No description available.

An excess of males among the mentally retarded has been noted in practically all surveys of a mentally retarded population. It has been hypothesized that X-linked genes may account for this excess. The main purpose of this study was to test the hypothesis using data on the mentally retarded in British Columbia. A second purpose was to calculate the frequency of non-specific X-linked mental retardation in the population. In addition, an attempt was made to delineate clinical types of X-linked mental retardation. Data on the mentally retarded in British Columbia were obtained from the B.C. Health Surveillance Registry. The Registry also provided information on sibships with two or more sibs affected with non-specific mental retardation. Family histories on sibships with two or more affected males were obtained from the Department of Medical Genetics, institutions for the mentally retarded, namely Woodlands School and Tranquille, and in some cases personal interviews. The number of mothers in British Columbia giving birth to two or more sons in a defined birth cohort was retrieved from the linked family records of the B.C. Record Linkage Project. Families with a pattern of X-linked inheritance for non-specific mental retardation were ascertained while family histories on sibships with two or more affected males were being recorded and by reviewing files of other non-specific mentally retarded males in the Department of Medical Genetics, Woodlands School and Tranquille. Clinical and psychological characteristics of the mental retardation in males from these families were obtained from medical files from the same sources. Among the mentally retarded in British Columbia, there is an overall 28.2% excess of males. The extent of this excess is similar to that observed in other studies. This excess of males is seen at all levels of retardation except at the profound level. Mental retardation of known causes does not significantly contribute to the excess, which is due primarily to nonspecific mental retardation. Non-specific mental retardation in two or more sibs may be genetic in origin. Data from sibships with both males and females affected do not support an hypothesis of multifactorial inheritance with specific sex thresholds accounting for the excess of mentally retarded males. A ratio of 3.1:1 of sibships with two or more affected males to sibships with two or more affected females suggests that X-linked inheritance may account for the excess of male affected sibships. Family history data on sibships with two or more affected males provide evidence that X-linked genes can account for the excess of male affected sibships. A minimum frequency of 1.83 per 1,000 males for X-linked mental retardation in the population of British Columbia was calculated using sibship data. This frequency can account for the entire excess of non-specific mentally retarded males in the province. Mental retardation inherited in an X-linked pattern may be due to either single genes on the X chromosome or autosomal dominant genes with sex-limited expression. Distinguishing between the two types of genes was not possible in the present study. Specific clinical subtypes of X-linked mental retardation could not be differentiated due to a large amount of variability which was found not only in the level of retardation but also in associated psychological, neurological and physical characteristics. Although further clinical, biochemical and cytogenetic investigations of affected males in families with X-linked mental retardation may elucidate subtypes of non-specific mental retardation, variabiliy in phenotypic expression has been identified as an important feature of X-linked mental retardation. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

