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Upplevelser av hinder och möjligheter till god vård för patienter med sällsynta sjukdomar:En litteraturöversiktKeränen, Aphinya, Dahlblom, Mikaela January 2022 (has links)
Introduktion: Ungefär fem procent av Sveriges befolkning drabbas av någon typ av sällsynt sjukdom, trots detta finns det stora kunskapsluckor i hur patienter med sällsynta sjukdomar upplever vården. Fyra patientgrupper med olika sällsynta sjukdomar valdes ut för detta arbete, amyotrofisk lateralskleros, Ehlers-Danlos syndrom, Huntingtons sjukdom och multipel skleros. Syfte: Syftet var att undersöka upplevelser av hinder och möjligheter till god vård för patienter med amyotrofisk lateralskleros (ALS), Ehlers-Danlos syndrom (EDS), Huntingtons sjukdom (HD) och multipel skleros (MS). Metod: En litteraturöversikt med tre artiklar per sjukdom som hade fokus på patientperspektivet inkluderades. Samtliga artiklar kvalitetsgranskades och analyserades. Resultat: Två huvudteman identifierades. Dessa var möjligheter och hinder till god vård. Möjligheter innefattar stöd vid diagnossamtal samt vårdpersonalens ansvar för samordning och personcentrerad vård. Hinder innefattade vårdpersonalens bristande kunskapsnivå, negativt bemötande inom vården, förlust av kontroll samt bristfällig och osäker vård. Slutsats: Examensarbetets resultat visar att patienter med amyotrofisk lateralskleros, Ehlers-Danlos syndrom, Huntingtons sjukdom och multipel skleros upplever möjligheter och hinder till god vård i mötet med vården där resultatet visar fler hinder till god vård än möjligheter. Det som upplevs vara en möjlighet till god vård för patienten ska kunna förstärkas inom vården och det som upplevs vara ett hinder till god vård för patienten ska kunna minimeras, allt detta med patientens behov centrum. / Introduction: Approximately five percent of Sweden’s population suffer from some type of rare disease, despite this, there are large knowledge gaps in how patients with rare diseases experience care. Four patient groups with different rare diseases were selected for this work, amyotrophic lateral sclerosis, Ehlers-Danlos syndrome, Huntington's disease, and multiple sclerosis. Objective: The aim was to investigate experiences of obstacles and opportunities for good care for patients with amyotrophic lateral sclerosis (ALS), Ehlers-Danlos syndrome (EDS), Huntington's disease (HD), and multiple sclerosis (MS). Method: A literature review with three articles per disease that focused on the patient perspective was included. All articles are quality reviewed and analyzed. Results: Two main themes were identified. These were opportunities and obstacles for good care. Opportunities included support during diagnostic calls and the healthcare worker’s responsibility for coordination and person-centered care. Obstacles included the healthcare worker’s lack of knowledge, negative treatment in care, loss of control, and inadequate and unsafe care. Conclusion: The result of the thesis shows that patients with multiple sclerosis, Ehlers-Danlos syndrome, amyotrophic lateral sclerosis, or Huntington’s disease experience opportunities and obstacles for good care in the encounter with healthcare where obstacles to good care were experienced to a greater extent according to the results. What was perceived as an opportunity for good care for the patient must be strengthened in healthcare and what was perceived as an obstacle to good care for the patient must be minimized, all this with the patient in mind.
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Studying Rare Patients with Commonly-Available Information: Social Mediomics for Researching Patient Histories in Autoimmune Hepatitis (AIH)Kulanthaivel, Anand 12 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Autoimmune Hepatitis (AIH), an incurable chronic condition of unknown cause where
the body attacks its own liver, is a rare disease, with a current diagnosed worldwide prevalence of
< 150,000. Inadequately treated, AIH can cause progressive liver damage and ultimately liver
failure. A wide variety of symptoms are associated with AIH including severe fatigue, joint pain,
depression, anxiety, and insomnia.
While precision medicine’s genomics has attempted to shed light on the disease, other
non-molecular “-omics” approaches can be taken in studying AIH patients, who often utilize
social media to gather information from other patients or care providers to apply to their own AIH
disease course. It is proposed that these patient-generated social mediomes can create self-report
health records for patients – and facets of their lives - otherwise unreachable by conventional
research.
