal tradizionale DMT2 per l’età alla diagnosi più precoce, tuttavia non implicando alcun effetto sul tasso d’incidenza della mortalità generale che è risultato simile nei due gruppi. Attraverso la tecnica del Targeted Resequencing abbiamo osservato che l’FDA è geneticamente eterogeneo, essendo costituito da mutazioni in geni MODY (24%), mutazioni in geni associati al DN (13%) e mutazioni in geni MODY + DN (2%). Il restante 61% dell’ereditabilità dell’FDA è stato investigato tramite il sequenziamento degli esomi (WES) di tali soggetti attraverso cui abbiamo identificato un nuovo gene-malattia (APPL1), dimostrando come tale approccio, applicato alle famiglie FDA, rappresenti una buona strategia per la scoperta di nuove vie di segnale o metaboliche che modulano l’omeostasi del glucosio e, quindi, il rischio di diabete
One size does not fit all glycemic targets for type 2 diabetes.
No full textMonogenic diabetes represents a heterogeneous group of disorders resulting from defects in single genes. Defects are categorized primarily into two groups: disruption of β-cell function or a reduction in the number of β-cells. A complex network of transcription factors control pancreas formation, and a dysfunction of regulators high in the hierarchy leads to pancreatic agenesis. Dysfunction among factors further downstream might cause organ hypoplasia, absence of islets of Langerhans or a reduction in the number of β-cells. Many transcription factors have pleiotropic effects, explaining the association of diabetes with other congenital malformations, including cerebellar agenesis and pituitary agenesis. Monogenic diabetes variants are classified conventionally according to age of onset, with neonatal diabetes occurring before the age of 6 months and maturity onset diabetes of the young (MODY) manifesting before the age of 25 years. Recently, certain familial genetic defects were shown to manifest as neonatal diabetes, MODY or even adult onset diabetes. Patients with neonatal diabetes require a thorough genetic work-up in any case, and because extensive phenotypic overlap exists between monogenic, type 2, and type 1 diabetes, genetic analysis will also help improve diagnosis in these cases. Next generation sequencing will facilitate rapid screening, leading to the discovery of digenic and oligogenic diabetes variants, and helping to improve our understanding of the genetics underlying other types of diabetes. An accurate diagnosis remains important, because it might lead to a change in the treatment of affected subjects and influence long-term complications
CYTOKINES AND AUTOIMMUNITY
No full textAbstract Although the immunopathology of most autoimmune diseases has been well defined, the mechanisms responsible for the breakdown of self-tolerance and which lead to the development of systemic and organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of cytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases
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
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
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