Browsing by Author "Starbuck, John M."

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    3D Assessment of Nasopharyngeal and Craniofacial Phenotypes in Ts65Dn Down Syndrome Mice Treated with a Dyrk1a Inhibitor
    (2014-04-11) Starbuck, John M.; Harrington, Emily; Kula, Katherine S.; Ghoneima, Ahmed A.; Roper, Randall J.
    Background: Down syndrome (DS) originates from having three copies of chromosome 21 (i.e. Trisomy 21). DS is associated with many detrimental phenotypes including intellectual disabilities, heart defects, abnormal craniofacial development, and obstructive sleep apnea, which develops from restricted nasopharyngeal airways and an underdeveloped mandible. Ts65Dn mice are trisomic for about half of the orthologs on human chromosome 21 and display many phenotypes associated with DS including craniofacial abnormalities. Dyrk1a is found in three copies in Ts65Dn mice and individuals with DS, and thought to be a root cause of the craniofacial phenotypes. Epigallocatechin 3-gallate (EGCG) is a green tea polyphenol and inhibitor of Dyrk1a activity. Purpose: We hypothesize that decreased Dyrk1a activity in Ts65Dn mice will ameliorate craniofacial dysmorphology. Methods: To test our hypothesis we compared Ts65Dn mice with two or three copies of Dyrk1a and compared Ts65Dn mice with and without prenatal EGCG treatment. EGCG treated mothers were fed 200mg/kg EGCG on gestational day 7. Six week old mice were sacrificed and their heads imaged using micro-computed tomography (μCT). From μCT images, we measured nasopharyngeal airway volume and anatomical landmarks (n = 54) from the facial skeleton, cranial vault, cranial base, and mandible. Mean nasopharyngeal airway volumes were graphically compared, and a landmark-based multivariate geometric morphometric approach known as Euclidean Distance Matrix Analysis (EDMA) was carried out to assess local differences in craniofacial morphology between trisomic mouse samples. Results: Our preliminary results indicate that EGCG treatment and reduced Dyrk1a copy number increases mean nasopharyngeal airway volume in Ts65Dn mice. Craniofacial morphometric differences were found among all samples. EGCG treatment increased portions of the mandible and decreased portions of the cranial vault and cranial base. Conclusion: Preliminary analyses suggest that both EGCG treatment and reduced Dyrk1a copy number affect craniofacial morphology.
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    3D CBCT analysis of the frontal sinus and its relationship to forensic identification
    (2014) Krus, Bianaca S.; Wilson, Jeremy John; Starbuck, John M.; Ward, Richard E.
    The positive identification of human remains that are decomposed, burnt, or otherwise disfigured can prove especially challenging in forensic anthropology, resulting in the need for specialized methods of analysis. Due to the unique morphological characteristics of the frontal sinus, a positive identification can be made in cases of unknown human remains, even when remains are highly cremated or decomposed. This study retrospectively reviews 3D CBCT images of a total of 43 Caucasian patients between the ages of 20-38 from the Indiana University School of Dentistry to quantify frontal sinus differences between adult males and females and investigate the usefulness of frontal sinus morphology for forensic identification. Digit codes with six sections and eleven-digit numbers were created to classify each individual sinus. It was shown that 3D CBCT images of the frontal sinus could be used to make a positive forensic identification. Metric measurements displayed a high degree of variability between sinuses and no two digit codes were identical. However, it was also shown that there were almost no quantifiable and significant sexually dimorphic differences between male and female frontal sinuses. This study confirms that sex determination should not be a primary goal of frontal sinus analysis and highlights the importance of creating a standard method of frontal sinus evaluation based on metric measurements.
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    Green tea extracts containing epigallocatechin-3-gallate modulate facial development in Down syndrome
    (Springer Nature, 2021-02-25) Starbuck, John M.; Llambrich, Sergi; Gonzàlez, Rubèn; Albaigès, Julia; Sarlé, Anna; Wouters, Jens; González, Alejandro; Sevillano, Xavier; Sharpe, James; De La Torre, Rafael; Dierssen, Mara; Vande Velde, Greetje; Martínez‑Abadías, Neus; Robert H. McKinney School of Law
    Trisomy of human chromosome 21 (Down syndrome, DS) alters development of multiple organ systems, including the face and underlying skeleton. Besides causing stigmata, these facial dysmorphologies can impair vital functions such as hearing, breathing, mastication, and health. To investigate the therapeutic potential of green tea extracts containing epigallocatechin-3-gallate (GTE-EGCG) for alleviating facial dysmorphologies associated with DS, we performed an experimental study with continued pre- and postnatal treatment with two doses of GTE-EGCG supplementation in a mouse model of DS, and an observational study of children with DS whose parents administered EGCG as a green tea supplement. We evaluated the effect of high (100 mg/kg/day) or low doses (30 mg/kg/day) of GTE-EGCG, administered from embryonic day 9 to post-natal day 29, on the facial skeletal development in the Ts65Dn mouse model. In a cross-sectional observational study, we assessed the facial shape in DS and evaluated the effects of self-medication with green tea extracts in children from 0 to 18 years old. The main outcomes are 3D quantitative morphometric measures of the face, acquired either with micro-computed tomography (animal study) or photogrammetry (human study). The lowest experimentally tested GTE-EGCG dose improved the facial skeleton morphology in a mouse model of DS. In humans, GTE-EGCG supplementation was associated with reduced facial dysmorphology in children with DS when treatment was administered during the first 3 years of life. However, higher GTE-EGCG dosing disrupted normal development and increased facial dysmorphology in both trisomic and euploid mice. We conclude that GTE-EGCG modulates facial development with dose-dependent effects. Considering the potentially detrimental effects observed in mice, the therapeutic relevance of controlled GTE-EGCG administration towards reducing facial dysmorphology in young children with Down syndrome has yet to be confirmed by clinical studies.
