1,729,823 research outputs found
Genetics of Familial Hypercholesterolemia: new diagnostic and research approaches
No full textIntroduction: Familial Hypercholesterolemia (FH, OMIM #143890) is an autosomal dominant disorder of lipoprotein metabolism characterized by high plasma levels of LDL cholesterol (LDL-C) with an estimated prevalence of 1 in 250 individuals in Western Europe. Lifelong exposure to elevated plasma levels of LDL-C leads to atherosclerosis at an early age, and as such FH patients are at a 2.2 to 25.8 fold higher risk for cardiovascular disease (CVD). FH is caused by genetic mutations that affect the structure and/or function of the LDL receptor (LDLR), a cell-surface receptor that removes LDL from the circulation. Variants in LDLR, APOB, and PCSK9 have been shown to result in clinical FH. To date, FH is an underdiagnosed and undertreated disease as exemplified by the fact that less than 1% of the worldwide familial hypercholesterolemia population is detected, diagnosed or treated according to current guidelines.
Aims: The primary aim was to promote a combined clinical and genetic approach for the diagnosis of FH in order to achieve a definitive and early diagnosis in patients, allow a prompt treatment and, thus, prevent the occurrence of CVD. Since a mutation in one of the three FH main genes is found in only 60-80% of patients with a definitive clinical diagnosis, the second aim of this PhD was to exploit genetic data, derived from the use of new DNA high-throughput sequencing (HTS) technologies, to find new molecular pathways (major or modifier genes) causing the disease. In particular, the possible association of genetic variants in ABCG5/ABCG8 and STAP1 with FH-like phenotype was investigated.
Methods and Results: Through a 55 genes targeted HTS, we set out a fast and cost-effective genetic screening for patients with a clinic suspect or a definite diagnosis of FH. In the first 2 years we analysed 32 patients and we were able to make a molecular definitive FH diagnosis in 14 of them. Our HTS design allowed also to obtain information about pharmacogenetics and genetic predisposition to other forms of dyslipidemia. The application of the 12 SNPs gene score in our FH cohort confirmed, as previously shown in literature, that the high LDL-C levels in FH patients could be due to an accumulation of several common genetic variants of small effect supporting the presence of the polygenic form of FH.
Through a lipid profiles evaluation in a big cohort of clinical FH patients and a co-segregation analysis in 4 FH families, it was then demonstrated that heterozygous variants in ABCG5/ABCG8 genes do not cause monogenic FH, although it cannot be ruled out that they can have a role in the regulation of serum cholesterol levels.
Lastly, the screening of plasma lipids and B cell profile of STAP1 variant carriers coupled with in vitro co-culture experiments allowed to demonstrate that variants in STAP1 are not associated with elevated LDL cholesterol in FH patients. Thus, in contrast to the previous literature findings, STAP1 cannot be considered the fourth FH gene.
Conclusions: This PhD thesis provides a large view on familial hypercholesterolemia, a disease with an ever higher estimated worldwide prevalence, and remarks the importance and feasibility of an
early diagnosis supported by a cost-effective genetics diagnosis approach to manage and prevent CVD. Indeed, genetics can definitely help to improve diagnosis efficiency and to quickly identify new patients within the families. Moreover, research of new genetic FH causes and the identification of novel molecular pathways causing the disease may be the groundwork to the development of novel and ever more safety and effective lipid lowering drugs
Resistance to hormonal therapy in prostate cancer
No full textSeveral therapeutic strategies are actually available in the management of prostate cancer: Targeting the androgen receptor (AR) is the goal both for initial androgen deprivation therapy (ADT) and second-generation androgen ablative agents (abiraterone and enzalutamide). Chemotherapy with taxanes, administered upon progression or as first line approach in association with ADT, is another therapeutic option. Unfortunately, none of these therapies is curative and patients are destined to develop a resistant phenotype. Progression to ADT leads to the attainment of a castration resistant disease whose mechanisms remain incompletely understood. Reactivation of AR has been shown to occur and second-generation of AR targeting drugs are usually prescribed. Upon progression to these agents AR signaling still remains the primary driver although it often becomes ligand independent, since it can be either restored through mutations on the ligand binding domain and/or formation of AR splicing variants or by passed through a cross talk with other oncogenic signaling pathways. AR-independent signaling pathways may represent additional mechanisms underlying castration resistant progression. It is clear that castration resistant prostate cancer is a group of diverse diseases and new treatment paradigms need to be developed
Caudal vertebra transfer: treatment of radio-ulnar nonunion and severe bone shortening in a dog
No full textA two-year-old, 9 kg male cross-breed dog was referred for treatment of a left radio-ulnar non-union that had resulted in non-weight-bearing lameness for 4 months. The radius was approximately 25% shorter than its contralateral counterpart.
Because of economic constraints, the hypertrophic non-union lesion was treated using two standard plates (2·7 mm limited contact dynamic compression plate (LC-DCP) ) and an autologous caudal bone graft obtained by amputation of the tail at the level of the sixth caudal vertebra, supplemented with a cancellous graft taken from the humerus. After excising as much soft tissue
as possible and drilling a cranial-caudal hole through the centre of the vertebral bodies, the seventh and eight caudal vertebrae were used to graft between the non-union ends of the radius and ulna respectively and retained in position using 10-hole 2·7 mm LC-DCPs . Screws were progressively removed from the plates, commencing on day 55, so as to increasingly transfer ..
Emphysematous cystitis: review of current literature, diagnosis and management challenges
No full text
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
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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