Thèses : « Congenital diseases »

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Beswick, Richard William. « Functional characterisation of the genes mutated in dyskeratosis congenita ». Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8705.

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Dyskeratosis congenita (DC) is a multi system disorder that exhibits considerable clinical and genetic heterogeneity. It is characterised by mucocutaneous features, bone marrow failure and a predisposition to cancer. Research has identified mutations affecting several telomerase components and patients often have short telomeres, implicating defective telomere maintenance in this disease. Affected components include dyskerin, NOP10 and NHP2, which together with GAR1 form a protein core common to telomerase and all other H/ACA ribonucleoprotein complexes (H/ACA RNPs). Initially characterised as H/ACA RNP components important for pseudouridylation and rRNA processing, their role in the functionally distinct telomerase complex and telomere maintenance is less defined. In order to better understand their implications in DC, this study investigated the importance of these core proteins for the integrity and function of telomerase in human cells. RNAi knockdown studies demonstrated that dyskerin, NOP10 and NHP2 are necessary for the accumulation of TERC (telomerase RNA component); dyskerin and NOP10 for telomerase activity. Moreover, dyskerin was found to be important for maintaining telomere length over time. The impact of NOP10 and NHP2 missense mutations was also analysed in vitro, which indicated that they impair TERC accumulation. The potential effect on pseudouridylation was also considered in this study; the analysis of other H/ACA RNA levels in these knockdown experiments and in a cohort of patients with DKC1 mutations revealed an irregular and inconsistent impact compared to that observed on TERC. Finally, defective telomere maintenance is heavily implicated as the primary cause of DC and very short telomeres have been proposed as a diagnostic marker. This study investigated telomere length in a patient cohort of unprecedented size. It demonstrated the prevalence of the telomere length defect, but telomere length was not found to correlate with either genetic subtype or disease severity, implicating the rate of telomere shortening as the correlating factor instead.

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Wallgren-Pettersson, Carina. « Congenital nemaline myopathy a longitudinal study / ». Helsinki, Finland : Finnish Society of Sciences and Letters, 1990. http://catalog.hathitrust.org/api/volumes/oclc/24051855.html.

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Hui, Ling, et 許凌. « Dobutamine stress echocardiography for children with acquired and congenital cardiac diseases ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29914954.

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Jannini, Alexandre Wolf. « Interrupção da gestação em situações de fetos portadores de malformações imcompativeis com a vida ultra-uterina : posicionamento de magistrados e membros do ministerio publico no Brasil ». [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311725.

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Orientador: Renato Passini Junior
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-11-09T15:30:07Z (GMT). No. of bitstreams: 1 Jannini_AlexandreWolf_M.pdf: 3134011 bytes, checksum: 9cae7dc9e2202285b4be1b0a5ae92bb0 (MD5) Previous issue date: 2008
Resumo: Introdução: A legislação não permite a interrupção da gestação em casos de malformações fetais incompatíveis com a vida extra-uterina, cabendo ao Poder Judiciário decidir quando há uma solicitação deste tipo. Objetivos: Investigar a opinião de Magistrados e membros do Ministério Público sobre o abortamento nos casos de malformações fetais incompatíveis com a vida extra-uterina, especialmente em relação à anencefalia. Método: Análise parcial de dados obtidos em duas pesquisas realizadas pelo Centro de Pesquisas em Saúde Reprodutiva de Campinas (CEMICAMP), que objetivaram estudar a opinião destes profissionais acerca do aborto induzido. Foram obtidos dados de 1493 Magistrados e 2614 Promotores de Justiça. Foi constituído um banco de dados com as informações de interesse das pesquisas originais, analisado com auxílio do programa estatístico SAS versão 9.02, envolvendo análise bivariada e múltipla, por regressão logística. Resultados: Para 78,5% dos Magistrados e 82,6% dos membros do Ministério Público, a interrupção da gestação deveria ser permitida nos casos de qualquer malformação fetal incompatível com a vida extra-uterina. Em casos de diagnóstico de anencefalia, estes valores foram de 79,2% e 84,1%, respectivamente. Na análise multivariada, as variáveis associadas à opinião dos pesquisados foram a religiosidade, importância da religião e das concepções religiosas pessoais sobre as respostas dadas, experiência de gravidez indesejada que resultou em aborto, sexo, estado marital e o fato de possuir filhos. Conclusões: A grande maioria dos Magistrados e membros do Ministério Público foi favorável ao abortamento nas hipóteses estudadas, sendo as variáveis ligadas à religião as que mais influenciaram seu posicionamento
Abstract: Introduction: In Brazil abortion in cases of fetal malformation or anencephaly is prohibited by law. Pregnant women who want to perform an abortion in such cases must seek for a judicial order. Objectives: Evaluate the opinion of brazilian magistrates and Prosecutors about abortion in cases of fetal malformation incompatible with life and anencephaly. Methodology: It was a partial data analysis from data obtained in two researchs carried out by Centro de Pesquisas em Saúde Reprodutiva de Campinas (CEMICAMP ), to evaluate the opinion and conduct of these professionals about induced abortion. There were data from 1453 Magistrates and 2614 Prosecutors. It was made a data bank with data from the original studies, that was processed and analyzed using the statistical package SAS version 9.02. Results: For 78.5% of the Magistrates and 82.6% of the Prosecutors abortion should be permitted in cases of severe fetal malformation incompatible with life. In cases of anencephaly abortion should be permitted for 79.2% of the Magistrates and for 84.1% of the Prosecutors. Religiosity, influence of religion and personal religious convictions among responses, experience with unwanted pregnancy that ended in abortion, gender, marital status and the fact of having children had shown, in multivariable analysis, association with the opinion about abortion in the hypothesis studied. Conclusion: The great majority of Magistrates and Prosecutors had a favorable opinion about abortion in both hypothesis evaluated. Variables associated with religion had the strongest association with the opinion about abortion in cases of fetal malformation and anencephaly.Abstract: Introduction: In Brazil abortion in cases of fetal malformation or anencephaly is prohibited by law. Pregnant women who want to perform an abortion in such cases must seek for a judicial order. Objectives: Evaluate the opinion of brazilian magistrates and Prosecutors about abortion in cases of fetal malformation incompatible with life and anencephaly. Methodology: It was a partial data analysis from data obtained in two researchs carried out by Centro de Pesquisas em Saúde Reprodutiva de Campinas (CEMICAMP ), to evaluate the opinion and conduct of these professionals about induced abortion. There were data from 1453 Magistrates and 2614 Prosecutors. It was made a data bank with data from the original studies, that was processed and analyzed using the statistical package SAS version 9.02. Results: For 78.5% of the Magistrates and 82.6% of the Prosecutors abortion should be permitted in cases of severe fetal malformation incompatible with life. In cases of anencephaly abortion should be permitted for 79.2% of the Magistrates and for 84.1% of the Prosecutors. Religiosity, influence of religion and personal religious convictions among responses, experience with unwanted pregnancy that ended in abortion, gender, marital status and the fact of having children had shown, in multivariable analysis, association with the opinion about abortion in the hypothesis studied. Conclusion: The great majority of Magistrates and Prosecutors had a favorable opinion about abortion in both hypothesis evaluated. Variables associated with religion had the strongest association with the opinion about abortion in cases of fetal malformation and anencephaly
Mestrado
Ciencias Biomedicas
Mestre em Tocoginecologia

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Lai, Tik-man Clare, et 賴迪雯. « Circulating biomarkers and right ventricular function in adolescents and young adults with congenital heart disease ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/197541.

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The population of adolescent and adults with congenital heart disease (CHD) has grown rapidly. Right ventricular (RV) dysfunction remains an important issue of concern in the long-term follow up of these patients. While circulating biomarkers have shown promise in the assessment and monitoring of adult patients with left heart diseases, little is known of the role of biomarkers in reflecting RV performance in CHD patients. Emerging circulating biomarkers that reflect underlying pathophysiologic processes have gained increasing attention. These include inflammatory cytokines namely tumour necrosis factor (TNF)-α, a biomarker of apoptosis annexin A5 (AnxA5), carboxy-terminal propeptide of type I procollagen (PICP) and amino-terminal propeptide of type III procollagen (PIIINP) that reflects collagen synthesis and turnover, low circulating levels of cardiac troponin T as detected by highly sensitive assay (hs-cTnT) that may reflect subclinical myocardial injury, and microRNAs found to be involved in cardiac remodeling. The studies in this thesis aimed to test the hypothesis that circulating biomarkers may be altered in patients with volume-overloaded right ventricles after repair of tetralogy (TOF) and pressure-overloaded right ventricles after atrial switch operation for complete transposition of the great arteries (TGA), and are related to indices of RV function. In patients after TOF repair, increased circulating PICP and PIIINP levels were associated with worse subpulmonary RV and left ventricular (LV) function. In particular, these propeptides correlated positively with LV mechanical dyssynchrony, implicating a possible role of increased collagen synthesis in its pathogenesis. Increased plasma levels of hs-cTnT were further found in 30% of female, but not male patients. Female patients with elevated hs-cTnT levels compared to those without had greater RV volumes and LV mechanical dyssynchrony. Independent correlates of hs-cTnT in patients as determined from multivariate analysis were sex and RV ejection fraction. MicroRNA profiling following validation confirmed alteration of circulating levels of miR-99b and miR-766 in repaired TOF patients, a pattern distinct from that reported for left heart diseases. The miRNA expression was, however, not related to the cardiac functional indices. Patients after atrial repair for TGA had significantly higher circulating AnxA5 and TNF-αlevels, but similar PICP, PIIINP levels, compared with controls. Elevated AnxA5 level was associated with impaired systemic RV myocardial deformation, increased subpulmonary ventricular eccentricity, and increased TNF-αlevel. Elevation of hs-cTnT is found in 39% of the patients. The positive correlation between hs-cTnT level and systemic RV volume may suggest a role of hs-cTnT in reflecting RV remodeling. Circulating microRNA expression profiling and further validation identified 11 upregulated microRNAs (miR-16, miR-106a, miR-144*, miR-18a, miR-25, miR-451, miR-486-3p, miR-486-5p, miR-505*, let-7e and miR-93). Among them, miR-18a and miR-486-5p correlated negatively with systemic ventricular myocardial acceleration during isovolumic contraction, a relatively-load independent measure of systemic RV contractility. To conclude, these biomarkers reflect in varying extent the structural, functional, biological alteration of the subpulmonary and systemic right ventricles of the CHD patients late after surgical repair. These data may provide new perspectives in the understanding of progressive RV dysfunction in the adult CHD population and hopefully shed more lights on novel therapeutic interventions.
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Paediatrics and Adolescent Medicine
Doctoral
Doctor of Philosophy

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Silva, Viviane Martins da. « Characterization of nursing diagnoses in children with congenital heart disease : Study at a specialized hospital in diseases cardiopulmonary ». Universidade Federal do CearÃ, 2007. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=1050.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
Os cuidados de enfermagem para crianÃas com cardiopatia congÃnita devem ser estabelecidos e executados tÃo logo se suspeite do diagnÃstico de defeito cardÃaco congÃnito, voltados sempre para a detecÃÃo precoce de sinais de descompensaÃÃo e manutenÃÃo de condiÃÃes Ãtimas para a cirurgia. Objetivou-se caracterizar o quadro de diagnÃsticos de enfermagem apresentados por crianÃas com cardiopatias congÃnitas. Estudo de natureza observacional, longitudinal desenvolvido nos meses de julho a novembro de 2004. A amostra foi composta por 45 crianÃas internadas em um hospital da rede pÃblica do municÃpio de Fortaleza-CearÃ. Para a coleta, foram utilizados entrevista e exame clÃnico de enfermagem. As crianÃas foram acompanhadas durante quinze dias de internamento desde a data de sua admissÃo. No perÃodo efetivaram-se seis avaliaÃÃes diagnÃsticas com intervalo de 48 horas. O processo de elaboraÃÃo e inferÃncia dos diagnÃsticos e problemas colaborativos seguiu as etapas de coleta, interpretaÃÃo / agrupamento das informaÃÃes e nomeaÃÃo de categorias. Foram encontrados 22 diagnÃsticos de enfermagem, 34 fatores relacionados e 13 problemas colaborativos diferentes nas 270 avaliaÃÃes realizadas. Observou-se associaÃÃo estatisticamente significante entre os diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia Ã atividade, Crescimento e desenvolvimento retardados e PerfusÃo tissular ineficaz. Estes diagnÃsticos apresentaram associaÃÃo com os fatores relacionados: DesequilÃbrio da ventilaÃÃo-perfusÃo, HiperventilaÃÃo, ReduÃÃo mecÃnica do fluxo sangÃÃneo, SecreÃÃes brÃnquicas e SecreÃÃes retidas. Os diagnÃsticos IntolerÃncia Ã atividade e Crescimento e desenvolvimento retardados mostraram associaÃÃo com o sexo feminino. Nos diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia Ã atividade, Crescimento e desenvolvimento retardados e DÃbito cardÃaco diminuÃdo, identificaram-se diferenÃas de mÃdia de sobrevida entre crianÃas atÃ 4 meses e acima de 4 meses. Os diagnÃsticos Troca de gases prejudicada, PadrÃo respiratÃrio ineficaz, IntolerÃncia Ã atividade e Risco para infecÃÃo ocorreram precocemente no perÃodo de internamento. Entre os diagnÃsticos, seis evidenciaram maiores oscilaÃÃes em suas trajetÃrias de ocorrÃncia no tempo: PadrÃo respiratÃrio ineficaz, IntolerÃncia Ã atividade, DesobstruÃÃo ineficaz das vias aÃreas, Hipertermia, PadrÃo de sono perturbado e Risco para intolerÃncia Ã atividade. Foram construÃdos cinco modelos paramÃtricos no domÃnio tempo, com vistas a predizer a ocorrÃncia desses diagnÃsticos de enfermagem. O ajustamento das equaÃÃes para os diagnÃsticos PadrÃo de sono perturbado e Hipertermia denotou grande dispersÃo entre os dados e a linha de tendÃncia, indicando que, alÃm do tempo, outras variÃveis determinam a proporÃÃo de crianÃas que manifestarÃo esses diagnÃsticos. Considera-se a importÃncia de se realizar pesquisas de caracterizaÃÃo do quadro de diagnÃsticos para determinaÃÃo das necessidades de assistÃncia de enfermagem Ã crianÃa cardiopata. O conhecimento da evoluÃÃo temporal das respostas do indivÃduo pode direcionar os cuidados de enfermagem para as reais necessidades do cliente, facilitando, assim, a escolha de intervenÃÃes mais adequadas

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Tivers, Michael Samuel. « The role of hepatic regeneration and angiogenesis in the response to surgical attenuation of congenital portosystemic shunts in dogs ». Thesis, Royal Veterinary College (University of London), 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618310.