In this feasibility study, I examined in an exploratory fashion the social mediome of a
large (N > 1000) gathering of AIH patients and caregivers as present on a Facebook Group to
determine the potential of mining various types health-related user information. The following
types of information were mined, with feasible indicating a reliability of F >= 0.670:
1) Types of health information shared and structures of information sharing (Feasible)
2) Types and directionality of support provided by and to users (Portions feasible)
3) Clinical factors (AIH-related and otherwise) disclosed by users
a. Medication intake (Feasible)
b. Signs and symptoms (including pain and injury) and diagnosed comorbidities
(Portions feasible)
c. Results of disease monitoring blood tests (Portions feasible)
4) Contextual (non-clinical; environmental; social) factors disclosed by users (Detection of
which type of factor discussed occasionally feasible).
The resulting knowledge is required to adequately describe the disease not only clinically, but
also environmentally and socially, and will form part of the basis for future disease studies.
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SYT11 as a Novel Gene in Congenital Myasthenic SyndromesLau, Jarred 04 January 2022 (has links)
The congenital myasthenic syndromes (CMS) are a group of rare genetic diseases affecting the neuromuscular junction (NMJ). These syndromes affect signal transmission and result in fatigable muscle weakness. In this study we performed exome analysis of 2 CMS patient cohorts and identified SYT11, a synaptotagmin inhibitor of clathrin mediated endocytosis (CME), and MGAT5B, a glycosylation protein, as potential novel CMS genes using bioinformatic analysis on the RD-Connect Genome Phenome Analysis Platform (GPAP). To validate them, we utilized morpholino knockdown models of zebrafish orthologues syt11a, syt11b, and mgat5b and conducted functional assays measuring chorion activity and escape response. Our results show that co-knockdown of syt11a/b or syt11b alone (and not mgat5b) results in a substantial neuromuscular deficit, with ablation of chorion activity and severely reduced escape response. Immunofluorescent studies showed both motor neuron growth and NMJ formation was inhibited by syt11a/b knockdown. In conclusion, syt11b causes a severe neuromuscular phenotype in zebrafish which supports SYT11 as a novel CMS-causing gene.
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High-Throughput Screening of Kinase siRNAs and Small Molecule Compounds Identify Novel Candidates for the Development of Myotonic Dystrophy Type 1 Therapies: A Step Towards Therapeutic Advancements in DM1Neault, Nafisa 11 December 2020 (has links)
Myotonic dystrophy type 1 (DM1) is the most common form of adult muscular dystrophy (1:8000) and is caused by an abnormal expansion of CTG repeats in the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA forms hairpin structures which sequester RNA-binding proteins (RBP) in intranuclear foci, such as the splicing regulator muscleblind-like 1 (MBNL1), which results in aberrant splicing of several mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating these RNA foci repletes free and thus functional MBNL1, rescuing DM1 spliceopathy and alleviating associated signs and symptoms such as myotonia. Importantly, the direct upregulation of MBNL1 has comparable beneficial outcomes. The focus of this thesis was to develop novel and practical therapeutic avenues for DM1 by employing high-throughput screening technology to identify key pathways and small molecule candidates which reduce CUG foci in patient cells, and ultimately correct DM1 spliceopathy and associated signs in vivo. First, a high-throughput kinome screen using an siRNA library targeting 692 kinase subunits identified PACT, HIPK4, and PKA2β as candidates for reducing CUG foci in patient fibroblasts. Knockdown of each gene resulted in a partial reduction in CUG foci, but ultimately did not correct aberrant splicing of insulin receptor (IR) or sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA1), two genes which are typically misspliced in DM1. A second set of screens focused on testing small molecules, several of which are FDA-approved for clinical use, in an effort to expedite drug discovery. One approach was to data-mine from a previously completed chemical screen, which used system-wide RNA sequencing to establish drug-gene interactions in mouse neuronal cultures treated with blood brain barrier-penetrant drugs, and specifically look for compounds which downregulate DMPK mRNA or upregulate MBNL mRNA (MBNL1 and MBNL2). No compounds were found to downregulate DMPK mRNA. However, several compounds upregulated MBNL mRNAs; the activity of one of these, nilotinib, was validated in human DM1 fibroblasts and converted myoblasts, mediating a small correction in SERCA1 spliceopathy. Administration of nilotinib to unaffected mice did not result in in vivo MBNL gene upregulation in mouse skeletal muscle, as was seen in vitro. Further testing of nilotinib in DM1 in vivo models is required. A final set of chemical screens in patient myoblasts using an FDA-approved drug library and a chemogenomic drug library identified several HDAC inhibitors which reduced foci and rescued SERCA1 spliceopathy in vitro in DM1 differentiated myoblasts. Of these, vorinostat (SAHA) was further tested in a mouse model of DM1 (HSALR), proving safe and effective in correcting aberrant muscle pathology as well as splicing defects of RYR1, SERCA1, and CLCN1. Functional validation, such as myotonia, remains to be completed, but given the strong evidence for CUG foci reduction and splicing correction, vorinostat has emerged as a promising novel candidate for DM1 therapy.
