Thesis (M.S.)--University of Michigan, 1987.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Congenital heart defects occur in approximately one percent of births every year, which makes it the most frequently occurring congenital defect in patients. The aim of this project was to use two mutant neural crest (NC) mouse models to study the mechanisms underlying congenital heart failure in utero. The first mouse model was a Pax3 systemic knockout, which was lethal by mouse gestational day 14, and had appreciably reduced numbers of migratory NC cells. The second mouse model was a Wnt1Cre-mediated NC genetic cell ablation model, which was surprisingly viable and survived to birth, despite an apparent lack of migratory NC cells. The resultant data indicated that both mouse models had similar heart structural defects including persistent truncus arteriosus, which was due to fewer or no migratory cardiac NC cells. However, in utero heart function was appreciably perturbed in Pax3 mutants when compared to that of the ablated mutant model. The loss of embryonic cardiac function in Pax3 mutants was directly attributed to a substantial decrease in the activity of the beta-adrenergic pathway. This was due to a lack of proper specification of trunk NC cells, leading to diminished levels of circulating catecholamine levels in the embryo. To definitively confirm this conclusion, poor cardiac function was successfully restored by pharmacological stimulation of the beta-adrenergic pathway via administration of isoproterenol and forskolin to pregnant dams, which led to embryonic survival of Pax3 mutants to birth. By comparison of these two mutant mouse models, perturbation in the beta-adrenergic pathway was identified as the underlying mechanism responsible for in utero heart failure and lethality in Pax3 mutant embryos. The results of this study are expected to be significant in developing future therapeutic targets for congenital heart failure in prenatal and newborn patients.

Currarino-Silverman syndrome is a rare disorder characterized by premature fusion of manubrio-sternal joint and the sternal segments, resulting in a high carinate chest deformity; it is frequently associated with congenital heart disease. Among the various heart lesions reported in this syndrome, mitral valve disease and coarctation of the aorta have not yet been described (to our knowledge). Our report consists of five children with this syndrome, four of whom had mitral valve disease, with an associated coarctation of the aorta in one patient. The fifth patient had an innocent heart murmur.

The body composition of children and adolescents with congenital heart disease and residual pulmonary regurgitation (PR) was compared to that of healthy age- and sex-matched controls. Testing included height, weight, skinfolds, skeletal widths, circumferences, bio-electrical impedance (for estimation of total body water from resistance index), hydrostatic weighing, bone mineral content from single photon absorptiometry, and an assessment of maturational status. Activity levels were assessed by questionnaires and an accelerometer. The two groups were found to be different in height, skeletal widths, bone mineral content, bone mineral index and total body water determined by bio-electrical impedance. After adjusting the data for height differences, the groups were different for skeletal widths and bone mineral index. The PR and control subjects had similar skinfolds and circumferences, as well as percent fat determined by body density, body water and bone mineral content.

BACKGROUND:Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.RESULTS:We describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.CONCLUSIONS:Our findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.