A form of familial sex-linked mental retardation has been associated with the expression of a fragile site near the terminal end of the long arm of the X chromosome. Previous reports on the fragile X chromosome showed expression of the fragile site to be limited to chromosome preparations from peripheral blood lymphocytes of mentally retarded males and their female relatives in families in which the disorder was segregating. Fragile site expression has also been shown to be a function of the medium employed in cell culture. The fragile X chromosome could only be demonstrated in lymphocytes cultured in medium 199 or media deprived of folic acid. This study was undertaken to develop a method for demonstrating the fragile X chromosome in cultured skin fibroblasts. Fibroblast cell lines from five patients (two mentally retarded males, two obligate carrier females, and a potential carrier female) from a family in which familial sex-linked mental retardation was known to be segregating were established and routinely maintained in a complete culture medium. Forty-three hours prior to chromosome harvest, cells from each patient were transferred to media deficient in folic acid. Under conditions of folic acid deprivation, it was possible to elicit expression of the fragile X chromosome in skin fibroblasts from all five patients studied. No fragile X chromosomes were detected in fibroblasts from three normal control subjects. In a preliminary assessment of the reliability of the fibroblast method, three patients (two mentally retarded males and a potential carrier female) from a second unrelated family in which the disorder is known to be segregating were studied with this method. The fragile X chromosome could be demonstrated in fibroblasts from both of the retarded male patients but could not be. demonstrated in fibroblast chromosome preparations from the potential carrier female. Lymphocytes for all patients studied were grown under similar folate deprived conditions for the purpose of comparing the effectiveness of fibroblast culture with lymphocyte culture in demonstrating the expression of the fragile X chromosome. Neither tissue was shown to consistently provide a higher frequency of expression of the fragile X chromosome. In addition to folate deprivation, it was shown that two other features of the fibroblast method influenced the frequency of expression of the fragile X chromosome. The fragile site was expressed at a significantly higher frequency in chromosome preparations in which the chromosomes were not severely contracted. The frequency of expression in fibroblasts was also shown to be significantly higher with a hypotonic treatment at chromosome harvest using 1% NaCitrate rather than 0.075M KC1. Because fragile site expression was shown to be a function of the degree of chromosome condensation, two agents, 5-BrdU and actinomycin-D, were studied to examine their decondensation effects on the frequency of expression. Neither BrdU nor actinomycin D proved effective in accentuating the frequency of expression. Since fibroblasts behave much like amniocytes in terms of cell culture and chromosome harvest, the development of a method for demonstrating the fragile X chromosome in cultured skin fibroblasts is a step toward the prospect of reliable antenatal diagnosis of familial sex-linked mental retardation associated with a fragile X chromosome. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

No description available.

Development of the rodent somatosensory cortex is well characterised and involves activity-dependent mechanisms that occur during the first postnatal week. Glutamate is a key neurotransmitter responsible for signalling events that result in formation of cortical barrels - aggregates of cells in the cortex corresponding to whiskers on the face pad. The molecular mechanisms that occur downstream of glutamate signalling are not fully understood and data here contributes to the unveiling of some of these mechanisms. Transgenic mice with deletions of genes that encode members of the post-synaptic complex associated with NMDARs were used to understand the role of individual genes in the formation of barrels. SynGAP, a ras GTPase activating protein (GAP) that negatively regulates the ERK-MAPK pathway downstream of NMDARs is required for the formation of barrels and data here agrees with other findings that the ras GAP NF1 has a similar role. Examination of RICS, a RhoGAP and Dusp6 - a phosphatase that inactivates ERK reveals that neither are necessary for the formation of barrels. This finding adds to previous data postulating that barrels form in an ERK-independent manner (Watson et al., 2006, Barnett et al., 2006). MAGUKs are important scaffolding molecules in the PSD and bind NMDARs to downstream signalling molecules such as SynGAP. Two of these MAGUKs SAP102 and PSD-95 have roles in hippocampal plasticity, and learning and memory and Sap102 mutations result in a form of X-linked human retardation (Tarpey et al., 2004). Deletion of either gene does not cause defects in the development of barrels, perhaps due to compensation mechanisms already described in hippocampus (Vickers et al., 2006 Cuthbert et al., 2007). Double knockout mice die by P3 and analysis of all other mutants revealed a defect in the formation of barrels and segregation of TCAs in Sap102-/y Psd-95+/-. Surprisingly this defect was not seen in Sap102+/- Psd-95-/- mice, agreeing with previous findings that SAP102 is better able to compensate for loss of PSD-95 (is up-regulated) than PSD-95 is for SAP102. An explanation for this effect may lie with the fact that Sap102 is X-linked and therefore females that are heterozygote for Sap102 are mosaic with a population of cells expressing SAP102 and a population not expressing SAP102. Using β-Galactosidase antibody to label one population of cells, female mice that had two populations of cells were examined. In these mice one population of cells were Sap102-Psd-95+/-, and did not previously segregate into normal barrels and the other population were Sap102+Psd-95+/- and should segregate normally. Both populations of cells segregated normally, indicating that the cells expressing SAP102 were rescuing the cells not expressing SAP102 by a cell non-autonomous mechanism. The final part of this thesis focuses on the role of glutamate-dependent signalling pathways in the regulation of CSPGs- key extracellular matrix proteoglycans that regulate the termination of the sensitive period. Analysis of 3 overlapping but distinct subsets of chondroitin-sulphate proteoglycans (CSPGs) reveals that expression of each of the three is different throughout development. After 2-3 weeks perineuronal nets (PNNs) labelled with Cat-315 and Cat-316 are visible and locate to specific regions within the cortical barrel-field. To determine whether the formation of PNNs is regulated by proteins involved in glutamate signalling, expression of the three CSPG subsets was analysed in mice with barrel defects due to mutations of Plcβ1, Mglur5, Syngap and Prkar2b. Interestingly, Prkar2b mutant adults but no other mutants have reduced Cat-315-PNNs, indicating that PKARIIβ regulates pathways that lead to formation of Cat-315-PNNs in adulthood. Cat-315 has previously been found to be regulated in the cortex of visually deprived cats and the cortex of whisker-trimmed mice, indicating that specific subsets of CSPGs are regulated by neuronal activity. Molecular pathways that lead to expression of Cat-315 positive PNNs involve PKARIIβ and the formation of PNNs may be an important step in the plasticity of circuits in barrels. Taken together, these results demonstrate that an important part of molecular signalling downstream of glutamate enabling barrels to form is played by molecules that maintain structure inside the synapse and outside the cell.