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Knowledge Translation in the Era of Precision Diagnostics: Examining the Use of Clinical Exome and Genome Sequencing for Rare Genetic Disease DiagnosisHartley, Taila 13 September 2023 (has links)
In just over a decade, exome sequencing and genome sequencing (ES/GS) has transitioned from a research method to an implemented test for patients with suspected rare genetic diseases (RGDs) worldwide, and healthcare systems are challenged to optimize its use within their jurisdictions. This thesis aimed to examine the rapidly evolving scientific evidence base related to ES/GS and how it has been translated into diagnostic care for families with RGDs to inform practice and policy in the future. Guided by the Knowledge-to-Action (KTA) conceptual framework, I designed and conducted three original studies: two aimed to generate evidence related to the KTA concept of Knowledge Creation, and the third studied the Action Cycle. In Article 1, we examined the knowledge base and determined that evidence related to the etiologies of RGDs and analytical processes related to ES/GS testing are progressing at a pace that has diagnostic implications. Next, in Article 2, we examined knowledge refinement and found that one knowledge user, organizations representing genetics professionals, have produced clinical recommendations related to a broad range of topics connected to ES/GS for RGD diagnosis, but the quality of clinical guidance documents is low, overall, and with specific reference to the rigour of the methods developers used. Finally, in Article 3, we studied the Action Cycle and found that implementing publicly-funded ES/GS using a set of clinical eligibility criteria in the Ontario healthcare system resulted in clinically-valid diagnoses for patients that met provincial benchmarks for diagnostic yield. Together, the results of these studies informed eight considerations for optimizing ES/GS testing with implications for healthcare practitioners, patients, guidance developers, payers, and researchers. Importantly, this thesis provides evidence of the necessity for continued evaluation and improved guidance development related to ES/GS to optimize this testing. It offers a foundation for future studies that may investigate knowledge translation into policy and practice in this and other rapidly evolving fields. Ultimately, these findings will enable better diagnostic care for families with RGDs.
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Discovery and Analysis of Patterns in Molecular Networks: Link Prediction, Network Analysis, and Applications to Novel Drug Target DiscoveryZhang, Minlu 20 April 2012 (has links)
No description available.
