Thesis (Ph. D.)--University of Wisconsin-Madison, 1974. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Down syndrome (DS), caused by an extra chromosome 21, affects 1 in 750 live births, and is characterized by cognitive impairment as well as several congenital defects. Currently, little is known about the molecular pathogenesis of DS and no direct genotype-phenotype relationship has yet been confirmed. The current screening test for DS subjects many women to undergo invasive procedures such as amniocentesis due to suboptimal sensitivity and specificity. Therefore, this study aimed to discover novel biomarkers to improve screening tests, and to discovery dysregulated molecular pathways in DS-affected fetus to better understand pathogenesis. To achieve this objective, proteomic analyses of amniotic fluid (AF) and amniotic fluid cells (amniocytes) were performed using mass spectrometry (MS), which allows discovery of a large number of proteins in complex biological samples. Since AF contains the most information of the developing fetus, we first generated the most comprehensive list of proteins present in AF by using high resolution MS. We then performed quantitative analyses of proteins from AF as well as amniocytes to reveal novel biomarkers and clues to altered molecular mechanisms of DS. Comparison between the proteome of AF from unaffected and DS-affected pregnancies allowed selection of 60 candidate biomarkers based on spectral counting. Two candidates, APP and TNC-C, were verified by immunoassays to show two-fold increase in AF from DS-pregnancies. Additionally, CPA4, MUC13, CEL, DPP4 and MMP2 were verified to be differentially expressed in trisomy 21-AF via selected reaction monitoring assays using triple-quadruple mass spectrometer. Amniocytes from DS-affected and unaffected fetuses were also quantitatively analyzed by using Stable Isotope Labelling of Amino acids in Cell culture technique. Over 4900 proteins were identified from amniocyte lysate and supernatant by LTQ-Orbitrap mass spectrometer, and 85% of these proteins were quantified based on MS/MS spectra ratios of peptides containing isotope-labelled amino acids. Proteins that consistently showed aberrant expression from affected amniocytes have been selected for further verification and molecular network analyses since they may play a role in DS pathogenesis.

M.A. (Counselling Psychology) / Sibling interaction is often an overlooked aspect of family functioning. For many years there has been an overemphasis on the importance of parental influences on children, yet common sense dictates that brothers and sisters must have some effect on each other even though this effect may not always be obvious. The sibling relationship is a life-long process, and is therefore highly influential throughout the life cycle ...

Assisted reproduction technology is increasingly used for treatment of couples with subfertility. These women are usually of more advanced maternal age and carry a higher risk of fetal Down syndrome. Results from early publications showed that biochemical markers for screening of fetal Down syndrome in the second trimester were different between pregnancies from in vitro fertilization (IVF) and natural conception. This could potentially increase the false positive rate and result in unnecessary invasive diagnostic procedures. Questions were raised as to whether the alterations were related to ovarian stimulation. This laid the fundamentals of a series of studies presented in this thesis with an aim to address the variations in the concentrations of markers of fetal Down syndrome and the fetal growth profile of pregnancies conceived following different assisted reproduction treatments. Studies were conducted on maternal serum and amniotic fluid alpha fetoprotein (AFP) and human chorionic gonadotrophin (hCG) in the second trimester in pregnancies conceived by assisted reproduction. A reduced level of AFP in maternal serum in pregnancies with fresh embryos together with an elevated level of hCG in both maternal serum and amniotic fluid in pregnancies with frozen thawed embryos were found. This pioneer piece of data showing the raised hCG in frozen thawed embryo pregnancies with unstimulated treatment cycles spoke against the ovarian driven hypothesis, but suggested placental dysfunction be a possible underlying pathophysiology. For markers adopted in the first trimester, the level of pregnancy associated protein A (PAPP-A) was significantly reduced in pregnancies from assisted reproduction. The data on free βhCG was heterogeneous. Apart from biochemical markers, the nuchal translucency was also increased in these singleton pregnancies but not in dichorionic twins. As the direction of deviations of these markers in unaffected pregnancies from assisted reproduction resembled those observed in pregnancies affected by Down syndrome, appropriate adjustment was necessary to reduce the false positive rate for these women. Altered biochemical markers, notably a low PAPP-A level, were also associated with adverse obstetric outcomes. The changes observed in pregnancies from assisted reproduction might be a manifestation of an intrinsic placental insufficiency or fetal developmental delay. A longitudinal study was performed to examine the intrauterine fetal growth profile in these pregnancies. The rate of increment in the mean sac size, which could represent an adaptive compensatory mechanism, was significantly greater in pregnancies from assisted reproduction compared to natural conception. We concluded that pregnancies conceived after assisted reproduction technology were different from pregnancies from natural conception in terms of the concentrations of biochemical and ultrasound markers of Down syndrome. Due to the wide variation in treatment protocols and patients’ background demographics, the exact underlying pathophysiology might be difficult to be explored. Couples undergoing assisted reproduction treatment should be counseled on the increased risk of adverse pregnancy course and perinatal outcome. / published_or_final_version / Medicine / Master / Doctor of Medicine

