Orofacial clefts are a group of congenital craniofacial deformities characterized by structural defects within and around the oral cavity. While some orofacial clefts are associated with an identifiable genetic or teratogenic syndrome, most are isolated or nonsyndromic. It has been well-documented that children born with nonsyndromic cleft lip and/or palate (NCL/P) are at-risk for poorer academic outcomes, especially within reading. Research into the cognitive functioning of patients with NCL/P has demonstrated that auditory-verbal memory and rapid naming are significant neuropsychological predictors of their lower reading achievement. Despite a solid compendium of research into the reading outcomes of those affected by NCL/P, very little research into the mathematical skills of this population exists. The current study examined whether the arithmetical computation skills of children, adolescents, and young adults with NCL/P differ significantly from healthy control participants. Comparisons of potential neuropsychological predictors of arithmetical computation were also conducted to determine whether these variables differ significantly for participants with NCL/P. Given the influence of language on both reading and mathematics and clear evidence of language impairments in individuals with NCL/P, it was hypothesized that arithmetical computation would be significantly lower for the NCL/P group. It was also hypothesized that the neuropsychological variables associated with lowered reading in NCL/P would be the strongest predictors of arithmetical computation. Results confirmed that arithmetical computation was significantly lower for the NCL/P group. Sustained attention, visual-spatial organization, auditory-verbal memory and rapid naming were significant predictors for the NCL/P group; rapid naming was the lone variable that was significantly more predictive of arithmetical computation for the NCL/P group than for control participants. These results suggest that inefficient verbal label retrieval related to short-term memory deficits underlie the computational difficulties of individuals with NCL/P. These findings have implications for approaches to remediation, as well as future research.

Thesis (M. Sc.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

The hedgehog morphogenic pathway is essential for the development of numerous organs and tissues in both vertebrates and invertebrates, and dysregulation of hedgehog signalling is also associated with a broad range of mammalian cancers. While a great deal of research has been dedicated to understanding the molecular interactions of the hedgehog signalling pathway itself, much work remains in understanding the downstream transcriptional output of the pathway, and how that output modulates cellular behaviour in target tissues to produce developmental outcomes. The hedgehog pathway is activated by hedgehog proteins and repressed by patched. Downstream of these regulators, the hedgehog signalling cascade involves modification and trafficking of a series of key proteins and ultimately leads to regulation of the GLI family of transcription factors, thereby modulating the transcriptional output of the pathway. This thesis builds on previous work investigating downstream targets of one GLI protein – GLI3 – in the mouse limb (McGlinn et al., 2005). This previous study identified genes that were dysregulated in the anterior limb of the Gli3-null, extra-toes strain of mice (Gli3Xt/Xt). Amongst the identified targets of GLI3 were a number of novel genes. However, further detailed analysis of these genes was not conducted, and therefore, this thesis investigates the embryonic expression or function of three of these novel downstream targets of GLI3, to clarify their regulation by the hedgehog pathway and identify their broader role throughout development. One published work and one paper submitted for publication are contained within this thesis, describing detailed expression of two novel SHH targets, Zinc finger protein 503 (Zfp503) and Pitrolysin metallopeptidase 1 (Pitrm1). Zfp503 belongs to a family of transcription factors that regulate aspects of development across a diversity of species. However, their role in mammals and avians has been poorly described. This manuscript presents a detailed description of Zfp503 expression in the mouse and chicken and examines regulation of Zfp503 in the limb by SHH and BMP signalling. My contribution to this paper was the analysis of WT Zfp503 expression in mouse and chick by section in situ hybridisation, and as such, I am listed as a middle author. Pitrm1 is a metallopeptidase with a broad range of predicted target molecules. Comparisons with family members in mammals and plants suggest Pitrm1 has mitochondrial function and is implicated in the pathology of Alzheimers disease. It is upregulated in response to hedgehog pathway activation in the anterior limb of two mouse models of hedgehog signalling– the Gli3Xt/Xt and Ptch1:Prx-Cre mouse line, which deletes patched1 in the developing limb. It is expressed in multiple developing tissues that are patterned by SHH, suggesting that Pitrm1 may be an important regulator of developmental processes downstream of SHH. For the Pitrm1 manuscript, I contributed the majority of the experimental data and prepared the manuscript, and therefore, I am the first listed author. A third downstream hedgehog target gene described in this thesis is Tmem26. Tmem26 is an entirely novel gene with unknown cellular function, although concurrent work in the Wicking laboratory suggests that Tmem26 regulates cell migration and morphology in cell culture. Tmem26 is negatively regulated by SHH in the anterior mouse limb at 11.5dpc, as shown by use of Gli3Xt/Xt and Ptch1:Prx-Cre mice. Tmem26 expression in wild-type mice is spatially restricted and strikingly evident in the facial prominences, particularly near the point of fusion of the developing lip and in the shelves of the secondary palate. This suggests that Tmem26 may be involved in lip and palate formation and possibly play a role in the common human birth disorders of cleft lip and cleft palate. Generation of a Tmem26 conditional knockout mouse line, followed by germline inactivation of Tmem26 using a ubiquitously expressed Cre line, did not reveal a craniofacial phenotype in embryos or adults. Knockout mice appear healthy and fertile with no obvious developmental defects. This does not preclude a role for Tmem26 in facial development however, as molecular redundancy may be able to compensate for Tmem26 loss in mice. Tmem26 is also expressed in cells and organs of the adult immune system and suggests an alternative possible role for Tmem26 in regulating immune function that could be further investigated using the Tmem26 conditional knockout mouse line.

No description available.

