Copies of author's previously published works inserted. / Bibliography: leaves 195-222. / x, 222, [46] leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to identify genes involved in craniosynostosis and to characterize mutations of these genes. / Thesis (Ph.D.)--University of Adelaide, Dept. of Paediatrics, 1998

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Master / Master of Philosophy

No description available.

No description available.

No description available.

Dissertation (PhD)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: Introduction: Fetal alcohol syndrome (FAS) consists of multi-system abnormalities and is caused by the excessive intake of alcohol during pregnancy. The teratogenic effect of alcohol on the human fetus has now been established beyond reasonable doubt and FAS is the most important human teratogenic condition known today. The syndrome, first described by Lemoine in1968 in the French literature and in the English literature by Jones and Smith in 1973, has since been corroborated by numerous animal and human studies. This study has grown out of several epidemiological, prenatal and infant studies in areas of the Western Cape that are currently being undertaken by the Foundation for Alcohol Related Research (FARR). Preliminary data from studies in Wellington have confirmed that a significant proportion of school-entry children have FAS. The prevalence ofF AS in this community exceeds that for Down syndrome by a factor of30 times. The frequency ofFAS in high-risk populations of the Western Cape is the highest reported anywhere in the world. With this background, and the paucity of FAS literature related to dentistry, the aim of this study was to determine the craniofacial and oral manifestations ofF AS in a sample of school-going children in the Western Cape. Methodology: This study is a descriptive, case-control, cross-sectional study using a random cluster sampling method. On the day of examination, children were weighed, and their height and head circumference were measured. They then had photographs and radiographs taken, followed by an oral examination. For each child, the following information was recorded on the data capture sheet: date of birth, gender, head circumference, weight and height, enamel opacities, dental fluorosis, plaque index, gingival bleeding index, dentition status, oral mucosal lesions and dentofacial anomalies. Results: The total sample of90 children with diagnosed FAS and 90 controls, were matched for age, gender and social class. There were no significant age differences between the two groups (p=0.3363) and the mean ages were 8.9 and 9.1 for the FAS and control groups respectively. Head circumference (HC) differed significantly between the two groups (p<O.OOO 1) and the three photographic diagnostic measurements were all influenced by head circumference. The prevalence of enamel opacities between FAS and controls was not significantly different and averaged around 15% for both groups. The opacities were found largely in the maxillary central incisor and lower first molar teeth. More than three quarters of both the cases and the controls demonstrated the presence of plaque and almost two thirds demonstrated gingival bleeding on probing. FAS patients had statistically significantly (p<O.OO 1) more dentofacial anomalies than the controls. The mean dmft score for the FAS sample was slightly higher, though not significantly different from that of the controls and the decayed component (d) made up the largest part of the index in both groups. None of the FAS children had any missing or filled teeth, and in the case of the controls these were also rarely found. Thirty nine children (21.67%) of the total sample were caries-free. Discussion: This study represents one of the largest sample sizes documenting the craniofacial and oral and dental manifestations of the FAS to date. Forty two per cent of the FAS sample manifested growth retardation and this was statistically significant (p<O.OOOl) when compared to their controls. Analysis of the face using anthropometry supports many of the previous clinical descriptions of the effects of neonatal alcohol exposure and offers some new perspectives on the FAS facial phenotype. The characteristic dysmorphic facial features found included ptosis of the upper eyelids, epicanthic folds, short upturned nose, thin vermillion border of the upper lip and a smooth philtrum. Overall the analysis of the caries data for this study in respect of differences between cases and controls was found to be