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Herman, Kazibwe. « Barriers experienced by parents/caregivers of children with clubfoot deformity attending specific clinics in Uganda ». Thesis, University of the Western Cape, 2006. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_9901_1194348551.

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Clubfoot is the most common congenital structural deformity that leads to physical impairments in children in many poor developing countries. Inadequately treated or neglected clubfoot has been found to be a common cause of ohysical disability globally among children and young growing adults. Many children are referred to the clinics for treatment but some parents do not comply with the treatment regimen whcih requires attending for consecutive treatment sessions. The purpose of this study was to investigate barriers to treatment attendance parents/caregivers of children with clubfoot encounter in complying with clubfoot treatment during the plaster csting phase in Uganda.

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Chow, Pak-cheong, et 周百昌. « Systematic review on efficacy of anticoagulation and antithrombotics in patients with congenital heart diseases ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B50222636.

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Background: Advance in cardiac intervention improved the survival of patients with congenital heart diseases (CHD). However, they may have propensity of thromboembolism and the use of antithrombotic agents was generally based on small studies and consensus opinion. Objective: To systematically review the current literature on the efficacy and safety of various antithrombotic agents in patients with CHD. Methods: Studies published in English during the period 1990 – 2012 were identified using keyword search from PubMed, Medline, EMBase, and Cochrane Library. Additional search from reference sections of the articles and clinical trial registry was performed. Data extracted included: type of studies, number of patients, follow-up period during which the patients were on the antithrombotic agents, number of thromboembolic (TE) events, and all, major and minor bleeding events. Event rate as the proportion of events of the patients and event per 100 patients-year were obtained for respective antithrombotic agent in each study. Composite event rate and event per 100 patients-year were estimated after weighting. Results: Forty studies consisted of 5144 patients were reviewed. Observation period of 8916.6 years was available in 25 studies. Diagnostic categories included: Fontan operation 15, systemic-to-pulmonary artery shunt 7, mechanical valve 8, atrial septal defect occlusion device 2, cyanotic heart 1, mixed 7. Antithrombotic prophylaxis was not used in 13 studies, warfarin in 26, aspirin alone in 22, combined aspirin and dipyridamole in 2. Clopidogrel with concomitant antithrombotic agents was reported in 5 studies. Overall composite TE event rate was 3.9% (95% CI 2.3 – 5.4%) and that of all bleeding rate was 2.8% (95% CI 0 – 5.5%), with 1.4% (95% CI 0.0 – 2.6%) for major and 2.2% (95% CI 0.0 – 4.3%) for minor bleeding. Composite TE rate for no prophylaxis (9.6%; 05% CI 3.7 – 15.5%) was significantly greater than that of warfarin (1.7%; 95% CI 0.1 – 3.3%) and aspirin (1.3%; 95% CI 0.0 – 3.0%). Both TE and all bleeding rate showed no difference between warfarin and aspirin, while major bleeding tended to be higher in warfarin than aspirin(0.9% vs 0.0%, p=0.06). Fontan patients had overall TE rate of 2.7% (95% CI 0.1 – 5.4%). Patients with no prophylaxis (10.2%; 95% CI 9.2 – 18%) had significantly greater TE rate than warfarin (1.4%; 95% CI 0.0 – 0.4%) or aspirin (1.2%; 95% CI 0.0 – 3.0%). All bleeding rate in Fontan patients was 0.5% (95% CI 0.0 – 4.3%). Both TE ad bleeding rates showed no difference between warfarin and aspirin. Overall TE rate for shunt was 7.2% (95% CI 3.7 – 14.3%), being similar between aspirin group and no antithrombotic group. Patients with mechanical valves had TE rate of 7.3% (95% CI 2.9 – 11.6%) and all bleeding rate of 7.2% (95% CI 4.2 – 10.2%). There was no statistical difference between warfarin and APA group. Patients with ASD occlusion device has TE rate of 0.1% (95% CI 0.0 – 0.2%). No bleeding event was reported in the studies. Conclusion: Patients with congenital heart diseases were at risk of developing thromboembolism which justified the use of anti-thrombotic prophylaxis. Further studies relating the thromboembolic risk profile of patients with CHD to the efficacy of anti-thrombotic agents might help in selection of anti-thrombotic agents.
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Community Medicine
Master
Master of Public Health

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Darwich, Rami. « Functional Analysis of KLF13 in the Heart ». Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34317.

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Congenital heart defects (CHD) are the largest class of birth defects in humans and are a major cause of infant mortality and morbidity. Deciphering the molecular and genetic etiologies central for heart development and the pathogenesis of congenital heart diseases (CHD) is a challenging puzzle. We have previously demonstrated that the zinc-finger kruppel-like transcription factor KLF13, expressed predominantly in the atria, binds evolutionarily conserved regulatory elements known as CACC-boxes and transcriptionally activates several cardiac promoters. KLF13 loss of function in Xenopus embryos was associated with cardiac developmental defects underscoring its critical role in the heart. In the current study, using in vivo and in vitro approaches, we examined KLF13’s mechanisms of action and its interaction with other cardiac regulators. To test the evolutionary conserved role in the mammalian heart, we deleted the Klf13 gene in transgenic mice using homologous recombination. Mice with homozygote deletion of Klf13 were born at reduced frequency owing to severe heart defects. We also report the existence of a novel isoform of KLF13, referred to here as KLF13b. Furthermore, we report that KLF13 interacts biochemically and genetically with the T-box transcription factor TBX5 which is a key regulator of heart development. Our data provide novel insight into the role of KLF13 in cardiac transcription and suggest that KLF13 maybe a genetic modifier of congenital heart disease. Furthering our knowledge of protein-protein interactions and gene transcription will enhance genotype-phenotype correlation and contribute to better understanding of the etiology of CHD.

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Dodd, Will. « Minor Congenital Anomalies of the Newborn Period Contributing to Diagnosis of Underlying Disease ». Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etsu-works/8937.

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Chong, Wan-yip, et 莊雲葉. « Aortic root dilation and stiffness in children after repair of Tetralogy of Fallot ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31971660.

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Gharibeh, Lara. « Gata6 Haploinsufficiency Leads to Aortic Valve, Conduction System and Limbs Defects ». Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37584.

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Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Congenital heart disease (CHD) is a risk factor for premature cardiovascular complications. Great advances have occurred in the past years leading to the identification of several genes essential for proper cardiac formation such as GATA4/5/6 mutated in some individuals with CHD. GATA6 is a zinc finger transcription factor whose presence is crucial for early embryonic development. GATA6 is expressed in many cell types of the heart including myocardial, endocardial, neural crest, and vascular smooth muscle. In human, mutations in GATA6 result in variable cardiac phenotypes. The objective of this thesis was to determine the roles that GATA6 play in the different cell types of the heart and to elucidate the molecular basis of the cardiac defects associated with Gata6 haploinsufficiency. For this, a combination of cell and molecular techniques were used in vitro and in vivo. First, we show that Gata6 heterozygozity leads to RL-type bicuspid aortic valve (BAV)- the most common CHD affecting 2% of the population. GATA6-dependent BAV is the result of disruption of valve remodeling and extracellular matrix composition in Gata6 haploinsufficient mice. Cell-specific inactivation of one Gata6 allele from Isl-1 positive cells, but not from endothelial or neural crest cells, recapitulates the phenotype of Gata6 heterozygous mice revealing an essential role for GATA6 in secondary heart field myocytes during valvulogenesis. We further uncovered a role for GATA6 as an important regulator of the cardiac conduction system and revealed that GATA6 expression regulates the activity of the cardiac pacemaker. GATA6 exerts its role via regulation of the cross-talk among the different cell types of the SAN. Lastly, some CHDs are characterized by abnormalities of both the limbs and the heart such as the Holt Oram syndrome (caused by mutation in TBX5 transcription factor). The molecular basis for limb-heart defects remain poorly understood. In the course of this work, we discovered that Gata6 haploinsufficiency resulted in a partially penetrant polysyndactyly (extra digits fused together) phenotype. Together, the data provide novel molecular and cellular insight into GATA6 role in normal and pathologic heat development. Our results also suggest that GATA6 should be added to the list of genes whose mutations are potentially associated with heart and limb abnormalities. Better knowledge of the molecular basis of CHD is a prerequisite for the development of diagnostic and therapeutic strategies to improve care of individuals with congenital heart disease.

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Čibiras, Sigitas Vladas. « Methods of interventional pediatric cardiology in treatment of congenital heart diseases : immediate and long-term results ». Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2010. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2010~D_20100204_100248-32962.

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Objective - to assess possibilities and specific characteristics of pediatric cardiology in treatment of congenital heart diseases (CHD), to evaluate efficacy of curative per-catheter procedures by means of analysis of immediate and long-term results. Retrospective study. The data of 422 patients who underwent 467 CHD palliative-curative procedures during the period since 1971 till 2007 were analyzed. It was postulated that balloon atrial septostomy resulted in statistically significant increase of atrial septal defect, increase of arterial blood oxygen saturation and decrease of interatrial preasure gradient (PG). Balloon pulmonary valvulotomy (BPV) is one of the most common curative procedures; this procedure has an effect of marked decrease of pressure gradient between the right ventricle and right atrium; development of pulmonary artery valve insufficiency is the most common complication of this procedure. The long - term results of BPV are less positive when higher PG prior the procedure is present and residual PG after the procedure is 36mmHg and higher. It was postulated, that closure of small (less than 3 mm) persistent ductus arteriosus using Cook coils may compete with surgical treatment successfully. It was stated, that the efficacy of balloon angioplasties of aorta, caval veins and pulmonary artery branches is transient; treatment using stents is more effective. It was postulated, that closure of congenital and postsurgical anomalies connections using coils is... [to full text]
Disertacijos objektas yra nustatyti intervencinės pediatrinės kardiologijos galimybes ir ypatumus, gydant įgimtas širdies ydas (ĮŠY), įvertinti gydomųjų perkateterinių procedūrų efektingumą, remiantis ankstyvųjų ir vėlyvųjų rezultatų analize. Tai retrospektyvus tyrimas. Analizuoti 422 ligonių duomenys, kuriems 1971 - 2007 m. buvo atliekamos 467 įgimtų širdies ydų paliatyvinės - gydomosios procedūros. Nustatyta, kad po balioninės tarpprieširdinės pertvaros septostomijos, statistiškai reikšmingai padidėja prieširdžių pertvaros defektas, didėja arterinio kraujo įsotinimas deguonimi ir mažėja spaudimų skirtumas (SS) tarp prieširdžių. Balioninė plaučių arterijos valvuloplastika (BPV) yra viena iš dažniausiai taikomų gydomųjų procedūrų, jos efektas – ryškus SS tarp dešiniojo skilvelio ir plaučių arterijos (PA) sumažėjimas, o pagrindinė komplikacija – PA vožtuvo nesandarumo vystymasis. BPV vėlyvieji rezultatai blogesni, kai yra didelis SS prieš procedūrą, o po procedūros liekamasis SS ≥ 36mmHg. Nustatyta, kad mažų iki 3mm AAL kimšimas Cook spiralėmis gali sėkmingai konkuruoti su operaciniu gydymu. Rasta, kad aortos, tuščiųjų venų ir plaučių arterijos šakų balioninės plastikos efektas trumpalaikis, o gydymas stentais daug sėkmingesnis. Nustatyta, kad anomalinių įgimtų ir pooperacinių kraujagyslinių jungčių užkimšimas spiralėmis yra saugus ir efektyvus gydymo metodas.

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Milstone, Zachary J. « Histone Deacetylase 1 and 2 are Essential for Early Cardiac Development ». eScholarship@UMMS, 2019. https://escholarship.umassmed.edu/gsbs_diss/1014.

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Congenital heart disease is the most common congenital anomaly, affecting approximately 1% of all live births each year. Although clinical interventions are improving, many affected infants do not survive to adulthood. Congenital cardiac defects originate from disturbances during development, making the study of mammalian cardiogenesis critical to improving outcomes for infants with congenital heart disease. Development of the mammalian heart involves epigenetically-driven specification and commitment of a diverse landscape of cardiac progenitors. Recent studies determined that chromatin modifying enzymes play a previously underappreciated role in the pathogenesis of congenital heart defects. This thesis investigates the functions of Hdac1 and Hdac2, highly homologous Class I histone deacetylases, during early murine cardiac development. We establish that Hdac1 and Hdac2 cooperatively regulate cardiogenesis in distinct cardiac progenitor populations during development. Together, our findings demonstrate that Hdac1 and Hdac2 are critical mediators of the earliest stages of mammalian cardiogenesis through a variety of spatiotemporally specific, redundant, and dose-sensitive roles and indicate they may play important roles in the pathogenesis of human congenital cardiac defects.

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Ravenscroft, Gianina. « A therapeutic approach for the skeletal muscle a-actin based congenital myopathies ». University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2009. http://theses.library.uwa.edu.au/adt-WU2010.0049.