published_or_final_version / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

Growth retardation in King salmon Oncorhynchus tshawytscha (Walbaum) is a common and significant problem affecting marine farming operations in New Zealand. While the basic marine culture requirements for the King salmon species are well understood, the etiology of seawater adaptation and growth retardation remains understudied. Consequently, this study was established to investigate the physiological state and causative factors of growth retardation in collaboration with a leading New Zealand aquaculture company, New Zealand King Salmon Ltd (NZKS). Hypoosmoregulatory indicators are not currently used by marine farmers in New Zealand due to the belief that King salmon are more adaptable to seawater than their more highly cultured counterparts, Coho and Atlantic, and can be transferred to seawater anytime after a critical weight is achieved. This study sought to investigate changes in hypoosmoregulatory ability and its relation to water temperatures commonly used in the hatchery environment. This was determined by changes in the activity of the predominating seawater-adapting gill enzyme Na+/K+-ATPase, as an indirect measure of its abundance during smoltification. Changes in plasma ion profiles and the ability to regulate ions after abrupt transfer were also measured and compared with enzymatic activity throughout the austral springtime smoltification period in commercial strains of under-yearling King salmon. It was found that King salmon do undergo a distinct austral spring-time temporal increase in hypoosmoregulatory processes. This was characterised by a 2-fold increase Na+/K+-ATPase activity which was concomitant with reduced plasma Na+ in freshwater and following a seawater challenge in fish between fork lengths of 140-160 mm. Despite no consistent reduction in Na±/K+-ATPase activity during desmoltification, it was shown that the percent of ATP dependent activity specific to Na+/K+-ATPase diminished over time. Increased residual ATP dependent activity is hypothesised to be a result of apical H+-VATPase activity as a compensatory mechanism to rapidly normalise plasma Na+ during desmoltification concomitant with elevated basolateral Na+/K+-ATPase. Water temperature has been linked with the advancement and shortening of the smoltification period in several species. Gill Na+/K+-ATPase activity and hypoosmoregulatory ability in King salmon were negatively affected by increasing water temperatures above 12°C in contrast to a constant 12°C. The level of growth retardation was dependent on the time of transfer to seawater and was found to increase during a period of reducing hypoosmoregulatory ability. The transfer of growth retarded King salmon back to freshwater resulted in a complete reversal of the growth retarded state, comparable to that observed in Coho and Atlantic salmon. Growth retarded fish were able to readapt back to freshwater with higher survival and growth rates compared to the transfer of normal growing sub-adult King salmon, strongly demonstrating that growth retarded fish are more adapted to freshwater. Osmoregulatory physiology, and endocrinology during the transfer of growth retarded and normal growing fish were investigated. Overall, these results have fundamental implications for the aquaculture of King salmon that are able to be applied by industry to improve current husbandry practices.

