Quantitative bone imaging biomarkers to diagnose temporomandibular joint osteoarthritis.

Bone degradation of the condylar surface is seen in temporomandibular joint osteoarthritis (TMJ OA); however, the initial changes occur in the subchondral bone. This cross-sectional study was performed to evaluate 23 subchondral bone imaging biomarkers for TMJ OA. The sample consisted of high-resolution cone beam computed tomography scans of 84 subjects, divided into two groups: TMJ OA (45 patients with TMJ OA) and control (39 asymptomatic subjects). Six regions of each mandibular condyle scan were extracted for computation of five bone morphometric and 18 grey-level texture-based variables. The groups were compared using the Mann-Whitney U-test, and the receiver operating characteristics (ROC) curve was determined for each variable that showed a statically significance difference. The results showed statistically significant differences in the subchondral bone microstructure in the lateral and central condylar regions between the control and TMJ OA groups (P< 0.05). The area under the ROC curve (AUC) for these variables was between 0.620 and 0.710. In conclusion, 13 imaging bone biomarkers presented an acceptable diagnostic performance for the diagnosis of TMJ OA, indicating that the texture and geometry of the subchondral bone microarchitecture may be useful for quantitative grading of the disease.

Minimally Invasive Approach for Diagnosing TMJ Osteoarthritis.

This study's objectives were to test correlations among groups of biomarkers that are associated with condylar morphology and to apply artificial intelligence to test shape analysis features in a neural network (NN) to stage condylar morphology in temporomandibular joint osteoarthritis (TMJOA). Seventeen TMJOA patients (39.9 ± 11.7 y) experiencing signs and symptoms of the disease for less than 10 y and 17 age- and sex-matched control subjects (39.4 ± 15.2 y) completed a questionnaire, had a temporomandibular joint clinical exam, had blood and saliva samples drawn, and had high-resolution cone beam computed tomography scans taken. Serum and salivary levels of 17 inflammatory biomarkers were quantified using protein microarrays. A NN was trained with 259 other condyles to detect and classify the stage of TMJOA and then compared to repeated clinical experts' classifications. Levels of the salivary biomarkers MMP-3, VE-cadherin, 6Ckine, and PAI-1 were correlated to each other in TMJOA patients and were significantly correlated with condylar morphological variability on the posterior surface of the condyle. In serum, VE-cadherin and VEGF were correlated with one another and with significant morphological variability on the anterior surface of the condyle, while MMP-3 and CXCL16 presented statistically significant associations with variability on the anterior surface, lateral pole, and superior-posterior surface of the condyle. The range of mouth opening variables were the clinical markers with the most significant associations with morphological variability at the medial and lateral condylar poles. The repeated clinician consensus classification had 97.8% agreement on degree of degeneration within 1 group difference. Predictive analytics of the NN's staging of TMJOA compared to the repeated clinicians' consensus revealed 73.5% and 91.2% accuracy. This study demonstrated significant correlations among variations in protein expression levels, clinical symptoms, and condylar surface morphology. The results suggest that 3-dimensional variability in TMJOA condylar morphology can be comprehensively phenotyped by the NN.

Three-dimensional analysis of condylar changes in surgical correction for open bite patients with skeletal class II and class III malocclusions.

The aim of this study was to quantify three-dimensional condylar displacements as a result of two-jaw surgery for open bite correction in patients with skeletal class II and class III malocclusion. Pre-surgical (T1) and post-surgical (T2) cone beam computed tomography scans were taken for 16 patients with skeletal class II (mean age 22.3±9.47years) and 14 patients with skeletal class III (mean age 25.6±6.27years). T2 scans were registered to T1 scans at the cranial base. Translational and rotational condylar changes were calculated by x,y,z coordinates of corresponding landmarks. The directions and amounts of condylar displacement were assessed by intra- and inter-class Mann-Whitney U-test or t-test. Class II patients presented significantly greater amounts of lateral (P=0.002) and inferior (P=0.038) translation than class III patients. The magnitudes of condylar translational displacements were small for both groups. Skeletal class III patients had predominantly medial (P=0.024) and superior (P=0.047) condylar translation. Skeletal class II patients presented greater condylar counterclockwise pitch (P=0.007) than class III patients. Two-jaw surgery for the correction of open bite led to different directions and amounts of condylar rotational displacement in patients with skeletal class II compared to class III malocclusion, with greater rotational than translational displacements.