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[Truncated abstract] Mutations in the skeletal muscle -actin gene (ACTA1) have been shown to be one cause of a broad group of muscle disorders all termed the congenital myopathies. Over 170 different mutations have now been identified across all 6 coding exons of ACTA1 in patients presenting with muscle weakness and any one or more of the following histopathological features: nemaline rods, intranuclear rods, fibre-type disproportion, excess of thin filaments and central cores. While the identification of the causative gene has been of great comfort for affected patients and their families, with pre-natal genetic testing becoming available, the ultimate aim is to develop a therapy for these disorders. Of the therapies currently being explored for the muscular dystrophies, up-regulation of an alternative gene seemed to be one of the most promising avenues for treatment of the ACTA1 diseases. Up-regulation of utrophin, the foetal homologue of dystrophin, has been shown to be a promising therapy for the treatment of Duchenne muscular dystrophy. The main aim of my research was to determine whether up-regulation of cardiac -actin, the predominant -actin expressed in foetal skeletal muscle and in the adult heart, could be used as a therapy for the ACTA1 diseases. A proof-of-concept experiment was performed whereby skeletal muscle -actin knock-out (KO) mice (all of which die by postnatal day 9) were crossed with transgenic mice over-expressing cardiac -actin (known as Coco mice) in postnatal skeletal muscle. ... While patients that are ACTA1 nulls have been identified in a number of mainly consanguineous populations, the majority of ACTA1 mutations result in dominant disease in which the mutant protein interferes with the function of the wild-type skeletal muscle -actin. Research described in this thesis also focuses on characterizing two transgenic mouse models of dominant ACTA1 disease at the ultra-structural, cellular and functional level; this is the first step towards a proof-of-concept experiment to determine whether cardiac -actin up-regulation can dilute out the pathogenesis of dominant ACTA1 disease. It has long been noted that patients with ACTA1 disease do not have ophthalmoplegia, even in the most-severely affected individuals. Protein analysis performed on extraocular muscle (EOM) biopsies obtained from humans, sheep and pigs showed that the EOMs co-express cardiac and skeletal muscle -actin, with cardiac -actin comprising 70 % of the striated -actin pool. Thus we propose that sparing of the EOMs in ACTA1 disease is at least in part due to cardiac -actin diluting out the pathogenesis associated with expression of the mutant skeletal muscle -actin. This finding provides further support for the hypothesis that dilution of mutant skeletal muscle -actin in dominant ACTA1 disease by up-regulation of cardiac -actin may be a viable therapy for this group of devastating muscle diseases. The research contained herein has advanced the understanding of the pathobiology of skeletal muscle -actin diseases and provides strong evidence in support of cardiac -actin up-regulation as a promising therapy for these diseases.

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Murakami, Alexandre Noboru. « Impacto da parceria entre banco de dados internacional e centro único de cardiologia e cirurgia cardiovascular pediátrica de referência no Brasil ». Faculdade de Medicina de São José do Rio Preto, 2018. http://hdl.handle.net/tede/418.

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Developing countries have been dealing with several difficulties concerning congenital heart diseases. Among them is lack of control of results through some specific database. The participation in the International Quality Improvement Collaborative Database for Congenital Heart Disease (IQIC) - Improving care in low- and middle-income countries provides an opportunity to improve quality of care targeting morbidity and mortality reduction, facilitated by the establishment of parameters and objective data to evaluate treatment offered. Objective: To analyze factors in the International Quality Improvement Collaborative Database for Congenital Heart Disease (IQIC) database of a single center of cardiology and pediatric cardiovascular surgery that influenced the quality of care to patients with congenital heart disease. Casuistic and Methods: Data collection from January 2011 to December 2017 independently and with external audit by IQIC database partnership. Data included preoperative information such as demographic data, nutritional status, associated chromosomal abnormalities, Risk Adjustment for Congenital Heart Surgery (RACHS-1) score, as well as postoperative information such as infections, complications in the first 30 days or until hospital discharge and / or patient death. Results: In the preoperative period, there was a clear trend of increasing newborn patient cases, in detriment of those 1 to 18 years of age. There was a reduction in cases of malnutrition from 70% in 2013 to 55% in 2017. The postoperative period reveled significant variation between groups’ surgical procedures in RACHS-1 risk category (P= 0.003), prevalence of risk categories 2 and 3, as well as an increase in cases of risk categories 4,5 and 6, mainly in the last two years. Infection and mortality showed favorable results for reduction, with statistical significance for surgical site infection (P= 0.03), bacterial sepsis and other infections (both P <0.001). The 30-day postoperative follow-up showed a satisfactory evolution for discrete reduction in mortality, but not statistically significant difference in both in-hospital death (P=0.16) and 30 days (P=0.14). Conclusion: The analysis of the seven years of the IQIC database showed significant decrease in infection, increase in complexity of cases and reduction of mortality of patients with congenital heart disease in our environment.
Países em desenvolvimento enfrentam diversas dificuldades em relação às cardiopatias congênitas, dentre elas a falta de controle de resultados por meio de banco de dados específico. A participação no banco de dados International Quality Improvement Collaborative for Congenital Heart Disease (IQIC) - Improving care in low- and middle-income countries forneceu oportunidade de melhoria da qualidade na assistência para a redução de morbidade e mortalidade infantil, facilitada pelo estabelecimento de parâmetros e dados objetivos para avaliação de tratamentos oferecidos. Objetivo: Analisar os fatores do banco de dados International Quality Improvement Collaborative for Congenital Heart Disease (IQIC) – Improving care in low and middle income countries de um centro único de cardiologia e cirurgia cardiovascular pediátrica que influenciaram a qualidade de atendimento aos pacientes com cardiopatias congênitas. Casuística e Método: Coleta de dados no período de Janeiro de 2011 a Dezembro de 2017 de forma independente e com auditoria externa em parceria com banco de dados IQIC. Os dados incluíram informações pré-operatórias, tais como: dados demográficos, estado nutricional, síndromes associadas e categoria de risco cirúrgico (Risk Adjustment for Congenital Heart Surgery - RACHS-1), assim como, informações pós-operatórias como infecções, complicações nos primeiros 30 dias até a alta hospitalar e ou óbito do paciente. Resultados: No período pré-operatório, observou-se nítida tendência de aumento de casos de pacientes recém-nascidos em detrimento aos de 1 a 18 anos. Encontrou-se redução de casos com desnutrição de 70% em 2013 para 55% em 2017. No período pós-operatório os procedimentos cirúrgicos classificados na categoria de risco RACHS-1 revelaram variação significante entre os grupos (P=0,003), prevalecendo as categorias de grau 2 e 3, assim como, aumento de casos de categorias de risco 4,5 e 6, principalmente nos dois últimos anos do estudo. A infecção e mortalidade demonstraram resultados favoráveis para a redução, com significância estatística para infecção de sítio cirúrgico (P=0,03), sepse bacteriana e outras infecções (P<0,001). O acompanhamento de 30 dias de pós-operatório mostrou evolução satisfatória para discreta redução dos óbitos, porém sem diferença estatística tanto para morte intra-hospitalar (P=0,16) como em 30 dias (P=0,14). Conclusão: A análise dos sete anos do banco de dados IQIC permitiu demonstrar a diminuição significante de infecção, aumento da complexidade das doenças e redução da mortalidade dos pacientes com cardiopatias congênitas em nosso meio.

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Gleadhill, Claire, et Demetrio Jr Macariola. « Time to Think Deeper when HSV is Presenting in an Unusual Way ». Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/153.

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This study demonstrates the first case report in which an NK Cell deficiency initially presented as an asymptomatic disseminated herpes simplex viremia (HSV). A pre-term 13- day- old patient presented with disseminated HSV after investigation because his twin brother was found to have HSV vesicular lesions. The patient remained asymptomatic throughout the entire hospital course. While 40% of neonates never exhibit vesicular lesions, most of the infants will be symptomatic with DIC and/or respiratory and/or hepatic failure. The HSV development in his twin brother prompted immediate multiple HSV PCR testing even though he was asymptomatic. The results were positive for HSV in both plasma & nasopharynx. He received intravenous acyclovir treatment for 21 days. Both CSF & brain MRI studies demonstrated no CNS involvement. He was discharged home with oral acyclovir for one year. Two months after being off acyclovir he developed herpetic vesicles which resolved with acyclovir treatment. Currently, he is on chronic acyclovir treatment. Lymphocyte enumeration tests demonstrated NK cell deficiency. Typically, HSV is a virulent symptomatic infection especially when it presents with viremia. Here we have a case of asymptomatic HSV viremia. Likewise, HSV infection does not usually recur after 1 year of acyclovir treatment. Here, we have a child presenting with what seems to be recurrent congenital HSV infection even with adequate treatment. These atypical HSV presentations may have been due to NK cell deficiency. We, therefore, propose that clinicians should consider NK cell deficiency as possible etiology when HSV presents in an atypical manner as described in our case.

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Ho, Xuan Tuan [Verfasser], et Pozza Robert [Akademischer Betreuer] Dalla. « Surgical and interventional treatments of congenital heart diseases in Da Nang Hospital, Vietnam / Xuan Tuan Ho ; Betreuer : Robert Dalla Pozza ». München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1237221722/34.

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Chen, Chao-Ying. « Cognitive, motor, and autonomic function in infants with complex congenital heart diseases, infants born preterm, and infants born full-term ». The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1408984094.

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Parrish, Loni. « A Replication and Extension of a Prediction Tool Identifying Need for Treatment Among Opioid Exposed Infants ». Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/etd/3758.

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The incidences of maternal opioid use and neonatal opioid withdrawal syndrome (NOWS) have increased by nearly 400% over the past decade. Isemann and colleagues (2017) developed prediction tools (TiTE/TiTE2) to differentiate, within the first two days of life, between infants who will require pharmacotherapy for NOWS from those infants who will not require pharmacotherapy for NOWS. The goal of the current experiment was to replicate and extend their prediction model. The present experiments successfully replicated Isemann et al., (2017) results and also established alternative cutoff values for requiring treatment that provide better balance between all four metrics. Moreover, new prediction models (TEN/TEN2) were proposed based on a factor analysis of modified Finnegan scores across the first 48 hours of life. Area Under the Curve-Receiver Operating Characteristic curve analyses indicated that the TEN2 was the best prediction model compared to the TiTE2 and the TEN.

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Tai, Chin-Yin. « Roles of Lissencephaly Gene, LIS1, in Regulating Cytoplasmic Dynein Functions : a Dissertation ». eScholarship@UMMS, 2002. https://escholarship.umassmed.edu/gsbs_diss/31.

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Spontaneous mutations in the human LIS1 gene are responsible for Type I lissencephaly ("smooth brain"). The distribution of neurons within the cerebral cortex of lissencephalic children appears randomized, probably owing to a defect in neuronal migration during early development. LIS1 has been implicated in the dynein pathway by genetic analyses in fungi. We previously reported that the vertebrate LIS1 co-localized with dynein at prometaphase kinetochores, and interference with LIS1 function at kinetochore caused misalignment of chromosomes onto the metaphase plate. This leads to a hypothesis that LIS1 might regulate kinetochore protein targeting. In order to test this hypothesis, I created dominant inhibitory constructs of LIS1. After removal of the endogenous LIS1 from the kinetochore by overexpression of the N-terminal self-association domain of LIS1, dynein and dynactin remained at the kinetochores. This result indicated that LIS1 is not required for dynein to localize at the kinetochore. Next, CLIP-170 was displaced from the kinetochores in the LIS1 full-length and the C-terminal WD-repeat overexpressers, suggesting a role for LIS1 in targeting CLIP-170 onto kinetochores. LIS1 was co-immunoprecipitated with dynein and dynactin. Its association with kinetochores was mediated by dynein and dynactin, suggesting LIS1 might interact directly with subunits of dynein and/or dynactin complexes. I found that LIS1 interacted with the heavy and intermediate chains (HC and IC) of dynein complex, and the dynamitin subunit of dynactin complex. In addition to kinetochore targeting, the LIS1 C-terminal WD-repeat domain was responsible for interactions with dynein and dynactin. Interestingly, LIS 1 interacted with two distinct sites on HC: one in the stem region containing the subunit-binding domain, and the other in the first AAA motif of the motor domain, which is indispensable for the ATPase function of the motor protein. This LIS1-dynein motor domain interaction suggests a role for LIS1 in regulating dynein motor activity. To test this hypothesis, changes of dynein ATPase activity was measured in the presence of LIS1 protein. The ATPase activity of dynein was stimulated by the addition of a recombinant LIS1 protein. Besides kinetochores, others and we have found LIS1 also localized at microtubule plus ends. LIS1 may mediate dynein and dynactin mitotic functions at these ends by interacting with astral microtubules at cortex, and associating with the spindle microtubules at kinetochores. Overexpression of LIS1 displaced dynein and dynactin from the microtubule plus ends, and mitotic progression was severely perturbed in LIS1 overexpressers. These results suggested that the role for LIS1 at microtubule plus ends is to regulate dynein and dynactin interactions with various subcellular structures. Results from my thesis research clearly favored the conclusion that LIS1 activates dynein ATPase activity through its interaction with the motor domain, and this activation is important to establish an interaction between dynein and microtubule plus ends during mitosis. I believe that my thesis work not only has provided ample implications regarding dynein dysfunction in disease formation, but also has laid a significant groundwork for more future studies in regulations of the increasing array of dynein functions.

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Simoni, Renata Zaccaria 1972. « Trombofilia hereditária em fetos com malformações de origem vascular = Genetic polymorphisms in fetuses with malformations of vascular origin ». [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309004.