unremarkable. The lack of difference in the primary and permanent dentitions between the cases and controls could have been anticipated in this population due to the high prevalence of dental caries among children from the Western Cape. The FAS children showed significantly lower dental ages when compared to the controls. Dental maturation has previously been shown to be mildly, but consistently, delayed in children with delayed development and therefore this is a not surprising finding for the FAS children in this study. Differences between skeletal age and chronological age were noted for both boys and girls, but as a whole, in the present study groups (FAS and controls) showed little variation in skeletal development. Measurements related to the face height and mandibular size appear to be the most important in distinguishing the FAS children from the controls. Most (5 out of8) of the discriminating linear measurements studied lie in the front of the skull area. Most of the discriminating measurements are vertical measurements and only two of the measurements are lines between soft tissue points. When comparing the photographic analyses of the facial features versus the cephalometric assessments; the four facial features most typical of aF AS child had a Positive Predictive Value (PPV) of92% and a Negative Predictive Value (NPV) of90% and the eight linear measurements from the cephalometric analyses had a PPV of 92% and a NPV of 95%. One can therefore conclude that the external facial features are probably more reliable in discriminating between the two groups than the cephalometric measures. For further analyses, other models where a single angular measurement explains a combination of linear measurements need to be investigated. This might further improve the discriminating abilities of the cephalometric measurements as a whole. Conclusions: This study has shown the importance of the oral and craniofacial features ofFAS. FAS can no longer be viewed as just a rare and peculiar childhood disorder. Awareness and recognition of children with FAS is important so that they can be correctly diagnosed and referred appropriately. Prevention of the secondary disabilities and most importantly, the prevention of FAS in subsequent programmes can be planned. The dentist who treats children with FAS must recognise that such patients might be emotionally and mentally handicapped and may make treatment difficult and there may be a need for the child to be treated with behaviour modification and/or premedication before restorative treatment. The dentist should also be aware of the need for an accurate medical history, and possible medical consultations, before treatment can be undertaken safely. / AFRIKAANSE OPSOMMING: Fetale alkoholsindroom (FAS) bestaan uit multisisteem abnormaliteite en word veroorsaak deur oormatige inname van alkohol tydens swangerskap. Die teratogeniese uitwerking van alkoholop die menslike fetus word nie meer betwyfel nie en FAS is die belangrikste menslike teratogeniese toestand tans bekend. Die sindroom, soos aanvanklik deur Jones en Smith in 1973 beskryf, is sedertdien deur vele studies op mens en dier bevestig. Hierdie studie het gegroei uit vele epidemiologiese-, prenatale- en kleuterstudies in dele van die Weskaap wat tans onderneem word deur die Stigting vir Alkoholverwante Navorsing. Voorlopige data van die studies in Wellington bevestig dat 'n betekenisvolle deel van skoolbeginners FAS het. Die prevalensie van FAS in hierdie gemeenskap oortref dié van Down se sindroom met 'n faktor van 30. Die frekwensie van FAS in die Weskaap is die hoogste wat in die wêreld gerapporteer is. Met hierdie agtergrond, en die skaarste aan FAS literatuur wat op tandheelkunde betrekking het, was die doel van hierdie studie om die kraniofasiale en mondmanifestasies van fetale alkoholsindroom in 'n monster van skoolkinders in die Weskaap te ondersoek. Metodologie: Hierdie studie was 'n beskrywende, gevallebeheerde deursneestudie waarin 'n lukrake gebondelde monstermetode gebruik is. Op die dag van die ondersoek is die kinders geweeg en hulle lengte en kopomtrek bepaal. Hierna is foto's en x-straalopnames geneem, gevolg deur 'n mondondersoek. Die volgende inligting is vir elke kind aangeteken: geboortedatum, geslag, kopomtrek, massa en lengte, glasuur-opasiteite, tandfluorose, plaakindeks, gingivale bloedingsindeks, gebitstatus, mukosale letsels en dentofasiale anomalieë. Resultate: Die totale monster, bestaande uit 90 kinders met gediagnoseerde fetale alkoholsindroom en 90 bypassende kontroles, is vergelyk