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Determinação da Base Molecular da Síndrome Ablefaria Macrostomia / Determining the Molecular Basis of Ablepharon Macrostomia SyndromeSilva, Eduarda Morgana da 18 June 2015 (has links)
A Síndrome Ablefaria Macrostomia (SAM) é uma condição rara, onde os pacientes apresentam características clínicas marcantes como o encurtamento ou ausência das pálpebras superiores e inferiores, ausência de sobrancelhas e cílios, macrostomia por defeitos na fusão dos lábios, entre outros. O padrão de herança da síndrome não está elucidado, tendo a herança autossômica dominante com expressividade variável sido sugerida. SAM possui sobreposição fenotípica com a Síndrome de Barber-Say e com a Síndrome de Fraser, porém nenhum gene já descrito apresentou mutação nos pacientes portadores da SAM. A abordagem genômica no estudo de doenças raras tem sido amplamente utilizada, devido principalmente ao surgimento da Nova Geração de Sequenciamento, que possui alto poder de descriminar as seqüencias nucleotídicas com grande cobertura, em um curto período de tempo. No presente estudo o sequenciamento completo do exoma foi realizado, com cinco indivíduos de uma mesma família, três membros afetados e dois não, e permitiu a análise das regiões codificantes nestes indivíduos. A base molecular da Síndrome Ablefaria Macrostomia é aqui sugerida como autossômica dominante, e decorrente da mutação nova não sinônima c.223G>A (p.E75K) no gene TWIST2. Essa mutação patogênica ocasiona a troca de um aminoácido pequeno de carga negativa, o ácido glutâmico, para um aminoácido de cadeia maior carregado positivamente, a lisina. A modelagem in silico da proteína Twist2 mostrou que a estrutura geral tridimensional da proteína não foi alterada, mas a troca do aminoácido ocorre na posição 75 dentro do domínio básico HLH, e pode impedir a formação de dímeros, ou a própria ligação ao DNA. Sugere-se ainda que a heterogeneidade de fenótipos associados a mutações no gene TWIST2, pode ser atribuída às interações que essa proteína é capaz de formar, e a ampla ação regulatória que ela desempenha em diversos genes do desenvolvimento. / Ablepharon-Macrostomia Syndrome (AMS) is a rare condition characterised by absent or hypoplastic eyelids, absent eyebrows and eyelashes, macrostomia caused by fusion defects of the mouth with unfused lateral commissures, as well as other clinical features. The inheritance pattern has not been confirmed and while autosomal dominant inheritance with variable expressivity has been suggested, recessive inheritance has not been ruled out. The phenotype of AMS overlaps that of Barber-Say and Fraser Syndrome, but any reported gene for these syndromes is mutated on AMS patients. The genomic approach for rare disease studies has been widely used mainly due to the emergence of Next Generation Sequencing, which is very effective at determining nucleotide sequences with large coverage in a short period of time. The whole exome sequencing of five family members was undertaken, with three affected and two unaffected, and the coding regions of the individuals were subsequently analysed. The molecular basis of AMS is suggested here as autosomal dominant, and due to a novel non-synonymous mutation c.223G>A (p.E75K), in TWIST2 gene. This pathogenic mutation causes glutamic acid, a small negatively charged amino acid, to be substituted for a larger and positively charged lysine. The in silico protein modeling of Twist2 shows that the general 3D-structure of the protein is not affected, but the amino acid change is located inside the basic Helix-Loop-Helix domain which could disrupt dimerization and DNA binding. It has also been suggested that the phenotype heterogeneity associated with mutations on TWIST2 gene can be attributed to the interactions that this protein is capable of, and the role that it plays in the regulation of several developmental genes.
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Determinação da Base Molecular da Síndrome Ablefaria Macrostomia / Determining the Molecular Basis of Ablepharon Macrostomia SyndromeEduarda Morgana da Silva 18 June 2015 (has links)
A Síndrome Ablefaria Macrostomia (SAM) é uma condição rara, onde os pacientes apresentam características clínicas marcantes como o encurtamento ou ausência das pálpebras superiores e inferiores, ausência de sobrancelhas e cílios, macrostomia por defeitos na fusão dos lábios, entre outros. O padrão de herança da síndrome não está elucidado, tendo a herança autossômica dominante com expressividade variável sido sugerida. SAM possui sobreposição fenotípica com a Síndrome de Barber-Say e com a Síndrome de Fraser, porém nenhum gene já descrito apresentou mutação nos pacientes portadores da SAM. A abordagem genômica no estudo de doenças raras tem sido amplamente utilizada, devido principalmente ao surgimento da Nova Geração de Sequenciamento, que possui alto poder de descriminar as seqüencias nucleotídicas com grande cobertura, em um curto período de tempo. No presente estudo o sequenciamento completo do exoma foi realizado, com cinco indivíduos de uma mesma família, três membros afetados e dois não, e permitiu a análise das regiões codificantes nestes indivíduos. A