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Orientador: Egle Cristina Couto de Carvalho
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Contexto e objetivo: Algumas malformações congênitas têm origem vascular, e a trombose durante a organogênese já foi aventada como possível mecanismo para esta ocorrência. O objetivo deste estudo foi avaliar a associação entre trombofilia fetal e malformações de origem vascular. Tipo de estudo e local: Foi realizado um estudo caso-controle, desenvolvido no ambulatório de Medicina Fetal do CAISM UNICAMP, de 2005 a 2010. Métodos: Foram incluídos no estudo 100 fetos com malformações de sistema nervoso central (SNC), gastrosquise, limb body wall e redução de membros (casos), submetidos a cordocentese como rotina do serviço, cujos resultados de cariótipo foram normais. Como controles, foram incluídos 100 fetos sem malformações cujo sangue de cordão fora previamente doado para o Banco de Sangue de Cordão do HEMOCENTRO UNICAMP. A pesquisa das mutações Fator V de Leiden, G20210A-FII e C677T-MTHFR foi realizada no sangue fetal dos dois grupos, e os resultados foram comparados. A análise descritiva foi feita utilizando Qui-quadrado e Teste Exato de Fisher. Para avaliar a associaçãoo entre as variáveis, foram utilizados o teste de Wilcoxon e a regressão logística. Resultados: Foram incluídos 78 fetos com malformações de SNC, 14 com gastrosquise, 3 com redução de membros e 2 com limb body wall. As mutações fator V de Leiden e G20210A-FII não foram encontradas nos casos e nos controles. A mutação C677T-MTHFR foi encontrada na forma heterozigota (CT) em 24 casos (24,8%) e em 6 controles. A mutação homozigota (TT) foi encontrada em 7 casos (7,2%) e em 1 controle. Estas diferenças foram estatisticamente significativas (p<0,0001). Quando avaliados os fetos com malformações de SNC (Artigo 1), a mutação CT foi encontrada com frequência significativamente maior nos casos do que nos controles (OR 10.309 IC95% 3.344-32.258), e a mutação TT também mostrou diferença significativa (OR 12.346 IC95% 1.388-111.11). A avaliação dos 14 fetos com gastrosquise (Artigo 2) não mostrou diferenças significativas quanto à presença da mutação CT ou TT entre os casos e os controles. Conclusão: A presença da mutação C677T-MTHFR no sangue fetal mostrou associação com malformações de SNC, tanto na forma homozigota quanto heterozigota
Abstract: Context and objective: Some congenital malformations have vascular origin, and a thrombosis during organogenesis is a possible mechanism for them. The aim of this study was to evaluate the association between fetal thrombophilia and malformations of vascular origin. Study type and location: A case-control study was performed at the Fetal Medicine Outpatient Clinic of CAISM UNICAMP, from 2005 to 2010. Methods: Ninety-seven fetuses with central nervous system malformations, gastroschisis, limb body wall and limb reduction were included in the study (cases), after routine cordocentesis showed normal karyotype results. A hundred fetuses without malformations were included as controls. These fetuses' cord blood had been donated to the Cord Blood Bank of HEMOCENTRO UNICAMP. DNA was extracted from fetal cord blood to study the mutations Factor V Leiden, G20210A-FII and MTHFR-C677T in both groups. Descriptive analysis was realized using Chi-square and Fisher's Exact Test. Wilcoxon test and logistic regression were used to analise the associations among variables. Results: We found 78 fetuses with central nervous system malformations, 14 with gastroschisis, 3 with member reduction and 2 with limb body wall. The mutations Factor V Leiden and G20210A-FII were not detected in cases nor in controls. The mutation MTHFR-C677T was encountered in 24 cases (24.8%) and in 6 controls its heterozygous form (CT). The homozygous mutation (TT) was found in 7 cases (7.2%) and in one control. These differences were statistically significant (p <0.0001). When the fetuses with central nervous system malformations were evaluated separately (Article 1), the frequency of the CT mutation was significantly higher in cases than in controls (OR 10.309 95% CI 3.344-32.258), as did the TT mutation (OR 12.346 95% CI 1.388-111.11). The 14 fetuses with gastroschisis were also evaluated separately (Article 2), and the results showed no statistically significant differences between cases and controls when concerning to the presence of the mutation MTHFR-C677T. Conclusion: The presence of the mutation MTHFR-C677T in fetal blood was associated with central nervous system malformations, both in homozygous and heterozygous form
Doutorado
Saúde Materna e Perinatal
Doutora em Ciências da Saúde

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梁平 et Ping Maurice Leung. « The role of cross-sectional and pulsed Doppler echocardiography in themanagement of patients with congenital heart disease : a changing practice ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1991. http://hub.hku.hk/bib/B30408908.

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Nixon, Christopher E. « 2ND TIER ASSAY FOR THE DETECTION OF CONGENITAL ADRENAL HYPERPLASIA BY VIRGINIA’S NEWBORN SCREENING LABORATORY : STEROID PROFILE BY HPLC-MS/MS ». VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/6075.

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Congenital Adrenal Hyperplasia (CAH) encompasses several disorders related to disruptions in the adrenal steroid production pathway. These disruptions may cause virilization of the external female sex organs, incorrect gender assignment, precocious puberty, and in the most severe form, may cause life-threatening salt wasting and adrenal crisis if not detected and treated early in the newborn period. 17α-Hydroxyprogesterone (17-OHP) is the primary target for immunofluorescence detection of CAH from dried blood spots in newborn screening (NBS). Unfortunately, current immunoassay techniques for the detection of CAH suffer from high false positive rates. The primary factors contributing to false positive determinations can include the natural increase of 17-OHP due to stress stimuli as well as cross-reactivity of the immunoassay antibody with other hormones and endogenous compounds in blood. Analysis of the adrenal steroid profile and corresponding analyte ratios using high performance liquid chromatography (HPLC)or ultra-high pressure liquid chromatography (UHPLC)combined with tandem mass spectrometry (MS/MS) has been shown to be a sensitive and selective technique for the significant reduction of the false positive reporting rate for CAH in newborn screening. In working toward optimization, validation, and implementation of an HPLC-MS/MS steroid profile for use by Virginia’s Newborn Screening laboratory as a 2nd tier analysis for CAH screening, a commercially-available core-shell HPLC column with a biphenyl stationary phase was determined to offer adequate retention and selectivity to achieve baseline resolution of isobaric target analytes under rapid reversed phase gradient conditions. Method linearity, precision, and accuracy were assessed using enriched dried blood spot materials. Double-blinded analyses of over 300 newborn dried blood spot specimens were used to determine clinical sensitivity and specificity of the assay, which is projected to substantially reduce the false positive reporting rate for CAH screening while meeting target sample turnaround times.

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Kushnir, Mark M. « Mass Spectrometric Applications for Diagnosing Metabolic and Endocrine Diseases ». Doctoral thesis, Uppsala University, Analytical Chemistry, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8658.

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Disease-specific compounds (biomarkers) are analyzed in clinical laboratories to assist with diagnosing diseases. This thesis describes development and validation of liquid chromatography tandem mass spectrometry (LC-MS/MS) based tests for diagnosing a diverse group of endocrine and metabolic diseases. The analytical methods used on-line and off-line sample extraction and analytical derivatization as means of enhancing the analytical sensitivity, specificity and clinical utility. All developed methods were extensively validated and reference intervals for the biomarker concentrations were established in blood samples of healthy adults and children. Advantages of the LC-MS/MS as an analytical technique include possibility of simultaneous measurement of multiple analytes and ability of confirming their identity. In this thesis we proposed and evaluated approaches for the assessment of the specificity of analysis in the methods that use tandem mass spectrometry detection. To enhance throughput of the LC-MS/MS tests for the biomarkers that have endogenous or exogenous isomers an approach was developed for quantitation of isomers from unresolved chromatographic peaks. Using methods developed in this thesis we performed a study of the steroidogenesis in ovarian follicles of healthy women and women with polycystic ovary syndrome (PCOS). Obtained data on the steroid concentrations and associations between the steroid metabolites in the pathway would be helpful for better understanding of the ovarian pathophysiology. Potential biomarkers of PCOS were identified in the thesis; further studies will be necessary to confirm their clinical utility.

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Bartos, Daniel C. « Mechanistic Basis for Atrial and Ventricular Arrhythmias Caused by KCNQ1 Mutations ». UKnowledge, 2013. http://uknowledge.uky.edu/physiology_etds/8.

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Cardiac arrhythmias are caused by a disruption of the normal initiation or propagation of electrical impulses in the heart. Hundreds of mutations in genes encoding ion channels or ion channel regulatory proteins are linked to congenital arrhythmia syndromes that increase the risk for sudden cardiac death. This dissertation focuses on how mutations in a gene (KCNQ1) that encodes a voltage-gated K+ ion channel (Kv7.1) can disrupt proper channel function and lead to abnormal repolarization of atrial and ventricular cardiomyocytes. In the heart, Kv7.1 coassembles with a regulatory protein to conduct the slowly activating delayed rectifier K+ current (IKs). Loss-of-function KCNQ1 mutations are linked to type 1 long QT syndrome (LQT1), and typically decrease IKs, which can lead to ventricular action potential (AP) prolongation. In patients, LQT1 is often characterized by an abnormally long corrected QT (QTc) interval on an electrocardiogram (ECG), and increases the risk for polymorphic ventricular tachycardias. KCNQ1 mutations are also linked to atrial fibrillation (AF), but cause a gain-of-function phenotype that increases IKs. Surprisingly, patients diagnosed with both LQT1 and AF are increasingly identified as genotype positive for a KCNQ1 mutation. The first aim of this dissertation was to determine a unique functional phenotype of KCNQ1 mutations linked to both arrhythmia syndromes by functional analyses via the whole-cell patch clamp technique in HEK293 cells. A proportion of patients with LQT1-linked KCNQ1 mutations do not have abnormal QTc prolongation known as latent LQT1. Interestingly, exercise can reveal abnormal QTc prolongation in these patients. During exercise, beta-adrenergic activation stimulates PKA to phosphorylate Kv7.1, causing an increase in IKs to prevent ventricular AP prolongation. Therefore, the second aim of this dissertation was to determine a molecular mechanism of latent LQT1 through functional analyses in HEK293 cells while incorporating pharmacological and phosphomimetic approaches to study PKA regulation of mutant Kv7.1 channels. The findings in this dissertation provide new insight into how KCNQ1 mutations disrupt the function of Kv7.1 in a basal condition or during beta-adrenergic activation. Also, this dissertation suggests these approaches will improve patient management by identifying mutation specific risk factors for patients with KCNQ1 mutations.

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Yap, Choon Hwai. « The fluid shear stress environment of the normal and congenital bicuspid aortic valve and the implications on valve calcification ». Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/45742.

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Calcific aortic valve disease is highly prevalent, especially in the elderly. Currently, the exact mechanism of the calcification process is not completely understood, limiting our ability to prevent or cure the disease. Ex vivo investigations, however, have provided evidence that the aortic valve's biological response is sensitive to mechanical forces, including fluid shear stresses, leading to the hypothesis that adverse fluid shear stress environment play a role in leading to valve calcification. This thesis seeks to investigate this hypothesis. A method for performing experimental measurement of time-varying shear stress on aortic valve leaflets under physiologic flow conditions was first developed, based on the Laser Doppler Velocimetry technique, and was systematically validated. This method was then applied to both the aortic surface and the ventricular surface of a normal tricuspid the aortic valve, and then on a congenital bicuspid aortic valve, using suitable in vitro valve models and an in vitro pulsatile flow loop. It was found that in the tricuspid valve, the peak shear stress on the aortic surface under adult resting condition was approximately 15-19 dyn/cm². Aortic surface shear stresses were elevated during mid- to late-systole, with the development of the sinus vortex, and were low during all other instances. Aortic surface shear stresses were observed to increase with increasing stroke volume and with decreasing heart rate. On the ventricular surface, shear stresses had a systolic peak of approximately 64-71 dyn/cm² under adult resting conditions. During late systole, due to the Womersley effect, shear stresses were observed to reverse in direction to a substantial magnitude for a substantial period of time. Further, it was found that a moderately stenotic bicuspid aortic valve can experience excessive unsteadiness in shear stress experienced by its leaflets, most likely due to the turbulent forward flow resulting from the stenosis, and due to the skewed forward flow. To demonstrate that the measured shear stresses can have an effect on the aortic valve biology, ex vivo experiments were performed in specific to determine the effects of these various shear stress characteristics on the biological response of porcine aortic valve leaflets, using the cone and plate bioreactor. It was found that unsteady shear stress measured in the bicuspid valve resulted in increased calcium accumulation. Further, it was found that low shear stresses and high frequency shear stresses resulted in increased calcium accumulation. Thus, shear stress was found to affect aortic valve pathology, and low and unsteady fluid shear stresses can enhance pathology.

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Buck, Cecília Oliveira Barbosa 1975. « Estudo clínico-epidemiológico das osteocondrodisplasias de manifestação perinatal na América do Sul ». [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308793.

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Orientador: Denise Pontes Cavalcanti
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Osteocondrodisplasias (OCD) ou displasias esqueléticas são um grupo heterogêneo de doenças genéticas que afetam o crescimento. e o desenvolvimento do esqueleto e possuem alta morbimortalidade associada. Apesar dos avanços recentes no diagnóstico pré-natal e no conhecimento das bases moleculares das OCD, o seu diagnóstico ainda se baseia em anamnese, exame físico e radiografias de esqueleto. A prevalência habitualmente referida de 2,0/10.000, baseada em poucos estudos com populações pequenas, é subestimada. O objetivo deste estudo foi avaliar a epidemiologia das OCD na América do Sul (AS) utilizando uma grande população de mais de 1,5 milhões de nascimentos. Os casos de OCD foram selecionados dos arquivos do ECLAMC (um programa colaborativo de base hospitalar, caso-controle, para vigilância de defeitos congênitos) por dois códigos específicos (75640-OCD e 75650-Osteogenesis Imperfecta). Todos os casos nascidos entre 2000-2007 foram revisados e os diagnósticos finais foram escalonados em quatro níveis de evidência diagnóstica (NED), sendo o NED1 (padrão-ouro) casos com boas radiografias ou estudo molecular confirmando o diagnóstico. No período do estudo, 132 hospitais em 9 paises sul-americanos observaram 1.544.496 nascimentos. Todos os 51.827 controles nascidos no mesmo período foram utilizados para comparação. Excluídos 44 casos, a prevalência geral foi de 3,2/10.000 (IC95% 2,9-3,5) (492 casos em 1.544.496 nascimentos) e 33,6 (25,3-42,3) nos natimortos. Casos letais foram 50% (natimortos e óbito neonatal precoce). O diagnóstico foi referido como pré-natal na maioria dos casos (359-73%). Os grupos de OCD mais frequentes, segundo a classificação internacional, foram: G-1 (FGFR3) - 31%; G-25 (OI) - 23,5%; G-9 (CCP) - 4,5%; G-2 (Colágeno 2) - 4%; G-18 (Bent bones) - 4%. As prevalências das OCD mais comuns foram: OI - 0,74 (0,61-0,89); D. Tanatofórica - 0,47 (0,36-0,59); Acondroplasia - 0,44 (0,33-0,56); D. Campomélica - 0,10 (0,05-0,16). A taxa de mutação/gameta/geração para Acondroplasia foi 1,74 (1,25-2,25) x 10-5. Idade paterna, paridade e consanguinidade foram maiores nos casos que nos controles (31,2 anos X 28,9 anos; 2,6 X 2,3; 5,4% X 1,0%; P < 0,001). Idade materna elevada nos casos em relação aos controles (26,4 anos X 25,4 anos, P < 0,001) não foi confirmada por regressão logística considerando idades paterna e materna e paridade como fatores de risco para OCD (OR=1,63 para idade paterna > 39 anos; 0,79 para idade materna > 34 anos e 1,3 para paridade > 1). Peso e idade gestacional foram menores nos casos que nos controles (2498,1 g X 3198,6 g, P < 0,001), permanecendo a diferença para o peso após estratificação apenas para gestações de 31-35, 36-40 e 41-44 semanas (P<0,001, P<0,001 e P<0,05, respectivamente). A prevalência geral de 3,2/10.000 encontrada parece mais verossímil, sustentada por uma população numerosa e heterogênea, com grande diversidade étnica em sua composição, onde interrupções da gestação não são permitidas. Este estudo também observou uma alta taxa de diagnóstico pré-natal das OCD na AS e confirmou: a elevada morbi-mortalidade associada às OCD, a idade paterna elevada (especialmente nos casos de herança dominante) e altas taxas de consangüinidade nos casos de OCD (especialmente os de herança recessiva) e na população controle da AS
Abstract: Osteochondrodysplasias (OCD) are a heterogeneous group of genetic diseases that affect skeletal growth and development with a high infant morbid-mortality. Despite the great advances in prenatal diagnosis and knowledge of OCD molecular bases in the last twenty years, OCD diagnosis still relies upon anamnesis, clinical examination and skeletal X-rays. The currently accepted birth prevalence rate of OCD (2.0/10,000), based on few studies with small populations, is underestimated. This study aimed to assess OCD epidemiology in South America (SA) based on a large population of more than 1.5 million births. The OCD cases were ascertained from ECLAMC (a case-control, collaborative hospital-based program for birth defects surveillance) database through two specific codes (75640 for "generic" OCD and 75650 for Osteogenesis Imperfecta). All cases born from 2000 to 2007 were revised and final diagnoses ranked in four diagnostic evidence levels (DEL), being the DEL1 (gold-standard) those cases with good X-rays or DNA test supporting a certain diagnosis. During the 8-year period, 132 hospitals from nine South-American countries examined 1,544,496 births. For comparative analysis, all 51,827 controls born in the same period were used. After excluding 44 cases, overall OCD birth prevalence was 3.2 per 10,000 (95% CI 2.9-3.5) (492 cases per 1,544,496 births) and 33.6 (25.3-42.3) among stillbirths. Lethal cases (stillbirths plus early neonatal death) were 50%. Prenatal ultrasound diagnosis was referred in most cases (359 - 73%). The most frequent OCD groups, according to the international classification, were: G-1 (FGFR3) - 31%; G-25 (OI) - 23,5%; G-9 (SRP) - 4,5%; G-2 (Collagen 2) - 4% and G-18 (Bent bones) - 4%. The prevalence of the main OCD types were: OI - 0.74 (0.61-0.89); Thanatophoric D. - 0.47 (0.36-0.59); Achondroplasia - 0.44 (0.33-0.56); Campomelic D. - 0.10 (0.05-0.16). The mutation rate/gamete/generation for Achondroplasia was 1.74 (1.25-2.25) x 10-5. Paternal age, parity and consanguinity rate were significantly increased in cases compared to controls (31.2 years X 28.9 years; 2.6 X 2.3; 5.4% X 1.0%; P < 0.001). Increased maternal age in cases against controls' (26.4 years X 25.4 years, P < 0.001) was not confirmed by logistic regression including paternal age (OR=1.63 for paternal age > 39 years), parity (OR=1.3 for parity > 1) and maternal age (OR=0.79 for maternal age > 34 years) as risk factors for OCD. Birth weight and gestational age were lower in cases than in controls (2498.1 g X 3198.6 g, P < 0.001), and the difference for birth weight remained significant for gestational ages 31-35, 36-40 and 41-44 weeks after stratification (P < 0.001, P < 0.001 and P < 0.05, respectively). The OCD overall birth prevalence rate of 3.2 per 10,000 found seems more verisimilar, supported by a large and heterogeneous population with great ethnic diversity and without pregnancy terminations. This study also indicates a high rate of prenatal OCD diagnosis in SA and confirms: the high OCD-associated infant morbid-mortality, the increased paternal age (especially for cases with autosomal dominant inheritance) and the high parental consanguinity rates in both OCD cases (especially those with autosomal recessive inheritance) and in SA control population
Doutorado
Genetica Medica
Doutor em Ciências Médicas