This study examined the effectiveness of an adaptation of Melodic Intonation Therapy (MIT) in increasing the communicative speech of young children with Down syndrome. Eight children were matched according to their mean length of utterance and divided into two groups, the melodic group and the spoken group. The same individual treatment was received by all during twelve weekly sessions, except for the manner in which target phrases were presented: spoken versus melodically intoned. Data was collected from language samples taken before and after treatment as well as from audiotapes of the children's verbal responses produced during the weekly sessions. Findings revealed greater gains for the melodic group than for the spoken group for total verbal output, length of response and production time, thereby providing evidence for the positive effect of MIT. Implications for future research were addressed and applications for implementing MIT with young children were discussed.

A forced-choice reaction time (RT) task was used to examine the efficiency of visual filtering (the inhibition of processing of irrelevant stimuli) and the concomitant ability to narrow the focus of the attentional lens in persons with Down syndrome (n = 10) and children of average intelligence (n = 13) matched for mental age (MA) (average MA = approximately 5.7 years). Conditions varied with regard to the presence or absence of distractors and their proximity to a target stimulus, and the presence or absence of a visual window within which the target stimulus was presented. Although the study yielded no significant results due to a lack of power, the mean correct reaction times (RTs) indicate that both the adults with Down syndrome and the typically developing children were less efficient at filtering close distractors as compared to far distractors or no distractors. As well, the results suggest that the presence of the visual window failed to facilitate performance in both groups. Further investigation is warranted to determine the status of visual filtering in persons with Down syndrome relative to their level of functioning at an MA level of approximately 5 years, a period that is critical in the development of attentional processes.

Down syndrome (DS), caused by an extra chromosome 21, affects 1 in 750 live births, and is characterized by cognitive impairment as well as several congenital defects. Currently, little is known about the molecular pathogenesis of DS and no direct genotype-phenotype relationship has yet been confirmed. The current screening test for DS subjects many women to undergo invasive procedures such as amniocentesis due to suboptimal sensitivity and specificity. Therefore, this study aimed to discover novel biomarkers to improve screening tests, and to discovery dysregulated molecular pathways in DS-affected fetus to better understand pathogenesis. To achieve this objective, proteomic analyses of amniotic fluid (AF) and amniotic fluid cells (amniocytes) were performed using mass spectrometry (MS), which allows discovery of a large number of proteins in complex biological samples. Since AF contains the most information of the developing fetus, we first generated the most comprehensive list of proteins present in AF by using high resolution MS. We then performed quantitative analyses of proteins from AF as well as amniocytes to reveal novel biomarkers and clues to altered molecular mechanisms of DS. Comparison between the proteome of AF from unaffected and DS-affected pregnancies allowed selection of 60 candidate biomarkers based on spectral counting. Two candidates, APP and TNC-C, were verified by immunoassays to show two-fold increase in AF from DS-pregnancies. Additionally, CPA4, MUC13, CEL, DPP4 and MMP2 were verified to be differentially expressed in trisomy 21-AF via selected reaction monitoring assays using triple-quadruple mass spectrometer. Amniocytes from DS-affected and unaffected fetuses were also quantitatively analyzed by using Stable Isotope Labelling of Amino acids in Cell culture technique. Over 4900 proteins were identified from amniocyte lysate and supernatant by LTQ-Orbitrap mass spectrometer, and 85% of these proteins were quantified based on MS/MS spectra ratios of peptides containing isotope-labelled amino acids. Proteins that consistently showed aberrant expression from affected amniocytes have been selected for further verification and molecular network analyses since they may play a role in DS pathogenesis.

Thesis (M.S.)--University of Michigan, 1964.

Thesis (M.S.)--University of Michigan, Ann Arbor, 1964. / Typescript (photocopy). Includes bibliographical references (leaves 47-50). Also issued in print.

Thèse (M.Med.Exp.) -- Université du Québec à Chicoutimi, extensionné de l'Université Laval, 1997. / Bibliogr.: f. [70]-76. Document électronique également accessible en format PDF. CaQCU