The Congenital Dyserythropoietic Anemias (CDA) are rare hereditary hemolytic disorders with large bi- to multi-nucleated erythroblasts in the bone marrow. Hemolysis is negative in a direct antiglobulin test (DAT). Based on morphology and clinical picture, three major forms of CDAs, type I, II, and III have been defined. CDA III, dominantly inherited, constitutes the rarest type with a majority of cases belonging to a family in Västerbotten, Sweden. The genetic background of CDA I and CDA II has been linked to mutations in CDAN1 and SEC23B respectively. The mutation of CDA III has been linked to 15q22 in earlier studies. In this project we have defined the causative genetic lesion in two families with CDA III. The novel mutation KIF23 c.2747C>G (p.P916R) was shown to segregate with CDA III in the Swedish and American CDA III families and was absent in 356 healthy controls. KIF23 encodes mitotic kinesin-like protein 1 (MKLP1), which plays a central role in the last step of cytokinesis. RNAi-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, resulting in increasing number of bi-nuclear cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23, encoding MKLP1, a conserved mitotic kinesin crucial for cytokinesis. Flow cytometry with eosin-5´-maleimide (EMA), anti-CD55 and anti-CD59 is commonly used when investigating non-autoimmune hemolytic anemias. Reduced fluorescence of EMA, typically detected in hereditary spherocytosis, is also seen in CDA II, while reduction of CD55 and CD59 characterizes paroxysmal nocturnal hemoglobinuria (PNH). We studied the flow cytometric profile of EMA, CD55, and CD59 on erythrocytes in CDA III. We found no abnormality of the erythrocyte membrane in CDA III and concluded that standard flow cytometry cannot be used to discriminate between CDA III and normal controls. In CDA I and CDA II a majority of patients, including those who are not transfusion dependent, suffer from iron overload, which, according to earlier studies, is not the case in CDA III. We found that individuals of the Västerbotten CDA III family carry mutations in the hemochromatosis (HFE) gene. Three CDA III patients with heterozygous or compound HFE mutations need treatment with phlebotomy due to iron overload. One of them carries heterozygous H63D mutation, which is not reported to lead to iron overload by itself in otherwise healthy individuals. We propose that molecular genetic testing of the HFE gene is indicated in all patients with CDA, including CDA III.

Single ventricle heart defects are present in two of every 1000 live births in the US. In this condition the systemic and pulmonary blood flow mix in the functioning ventricle, resulting in insufficient blood oxygenation to sustain life. As part of the palliation of these defects, the staged surgical procedure, known as the Fontan procedure, is performed. Here, the venous returns are directed to the pulmonary arteries, bypassing the right heart and forming the Total Cavopulmonary Connection (TCPC). Even though the palliation improves life expectancy, there are numerous long-term complications that become more prevalent as patients reach adulthood. Many of these complications have been related to the function of the single ventricle circulation, especially to the abnormal TCPC hemodynamics, for which this has been the focus of research throughout the years. Recent progress has been made with the availability of improved medical imaging techniques and computational modeling tools; however, there is limited information on how these evolve in time. In order to improve the Fontan palliation, image-based surgical planning has been used in the most complex cases to prospectively design the TCPC, aiming to improve the hemodynamics. Even though this paradigm has shown promising results, improvement is needed to provide more realistic predictions of the post-operative outcomes. To address this, in this thesis we have developed a novel surgical planning framework that allows us to: (i) model the interaction of the TCPC and global circulation hemodynamics, and (ii) assess the robustness of the surgical option proposed. Here, the single ventricle circulation is modeled using a lumped parameter model, coupled to a computational fluid solver to describe the local TCPC hemodynamics. With this framework, we can predict the immediate post-operative state, model various physiological scenarios, and assess the impact on the local hemodynamics and global circulation. This will allow us to provide information on the effect on the global hemodynamics to the clinical team. In addition to the surgical planning advancements obtained in this thesis, we have performed the largest longitudinal Fontan study to date in which we have evaluated the evolution of the Fontan physiology in time and the effect it has on the energy efficiency of the TCPC. In this thesis, we have studied the short and long-term effects that geometrical and physiological changes have on the Fontan hemodynamics. With this, we have improved the understanding of the Fontan physiology in terms of the short-term effects of Fontan palliation and the long-term deterioration of the changing single ventricle physiology.

published_or_final_version / Sports Science / Master / Master of Science in Sports Science

The effects of air pollutants CO, NO₂, O₃, PM₁₀ and SO₂ on congenital heart anomalies are represented by the odds ratio of each disease per unit increase in the concentration of each pollutant. In this study, the effects of air pollutants are summarized using multivariate GLS approach with correlation between outcomes being taken into account, where the correlations are sampled from uniform [-1,1]. Meta-analysis conducted here found no statistically significant increase in odds ratio of any disease. This result is different from what Vrijheid et al. 2011 suggested when correlation is not considered using the same set of data. The difference in conclusions from the two meta-analysis indicate that correlation between outcomes may play an important role when synthesizing effect sizes. Thus, before conduct meta-analysis, a thorough consideration about whether to incorporate the correlation in synthesizing should be given. / text