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Hept, Megan A. « ANALYZING THE PHENOTYPIC EFFECT OF THREE CANDIDATE GENES ASSOCIATED WITH NONSYNDROMIC CRANIOSYNOSTOSIS USING A ZEBRAFISH MODEL ». VCU Scholars Compass, 2017. http://scholarscompass.vcu.edu/etd/5021.

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In normal cranial suture development, the cranial sutures close at predetermined periods of development to allow the brain the capability to grow in a malleable environment. However, in craniosynostosis, cranial sutures prematurely fuse before birth which can lead to a wide range of developmental issues and complications. Craniosynostosis can be categorized as nonsyndromic which involves the sole fusion of one or more of the cranial sutures, or syndromic in which cranial sutures fuse as well as other abnormalities associated with a genetic disorder. Past research has identified three candidate genes that could be possible disease causing mutations in nonsyndromic sagittal craniosynostosis. The mutations were found were in ITGAV, SLC30A9, and BAMBI. Using zebrafish as a model organism, we assessed the phenotypic effects of mutating itgav, slc30a9, and bambia associated with craniosynostosis. Phenotypic analysis of heterozygous itgav mutants showed when itgav is mutated there is increased bone formation and abnormal suture development. Due to the phenotype seen in zebrafish, it is proposed when mutated, ITGAV can help produce craniosynostosis.

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Zhian, Samaneh. « Molecular Genetic Analysis of CRELD1 in Patients with Heterotaxy Disorder ». PDXScholar, 2011. https://pdxscholar.library.pdx.edu/open_access_etds/410.

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Heterotaxy refers to the abnormal arrangement of internal organs in relation to each other. Model organism studies have shown that functions of more than eighty genes are required for normal asymmetric left-right organ development. CRELD1 has been shown to be necessary for proper heart development and mutations in CRELD1 are known to increase risk of cardiac atrioventricular septal defects (AVSD). AVSD is the most common form of heart defect associated with heterotaxy, and we have previously shown that some individuals with heterotaxy-related AVSD have mutations in CRELD1. Therefore, we propose to examine the CRELD1 gene in a large sample of patients with heterotaxy syndrome. Our goal was to determine if mutations in CRELD1 are associated with other manifestations of heterotaxy or if they only coincide with AVSD. To achieve this aim, a sample size of 126 patients with heterotaxy collected by Dr. Belmont, Baylor college of Medicine, Texas, with approximately 66% of the heterotaxy population with different types of heart defects, were used for this study. Ten exons, promoter regions, and regulatory elements in the introns of CRELD1 gene were sequenced and analyzed. In this study three different heterozygous missense mutations in CRELD1 were identified in three unrelated individuals. These three individuals were diagnosed with different forms of heart defects in addition to AVSD. All three mutations were identified in highly conserved regions of CRELD1 possibly altering the CRELD1 properties. This demonstrates that mutations in CRELD1 may increase the susceptibility of AVSD in heterotaxy population. This information can help us to find factors effecting disease susceptibility in heterotaxy patients since the heart defects are a complex trait with incomplete penetrance.

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Holt, Sheryl L. « RETROSPECTIVE FRAMES OF DISABILITY : THEMES DERIVED FROM PARENTS OF CHILDREN WHO GREW UP WITH CONGENITAL DISABILITY ». UKnowledge, 2016. http://uknowledge.uky.edu/rehabsci_etds/30.

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Introduction: For children born with physical disabilities, the perspectives and actions of their parents prove significant to their childhood developmental outcomes clinically, educationally, socially, and with regard to community participation. The lived world and perceptions of parents who have children with disabilities however is not well investigated. This study sought to understand parents’ framing of theirs and their children’s disability experiences. Family systems together with family systems intervention models, and disability theory were used to provide structure to interview instrumentation and subsequent analysis. Child-centered and ecologic influences were also used to track the transformative processes over time that infuses parental themes. Methods: Methods for this study followed traditions of heuristic phenomenology. Open-ended parental interviews, written and spoken, together with field notes were used to explore the meanings given to disability. Analysis focused on collective descriptions and critical themes. Results: The nine parents in this study revealed four dominant themes around which their children’s lived lives were both understood and framed. Navigating normal for us; Our pride and joy; Anything but disability; Lived lives, looking back. Each is expressed in the words of parents who reared a child with disabilities into adulthood. Discussion and Recommendations: Parental disability frameworks differ from medical model frameworks and those of disability studies but share similarities with each. The parent themes provided holistic views of what these families have lived and learned. Their perspectives provide potentially vital markers and points of inquiry for interventionists and team members who work with children and families. Themes may also offer categorical means to explore well-being and child outcomes. Additionally, the themes were transformative and empowering for parents, both in the discussion of individual matters and in their narratives. All participants iterated that they welcomed having their voices invited and heard.

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Rangan, Apoorva. « CRISPR-Cas9 Mediated Restoration of Dystrophin Expression and Inhibition of Myostatin : A Novel Gene Therapy for Duchenne Muscular Dystrophy ». Scholarship @ Claremont, 2016. http://scholarship.claremont.edu/cmc_theses/1305.

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Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disease, caused by a frame-shift mutation in the dystrophin gene. Current gene therapies for DMD target dystrophin transcripts in existing skeletal and cardiac muscle, rather than adipose and fibrotic tissues. These approaches may be unable to repair muscle functionality in DMD patients who have already undergone extensive muscle damage and wasting. Thus, successful DMD therapies must consider the underlying genetic cause and pathology. Inhibition of the gene myostatin, a negative regulator of muscle growth, has been shown to ameliorate muscle loss. Here, the CRISPR-Cas9 gene-editing platform is proposed to restore dystrophin expression and inhibit myostatin as a novel gene therapy in DMD patient derived induced pluripotent stem cells. Successful CRISPR-Cas9 mediated gene editing would be determined using PCR amplification, western blot analysis, immunofluorescence staining, and off target sequence analysis in differentiated skeletal muscle cells.

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Gonçalves, Frances Lilian Lanhellas 1979. « Avaliação da proteção das alças intestinais fetais utilizando hidrogel (biomaterial) no modelo experimental de gastrosquise ». [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310458.

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Orientador: Lourenço Sbragia Neto
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Gastrosquise é um defeito congênito da parede abdominal anterior no qual as alças intestinais ficam herniadas e em contato com o líquido amniótico (LA). Assim, a exposição ao LA resulta em várias disfunções intestinais pós-natal. Para reduzir o tempo de exposição ao LA em modelo animal, usou-se um hidrogel de N-isopropilacrilamida (NIPAAm) copolimerizado com ácido acrílico (Aac), que rapidamente intumesce na presença de LA. O hidrogel foi usado para cobrir as alças expostas até o fim da gestação. A gastrosquise foi induzida em fetos de ratas fêmeas da raça Sprague-Dawley através de um corte paramediano à direita do cordão umbilical para exposição parcial das alças com 18,5 dias de gestação. Os fetos foram separados em quatro grupos: controle (C), apenas gastrosquise (G), gastrosquise + cobertura das alças com adesivo de fibrina - Beriplast® (GA) e gastrosquise + cobertura das alças com adesivo de fibrina e aderido um pedaço de hidrogel seco (GAH). Os animais foram colhidos por cesárea com 21,5 dias de gravidez e o hidrogel foi cuidadosamente removido. Os fetos e as alças intestinais foram pesados e análise morfométrica foi realizada. Resultados mostraram que o hidrogel após intumescimento pesou 34X que seu peso seco; ele possui carga elétrica assim como a maioria das proteínas presentes no LA e sua retirada não provocou lesão à camada serosa do intestino exposto como visto na MEV. A comparação dos grupos C e GAH com os grupos G ou GA mostrou que o peso, o diâmetro, a espessura das camadas e da parede intestinais foi significativamente menor nos grupos C e GAH quando comparados aos grupos G e GA indicando processo inflamatório. Sendo assim, a aplicação do hidrogel aderido pelo adesivo de fibrina mostrou servir como uma efetiva proteção das alças herniadas, com uma redução significante da inflamação na gastrosquise.
Abstract: Gastroschisis is a congenital defect of the anterior abdominal wall which leads the fetal bowel to herniate into the amniotic cavity. There, exposition to amniotic fluid (AF), results in severe postnatal intestinal dysfunction. In order to reduce exposition time to AF in an animal model, has used a hydrogel of N-isopropylacrylamide (NIPAAm) copolymerized with acrylic acid (Aac), which undergoes rapid swelling in the amniotic fluid. The hydrogel was used to coat the bowel hernia until pregnance is completed. Gastroschisis was induced in the fetuses of female Sprague-Dawley rats by partial evisceration of the bowel through a right paramedian opening of the abdominal wall in day 18,5 of pregnancy. The fetuses were separated in four groups: control (C), gastroschisis alone (G), gastroschisis + coating of the bowel hernia with fibrin adhesive -Beriplast® (GA) and gastroschisis + coating of the bowel hernia with fibrin adhesive topped by a piece of adhered dry hydrogel (GAH). Animals were harvested by cesarean section at day 21.5 of pregnancy and the hydrogel was carefully removed. Fetuses and intestinal tract were weighed and morphometric analysis was performed. Results showed that the hydrogel weight was 34X heavier than its dry weight; its electric charge and also the AF charge were negative and there was no damage to serosa layer of the intestine exposed. Comparison of the C and GAH groups with G and GA showed that the bowel weight, diameter, the layers and wall thickness was significantly reduced in C and GAH compared to G and GA. Thus, application of the hydrogel bound onto the fibrin adhesive was shown to provide an effective protection of the herniated bowel, with a significant reduction of inflammation in gastroschisis.
Mestrado
Pesquisa Experimental
Mestre em Cirurgia

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Gruntman, Alisha. « A Translational Pathway for Recombinant Adeno-Associated Virus Human Gene Therapy : From Target Identification and Animal Modeling of the Disease to Non-Human Primate and Human Studies ». eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/882.

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Many steps go into developing a clinical viral gene therapy. The course starts with appropriate disease selection and moves through the many hurdles of in-vitro testing, animal model validation and proof-of-concept studies, all the way through pre-clinical large animal studies. In this thesis, I propose to outline the process of developing a translation pathway for a gene therapy using recombinant adeno-associated virus (rAAV). I will expand on this outline using data that I have generated during the course of my Ph.D. that ranges from animal model validation all the way through pre-clinical vector stability studies. Two disease models will be discussed throughout this thesis, Cockayne Syndrome (CS) and Alpha-1 Antitrypsin Deficiency (AATD). Cockayne Syndrome is a rare autosomal recessive genetic disorder involving mutations in either the CSA or CSB gene, leading to defects in DNA repair. Clinically this presents as progressive degeneration of the central nervous system, retina, cardiovascular system, and cochlea, which leads to mental retardation, post-natal growth defects, ocular abnormalities, and shortened life expectancy. Alpha-1 antitrypsin is a serine protease inhibitor largely produced in the liver that mainly functions to inhibit neutrophil elastase within the lung. AATD leads to an increased risk of emphysema, with shortened life expectancy, and also results in accumulations of mutant AAT polymers in the liver, sometimes leading to liver failure. Using these two disease models I will outline the upstream and downstream pre-clinical work as well as the transition to clinical trials of a rAAV based gene therapy.

