Orodental malformations associated with human MSX1 sequence variants.

BACKGROUND: MSX1 sequence variants have been known to cause human tooth agenesis (TA) with or without orofacial clefts. However, their roles during the whole processes of tooth development are not fully understood. This study aimed to characterize a 4-membered family with TA carrying a novel MSX1 pathogenic variant and investigate the disease mechanism. METHODS: The authors conducted whole exome analysis to define the disease-causing sequence variant. They performed microcomputed tomography, morphometric analyses, transcriptome profiling, and molecular characterization to study the affected teeth and the gene variant. RESULTS: The authors identified an MSX1 pathogenic variant, p.Glu232∗, in affected family members with TA and concomitant orodental anomalies, namely, prominent maxillary labial frenum, central incisor diastema, median maxillary anterior alveolar cleft, tooth fusion, mandibular molar dysmorphology, thin dentin layer, and slender dental roots. MSX1-defective teeth were not apparently microdontic but had thin dentin layers. The mandibular molars showed a homeotic transformation to maxillary counterparts. Genes involved in extracellular matrix organization and dentinogenesis, such as DMP1 and MMP20, were downregulated in dental pulp tissues of MSX1-defective teeth. The p.Glu232∗-truncated MSX1 properly localized to the nucleus but partially lost its transactivation ability. Analyzing reported cases indicated that truncation sequence variants within the homeobox domain of MSX1 caused a more severe TA phenotype than those outside of the homeobox domain, probably due to dominant negativity compared with haploinsufficiency. CONCLUSIONS: This study provides in vivo evidence that MSX1 contributes to developmental processes of various orodental tissues in humans. PRACTICAL IMPLICATIONS: Clinically, hypertrophic labial frenum, incisor diastema, and median maxillary anterior alveolar cleft might be considered diagnostic for MSX1-associated TA.

Changes in Cone-Beam Computed Tomography Pediatric Airway Measurements After Adenotonsillectomy in Patients With OSA.

Importance: Early intervention using cone-beam computed tomography (CBCT) and adenotonsillectomy for children with obstructive sleep apnea (OSA) may prevent impaired growth, adverse cardiovascular consequences, learning deficits, and poor quality of life. Objective: To assess changes in CBCT airway measurements and polysomnography (PSG) parameters that occur after adenotonsillectomy in children with OSA and to determine whether CBCT changes are correlated with apnea-hypopnea index (AHI) reduction. Design, Setting, and Participants: This prospective cohort study was conducted at a tertiary medical center from 2013 to 2016. Children aged 7 to 13 years with PSG-confirmed OSA (ie, AHI ≥1) were recruited. Data analysis was performed from March to July 2021. Exposures: All participants underwent CBCT and PSG before and after adenotonsillectomy. Main Outcomes and Measures: Changes in PSG and CBCT parameters after adenotonsillectomy were analyzed. Results: A total of 49 children (mean [SD] age, 9.5 [1.8] years; 34 boys [69.4%]) were recruited. Eighteen participants (36.7%) had obesity. After adenotonsillectomy, AHI significantly decreased from 11.4 to 1.2 events per hour (mean difference, -10.24 events per hour; 95% CI, -13.84 to -6.64 events per hour). The following CBCT parameters significantly increased: total airway volume (from 11 265 to 15 161 mm3; mean difference, 3896.6 mm3; 95% CI, 2788.0 to 5005.2 mm3), nasopharyngeal volume (from 2366 to 3826 mm3; mean difference, 1459.7 mm3; 95% CI, 1122.9 to 1796.5 mm3), minimal nasopharyngeal airway area (from 128 to 191 mm2; mean difference, 63.1 mm2; 95% CI, 47.4 to 78.8 mm2), mean nasopharyngeal airway area (from 144 to 231 mm2; mean difference, 86.8 mm2; 95% CI, 67.0 to 106.5 mm2), oropharyngeal volume (from 8898 to 11 335 mm3; mean difference, 2436.9 mm3; 95% CI, 1477.0 to 3396.8 mm3), minimal oropharyngeal airway area (from 82 to 158 mm2; mean difference, 76.2 mm2; 95% CI, 57.0 to 95.4 mm2), and mean oropharyngeal airway area (from 182 to 234 mm2; mean difference, 52.5 mm2; 95% CI, 33.6 to 71.4 mm2). Among all parameters, only body mass index percentile showed large effect size between the group with residual OSA (postoperative AHI ≥1) and the group with resolved disease, with the residual OSA group having a higher body mass index percentile (87.8 vs 61.4; mean difference, 26.33; 95% CI, 10.00 to 42.66). A quantile regression model revealed that total airway volume and minimal oropharyngeal airway area were significantly correlated with reductions in AHI. Conclusions and Relevance: These findings suggest that in children undergoing adenotonsillectomy, improvements in total airway volume and oropharyngeal minimal airway area were correlated with reduction of AHI. Future studies are needed to assess whether CBCT has a role in the evaluation of children with OSA who are being considered for adenotonsillectomy.

Cyclic mechanical stretch regulates the AMPK/Egr1 pathway in tenocytes via Ca2+-mediated mechanosensing.