ten opsigte van ouderdom, geslag en sosiale klas. Daar was geen betekenisvolle ouderdomsverskille tussen die twee groepe nie (p- =0.3363). Kopomtrek het betekenisvol tussen die twee groepe verskil (p<0.0001), en die drie fotografiese diagnostiese afmetings is almal beïnvloed deur kopomtrek. Die prevalensie van glasuur-opasiteite tussen die FAS- en kontrolegroep was nie betekenisvol nie en het rondom 15% vir beide gewissel. Die opasiteite is hoofsaaklik gesien in maksillêre sentrale snytande en mandibulêre eerste molare. Meer as driekwart van beide groepe het plaak getoon, en byna tweederdes het gingivale bloeding met sondering gehad. Die gevallegroep het statisties betekenisvol meer (p<O.OO1) dentofasiale anomalieë getoon. Die gemiddelde dmft telling vir die FAS groep was effens hoër, alhoewel nie betekenisvol nie, as die kontrolegroep, en die "delayed" (vertraagde erupsie) komponent (d) het die grootste deel van die indeks uitgemaak in beide groepe. Geen van die FAS kinders het enige afwesige tande (m) of hers telde tande (f) gehad nie, soos ook gevind in die kontrolegroep. Nege-en-dertig kinders (21.67%) van die totale monster was kariesvry. Bespreking: Hierdie studie verteenwoordig een van die grootste monstergroottes tot op datum waarin ondersoek ingestel is na die kraniofasiale en mond- en tandmanifestasies van die fetale alkoholsindroom. Twee-en-veertig persent van die FAS monster het vertraagde groei getoon en dit was statisties-betekenisvol (p<O.OOOl)vergeleke met die kontrolegroep. Antropometriese analise van die gesig steun die vele kliniese beskrywings van neonatale blootstelling aan alkohol, en bied ook nuwe perspektiewe op die FAS gesigsfenotipe. Die kenmerkende dismorfiese gesigseienskappe wat gevind word, sluit ptose van die boonste ooglede, epikantusvoue, kort opgedraaide neus, dun vermiljoen rand van die bolip en 'n gladde filtrum in. In die geheel was die analise van die karies data ten opsigte van verskille tussen gevalle en kontroles onopvallend. Die afwesigheid van 'n verskil in die primêre en sekondêre gebitte in die gevalle en kontroles kon in hierdie bevolking verwag gewees het as gevolg van die hoë voorkoms van tandkaries onder kinders in die Weskaap. Die FAS kinders het betekenisvol-laer gebitouderdomme gehad as die kontrolegroep. Gebitmaturasie is in geringe maar deurlopende mate vertraag in kinders met vertraagde ontwikkelings, soos voorheen al getoon, en is daarom nie verbasend vir die FAS kinders in hierdie studie nie. Verskille tussen skeletale ouderdom en chronologiese ouderdom is gevind in beide seuns en dogters, maar in die geheel het dié huidige groepe (FAS en kontroles) min variasie in skeletale ontwikkeling getoon. Dit wil voorkom of afmetings wat verband hou met die gesigshoogte en grootte van die mandibula die belangrikste is om FAS kinders van die kontrolegroep te onderskei. Meeste (5 uit 8) van die diskriminerende lineêre afmetings wat bestudeer is, lê op die voorkant van die skedel. Die meeste is vertikale afmetings, terwyl slegs twee lyne tussen sagte weefsel punte. Waneer die fotografiese analises van die gesigseienskappe vergelyk word met die sefalometriese waarnemings, word gevind dat die vier gesigseienskappe tipies van 'n FAS kind 'n Positiewe Voorspelbare Waarde (PVW) van 92% en 'n Negatiewe Voorspelbare Waarde (NVW) van 90% het, en die agt lineêre afmetings vanaf die sefalometriese analise 'n PVW van 92% en 'n NPV van 95% het. Daar kan dus afgelei word dat die eksterne gesigseienskappe waarskynlik meer betroubaar is om te onderskei tussen die twee groepe. Vir verdere analise behoort ander modelle waar 'n enkel hoekige afmeting 'n kombinasie van lineêre afmetings verduidelik, ondersoek te word. Dit mag die diskriminerende vermoëns van sefalometriese afmetings in die geheel verder bevorder. Gevolgtrekking: Hierdie studie het die belang van orale en kraniofasiale eienskappe van FAS getoon. Die toestand kan nie langer as 'n seldsame en eienaardige aandoening van kinders beskou word nie, en bewustheid en herkenning van fetale alkoholsindroom pasiënte is belangrik sodat hulle korrek gediagnoseer en op gepaste wyse verwys kan word. Die tandarts wat FAS pasiënte behandel, moet besef dat sulke pasiënte emosioneel en geestelik belemmer mag wees en dus hantering en behandeling bemoeilik. Daar mag 'n behoefte ontstaan vir gedragsmodifikasie enlofpremedikasie voor herstellende behandeling. Verder moet die tandarts bewus wees van die behoefte aan 'n akkurate mediese geskiedenis, en moontlik konsultasie met 'n geneesheer, voor behandeling veilig ingestel kan word.