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Gruntman, Alisha. « A Translational Pathway for Recombinant Adeno-Associated Virus Human Gene Therapy : From Target Identification and Animal Modeling of the Disease to Non-Human Primate and Human Studies ». eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/882.

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Many steps go into developing a clinical viral gene therapy. The course starts with appropriate disease selection and moves through the many hurdles of in-vitro testing, animal model validation and proof-of-concept studies, all the way through pre-clinical large animal studies. In this thesis, I propose to outline the process of developing a translation pathway for a gene therapy using recombinant adeno-associated virus (rAAV). I will expand on this outline using data that I have generated during the course of my Ph.D. that ranges from animal model validation all the way through pre-clinical vector stability studies. Two disease models will be discussed throughout this thesis, Cockayne Syndrome (CS) and Alpha-1 Antitrypsin Deficiency (AATD). Cockayne Syndrome is a rare autosomal recessive genetic disorder involving mutations in either the CSA or CSB gene, leading to defects in DNA repair. Clinically this presents as progressive degeneration of the central nervous system, retina, cardiovascular system, and cochlea, which leads to mental retardation, post-natal growth defects, ocular abnormalities, and shortened life expectancy. Alpha-1 antitrypsin is a serine protease inhibitor largely produced in the liver that mainly functions to inhibit neutrophil elastase within the lung. AATD leads to an increased risk of emphysema, with shortened life expectancy, and also results in accumulations of mutant AAT polymers in the liver, sometimes leading to liver failure. Using these two disease models I will outline the upstream and downstream pre-clinical work as well as the transition to clinical trials of a rAAV based gene therapy.

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Macêdo, Juliana Targino Silva Almeida e. « Linfedema primário e outros defeitos congênitos diagnosticados em bovinos de 1964 a 2010 pelo laboratório de patologia veterinária da Universidade Federal de Santa Maria ». Universidade Federal de Santa Maria, 2010. http://repositorio.ufsm.br/handle/1/4052.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico
In one research, cases of congenital lymphedema were observed affecting 17 Red Angus calves and their crosses from two farms in the central region of the state of Rio Grande do Sul, Brazil. Affected calves presented variable degrees of subcutaneous edema at birth, involving mainly the hind limbs, but also other body regions. The injection of methylene blue dye in a 5% solution into the interdigital space of the hind limbs of three affected calves and one normal control indicated an interruption of the lymph flow in the affected calves; this suggests a failure of the distal peripheral lymphatics to connect with the central trunks. At necropsy of three affected calves, subcutaneous edema was variably observed in the hind limbs, prepuce and ventral abdomen. Edema of body cavities was not observed. In two cases there was hipoplasia of the popliteal lymph nodes associated to dilatation of lymphatic vessels. DNA tests demonstrated that all affected calves were born from cows sired by the same bull suggesting an inherited basis for the disease. Furthermore unrelated cows of different breeds sired by Bull 1 delivered affected calves which suggest that condition is an autosomic dominant trait. Considering the large numbers of cows sired by Bull 1 relative few calves were affected; this could be explained by a low penetrance of the trait. In another research, cases of congenital defects (CDs) in cattle diagnosed at the Laboratory of Veterinary Pathology of the Federal University of Santa Maria from 1964 to 2010 were reviewed. During the studied period, tissues collected from the necropsy of 7,132 cattle were examined and 31 calves (0.4%) with CDs were found. These CDs were classified into 34 different types and ascribed to the body system primarily affected. The results of this survey indicate that the majority o CDs in cattle in the central Rio Grande do Sul are sporadic; nevertheless their continued study is important for determining the etiology and control.
Em uma pesquisa, casos de linfedema congênito foram observados acometendo 17 bezerros cruza Red Angus na região Central do Rio Grande do Sul. Os bezerros afetados apresentavam graus variáveis de edema subcutâneo ao nascimento, envolvendo principalmente os membros pélvicos, mas também outras regiões do corpo. A injeção de solução a 5% de azul de metileno no espaço interdigital dos membros pélvicos de três bezerros afetados e um controle, indicaram uma interrupção no fluxo da linfa, sugerindo uma falha dos linfáticos periféricos distais em conectar os troncos centrais. Na necropsia de três bezerros afetados, edema subcutâneo foi observado de modo variável nos membros pélvicos, prepúcio e abdômen ventral. Não foi observado edema nas cavidades orgânicas. Em dois casos, observou-se hipoplasia dos linfonodos poplíteos associadas à dilatação dos vasos linfáticos. Testes de DNA demonstraram que todos os bezerros afetados nasceram de vacas inseminadas pelo mesmo touro (Touro 1), sugerindo uma base genética para a doença. Além disso, vacas não relacionadas e de outras raças cobertas pelo Touro 1 pariram bezerros afetados indicando uma condição autossômica dominante. Considerando o grande número de vacas cobertas pelo Touro 1, relativamente poucos bezerros foram afetados; isso pode ser explicado por uma condição hereditária de baixa penetrância. Em outra pesquisa, foram revisados casos de defeitos congênitos (DCs) diagnosticados em bovinos no Laboratório de Patologia da Universidade Federal de Santa Maria entre 1964-2010. Durante o período estudado, foram examinados materiais provenientes da necropsia de 7.132 bovinos e foram encontrados 31 bezerros (0,4%) com DCs, os quais foram classificados em 34 tipos e alocados nos sistemas orgânicos primariamente afetados. Os resultados indicam que a maioria dos DCs em bovinos na Região Central do Rio Grande do Sul é esporádica. No entanto, seu estudo continuado é importante para o estabelecimento de sua etiologia e controle.

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Moreno, Cristiane de Araujo Martins. « Estudo clínico, histológico e molecular na miopatia congênita nemalínica e na miopatia congênita com alterações mínimas ». Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-06022017-150033/.

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Introdução: As miopatias congênitas são doenças musculares genéticas caracterizadas por hipotonia e fraqueza muscular de início precoce na infância. Histologicamente são caracterizadas por alterações estruturais no músculo esquelético (corpos nemalínicos, cores ou centralização nuclear), no entanto, existem casos com alterações leves e inespecíficas, alterações mínimas, tais como, desproporção no tamanho das fibras e desarranjo na arquitetura interna das fibras (falhas focais na atividade oxidativa). Quanto ao aspecto molecular, vários genes já foram identificados em associação com os diversos subtipos, porém com grande sobreposição de achados histológicos e clínicos. Objetivo: Caracterização clínica, histológica e molecular de pacientes Brasileiros com miopatia nemalínica e com miopatia congênita com achados histológicos mínimos. Métodos: Avaliação clínica e histológica (revisão dos achados das biopsias musculares) de pacientes com diagnóstico de miopatia congênita nemalínica e com alterações mínimas, provenientes de dois centros de investigação em doenças neuromusculares da cidade de São Paulo (HC-FMUSP e UNIFESP). O estudo molecular foi realizado através de sequenciamento Sanger para os genes ACTA1, TPM3, MYH7 e SEPN1 e/ou sequenciamento de nova geração para painel de genes musculares e/ou exoma. Resultados: Foram avaliados 23 pacientes com miopatia nemalínica (20 famílias) e 22 pacientes com alterações mínimas (20 famílias). O diagnóstico molecular foi concluído em sete famílias com miopatia nemalínica, sendo quatro com variantes missense, em heterozigose, no gene ACTA1 já associadas previamente a miopatia nemalínica, e três famílias, com variantes não conhecidas, em heterozigose, no gene NEB com alta predição de patogenicidade. Na coorte de miopatias congênitas com alterações mínimas o diagnóstico molecular foi concluído em nove famílias, sendo uma com variante conhecida no gene CHRNE, descrita em miastenia congênita; duas famílias com variantes no gene TPM3, sendo uma inédita, em homozigose, e outra, em heterozigose, já conhecida; duas famílias com variantes novas, em heterozigose, no RYR1, uma no gene TTN e três famílias com variantes já conhecidas no gene no MYH7 com fenótipo de miopatia distal de Laing. A despeito da realização de sequenciamento de exoma, sete famílias ainda permanecem sem gene candidato. Conclusões: Os achados clínicos, histológicos e moleculares dos pacientes da coorte de miopatia nemalínica seguem aos padrões descritos da literatura. O estudo dos pacientes com miopatia congênita com alterações mínimas se revelou complexo e variável, tanto no fenótipo quanto no genótipo. As mutações novas no gene NEB, RYR1, TTN, TPM3 e MYH7 confirmam a importância e patogenicidade destes genes nas miopatias congênitas e ampliam o seu espectro de alterações. Diante da quantidade de genes candidatos e do tamanho de alguns genes envolvidos com essas miopatias, técnicas de sequenciamento de nova geração são de grande valor
Introduction: Congenital myopathy are a group of genetic muscle diseases characterized by hypotonia and weakness in early childhood. They are characterized by structural abnormalities in muscle biopsy (nemaline bodies, central-cores or nuclear centralization). However, it can present within mild and unspecific findings like fiber type disproportion and abnormalities on oxidative staining (minimal changes). Regarding the molecular aspects, there are many genes associated with the congenital myopathies with an important overlapping between the histological and phenotypical findings. Objectives: Clinical, histological and molecular characterization of Brazilian patients with nemaline myopathy and congenital myopathy with minimal changes. Methods: Clinical and histological evaluation (review of muscle biopsy) of patients with nemaline myopathy and congenital myopathy with minimal changes from two centers of neuromuscular diseases (HC-FMUSP e UNIFESP). The molecular study was performed using Sanger sequencing for ACTA1, TPM3, SEPN1 and MYH7 genes and/or neuromuscular panel and/or exome. Results: Twenty-three patients with nemaline myopathy (20 families) and 22 patients with congenital myopathy with minimal changes (20 families) were evaluated. The molecular diagnose were concluded in seven families with nemaline myopathy, with four families having missense, heterozygous and pathogenic ACTA1 variants and three families having unknown heterozygous and pathogenic variants in NEB gene. In the congenital myopathy with minimal findings group, the diagnose was concluded in 9 families. One presenting with a pathogenic variant in CHRNE gene previously described in congenital myasthenia, two families with pathogenic variants in TPM3, one novel homozygous and one heterozygous previously reported. Two families presented with novel and pathogenic RYR1 variants, one with novel and pathogenic TTN variants and 3 families presented with heterozygous variants in MYH7 myopathy with Laing distal myopathy phenotype. Despite the NGS realization, 7 families remain without a gene candidate. Conclusions: The clinical, histological and molecular findings of nemaline myopathy cohort follow the literature pattern. In contrast, the study for minimal change patients appear complex and variable, either on phenotype or on genotype. The new gene mutations for NEB, RYR1, TTN, TPM3 and MYH7 reinforce relevance and pathogenicity of these genes in the congenital myopathies and expand the mutation spectrum. In light of diversity of candidate genes and the size of some genes involved with these myopathies, next generation sequencing techniques have been proved essential

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Cruz, Pedro M. Rodríguez. « Undefined myasthenias : clinical and molecular characterisation and optimised therapy ». Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:90f1b53c-a5ec-4fe3-8589-8ea076fc4cbf.

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Congenital myasthenic syndromes (CMS) are a group of heterogeneous disorders caused by mutations in genes encoding for proteins that are essential for neuromuscular transmission. All CMS share the clinical feature of fatigable muscle weakness. The differential diagnosis of CMS is wide, with a range of diseases going from autoimmune myasthenia gravis to muscle disorders. In this thesis, it was shown that measuring antibodies to clustered acetylcholine receptors (AChRs) by cell-based assay is helpful in the differential diagnosis of CMS. The findings of the current investigations showed that mutations in COL13A1, encoding the Collagen Type XIII α1 chain, were responsible for the symptoms of several patients with previously undefined myasthenias. In addition, this work described the clinical and complementary features of a novel CMS subtype due to mutations in the glycosylation pathway gene GMPPB. Investigations on a novel MUSK missense mutation (p.Ala617Val) uncovered previously unrecognised mechanisms of how levels of MuSK phosphorylation are critical to maintain synaptic structure, and guided suitable treatment for the patient. The study on the clinical and molecular basis of stridor, a novel clinical feature recently identified in patients with DOK7-CMS, prompted the identification of a novel DOK7 isoform, which warrants further investigation to elucidate its role in AChR clustering. Finally, the therapy of patients with severe AChR-deficiency was optimised thanks to a case series study that showed a robust improvement following the addition of β2-adrenergic agonists to their long-term treatment regime that included pyridostigmine.

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Clemson, Christine Moulton. « Development of a Multi-Site Phase II Clinical Trial of Valproic Acid for Retinitis Pigmentosa ». eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/470.

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The body of work presented here is a compendium of the multiple steps required for an investigator initiated trial of an existing medication (Valproic Acid- VPA) for a new indication (Retinitis Pigmentosa – RP). The chapters are listed in logical and chronological order of the process. In order to access patient records an expedited Institutional Review Board (IRB) application for retrospective chart review was submitted (Chapter 1). These records enabled the statistical analysis which not only laid the framework for the trial design, but also became the basis for two manuscripts (Chapter 2). Protocol development informed by the preliminary human studies (Chapter 3) was an instrumental part of the Investigational New Drug (IND) application (Chapter 3.5). This protocol along with the extensive case report forms that detail the intended data to be collected are included in the IND application. Because the Phase II clinical trial proposed attempting to identify the specific RP mutations of the subjects utilizing a National Eye Institute (NEI) study that enabled free genotyping services, two IRB applications were submitted (Chapter 3.6). The first was for approval of the NEI genotyping protocol, the second involved the VPA intervention. Two very different sources of funding for this trial were attempted (Chapter 4) – the NIH via the Challenge Grant mechanism and a private eye disease foundation (Foundation Fighting Blindness). In Chapter 5 I detail the alternate study designs that were considered and developed for this trial (and ultimately abandoned). Finally, in Chapter 6, I formally detail my suggestions to aid in the development of a comprehensive investigator initiated core facility at UMMMC. The goal of this project was two-fold. The first was to learn the entire process of trial and protocol design both from a Umass Institutional perspective as well as from the perspective of the FDA. The second goal was the very real prospect of helping patients with a blinding disease. This work was successful on both counts. IRB approval was received for all the submitted applications. The complexity and uniqueness of many aspects of these submissions culminated in a comprehensive learning experience. The process of working with the Umass Research Pharmacy as well as developing the industry contacts and know-how to develop a workable and financially feasible placebo were both particularly important learning experiences. FDA approval of the IND submission was also received, and the process of pre-communication and delving into the considerable and ever-changing rules and regulations resulted in an extensive and valuable knowledge base. While the practicality of funding has limited the ability of this trial to move forward at this point, given the extensive framework laid by this body of work, we are actively pursuing other opportunities. The third outcome of this work, while not as intentional, was the considerable process of determining the specific competencies and infrastructure that exist at UMMMC to enable investigator initiated drug intervention studies. While this institution is clearly moving rapidly in the direction of translational research, the many needs of these studies are often only clearly understood when the process is specifically undertaken. In completing the approval of this Phase II clinical trial, I was not only able to better understand and define the existing capabilities of UMMMC for this kind of research, I was able to add to that infrastructure when the existing knowledge or skill set was not available. In this manner, I was able to inform and guide many of the support personnel who guided me and have become a part of the strategic direction of UMMMC towards clinical translational research.