base molecular da Síndrome Ablefaria Macrostomia é aqui sugerida como autossômica dominante, e decorrente da mutação nova não sinônima c.223G>A (p.E75K) no gene TWIST2. Essa mutação patogênica ocasiona a troca de um aminoácido pequeno de carga negativa, o ácido glutâmico, para um aminoácido de cadeia maior carregado positivamente, a lisina. A modelagem in silico da proteína Twist2 mostrou que a estrutura geral tridimensional da proteína não foi alterada, mas a troca do aminoácido ocorre na posição 75 dentro do domínio básico HLH, e pode impedir a formação de dímeros, ou a própria ligação ao DNA. Sugere-se ainda que a heterogeneidade de fenótipos associados a mutações no gene TWIST2, pode ser atribuída às interações que essa proteína é capaz de formar, e a ampla ação regulatória que ela desempenha em diversos genes do desenvolvimento. / Ablepharon-Macrostomia Syndrome (AMS) is a rare condition characterised by absent or hypoplastic eyelids, absent eyebrows and eyelashes, macrostomia caused by fusion defects of the mouth with unfused lateral commissures, as well as other clinical features. The inheritance pattern has not been confirmed and while autosomal dominant inheritance with variable expressivity has been suggested, recessive inheritance has not been ruled out. The phenotype of AMS overlaps that of Barber-Say and Fraser Syndrome, but any reported gene for these syndromes is mutated on AMS patients. The genomic approach for rare disease studies has been widely used mainly due to the emergence of Next Generation Sequencing, which is very effective at determining nucleotide sequences with large coverage in a short period of time. The whole exome sequencing of five family members was undertaken, with three affected and two unaffected, and the coding regions of the individuals were subsequently analysed. The molecular basis of AMS is suggested here as autosomal dominant, and due to a novel non-synonymous mutation c.223G>A (p.E75K), in TWIST2 gene. This pathogenic mutation causes glutamic acid, a small negatively charged amino acid, to be substituted for a larger and positively charged lysine. The in silico protein modeling of Twist2 shows that the general 3D-structure of the protein is not affected, but the amino acid change is located inside the basic Helix-Loop-Helix domain which could disrupt dimerization and DNA binding. It has also been suggested that the phenotype heterogeneity associated with mutations on TWIST2 gene can be attributed to the interactions that this protein is capable of, and the role that it plays in the regulation of several developmental genes.
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The Rare Disease Assumption: The Good, The Bad, and The UglyBrems, Matthew William 01 June 2015 (has links)
No description available.
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Determining the mechanism of pathogenesis of mucolipidosis type IV and related lysosomal storage disorders for development of novel therapiesPeterneva, Ksenia January 2014 (has links)
Mucolipidosis type IV (MLIV) is a rare, autosomal recessive, neurodegenerative, lysosomal storage disorder. MLIV is caused by mutations in a gene (MCOLN1) encoding a TRP channel family member known as Mucolipin 1 or TRPML1. TRPML1 is a lysosomal transmembrane protein that appears to be required for normal lysosomal pH regulation, recycling of molecules and membrane reorganisation including lysosomal biogenesis, fusion and exocytosis. The exact function of the channel is unknown but it is permeable to multiple ions including Ca<sup>2+</sup>, Na<sup>+</sup> and K<sup>+</sup>, possibly also Fe<sup>2+</sup> and Zn<sup>2+</sup>. How normal TRPML1 function regulates lysosomal processes is not clearly understood. Mutations in the MCOLN1 gene can lead to complete loss of TRPML1 function, partial loss of function or mislocalisation, all of which lead to lysosomal dysfunction, lysosomal lipid storage and ultimately neurodegeneration. The disease processes that lead to neurodegeneration are poorly understood and at present no therapy exists for MLIV. We have discovered that TRPML1 results in regulating lysosomal Ca<sup>2+</sup> homeostasis that is the opposite of the Ca<sup>2+</sup> dysregulation associated with Niemann-Pick type C disease (NPC). Our findings indicate that disrupted function of TRPML1 leads to enhanced Ca<sup>2+</sup> release via the NAADP receptor, recently shown to be the lysosomal two-pore channel TPC2. This indicates that TRPML1 is not the NAADP receptor as suggested by others, indeed NAADP mediated Ca<sup>2+</sup> release is enhanced with multiple NAADP induced lysosomal Ca<sup>2+</sup> release events occurring in TRPML1 null cells compared to single releases in normal cells. This phenotype appears to be responsible for the cellular dysfunction associated with MLIV disease cells, enhanced lysosomal fusion, defective endocytosis and potentially even altered lysosomal pH. Several of these phenotypes are normalised by the NAADP receptor specific antagonist Ned-19. These findings illustrate that the NAADP receptor is central to MLIV disease pathology and may be a novel candidate for disease therapy.
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