This study investigated the effect of speaking rate on aerodynamic and acoustic measures of velopharyngeal (VP) function in 27 adult speakers (14 M, 13 F). The pressure-flow method (Warren & Dubois, 1964) was used to collect aerodynamic data of /m/ and /p/ segments in the word “hamper” and the utterances “Mama made some lemon jam” (MMJ) and “Buy Bobby a puppy” (BBP). A Nasometer was used to collect nasalance scores and nasalance distance for MMJ and BBP. Measures were collected under 4 speaking rate conditions (normal, fast, slow, and slowest). Results indicated that nasal airflow and VP orifice area were unaffected by speaking rate whereas intraoral pressure decreased as speaking rate slowed. Nasalance was greater for BBP at slow speaking rates and nasalance distance (MMJ – BBP) decreased at slow rates. The data was interpreted with respect to expectations set forward in the literature on normal and disordered speech motor control.

This study investigated the effect of palate morphology and anthropometric measures of the head and face on lingual consonant target (positional) variability of twenty one adult speakers (eleven male, ten female). An electromagnetic tracking system (WAVE, NDI, Canada) was used to collect tongue movements while each speaker produced a series of VCV syllables containing a combination of consonants /t, d, s, z, ʃ, tʃ, k, g, j/ and three corner vowel /i, ɑ, u/. Distributions of x, y, and z coordinates representing maximum tongue elevation during the consonants were used to represent target variability across contexts. Palate and anthropometric measures were obtained for each participant. A correlational analysis showed that target variability of the consonants produced in the front of the mouth (e.g. alveolar and palatal) was explained, to a degree, by palate morphology. The variability of velar consonants was not explained by the structural measures.

This study investigated the effect of palate morphology and anthropometric measures of the head and face on lingual consonant target (positional) variability of twenty one adult speakers (eleven male, ten female). An electromagnetic tracking system (WAVE, NDI, Canada) was used to collect tongue movements while each speaker produced a series of VCV syllables containing a combination of consonants /t, d, s, z, ʃ, tʃ, k, g, j/ and three corner vowel /i, ɑ, u/. Distributions of x, y, and z coordinates representing maximum tongue elevation during the consonants were used to represent target variability across contexts. Palate and anthropometric measures were obtained for each participant. A correlational analysis showed that target variability of the consonants produced in the front of the mouth (e.g. alveolar and palatal) was explained, to a degree, by palate morphology. The variability of velar consonants was not explained by the structural measures.

Hoxa2 null embryos display a high incidence of cleft secondary palate which has previously been described as secondary to altered tongue development. The experiments described in this thesis demonstrate that expression of Hoxa2 does occur within the developing palate, with the highest levels appearing in the early stages of palatogenesis (E12.5 and E13.5). Increased cell proliferation was observed throughout the palate in the absence of Hoxa2, without a detectable difference in apoptosis or the ability of the shelves to fuse. In addition, the palate shelves of the null embryos failed to elevate above the tongue, suggesting a mechanism by which the increased cell proliferation results in cleft palate.<p> Numerous downstream targets of Hoxa2 were also identified in the palate (Msx1, Bmp4, Barx1, Ptx1, Six2, Lef1 and Tbx1). In all cases, Hoxa2 appears to act as a transcriptional repressor. Increases in palatal Msx1, Bmp4 and Barx1 expression have all been previously described to lead to increases in cell proliferation. Hoxa2, Ptx1, Lef1 and Tbx1 may be involved in a novel pathway that regulates proliferation in the palate. In addition, three novel gene targets were identified in the palate, Six2, Fgf8 and Htra3.<p> Together these data show that there is a direct role for Hoxa2 in regulating palate development, apparently through regulating the expression of downstream genes involved in maintaining normal cell proliferation rates.

This study investigated the effect of speaking rate on aerodynamic and acoustic measures of velopharyngeal (VP) function in 27 adult speakers (14 M, 13 F). The pressure-flow method (Warren & Dubois, 1964) was used to collect aerodynamic data of /m/ and /p/ segments in the word “hamper” and the utterances “Mama made some lemon jam” (MMJ) and “Buy Bobby a puppy” (BBP). A Nasometer was used to collect nasalance scores and nasalance distance for MMJ and BBP. Measures were collected under 4 speaking rate conditions (normal, fast, slow, and slowest). Results indicated that nasal airflow and VP orifice area were unaffected by speaking rate whereas intraoral pressure decreased as speaking rate slowed. Nasalance was greater for BBP at slow speaking rates and nasalance distance (MMJ – BBP) decreased at slow rates. The data was interpreted with respect to expectations set forward in the literature on normal and disordered speech motor control.

Hoxa2 null embryos display a high incidence of cleft secondary palate which has previously been described as secondary to altered tongue development. The experiments described in this thesis demonstrate that expression of Hoxa2 does occur within the developing palate, with the highest levels appearing in the early stages of palatogenesis (E12.5 and E13.5). Increased cell proliferation was observed throughout the palate in the absence of Hoxa2, without a detectable difference in apoptosis or the ability of the shelves to fuse. In addition, the palate shelves of the null embryos failed to elevate above the tongue, suggesting a mechanism by which the increased cell proliferation results in cleft palate.<p> Numerous downstream targets of Hoxa2 were also identified in the palate (Msx1, Bmp4, Barx1, Ptx1, Six2, Lef1 and Tbx1). In all cases, Hoxa2 appears to act as a transcriptional repressor. Increases in palatal Msx1, Bmp4 and Barx1 expression have all been previously described to lead to increases in cell proliferation. Hoxa2, Ptx1, Lef1 and Tbx1 may be involved in a novel pathway that regulates proliferation in the palate. In addition, three novel gene targets were identified in the palate, Six2, Fgf8 and Htra3.<p> Together these data show that there is a direct role for Hoxa2 in regulating palate development, apparently through regulating the expression of downstream genes involved in maintaining normal cell proliferation rates.