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Utkus, Algirdas. « Retosios ligos, jų fenomika ir genetinis konsultavimas ». Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2009. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2009~D_20090526_111352-29090.

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Retosios ligos (RL) – tai ypač mažai paplitusios ligos (gyvybei pavojų keliančios arba lėtai sekinančios ligos), kuriomis Europos Sąjungoje (ES) serga ne daugiau kaip 5 iš 10 000 asmenų. Pirmą kartą terminą „retosios ligos“ 1978 metais pavartojo Neilas A. Holtzmanas. Kiekviena RL ES serga apie 246 000 žmonių. Iš viso RL, kurių žinoma 5 000 – 8 000, kokiu nors gyvenimo etapu suserga apie 6% ES gyventojų ir tai yra 29 – 36 mln. ligonių. Lietuvoje sergančių RL galėtų būti apie 200 000 žmonių. Dauguma RL yra genetinės ligos (jos sudaro 80%), o likusios – kitų kategorijų retos vėžio formos, autoimuninės ligos, įgimtos raidos anomalijos, toksinės ir infekcinės ligos. Habilitacijos procedūrai teikiamų mokslo darbų apžvalgoje nagrinėtos 22 mokslinės publikacijos. Istoriniai šaltiniai apie RL gali būti anatominių preparatų muziejai, antikvarinės knygos medicinine tematika, tautosaka. Apžvalgoje nagrinėta Vilniaus universiteto Medicinos fakulteto anatominių preparatų kolekcija, kurioje nustatytas unikalus žmogaus anotocefalijos atvejis ir 11 kitų nozologinių RL (įgimtų anomalijų) vienetų. Pagrindinės priemonės žinioms apie RL turtinti ir klinikiniams moksliniams tyrimams plėtoti yra registrai ir duomenų bazės. Tai vienintelis būdas kaupti duomenis, kad būtų galima gauti pakankamo dydžio imtis epidemiologiniams ir (arba) klinikiniams tyrimams. Apžvalgoje nagrinėtos autopsijų ir Lietuvos paveldimų ligų ir įgimtų anomalijų (LIRECA) duomenų bazės, kurių analizės metu taikyti statistiniai... [toliau žr. visą tekstą]
Rare diseases (RD) – life menacing or slowly emaciating diseases of extremely low incidence (less than 5 cases in 10,000 EU inhabitants). The term was launched by Neil A. Holtzman in 1978. There are about 5,000 – 8,000 RD, each manifesting itself in some life stage of about 6% of EU population, that amounts from 29 to 36 million people. In Lithuania that would make about 200,000 people. The majority of RD are genetic (80%), the remaining consist of rare cancer forms, autoimmune diseases, inborn developmental anomalies, toxic or contagious illnesses. The author presented an analytical review of 22 publications on RD. Historical indications about RD could be found in anatomical museums, ancient medical books, and folk art. In the collection of anatomical specimens of Medical Faculty of Vilnius University the author has discovered a unique case of human anotocephaly and eleven more nosological entities of RD (congenital anomalies). The main sources for information on RD are registers and data bases. This is the only way to obtain sufficient samples for epidemiologic and/or clinical research. Lithuanian Register of Congenital Anomalies (LIRECA) and autopsies data base were reviewed by the author and analyzed by statistical research models applicable in registration of RD, in particular Poisson linear model and logistic (binomic) regression. Analysis of standardized remainders confirmed their adequacy and suitability. Biological asymmetry was evaluated by analysis of... [to full text]

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PEREIRA, Clairton Marcolongo. « Defeitos congênitos diagnosticados em ruminantes na região Sul do Rio Grande do Sul ». Universidade Federal de Pelotas, 2010. http://repositorio.ufpel.edu.br/handle/ri/2557.

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Made available in DSpace on 2014-08-20T14:38:00Z (GMT). No. of bitstreams: 1 dissertacao_clairton_pereira.pdf: 3571578 bytes, checksum: 9c290ec5c39aa24d7b6ec235d88b0321 (MD5) Previous issue date: 2010-02-22
Congenital defects and hereditary diseases in cattle, sheep and buffaloes were studied through a review of necropsy files of the Laboratório Regional de Diagnóstico (LRD) of the Faculdade of Veterinária of the Universidade Federal de Pelotas (UFPel) between 1978 and 2009. The occurrence of congenital defects and/or hereditary diseases in cattle, sheep and buffaloes were 0.89%, 0.36% e 7.55% respectively from all received material. The defects were classified according the affected system. From 48 of congenital defects and/or hereditary diseases observed in cattle 21 (43.75%) affected the skeletal system (chondrodysplasia, scoliosis, lateral deviation of mandible, palatoschisis and unclassified malformation) nine (18.75%) the central nervous system (hypoplasia of olfatory and frontal lobes, cerebellar cortical degeneration, spina bifida, congenital hypomielinogenesis, hereditary hypermetria, cerebellar hypoplasia and pachygiria), nine (18.75%) the muscular system (arthrogryposis), three (6.25%) the cardiovascular system (patent ductus arteriosus and unclassified malformation), one (2.08%) the lymphatic system (hereditary lymphatic hypoplasia), one (2.08%) o alimentary system (atresia ani) and one (2.08%) the eye (congenital cataract). In five cases (10.42%) different systems were affected (diprosopus and decephalus dipos dibraqius). In sheep all observed defects affected various systems (anomalous twins and aprosopia). Of eight cases of congenital defects/hereditary diseases diagnosed in buffaloes three (37.5%) affected the muscular system (arthrogriposis and double muscle), two (25%) the integument (mechanobullous dermatosis and albinism), one (12.5%) the central nervous system (hydranencephaly), one (12.5%) the central nervous system/ integument (hydranencephaly/albinism) and one (12.5%) the alimentary system (megaesofagus). It was concluded that the sporadic congenital defects cause little economical losses in cattle. Environmental congenital defects can cause losses in certain localized geographic areas or farms. The hereditary diseases were important by mortality of animals and by spread of undesirable genes in cattle breeding from milk production region in Southern Brazil. In sheep the congenital defects are rare. In water buffaloes the high prevalence of hereditary diseases was a consequence of the high consanguinity of herd and management measures need to be taken to avoid the spread of recessive genes that are difficult to control.
Foi realizado um estudo das malformações congênitas/doenças hereditárias diagnosticadas em bovinos, ovinos e bubalinos através da revisão dos protocolos de necropsia do Laboratório Regional de Diagnóstico (LRD) da Faculdade de Veterinária da Universidade Federal de Pelotas (UFPel) entre 1978 e 2009. A ocorrência de defeitos congênitos e/ou doenças hereditárias em bovinos, ovinos e bubalinos representou 0,89%, 0,36% e 7,55% respectivamente, de todos os materiais dessas espécies recebidos. Os defeitos foram classificados de acordo com o sistema afetado. Dos 48 casos de defeitos congênitos e/ou doenças hereditárias diagnosticados em bovinos 21 (43,75%) afetaram o sistema esquelético (condrodisplasia, escoliose, desvio lateral da mandíbula, fenda palatina e malformação não classificada) nove (18,75%) o sistema nervoso central (hipoplasia dos lobos frontais e olfatórios, degeneração cerebelar cortical, espinha bífida, hipomielinogênese congênita, hipermetria hereditária, hipoplasia cerebelar e paquigiria), nove (18,75%) o sistema muscular (artrogripose), três (6,25%) o sistema cardiovascular (persistência do ducto arterioso e malformação não classificada), um (2,08%) o sistema linfático (hipoplasia linfática), um (2,08%) o sistema gastrintestinal (atresia anal) e um (2,08%) o olho (catarata congênita). Em cinco casos (10,42%) vários sistemas estavam afetados (diprosopo e dicéfalo dipos dibráquio). Todos os casos de defeitos congênitos observados em ovinos (gêmeos anômalos e aprosopia) afetaram vários sistemas. Dos oito casos de defeitos congênitos e/ou doenças hereditárias diagnosticados em búfalos três (37,5%) afetaram o sistema muscular (artrogripose e hiperplasia muscular), dois (25%) o sistema tegumentar (dermatose mecânico-bolhosa e albinismo), um (12,5%) o sistema nervoso central (hidranencefalia), um (12,5%) o sistema nervoso central/tegumentar/fotorreceptor (hidranencefalia/albinismo), e um (12,5%) o sistema gastrintestinal (megaesôfago). Concluiu-se que os defeitos congênitos esporádicos têm pouca importância em bovinos. Defeitos congênitos de causas ambientais podem trazer prejuízos econômicos importantes em determinadas regiões ou estabelecimentos. As doenças comprovadamente hereditárias são importantes não só pela mortalidade mas, também, pela possibilidade de disseminação de genes indesejáveis nas diferentes raças, principalmente aquelas criadas em pequenas propriedades rurais da bacia leiteira da região. Em ovinos os defeitos congênitos são raros. Em bubalinos a alta frequência de doenças hereditárias na raça Murrah foi atribuída a alta consanguinidade do rebanho e medidas de controle devem ser tomadas para evitar-se a contínua disseminação, principalmente dos genes recessivos que são mais difíceis de controlar.

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Rowlinson, Giselle Victoria. « Connexins in congenital heart disease ». Thesis, Imperial College London, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550483.

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Gap junctions are clusters of transmembrane channels, composed of connexins (Cx), that facilitate electrical and chemical communication between the cytoplasmic compartments of contiguous cells. Three connexins are expressed in cardiac myocytes, Cx40, Cx43 and Cx45. Targeted deletion of these connexin genes in mice results in cardiac malformations and conduction abnormalities. From this background, the question arises as to whether connexins play a role in human congenital heart disease. Atrial and ventricular tissue samples were studied from patients undergoing cardiac surgery. Immunoconfocal microscopy and western blot analysis of atrial tissue revealed that expression of CX40 and CX43 in children and adults with congenital heart disease is the same as that in the normal adult atrium, irrespective of the underlying malformation. Normal adult ventricular working myocytes express only CX43. Study of control ventricular samples in children confirmed that, as in adults, CX43 only is expressed. However, immunoconfocal microscopy of samples from patients with right ventricular outflow obstruction (tetralogy of Fallot and double chambered right ventricle) revealed that in addition to CX43, CX40 is also highly expressed. Expression is heterogeneous and CX40 is eo-localised with CX43. Quantitative western blot analysis showed that up to 10% of the total connexin expressed in these samples is CX40. As patients re-operated following previous repair (with markedly different underlying haemodynamics) still demonstrated high CX40 expression in the working myocardium, these results suggest that a lack of normal CX40 repression during development leads to heart malformations . . Gap junction channels formed from each connexin isofonn have distinctive biophysical properties. Connexin eo-expression further alters these properties. To investigate the functional consequences of the connexin eo-expression patterns observed in the ventricular samples, in vitro cell models were used. Intercellular communication was assessed using cell-to-cell Lucifer Yellow dye transfer in an inducible RLE cell line and conducjion properties were studied in an atrial myocyte (HL-l) cell line. The findings are consistent with the idea that altered function arising from abnormal embryonic connexin expression is a contributor to some types of human cardiac malformation.

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Grech, Victor. « Congenital heart disease in Malta ». Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286359.

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Khetyar, Maher. « Genetics of congenital heart disease ». Thesis, St George's, University of London, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754064.

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Congenital Heart Disease (CHD) is the leading non-infectious cause of death among children less than one year. CHD is genetically heterogeneous, but analysis of large multi-generational families has led to the identification of a number of genes for CHD. In this project I investigated the molecular genetic basis of CHD in a large Kuwaiti family with clinically diagnosed truncus arteriosus. Using a homozygosity mapping approach I identified a region of interest on chromosome 8p21. I proceeded to sequence candidate genes in this region. One of the novel genes identified was predicted to be the human homolog of mouse Nkx2.6, a gene encoding a homeobox transcription factor expressed in the sinus venosa and the myocardium of the outflow tract in the developing mouse heart. Sanger sequencing identified a Phel51Leu mutation which segregated with disease in the family. Next I investigated whether mutations in Nkx2.6, or the related gene Nkx2.5, were a common cause of type I truncus arteriosus in 12 unrelated individuals. However I found no mutations, suggesting the pattern of inheritance in this phenotype is likely to be complex and potentially multifactorial. Finally I investigated the molecular genetic basis of another congenital heart defect known as Patent Ductus Arteriosus (PDA) in a multigenerational Kuwaiti family with six affected members. A condition known as Char Syndrome is characterized by a combination of major features one of which is PDA and can be caused by mutations in the TFAP2B gene which encodes the Transcription Factor AP-2 Beta. I therefore hypothesised that mutations in TFAP2B may also be responsible for PDA in the Kuwaiti family. I identified a predicted splice site variant in this gene that segregated with disease status. A full clinical history and physical examination confirmed that no affected members of this family have any of the remaining features of Char Syndrome suggesting that mutations in TFAP2B can also cause isolated PDA.

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Fonseca, Sonya G. « Role of WFS1 in Regulating Endoplasmic Reticulum Stress Signaling : A Dissertation ». eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/414.