The purpose of this study was to determine the prevalence of known etiological factors in mildly mentally handicapped students across minority and nonminority groups and to examine the similarities of these patterns. A comparison of early diagnoses was also made. The total population of all children labeled Educable Mentally Handicapped (EMH) and attending regular elementary schools within one of the largest districts in the southwest served as the sample for the present study. There were 128 children, 64 minorities and 64 nonminorities. The student records were reviewed for data regarding etiological factors, previous diagnoses and early medical factors. A pilot study which involved administering a questionnaire to a sample to twenty-eight social workers was conducted to ascertain the validity of obtained data. Eight specific hypotheses were addressed. A Chi-Square analysis yielded information about the patterns of category similarities (congenital, prenatal, perinatal, postnatal and familial), between two groups as well as the presence of professional diagnosis. A set of five factorial analysis of variance were performed to examine the impact of age, number of symptoms, presence of professional diagnosis and length of hospital stay on IQ scores of children in both groups. A discriminant function analysis was performed to determine the discriminatory power of four variables (IQ, length of hospital stay, number of symptoms and presence of professional diagnosis). The prevalence of perinatal and postnatal symptoms and diagnoses occurred with high frequency for both groups. Congenital factors occurred significantly more for the nonminority group. The findings indicated that there were no significant differences across minority and nonminority groups in terms of intellectual functioning due to the impact of the four previously mentioned variables. Consistent with the ANOVA results, the information obtained from the discriminant function analysis suggests similarity of the two groups in terms of the four variables. The results were discussed in relation to the utility of early etiological information and the importance of such research. The implications of such findings for placement of children in general in these classes or for the children from minority groups in particular, were emphasized.

It is a terrible shock to parents when they hear from a medical specialist that their child is not normal like other children, bUt retarded. Such parents are traumatized to the same extent as other parents may be when they lose a child to death. They go through the same phases of shock, denial, anger and mourning. A complicating factor is that these parents cannot recover from this loss as they are reminded of this sorrowful fact on a daily basis and to an increasingly difficult level. The aim of this investigation is firstly to determine the effect that severely retarded child has on the functioning of the family. Secondly, to determine what the needs of such a family are in respect of pastoral care; and finally, to provide guidelines for the care of a family with a severely retarded child. This research Is based on the practical-theological model of Zerfass and comprises: • A basis-theory that reveals Biblical perspectives that have been researched about the topic; • A meta-theoretical assessment based on the literature survey (also in related fields), as well as empirical research. The empirical study Is based on a number of interviews that were undertaken with families who have severely retarded children; • Theory for application that proposes guidelines for the pastoral care of the family with a severely retarded child in their care. The research resuits reveal lacunas that exist in available literature in respect of pastoral care for families with a severely retarded child. It is also clear from the resuits of the empirical research that ignorance about this type of pastoral care is common. The conclusion of this research is that these families who have severely retarded children do not enjoy the benefit of proper pastoral care. This happens because both pastoral care-givers as well as members of the parish underestimate the influence that such a child has on the family. The research results could assist in educating people who are, to a large extent, Ignorant in this regard; as wen as equipping pastoral care-givers with guidelines to care for families with severely retarded children. / Thesis (Ph.D. (Practical Theology))--North-West University, Potchefstroom Campus, 2007.

The purpose of this study is to add to the body of knowledge concerning intelligence, self-concept, and social competency as related to the habilitation of retardates by investigating the following problem: what is the relationship between intelligence, self-concept, and social competency among the mentally retarded?