Counterclockwise maxillomandibular advancement surgery and disc repositioning: can condylar remodeling in the long-term follow-up be predicted?

This study investigated predictive risk factors of condylar remodeling changes after counterclockwise maxillomandibular advancement (CCW-MMA) and disc repositioning surgery. Forty-one female patients (75 condyles) treated with CCW-MMA and disc repositioning had cone beam computed tomography (CBCT) scans taken pre-surgery, immediately after surgery, and at an average 16 months post-surgery. Pre- and post-surgical three-dimensional models were superimposed using automated voxel-based registration on the cranial base to evaluate condylar displacements after surgery. Regional registration was performed to assess condylar remodeling in the follow-up period. Three-dimensional cephalometrics, shape correspondence (SPHARM-PDM), and volume measurements were applied to quantify changes. Pearson product-moment correlations and multiple regression analysis were performed. Highly statistically significant correlation showed that older patients were more susceptible to overall condylar volume reduction following CCW-MMA and disc repositioning (P≤0.001). Weak but statistically significant correlations were observed between condylar remodeling changes in the follow-up period and pre-surgical facial characteristics, magnitude of the surgical procedure, and condylar displacement changes. After CCW-MMA and disc repositioning, the condyles moved mostly downwards and medially, and were rotated medially and counterclockwise; displacements in the opposite direction were correlated with a greater risk of condylar resorption. Moreover, positional changes with surgery were only weakly associated with remodeling in the follow-up period, suggesting that other risk factors may play a role in condylar resorption.

Acute alcohol exposure during neurulation: Behavioral and brain structural consequences in adolescent C57BL/6J mice.

Prenatal alcohol exposure (PAE) can induce physical malformations and behavioral abnormalities that depend in part on thedevelopmental timing of alcohol exposure. The current studies employed a mouse FASD model to characterize the long-term behavioral and brain structural consequences of a binge-like alcohol exposure during neurulation; a first-trimester stage when women are typically unaware that they are pregnant. Time-mated C57BL/6J female mice were administered two alcohol doses (2.8g/kg, four hours apart) or vehicle starting at gestational day 8.0. Male and female adolescent offspring (postnatal day 28-45) were then examined for motor activity (open field and elevated plus maze), coordination (rotarod), spatial learning and memory (Morris water maze), sensory motor gating (acoustic startle and prepulse inhibition), sociability (three-chambered social test), and nociceptive responses (hot plate). Regional brain volumes and shapes were determined using magnetic resonance imaging. In males, PAE increased activity on the elevated plus maze and reduced social novelty preference, while in females PAE increased exploratory behavior in the open field and transiently impaired rotarod performance. In both males and females, PAE modestly impaired Morris water maze performance and decreased the latency to respond on the hot plate. There were no brain volume differences; however, significant shape differences were found in the cerebellum, hypothalamus, striatum, and corpus callosum. These results demonstrate that alcohol exposure during neurulation can have functional consequences into adolescence, even in the absence of significant brain regional volumetric changes. However, PAE-induced regional shape changes provide evidence for persistent brain alterations and suggest alternative clinical diagnostic markers.

Twist1-induced activation of human fibroblasts promotes matrix stiffness by upregulating palladin and collagen α1(VI).