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The endoplasmic reticulum (ER) is a multi-functional cellular compartment that functions in protein folding, lipid biosynthesis, and calcium homeostasis. Perturbations to ER function lead to the dysregulation of ER homeostasis, causing the accumulation of unfolded and misfolded proteins in the cell. This is a state of ER stress. ER stress elicits a cytoprotective, adaptive signaling cascade to mitigate stress, the Unfolded Protein Response (UPR). As long as the UPR can moderate stress, cells can produce the proper amount of proteins and maintain a state of homeostasis. If the UPR, however, is dysfunctional and fails to achieve this, cells will undergo apoptosis. Diabetes mellitus is a group of metabolic disorders characterized by persistent high blood glucose levels. The pathogenesis of this disease involves pancreatic β-cell dysfunction: an abnormality in the primary function of the β-cell, insulin production and secretion. Activation of the UPR is critical to pancreatic β-cell survival, where a disruption in ER stress signaling can lead to cell death and consequently diabetes. There are several models of ER stress leading to diabetes. Wolcott-Rallison syndrome, for example, occurs when there is a mutation in the gene encoding one of the master regulators of the UPR, PKR-like ER kinase (PERK). In this dissertation, we show that Wolfram Syndrome 1 (WFS1), an ER transmembrane protein, is a component of the UPR and is a downstream target of two of the master regulators of the UPR, Inositol Requiring 1 (IRE1) and PERK. WFS1 mutations lead to Wolfram syndrome, a non-autoimmune form of type 1 diabetes accompanied by optical atrophy and other neurological disorders. It has been shown that patients develop diabetes due to the selective loss of their pancreatic β-cells. Here we define the underlying molecular mechanism of β-cell loss in Wolfram syndrome, and link this cell loss to ER stress and a dysfunction in a component of the UPR, WFS1. We show that WFS1 expression is localized to the β-cell of the pancreas, it is upregulated during insulin secretion and ER stress, and its inactivation leads to chronic ER stress and apoptosis. This dissertation also reveals the previously unknown function of WFS1 in the UPR. Positive regulation of the UPR has been extensively studied, however, the precise mechanisms of negative regulation of this signaling pathway have not. Here we report that WFS1 regulates a key transcription factor of the UPR, activating transcription factor 6 (ATF6), through the ubiquitin-proteasome pathway. WFS1 expression decreases expression levels of ATF6 target genes and represses ATF6-mediated activation of the ER stress response (ERSE) promoter. WFS1 recruits and stabilizes an E3 ubiquitin ligase, HMG-CoA reductase degradation protein 1 (HRD1), on the ER membrane. The WFS1-HRD1 complex recruits ATF6 to the proteasome and enhances its ubiquitination and proteasome-mediated degradation, leading to suppression of the UPR under non-stress conditions. In response to ER stress, ATF6 is released from WFS1 and activates the UPR to mitigate ER stress. This body of work reveals a novel role for WFS1 in the UPR, and a novel mechanism for regulating ER stress signaling. These findings also indicate that hyperactivation of the UPR can lead to cellular dysfunction and death. This supports the notion that tight regulation of ER stress signaling is crucial to cell survival. This unanticipated role of WFS1 for a feedback loop of the UPR is relevant to diseases caused by chronic hyperactivation of ER stress signaling network such as pancreatic β-cell death in diabetes and neurodegeneration.

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Jiang, Yan. « Chromatin Remodeling in Transgenic Mouse Brain : Implications for the Neurobiology of Depression : A Dissertation ». eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/423.

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Histone lysine methylation is an important epigenetic mark for regulation of gene expression and chromatin organization. Setdb1 (Set domain, bifurcate 1), one of the histone lysine methyltransferases, specifically methylates histone H3 at lysine 9 (H3K9) and participates in transcriptional repression and heterochromatin formation. The major task of my thesis work was to investigate the epigenetic roles of Setdb1 in regulating brain functions. I started my thesis work by examining Setdb1 expression pattern during mouse brain development. The most robust signal of Setdb1 was detected in the fetal brains at embryonic day 12.5, with a ubiquitous distribution in all the proliferative zones, as well as the cortical plate and other regions comprised of postmitotic neurons. The expression of Setdb1 decreased as the brain developed, and this down-regulation profile was correlated to neuronal maturation as examined in a primary culture model of mouse cortical neurons. I then generated CK-Setdb1 transgenic mice, in which a myc-tagged full length mouse Setdb1 was constantly expressed in postmitotic neurons under the control of the CaMK II alpha promoter (CK). The expression of mycSetdb1 was detected in NeuN positive cells throughout most forebrain regions including cerebral cortex, striatum and hippocampus. A sustained increase of Setdb1 in CK-Setdb1 transgenics was verified at both mRNA and protein levels. Furthermore, an increase of H3K9 trimethylation was detected at major satellite DNA repeats in CK-Setdb1forebrains, which indicated that transgene-expressed mycSetdb1 was functionally active in adult brains. The behavioral phenotype of CK-Setdb1 transgenics was examined by using two separate founder lines. Gross neurological functions including body weight, locomotion activity, motor coordination, and breeding behavior were generally normal in CK-Setdb1 mice. CK-Setdb1 mice were further subjected to behavioral paradigms related to mood and cognitive functions. Intriguingly, as compared to the littermate controls, CK-Setdb1 mice represent a lower level of depression as indicated by decreased total immobility in two different behavioral despair tests. Moreover, CK-Setdb1 mice showed an accelerated extinction in the learned helplessness paradigm after a delayed interval (7 days), indicating a faster recovery from an established status of despair. The potential confounding factors, like memory deficits, were ruled out as CK-Setdb1 mice showed normal or even improved performances in different memory-related paradigms. Anxiety scores and stimulant drug response were normal in CK-Setdb1mice. Taken together, these findings suggested that a specific antidepressant-like phenotype was elicited by the over-expression of Setdb1 in adult mice forebrains. To further study the molecular mechanism underlying Setdb1-associated antidepressant-like behavioral changes, I screened for Setdb1-binding sites in a genome-scale by ChIP-on-chip using a tiling microarray from Affymetrix. Unexpectedly, Setdb1 showed a very restricted binding profile with a high specificity towards ionotropic glutamate receptor genes including the NMDA receptor 2B subunit gene Grin2b, which is a new target for the treatment for major depression. An increase of H3K9 dimethylation at Setdb1-binding site on Grin2b locus was detected in CK-Setdb1 hippocampus, which was correlated to a decrease of Grin2b expression as well as an accelerated desensitization of NMDA receptor. Furthermore, Chromosome Conformation Capture (3C) on Grin2b locus revealed a repressive chromatin loop structure, which tethered the distal Setdb1-binding site (~ 32 Kb downstream of transcriptional start site (TSS)) to a proximal intronic region (~12 Kb downstream of TSS) that is enriched for the binding of KAP1, a well-studied Setdb1-interacting transcriptional corepressor. Taken together, our data indicated that Setdb1 repressed Grin2b expression via H3K9 hypermethylation and higher-order chromatin loop formation, which may contribute to the antidepressant-like phenotype we observed in CK-Setdb1mice. The second part of my thesis work was to investigate the role of Setdb1 in the animal model of a neurodevelopmental disorder - Rett syndrome (RTT). Loss-of-function mutations of the gene encoding methyl-CpG binding protein 2 (MECP2) is the primary cause of RTT. There is an overlap between Setdb1- and Mecp2-associated repressive chromatin machineries, which both include histone deacetylase complex, H3K9 methyltransferase, DNA methyltransferase and heterochromatin protein 1 (HP1). Moreover, in contrast to Setdb1, which is downregulated during the cortical neuronal differentiation, Mecp2 is upregulated and the expression level is positively correlated to neuronal maturation. Therefore, we hypothesized that there is a functional redundancy between Setdb1 and Mecp2, and the up-regulation of Setdb1 in mature neurons will compensate for brain deficiency due to the loss of Mecp2. To test this hypothesis, I crossed CK-Setdb1 transgenic mice with nestincre-Mecp2 conditional knockout mice (Mecp2-/y). The behavior changes of CK-Setdb1/Mecp2-/y mice, including body weight, locomotion, motor coordination, and life span, were then compared to Mecp2-/y mice. No significant improvements in behaviors or survival were observed from CK-Setdb1/Mecp2-/y mice. Because the activation of CK promoter is limited to defined population of postmitotic neurons in forebrain, I tested our hypothesis by generating another strain of Setdb1 overexpression mice – tauSetdb1, in which the expression of mycSetdb1 is under the control of an endogenous pan-neuronal active promoter Tau. However, the introduction of tauSetdb1 also failed to rescue Mecp2 deficiency. The life span of tauSetdb1/ Mecp2-/y was even shorter as compared to Mecp2-/y mice (Kaplan-Meier, p=0.07). In conclusion, up-regulation of Setdb1 in adult brain was not sufficient to rescue Mecp2deficiency in the mouse model of RTT. One of the most challenges to study neuronal dysfunctions in brain diseases is the cellular heterogeneity of central nervous system. Current techniques for chromatin studies, including chromatin immunoprecipitation (ChIP) assays, usually lack of single cell resolution and are unable to examine the neurobiological changes in defined cell populations. In the third part of my thesis work, I developed a modified protocol to isolate neuronal nuclei from brain homogenates via Fluorescence-Activated Cell Sorting (FACS). In general, total nuclei was extracted from frozen brains, neuronal nuclei were then immuno-tagged with NeuN and sorted via FACS. Besides the NeuN labeling-FACS protocol, I also generated CK-H2BeGFP transgenic mice, in which a histone H2B-eGFP (enhanced green fluorescent protein) fusion protein was expressed in the nuclei of postmitotic neurons in mouse forebrain. Nuclei extracted from CKH2BeGFP brain were directly applied for FACS sorting. By using this protocol, we routinely got around 6-8 x106neuronal nuclei from one adult mouse forebrain, which was sufficient for ChIP applications followed by single gene PCR and microarray studies. In conclusion, our protocol permits large-scale studies of chromatin modifications or any other nuclei events in defined cell populations from distinct brain regions. Taken together, my dissertation work will lead to a better understanding of the epigenetic roles of histone H3K9 methyltransferase Setdb1 in brain functions, and may provide new targets for the therapeutic treatment of major depression.

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Quigley, Caitlin M. « The Drosophila Homolog of the Intellectual Disability Gene ACSL4 Acts in Glia to Regulate Morphology and Neuronal Activity : A Dissertation ». eScholarship@UMMS, 2007. http://escholarship.umassmed.edu/gsbs_diss/839.

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Recent developments in neurobiology make it clear that glia play fundamental and active roles, in the adult and in development. Many hereditary cognitive disorders have been linked to developmental defects, and in at least two cases, Rett Syndrome and Fragile X Mental Retardation, glia are important in pathogenesis. However, most studies of developmental disorders, in particular intellectual disability, focus on neuronal defects. An example is intellectual disability caused by mutations in ACSL4, a metabolic enzyme that conjugates long-chain fatty acids to Coenzyme A (CoA). Depleting ACSL4 in neurons is associated with defects in dendritic spines, a finding replicated in patient tissue, but the etiology of this disorder remains unclear. In a genetic screen to discover genes necessary for visual function, I identified the Drosophila homolog of ACSL4, Acsl, as a gene important for the magnitude of neuronal transmission, and found that it is required in glia. I determined that Acsl is required in a specific subtype of glia in the Drosophila optic lobe, and that depletion of Acsl from this population causes morphological defects. I demonstrated that Acsl is required in development, and that the phenotype can be rescued by human ACSL4. Finally, I discovered that ACSL4 is expressed in astrocytes in the mouse hippocampus. This study is highly significant for understanding glial biology and neurodevelopment. It provides information on the role of glia in development, substantiates a novel role for Acsl in glia, and advances our understanding of the potential role that glia play in the pathogenesis of intellectual disability.

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49

Quigley, Caitlin M. « The Drosophila Homolog of the Intellectual Disability Gene ACSL4 Acts in Glia to Regulate Morphology and Neuronal Activity : A Dissertation ». eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/839.

Texte intégral

Résumé :

Recent developments in neurobiology make it clear that glia play fundamental and active roles, in the adult and in development. Many hereditary cognitive disorders have been linked to developmental defects, and in at least two cases, Rett Syndrome and Fragile X Mental Retardation, glia are important in pathogenesis. However, most studies of developmental disorders, in particular intellectual disability, focus on neuronal defects. An example is intellectual disability caused by mutations in ACSL4, a metabolic enzyme that conjugates long-chain fatty acids to Coenzyme A (CoA). Depleting ACSL4 in neurons is associated with defects in dendritic spines, a finding replicated in patient tissue, but the etiology of this disorder remains unclear. In a genetic screen to discover genes necessary for visual function, I identified the Drosophila homolog of ACSL4, Acsl, as a gene important for the magnitude of neuronal transmission, and found that it is required in glia. I determined that Acsl is required in a specific subtype of glia in the Drosophila optic lobe, and that depletion of Acsl from this population causes morphological defects. I demonstrated that Acsl is required in development, and that the phenotype can be rescued by human ACSL4. Finally, I discovered that ACSL4 is expressed in astrocytes in the mouse hippocampus. This study is highly significant for understanding glial biology and neurodevelopment. It provides information on the role of glia in development, substantiates a novel role for Acsl in glia, and advances our understanding of the potential role that glia play in the pathogenesis of intellectual disability.

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50

Eberth, John E. « Chondrodysplasia-Like Dwarfism in the Miniature Horse ». UKnowledge, 2013. http://uknowledge.uky.edu/gluck_etds/11.

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Dwarfism is considered one of the most recognized congenital defects of animals and humans and can be hereditary or sporadic in cause and expression. There are two general morphologic categories within this vastly diverse disease. These categories are disproportionate and proportionate dwarfism and within each of these there are numerous phenotypes which have been extensively described in humans, and to a lesser extent in dogs, cattle, mice, chickens, and other domestic species. Ponies and Miniature horses largely differ from full size horses only by their stature. Ponies are often defined as those whose height is not greater than 14.2 hands; however the maximum height for Miniature horses is constitutionally defined as 8.2 hands. Dwarfism is not considered a desirable genetic trait for Miniature horses. A majority of these conformationally inferior horses showed consistent physical abnormalities typical of disproportionate dwarfisms as seen in other mammal species. A whole genome scan with the Illumina Equine SNP50 chip clearly implicated a region on ECA1 as being associated with dwarfism of horses. The region implicated on the horse chromosome 1 (Equus Caballus; ECA1) contained a candidate gene for dwarfism, aggrecan (ACAN). Mutations were found in Exons 2, 6, 11 and 15 with each mutation associated with a distinct type of dwarfism. These mutations are independently transmitted throughout the population. Absence of normal homozygotes for these mutations and absence of normal horses which were heterozygous for these mutations indicated that these alleles caused dwarfism in those genotypes. These genotypes did not explain all observed dwarves in this population.

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Thèses sur le sujet « Congenital diseases »

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