Introduction: Dento-alveolar anomalies associated with Orofacial clefts (OFCs) can present with a wide range of variation. This vast diversity makes it difficult to pinpoint their specific etiology. For instance, differentiating anomalies that arise as a consequence of the physical effects of the cleft itself or from the same biological processes that result on clefting, from those that likely occur as a sequela from the surgical repair is a challenge. One approach that can aid this differentiation is to study if first degree relatives of children with clefts whom themselves do not have an overt cleft but may carry genetic cleft risk, are more likely to present some of these anomalies. If so, the elevated risk on these seemingly unaffected relatives will indicate that the particular anomaly arises as a consequence of the molecular pathways that give rise to cleft risk rather than from the physical consequences of the cleft or the surgical repairs. Understanding the different etiological factors underlying dental anomalies within the cleft phenotypic spectrum is a fundamental step for prevention and better management of such anomalies. Amongst the most common dento-alveolar anomalies seen in children born with OFC are tooth size-arch length discrepancies and dento-alveolar shape irregularities, mostly studied in the maxillary arches. Such arch irregularities lead to moderate or severe malocclusions. It is not well known if unaffected family members (UFM) of children with clefts are also susceptible to such dento-alveolar shape irregularities and thus their etiology is not well understood. This study aims to characterize 3D variation in dento-alveolar shape as part of the cleft phenotypic spectrum in UFMs of individuals with OFCs compared to controls with no history of OFC. Methods: A total of 760 maxillary and 760 mandibular casts were digitally scanned using a NextEngine Laser scanner and digitized by two raters with 92 landmarks for maxilla and 94 landmarks for mandible, covering gingival margins and occlusal surfaces via Landmark Editor Software. A reliability of 88.15% was obtained for an interrater agreement error of less than 1mm for all landmarks obtained. 3D coordinates were extracted and registered using a Procrustes fit procedure. Procrustes residuals were analyzed via canonical variate analyses to capture differences in 3D shape between cases and controls. Of the 760 maxillary individuals attempted, 535 (Cases N=133, Controls=402) had all 92 landmarks and 688 (Cases=192, Controls496) had at least 40 landmarks in the canine to canine region. Of the 760 mandibular individuals attempted, 434 (Cases N=99, Controls=335) had all 94 landmarks and 611 (Cases=180, Controls=431) had at least 40landmarks in the canine to canine region. Thus analyses were done separately for each subsample. Results: Case-control differences were not significant (P=0.11) for overall maxillary dental arch shape. However, for the maxillary canine to canine dataset, significant differences were found (P=0.02 for raw Procrustes distance, P<0.0001 for Mahalanobis distance). Case-control differences were significant (P=0.02) for overall mandibular dental arch shape. Significant shape differences were also found for the mandibular canine to canine dataset (P=0.01 for raw Procrustes distance, P<0.0001 for Mahalanobis distance). In other words, there is better separation between cases and controls for the mandibular dataset compared to the maxillary dataset (P=0.11 for the maxillary full arch). Cases had maxillary and mandibular anterior dentitions that were overall retrusive, with anterior teeth that significantly tapered towards the incisal third with larger interproximal incisal embrasures and height to width rations that deviate from ideal ratios (i.e. width is ~70% of the height) due to an overall decrease in crown height. Also, incisal edges seem to flare outwards from the arch line when compared to controls. Moreover, case arch forms trend towards a “v” shape, resembling a Bonwill-Hawley arch shape compared to a “u” shape in the controls. Conclusions: Upper anterior, lower anterior and overall arch shape significantly differ between UFM of individuals with OFC and controls. The most significant differences were located in the maxillary and mandibular anterior dentitions, where cases were more retrusive overall with incisal edges that were tapered and flared, displaying large embrasures and tapered and flared, displayed large embrasures when compared to controls. The phenotypic differences identified in this study contribute to the understanding of the cleft phenotypic spectrum aiding future studies of cleft etiology and cleft risk prediction.

This study aimed to examine whether trigeminal nerve injury induces chronic nociceptive behaviour and central sensitization (CS) in functionally identified medullary dorsal horn (MDH) nociceptive neurons in mice, and whether CS in acute and chronic orofacial pain models and nociceptive behaviour in the chronic model are affected by systemic administration of pregabalin. Infraorbital nerve injury induced chronic facial mechanical allodynia as well as MDH CS; acute noxious tooth pulp stimulation also induced MDS CS. Systemic administration of pregabalin attenuated the nerve injury-induced allodynia as well as the MDH CS in both the chronic and acute pain models. These findings reveal that MDH CS occurs in mouse models of acute and chronic orofacial pain and that pregabalin may prove useful clinically in acute and chronic orofacial pain states.