The transcription factor Twist1 is involved in the epithelial-mesenchymal transition and contributes to cancer metastasis through mostly unknown mechanisms. In colorectal cancer, Twist1 expression is mainly restricted to the tumor stroma. We found that human fibroblast cell lines stably transfected with Twist1 acquired characteristics of activated cancer-associated fibroblasts (CAFs), such as hyperproliferation, an increased ability to migrate and an alignment of the actin cytoskeleton. Further, Twist1-activated fibroblasts promoted increased matrix stiffness. Using quantitative proteomics, we identified palladin and collagen α1(VI) as two major mediators of the Twist1 effects in fibroblast cell lines. Co-immunoprecipitation studies indicated that palladin and Twist1 interact within the nucleus, suggesting that palladin could act as a transcription regulator. Palladin was found to be more relevant for the cellular biomechanical properties, orientation and polarity, and collagen α1(VI) for the migration and invasion capacity, of Twist1-activated fibroblasts. Both palladin and collagen α1(VI) were observed to be overexpressed in colorectal CAFs and to be associated with poor colorectal cancer patient survival and relapse prediction. Our results demonstrate that Twist1-expressing fibroblasts mimic the properties of CAFs present at the tumor invasive front, which likely explains the prometastatic activities of Twist1. Twist1 appears to require both palladin and collagen α1(VI) as downstream effectors for its prometastatic effects, which could be future therapeutic targets in cancer metastasis.

Three-dimensional regional displacement after surgical-orthodontic correction of Class III malocclusion.

OBJECTIVES: To investigate how displacements of maxillo-mandibular structures are associated with each other at splint removal and 1 year post-surgery following 1-jaw and 2-jaw surgeries for correction of Class III malocclusion. SETTING AND SAMPLE POPULATION: Fifty patients who underwent surgical correction with maxillary advancement only (n = 25) or combined with mandibular setback (n = 25) were prospectively enrolled in this study. METHODS: Cone-beam computed tomographies were taken pre-surgery, at splint removal and at 1 year post-surgery. Three-dimensional cranial base superimpositions and shape correspondence were used to measure the outcomes from pre-surgery to splint removal (surgical changes) and splint removal to 1 year post-surgery (post-surgical adaptations). Pearson's correlation coefficients were used to evaluate the association between the regional displacements. RESULTS: Both surgery groups presented mandibular clockwise rotation with surgery and post-surgical adaptive counterclockwise rotation. In patients treated with maxillary advancement only, the surgical changes of the maxilla were significantly correlated with chin changes. The amount and direction of chin autorotation were significantly correlated with right and left ramus autorotation. Right and left condylar displacements were significantly correlated. One year post-surgery, adaptive displacements and bone remodeling of both rami were correlated with the chin and condylar changes. For the 2-jaw group, the few correlations between the positional and remodeling changes in the anatomic regions of interest observed due to the surgery were different than those observed after post-surgical adaptations, suggesting that these changes occurred independently. CONCLUSION: Our results indicate that surgical displacements and post-surgical adaptations are often correlated in one-jaw surgery and are, in general, independent in two-jaw surgery.

3D superimposition and understanding temporomandibular joint arthritis.

OBJECTIVES: To investigate the 3D morphological variations in 169 temporomandibular ioint (TMJ) condyles, using novel imaging statistical modeling approaches. SETTING AND SAMPLE POPULATION: The Department of Orthodontics and Pediatric Dentistry at the University of Michigan. Cone beam CT scans were acquired from 69 subjects with long-term TMJ osteoarthritis (OA, mean age 39.1±15.7 years), 15 subjects at initial consult diagnosis of OA (mean age 44.9±14.8 years), and seven healthy controls (mean age 43±12.4 years). MATERIALS AND METHODS: 3D surface models of the condyles were constructed, and homologous correspondent points on each model were established. The statistical framework included Direction-Projection-Permutation (DiProPerm) for testing statistical significance of the differences between healthy controls and the OA groups determined by clinical and radiographic diagnoses. RESULTS: Condylar morphology in OA and healthy subjects varied widely with categorization from mild to severe bone degeneration or overgrowth. DiProPerm statistics supported a significant difference between the healthy control group and the initial diagnosis of OA group (t=6.6, empirical p-value=0.006) and between healthy and long-term diagnosis of OA group (t=7.2, empirical p-value=0). Compared with healthy controls, the average condyle in OA subjects was significantly smaller in all dimensions, except its anterior surface, even in subjects with initial diagnosis of OA. CONCLUSION: This new statistical modeling of condylar morphology allows the development of more targeted classifications of this condition than previously possible.

