No description available.

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

A forced-choice reaction time (RT) task was used to examine the relations between covert orienting (shifts of visual attention independent of eye movement) and filtering (the inhibition of processing of irrelevant stimuli) components of attention in persons with Down syndrome (n = 17) and children of average intelligence (n = 17) matched for mental age (MA), (MA = approximately 5 years). Conditions varied with regard to presence or absence of distractors, and the validity (valid, invalid, or neutral) of location cues. RT/p(correct) scores of both groups were longer in distractor-present conditions and in conditions when the location cue provided incorrect information (invalid cue). In addition, RT/p(correct) scores of both groups were longer when it was necessary to simultaneously search for a target and filter out irrelevant information, than when each of these attention demanding tasks was utilized separately. However, there were no differences in performance between persons with Down syndrome and MA matched children of average intelligence. This evidence is used to challenge the notion of an overall deficit in selective attention abilities in persons with Down syndrome as compared to MA matched children of average intelligence. Findings are also discussed in terms of their support for a capacity sharing relationship between covert orienting and filtering.

This study investigated friendship formations of two girls with Down Syndrome who were integrated into a unit of 34 ten and eleven-year-old girls at a residential summer camp. While acting as participant observer, in the role of co-counsellor, I recorded behavioural observations and informal interviews in a journal, friendship log and personal log. A quantitative data analysis investigated the frequency with which campers elected to be with these two girls, as well as the number of campers who chose them as their best friends, as preferred bunkmates for next year and as those with whom they would want to keep in touch. A qualitative data analysis investigated the comments made by campers and counsellors concerning the program and the two girls of interest to this study. Results indicated that these two girls formed friendships during this month-long program. Limitations of this investigation are considered and some suggestions for further research are explored.

The goal of this study was to examine theory of mind and deliberate rule use in children with Down syndrome as compared to children of normal intelligence. Theory of mind was defined as the ability to understand that other people have thoughts, beliefs and desires. Deliberate rule use was considered to be the extent to which children were able to learn and subsequently switch between a set of ad hoc rules unrelated to mental states. Participants included 10 individuals with Down syndrome and 10 individuals of normal intelligence matched for mental age. The primary finding of this study was that individuals with Down syndrome do not possess a theory of mind at a mental age of 5 years. Furthermore, individuals with Down syndrome possess domain specific knowledge of embedded rules, whereas, individuals with normal intelligence apply an embedded rule structure that effects mental and non-mental state tasks equally. The embedded rule use of individuals with Down syndrome was characterized by: (a) an inability to effectively use embedded rules in theory of mind and deductive card sort tasks; and, (b) the ability to use embedded rules in a task assessing physical causality.

Persons with Down syndrome and MA matched typically developing children were tested on two measures each of hot and cool executive function (EF). Tasks were selected to be developmentally appropriate for mental ages between 3 and 6 years. Participants with Down syndrome performed at the same level as verbal mental age (VMA, M = 47.53 months) matched typically developing children on the Children's Gambling Task (Kerr & Zelazo, 2001), a delay of gratification task (Thompson, Barresi, & Moore, 1997) the Dimensional Change Card Sort (DCCS; Frye, Zelazo, & Palfai, 1995), and the Self-Ordered Pointing task (Petrides & Milner, 1982), but showed a disadvantage on the DCCS, a cool EF task, when matched on performance mental age (PMA, M = 58.34 months). These results reflect the complex cognitive profiles of persons with Down syndrome and highlight the need for more precise matching procedures.

Several studies claim to have demonstrated an increased frequency of Down syndrome (DS) dermatoglyphics and other DS characteristics in parents of DS children, which could be explained by unrecognized parental mosaicism for trisomy 21. The goal of this study was to test the following hypothesis: In some cases of DS the cause will be parental gonadal mosaicism for trisomy 21. These parents will also be mosaic in tissues other than the gonads and will therefore have quantitative deviations in the direction of the DS phenotype. Upon examination of such traits in 162 parents with one DS child it was found that 22 parents had dermatoglyphic characteristics within the DS distribution of the Preus diagnostic index (no significant increase), 6 had DS quantitative phenotypic traits, and 1 had both. There was no evidence of bimodality in the distribution of these traits, or of a correlation between these traits with one another or with the Preus dermatoglyphic index for DS. There were no trisomy 21 cells in 200 lymphoblast cells counted for each of the 5 subjects with the most DS-like dermatoglyphic characteristics. The one subject who has both DS dermatoglyphics and a trend toward DS phenotype had 1/300 trisomy 21 cells in lymphoblast culture and 0/100 cells in fibroblast culture. Neither these data nor these from the literature, provide support for the suggestion that parental mosaicism for trisomy 21 is associated with an increase in DS-like physical characteristics.

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.