This study aimed to examine whether trigeminal nerve injury induces chronic nociceptive behaviour and central sensitization (CS) in functionally identified medullary dorsal horn (MDH) nociceptive neurons in mice, and whether CS in acute and chronic orofacial pain models and nociceptive behaviour in the chronic model are affected by systemic administration of pregabalin. Infraorbital nerve injury induced chronic facial mechanical allodynia as well as MDH CS; acute noxious tooth pulp stimulation also induced MDS CS. Systemic administration of pregabalin attenuated the nerve injury-induced allodynia as well as the MDH CS in both the chronic and acute pain models. These findings reveal that MDH CS occurs in mouse models of acute and chronic orofacial pain and that pregabalin may prove useful clinically in acute and chronic orofacial pain states.

Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 160-170) Also available in print.

Thesis (M.S.)--University of Michigan, 2003. / Includes bibliographical references.

Thesis (M.S.)--University of Kentucky, 2004. / Title from document title page (viewed January 7, 2005). Document formatted into pages; contains: viii, 71p. : ill. Includes abstract and vita. Includes bibliographical references (p. 58-70).

Thesis (doctoral)--Göttingen, 1933.

Thesis (doctoral)--Göttingen, 1933.

Resumo: A neuralgia trigeminal (NT) é um exemplo de uma forma de dor neuropática limitada à região orofacial inervada pelo nervo trigêmeo e é relativamente menos estudada e compreendida que outras formas de dor neuropática. Nestas outras formas de dor neuropática já é bastante conhecido que a ativação do sistema imune exerce um papel crucial em ambos os processos sensoriais anormais, periférico e central, durante o estado de dor neuropática. Entre as citocinas pró-inflamatórias, o fator de necrose tumoral ? (TNF-?) é considerado um fator importante na iniciação da cascata de ativação de citocinas e iniciação da dor neuropática de maneira geral. No entanto, não existem estudos que avaliem com detalhes a participação desta citocina na dor neuropática trigeminal. O objetivo desse trabalho foi avaliar o envolvimento do TNF-? na hiperalgesia térmica e mecânica orofacial induzida pela constrição crônica do nervo infraorbital (CNIO), um modelo de dor neuropática na região orofacial, utilizando o etanercept (Eta), um anticorpo quimérico que bloqueia a ação do TNF-?. Para efeitos comparativos, foi avaliado o efeito deste anticorpo sobre a hiperalgesia térmica e mecânica inflamatória induzida pela carragenina (Cg, 50 e 100 ?g/sítio) administrada no lábio superior dos mesmos. Os animais foram tratados com Eta (0,5 e 5,0 mg/kg, s.c.) ou com Dexametasona (Dex, 0,5; 1,0 e 2,0 mg/kg, s.c.) em diferentes esquemas terapêuticos. O tratamento dos animais com Eta (0,5 e 5,0 mg/kg) e Dex (1,0 mg/kg) 1h e 2h antes da administração de Cg, respectivamente, aboliu a hiperalgesia térmica e mecânica inflamatória. Da mesma forma, o tratamento sistêmico de ambas as drogas no dia da cirurgia e no dia subsequente (dias 0 e 1) foi efetivo em abolir a hiperalgesia ao calor e frio observada 4 dias após a CNIO. De maneira similar, ambos os tratamentos administrados no dia da cirurgia e nos 2 dias subsequentes (dia 0, 1 e 2) foram efetivos em reduzir a hiperalgesia mecânica induzida pela CNIO avaliada nos dias 10 e 13 após a cirurgia. Entretanto, diferente da Dex, o Eta administrado nos dias 2, 3 e 4 ou dias 10, 11 e 12 após a CION aboliu a hiperalgesia térmica (frio e calor) e mecânica, respectivamente. Esses resultados sugerem que o TNF-? tem um papel importante na hiperalgesia térmica e mecânica induzida por inflamação ou neuropatia na região orofacial. No caso da dor neuropática trigeminal esta participação parece ser importante não somente na fase inicial, mas também para a manutenção da hiperalgesia térmica e mecânica. Estes dados podem contribuir para o estabelecimento de novas estratégias terapêuticas para controlar a dor orofacial, especialmente a NT.

Resumo