3D osteoarthritic changes in TMJ condylar morphology correlates with specific systemic and local biomarkers of disease.

OBJECTIVE: To assess 3D morphological variations and local and systemic biomarker profiles in subjects with a diagnosis of temporomandibular joint osteoarthritis (TMJ OA). DESIGN: Twenty-eight patients with long-term TMJ OA (39.9 ± 16 years), 12 patients at initial diagnosis of OA (47.4 ± 16.1 years), and 12 healthy controls (41.8 ± 12.2 years) were recruited. All patients were female and had cone beam CT scans taken. TMJ arthrocentesis and venipuncture were performed on 12 OA and 12 age-matched healthy controls. Serum and synovial fluid levels of 50 biomarkers of arthritic inflammation were quantified by protein microarrays. Shape Analysis MANCOVA tested statistical correlations between biomarker levels and variations in condylar morphology. RESULTS: Compared with healthy controls, the OA average condyle was significantly smaller in all dimensions except its anterior surface, with areas indicative of bone resorption along the articular surface, particularly in the lateral pole. Synovial fluid levels of ANG, GDF15, TIMP-1, CXCL16, MMP-3 and MMP-7 were significantly correlated with bone apposition of the condylar anterior surface. Serum levels of ENA-78, MMP-3, PAI-1, VE-Cadherin, VEGF, GM-CSF, TGFßb1, IFNγg, TNFαa, IL-1αa, and IL-6 were significantly correlated with flattening of the lateral pole. Expression levels of ANG were significantly correlated with the articular morphology in healthy controls. CONCLUSIONS: Bone resorption at the articular surface, particularly at the lateral pole was statistically significant at initial diagnosis of TMJ OA. Synovial fluid levels of ANG, GDF15, TIMP-1, CXCL16, MMP-3 and MMP-7 were correlated with bone apposition. Serum levels of ENA-78, MMP-3, PAI-1, VE-Cadherin, VEGF, GM-CSF, TGFß1, IFNγ, TNFα, IL-1α, and IL-6 were correlated with bone resorption.

Regional 3D superimposition to assess temporomandibular joint condylar morphology.

OBJECTIVES: To investigate the reliability of regional three-dimensional registration and superimposition methods for assessment of temporomandibular joint condylar morphology across subjects and longitudinally. METHODS: The sample consisted of cone beam CT scans of 36 patients. The across-subject comparisons included 12 controls, mean age 41.3 ± 12.0 years, and 12 patients with temporomandibular joint osteoarthritis, mean age 41.3 ± 14.7 years. The individual longitudinal assessments included 12 patients with temporomandibular joint osteoarthritis, mean age 37.8 ± 16.7 years, followed up at pre-operative jaw surgery, immediately after and one-year post-operative. Surface models of all condyles were constructed from the cone beam CT scans. Two previously calibrated observers independently performed all registration methods. A landmark-based approach was used for the registration of across-subject condylar models, and temporomandibular joint osteoarthritis vs control group differences were computed with shape analysis. A voxel-based approach was used for registration of longitudinal scans calculated x, y, z degrees of freedom for translation and rotation. Two-way random intraclass correlation coefficients tested the interobserver reliability. RESULTS: Statistically significant differences between the control group and the osteoarthritis group were consistently located on the lateral and medial poles for both observers. The interobserver differences were ≤0.2 mm. For individual longitudinal comparisons, the mean interobserver differences were ≤0.6 mm in translation errors and 1.2° in rotation errors, with excellent reliability (intraclass correlation coefficient >0.75). CONCLUSIONS: Condylar registration for across-subjects and longitudinal assessments is reliable and can be used to quantify subtle bony differences in the three-dimensional condylar morphology.

One-year assessment of surgical outcomes in Class III patients using cone beam computed tomography.