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    Influence of prenatal EGCG treatment and Dyrk1a dosage reduction on craniofacial features associated with Down syndrome
    (Oxford Academic, 2016-11-15) McElyea, Samantha D.; Starbuck, John M.; Tumbleson-Brink, Danika M.; Harrington, Emily; Blazek, Joshua D.; Ghoneima, Ahmed; Kula, Katherine; Roper, Randall J.; Biology, School of Science
    Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene–phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.
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    Nasal Airway and Septal Variation in Unilateral and Bilateral Cleft Lip and Palate
    (Wiley, 2014-10) Starbuck, John M.; Friel, Michael T.; Ghoneima, Ahmed; Flores, Roberto L.; Tholpady, Sunil; Kula, Katherine; Department of Orthodontics and Oral Facial Genetics, School of Dentistry
    Cleft lip and palate (CLP) affects the dentoalveolar and nasolabial facial regions. Internal and external nasal dysmorphology may persist in individuals born with CLP despite surgical interventions. 7–18 year old individuals born with unilateral and bilateral CLP (n = 50) were retrospectively assessed using cone beam computed tomography. Anterior, middle, and posterior nasal airway volumes were measured on each facial side. Septal deviation was measured at the anterior and posterior nasal spine, and the midpoint between these two locations. Data were evaluated using principal components analysis (PCA), multivariate analysis of variance (MANOVA), and post-hoc ANOVA tests. PCA results show partial separation in high dimensional space along PC1 (48.5% variance) based on age groups and partial separation along PC2 (29.8% variance) based on CLP type and septal deviation patterns. MANOVA results indicate that age (P = 0.007) and CLP type (P ≤ 0.001) significantly affect nasal airway volume and septal deviation. ANOVA results indicate that anterior nasal volume is significantly affected by age (P ≤ 0.001), whereas septal deviation patterns are significantly affected by CLP type (P ≤ 0.001). Age and CLP type affect nasal airway volume and septal deviation patterns. Nasal airway volumes tend to be reduced on the clefted sides of the face relative to non-clefted sides of the face. Nasal airway volumes tend to strongly increase with age, whereas septal deviation values tend to increase only slightly with age. These results suggest that functional nasal breathing may be impaired in individuals born with the unilateral and bilateral CLP deformity.
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    A Three-Dimensional Analysis of Maxillary Sinus Congestion in Unilateral Cleft Lip and Palate
    (Office of the Vice Chancellor for Research, 2014-04-11) Hale, Lindsay; Starbuck, John M.; Ghoneima, Ahmed A.; Kula, Katherine S.
    Cleft lip and palate (CLP) perturbs osseous and soft-tissue development of the nasolabial regions, often resulting in chronic maxillary sinusitis and mucosal thickening (MT) of the maxillary sinus. This preliminary study quantifies maxillary sinus MT in children with surgically repaired unilateral CLP. We hypothesize that maxillary sinus MT is increased in children with CLP relative to controls. We define "MT" as the difference between the entire maxillary sinus volume and airspace volume. Cone beam computed tomography (CBCT) images of 8-14 yr. old age- and sex-matched unilateral CLP patients (n = 10) and controls (n = 10) were obtained (IRB approval # 1210009813). Both maxillary sinus and airspace surface areas (SAs) were measured on each individual CBCT slice in coronal view. SA measurements were summed and multiplied by voxel size (0.4mm) to obtain a volume. Paired t-tests determined whether maxillary sinus volume, air volume, MT (i.e. maxillary sinus volume – airspace volume), and percentage of MT (i.e. MT/maxillary size x 100) differed. A p-value of ≤ 0.05 was considered significant. Intra-class correlation assessed reliability and was high (0.99). Significant differences were found for several measurements: Maxillary airspace (non-cleft side vs. right side control p-value = 0.002; cleft-side vs. left side control p-value = 0.004), MT (cleft-side vs. left side p-value = 0.009), and percentage of MT (non-cleft side vs. right side control p-value = 0.002, cleft-side vs. left side control p-value = 0.002). Maxillary airspace was decreased by 30% (non-cleft side) and by 33% (cleft side). Percentage of average MT was 40% (non-cleft side) and 42% (cleft side) of CLP patients, but only 9% (left and right side) in controls. Surgically repaired CLP patients exhibit decreased maxillary airspace and increased MT relative to controls. CLP deformities are associated with MT. 3D imaging is useful for quantitatively evaluating MT of the maxillary sinus.