published_or_final_version / abstract / Biochemistry / Doctoral / Doctor of Philosophy

Craniosynostosis is the premature fusion of one or more cranial sutures in the developing skull. If left untreated, craniosynostosis can result in developmental delays, blindness, deafness, and other impairments resulting from an increase in the intracranial pressure. In many cases, the treatment consists of complex calvarial vault reconstruction with the hope of restoring a normal skull appearance and volume. Re-synostosis, the premature re-closure following surgery, occurs in up to 40% children who undergo surgery. If this occurs, a second surgery is needed to remove portions of the fused skull in an attempt to correct the deformities and/or relieve an increase in intracranial pressure. These subsequent surgeries are associated with an incredibly high incidence of life threatening complications. To address this unmet clinical need we have developed strategies to delay the post-operative bone growth in a clinically relevant murine model of re-synostosis. The overall objective of this thesis was to develop a hydrogel based therapy to delay rapid bone regeneration in a murine model of re-synostosis. The overall hypothesis was that delivery of key BMP inhibitors involved in regulating normal suture development and regeneration will delay the rapid bone growth that in seen in a pediatric murine model of re-synostosis. The overall approach is to use micro-computed tomography (µCT) to determine the time course of suture fusion and to identify genes associated with key developmental time points, to develop a pediatric specific mouse model that displays rapid re-synostosis, and lastly to develop a hydrogel based therapy to delay the re-synostosis of this cranial defect.

As craniossinostoses são malformações do crânio decorrentes da ausência ou do fechamento precoce de uma ou de múltiplas suturas cranianas. O tratamento tem por objetivo a correção dos defeitos estéticos e controle da pressão intracraniana. Os distratores ósseos internos são uma opção cirúrgica interessante, pois possibilitam a movimentação óssea em determinada direção, e, consequentemente, uma modificam [sic] a conformação craniana. Esta dissertação descreve o desenvolvimento de um protótipo de distrator ósseo craniano de acionamento magnético percutâneo submetido a testes de bancada. O distrator desenvolvido foi prototipado em resina, contendo as seguintes partes: o cursor, a base, o mecanismo de trava unidirecional em cremalheira e o invólucro de proteção. O sistema de ativação apresenta uma peça ferromagnética interna, um imã externo de ativação e dois parafusos de fixação. O modelo de bancada elaborado simulou as forças necessárias para a distração das placas ósseas cranianas. Os testes de bancada demonstraram que o acoplamento magnético entre o imã externo e os discos ferromagnéticos internos foi capaz de promover um deslocamento máximo de 28 mm entre as placas, equivalente a uma força de 10,88 N. O mecanismo de trava em cremalheira para deslocamento unidirecional foi eficaz ao bloquear o retrocesso do cursor e desta forma manteve a distração. / Craniosynostosis occurs as a result of the absence or premature closure of one or multiple cranial sutures. Its treatment aims at correcting the esthetic defects as well as to control the intra-cranial pressure. The use of internal bone distractors is a valuable surgical option, promoting direct bone movement, and thus modifying the skull contours. This dissertation includes the description of the development and bench testing of a magnetic calvarial bone distractor remotely activated. The distractor is made out of four parts, all prototyped using resin: the cursor, the base, the one-way locking system and the protection cap. The activation system is composed by one internal iron-magnetic plate, one external activation magnet and two fixation screws. The test bench was designed to simulate the expected forces to which the distractor should counteract. The bench testing showed that the magnetic coupling between the external magnet and the iron-magnetic plate was strong enough for the distractor to carry out a maximum 28-mm distraction, being equivalent to a 10.88 N force. The one-way locking system was efficient in preventing the distractor cursor to recede, maintaining the gap between the two plates stable.