The purpose of this study was to apply a novel method to evaluate surgical outcomes at 1 year after orthognathic surgery for Class III patients undergoing two different surgical protocols. Fifty patients divided equally into two groups (maxillary advancement only and combined with mandibular setback) had cone beam computed tomography (CBCT) scans taken pre-surgery, at splint removal, and at 1-year post-surgery. An automatic cranial base superimposition method was used to register, and shape correspondence was applied to assess, the overall changes between pre-surgery and splint removal (surgical changes) and between splint removal and 1-year post-surgery at the end of orthodontic treatment (post-surgical adaptations). Post-surgical maxillary adaptations were exactly the same for both groups, with 52% of the patients having changes >2mm. Approximately half of the post-surgical changes in the maxilla for both groups were vertical. The two-jaw group showed significantly greater surgical and post-surgical changes in the ramus, chin, and most of the condylar surfaces (P<0.05). Post-surgical adaptation on the anterior part of the chin was also more significant in the two-jaw group (P<0.05). Regardless of the type of surgery, marked post-surgical adaptations were observed in the regions evaluated, which explain the adequate maxillary-mandibular relationship at 1-year post-surgery on average, with individual variability.

Quantification of condylar resorption in temporomandibular joint osteoarthritis.

OBJECTIVE: This study was performed to determine the condylar morphologic variation of osteoarthritic (OA) and asymptomatic temporomandibular joints (TMJs) and to determine its correlation with pain intensity and duration. STUDY DESIGN: Three-dimensional surface models of mandibular condyles were constructed from cone-beam computerized tomography images of 29 female patients with TMJ OA (Research Diagnostic Criteria for Temporomandibular Disorders group III) and 36 female asymptomatic subjects. Shape correspondence was used to localize and quantify the condylar morphology. Statistical analysis was performed with multivariate analysis of covariance analysis, using Hotelling T(2) metric based on covariance matrices, and Pearson correlation. RESULTS: The OA condylar morphology was statistically significantly different from the asymptomatic condyles (P < .05). Three-dimensional morphologic variation of the OA condyles was significantly correlated with pain intensity and duration. CONCLUSION: Three-dimensional quantification of condylar morphology revealed profound differences between OA and asymptomatic condyles, and the extent of the resorptive changes paralleled pain severity and duration.

Análisis comparativo de la angulación cráneovertebral en teleradiografías tomadas en posición de reposo y en posición de oclusión en niños / Comparative analysis of the craneal-vertebral angulation in teleradiographies taken on rest position and on occlusion position in children

Se estableció el grado de variación que experimenta la angulación cráneovertebral de una pasición reposo a una posición de oclusión dentaria, en un mismo sujeto. Para estó, se seleccionó una muestra al azar de 30 niños del área occidente y se tomaron teleradiografías laterales en reposo y en oclusión dentaria. Se evaluaron del trazado cefalométrico cráneovertebral de Solow, 6 ángulos (SN/OPT, SN/CVT, FH/OPT, FH/CVT, NL/OPT Y NL/CVT). Los resultados se analizaron a través del test t pareado, encontrándose diferencias estadísticamente significativas en los ángulos SN/OPT, FH/OPT Y NL/OPT, en los cuales se produjo un aumento o una disminución de su angulación, en posición de oclusión dentaria con respecto a posición de reposo; determinando una extensión o flexión de la cabeza respectivamente. Se concluyó entonces, que la angulación cráneovertebral, no es la misma en posición de reposo y de oclusión, debido a que al momento de ocluir, el individuo experimenta una variación postural importante, con mayor tendencia al movimiento de flexión que de extensión de la cabeza

Helicobacter pylori y anticuerpos antiislotes pancreáticos en la diabetes mellitus / Helicobacter pylori and islet cells antibodies in diabetes mellitus

Se estudiaron 66 sujetos ICA +: 21 diabéticos tipo 1, 24 diabéticos clasificados inicialmente como de tipo 2 y 21 familiares de primer grado de diabéticos tipo 1, se compararon con 101 individuos ICA -: 20 diabéticos tipo 2, 20 FPG, 21 niños y 40 adultos controles no diabéticos para analizar si la respuesta inmunológica a H. pylori está asociada con anticuerpos antiislotes pancreáticos (ICA). Los ICA se determinaron por el método de inmunofluorescencia indirecta con incubación prolongada y los niveles de anticuerpos (IgG) contra H. pylori (HP), por un ELISA utilizando un kit comercial. Se observó frecuencia de anticuerpos (IgG) contra H. pylori del 38,0(por cineto) (25/66) en los sujetos ICA + y del 39,6(por ciento) (40/101) en los ICA-. No se halló correlación entre la presencia de anticuerpos (IgG) contra H. pylori y los ICA en los grupos estudiados. No hubo diferencias en relación con la presencia de anticuerpos IgG contra H. pylori entre la DM y los controles (47,7(por ciento) [31/65] vs. 40,9(por ciento) [25/61]). Se encontró alto porcentaje de anticuerpos (IgG) contra H. pylori en los diabéticos tipo 1 (33(por ciento), 7/21) en relación con los controles (14(por ciento), 3/21), pero sin diferencias significativas. Existe mayor frecuencia de anticuerpos contra Helicobacter en los controles adultos, en comparación con los niños (55por ciento), 22/40 vs. 14(por ciento), 3/21, p = 0,0025). La frecuencia de anticuerpos contra H. pylori está mucho más elevada en los controles adultos quizá por la mayor posibilidad de exposición a reinfecciones. A pesar de estos resultados, no excluimos que la infección por H. pylori esté relacionada con la diabetes tipo 1, porque algunos estudios sugieren que la IgG contra H. pylori no persiste por largo tiempo(AU)

66 ICA-positive patients were studied: 21 type 1 diabetics, 24 diabetics initially classified as type 2 and 21 first-degree relatives of type 1 diabetics. They were compared with 101 ICA-negative patients: 20 type 2 diabetics, 20 first-degree relatives, 21 children and 40 non-diabetic adult controls to analyze if the immunolgical response to H. pylori is associated with islet cell antibodies (ICA). The ICA were determined by the indirect immunofluorescence method with prolongued incubation and the levels of antibodies (IgG) versus H. pylori (HP) by an ELISA using a commercial kit. It was observed a frequency of antibodies (IgG) versus H. pylori of 38.0 percent (25/66) in ICA-positive patients and of 39.6 percent (40/101) in ICA-negative patients. No correlation was found between the presence of antibodies (IgG) versus H.pylori and the ICA in the studied groups. There were no differences as regards the presence of IgG anitbodies versus H. pylori between diabetes mellitus and the controls (47.7 percent [31/65] vs. 40.9 percent [ 25/61]). It was observed a high percentage of antibodies (IgG) vs. H. pylori in type 1 diabetics (33 percent, 7/21) in relation to the controls (14 percent, 3/21), but with no significant differences. The frequence of antibodies vs. Helicobacter in adult controls is higher than in children (55 percent, 22/40 vs. 3/21, p=0.0025). The frequency of antibodies vs. H. pylori is much more elevated in the adult controls may be because of the greater possibility of exposure to reinfections. In spite of these results, we do not exclude the idea that the infection due to H. pylori is related to type I diabetes, since some studies suggest that IgG versus H. pylori does not persist for a long time(AU)

Relaciones verticales entre la lengua y el hueso hioides en el niño. Parte II / Vertical relationship between the tongue and the hyoid bone in the child. Part II

Sobre una muestra de 35 niños, de 6 años 10 meses como promedio de edad, se realizaron trazados cefalométricos a partir de telerradiografías de perfil tomadas en reposo mandibular. Se determinó la posición del hioides siguiendo el protocolo descrito por Bibby y se obtuvo una posición promedio de 0,37 mm. por debajo de un plano dado por C3 y SB y para la lengua una posición promedio de 44,18 mm. por sobre este mismo plano. Se realizó un estudio de correlación para ambas variables, la que indicó una débil relación cuantitativa entre las variables estudiadas (r = -0,32). Utilizando los mismos trazados, se describió la posición del dorso lingual y su relación con la bóveda palatina utilizando el método descrito en Rakosi, la que se correlacionó con las observaciones clínicas de postura lingual en reposo. Dichos resultados se presentan como estudio preliminar