PURPOSE: Mechanical stimuli are essential for the maintenance of tendon tissue homeostasis. The study aims to elucidate the mechanobiological mechanisms underlying the maintenance of tenocyte homeostasis by cyclic mechanical stretch under high-glucose (HG) condition. MATERIALS AND METHODS: Primary tenocytes were isolated from rat Achilles tendon and 2D-cultured under HG condition. The in vitro effects of a single bout, 2-h cyclic biaxial stretch session (1 Hz, 8%) on primary rat tenocytes were explored through Flexcell system. Cell viability, tenogenic gene expression, intracellular calcium concentration, focal adhesion kinase (FAK) expression, and signaling pathway activation were analyzed in tenocytes with or without mechanical stretch. RESULTS: Mechanical stretch increased tenocyte proliferation and upregulated early growth response protein 1 (Egr1) expression. An increase in intracellular calcium was observed after 30 min of stretching. Mechanical stretch phosphorylated FAK, calmodulin-dependent protein kinase kinase 2 (CaMKK2), and 5' adenosine monophosphate-activated protein kinase (AMPK) in a time-dependent manner, and these effects were abrogated after blocking intracellular calcium. Inhibition of FAK, CaMKK2, and AMPK downregulated the expression of Egr1. In addition, mechanical stretch reinforced cytoskeletal organization via calcium (Ca2+)/FAK signaling. CONCLUSIONS: Our study demonstrated that mechanical stretch-induced calcium influx activated CaMKK2/AMPK signaling and FAK-cytoskeleton reorganization, thereby promoting the expression of Egr1, which may help maintain tendon cell characteristics and homeostasis in the context of diabetic tendinopathy.

Architectural changes in alveolar bone for dental decompensation before surgery in Class III patients with differing facial divergence: a CBCT study.

This study aimed to investigate alveolar bone change around mandibular anterior teeth during orthodontic decompensation in patients with skeletal Class III malocclusion and different vertical facial patterns. The records of 29 consecutive Class III patients selected from those pending two-jaw orthognathic surgery were divided into low (≤ 28°), average (30°-37°), and high (≥ 39°) mandibular plane angle (MPA) groups. The DICOM files of CBCT scans and STL files of digital dental models, taken before (T1) and after (T2) presurgical orthodontic treatment, were imported into Dolphin imaging software to reconstruct dentoskeletal images. T1 and T2 images were superimposed and analyzed for bone thickness and height at the level of root apex on each mid-sagittal slice of six mandibular anterior teeth. Differences between T1 and T2 were analyzed by non-parametric tests and mixed-effect model analysis. The results showed that the measurements of alveolar bone height generally decreased after treatment, regardless of MPA. The facial divergence, incisor irregularity, tooth site, treatment time, and change in proclination were identified as the significant factors affecting alveolar bone thickness and height during treatment. The presurgical orthodontic treatment to decompensate mandibular anterior teeth should be very careful in all MPA groups.

Simplified orthognathic surgical treatment using non-surgical asymmetric maxillary expansion: A case report.

BACKGROUND: Transverse problems can be exacerbated by highly compensated occlusion in patients with skeletal asymmetry, which makes pre-surgical decompensation harder to achieve. OBJECTIVE: This case report describes a case of combined orthognathic surgery with facial asymmetry. We used pre-orthodontic surgical simulation to visualize the goal for presurgical orthodontics, planning for a one-jaw surgical treatment option. METHODS: The planned asymmetric expansion was performed using a maxillary skeletal expander (MSE II) with surgical corticopuncture over only the left side before MSE activation. Surgery was performed to achieve mandibular left outward yaw rotation to correct the patient's facial asymmetry after the planned amount of expansion was reached. RESULTS: The results showed substantial improvement of facial aesthetics as well as skeletal symmetry. Cooperation and communication between surgeon and orthodontist ensured that the final results were satisfactory.

970 nm low-level laser affects bone metabolism in orthodontic tooth movement.

OBJECTIVE: During orthodontic tooth movement (OTM), the speed of movement depends on the rate of bone turnover. In this study, we used a rat model to investigate the effect of 970 nm low-level laser therapy (LLLT) on OTM under different dose and frequency protocols. METHODS: We first compared the OTM rates between the OTM only control and the OTM + LLLT group (1250 J/cm2) in Experiment 1 and showed that LLLT significantly increased OTM. In Experiment 2, we employed 3 different LLLT protocols: the low-dose group and the high-dose group receiving 5 doses of 750 J/cm2 and 15,000 J/cm2 of LLLT every 3 days, respectively, and the early high-dose group which received 5 daily doses at 15,000 J/cm2 at the beginning of the experiments. The OTM-only control group received no LLLT. Tooth movement rate was measured through sequential silicone impressions. MicroCT was also performed to evaluate bone de-mineralization rate. Bone histmorphometry was used to compare the bone turnover rate between LLLT group and control group. Finally, TRAP, Osteocalcin, and VEGF expression is evaluated by immunohistochemistry (IHC) in tissue sections. RESULTS: When LLLT treatment was given every three days, both the 1250 J/cm2 and 15,000 J/cm2 groups showed significantly increased OTM compared to the control group. No significant difference was observed in the 750 J/cm2 group, or in the early irradiation group, when compared with controls, although 750 J/cm2 showed the same trend of accelerating OTM. The MicroCT result of rat maxilla demonstrated that LLLT increased bone remodeling and showed decreased bone mineral density and bone volume/total volume in the furcation areas of the maxillary first molars at the end of experiment. LLLT without OTM increased bone turnover as evidenced by fluorochrome incorporation. Immunohistochemistry analyses revealed high osteocalcin expression at later stages of OTM in the LLLT group, while VEGF expression was highly induced in the LLLT + OTM group at an early stage. CONCLUSION: Our results suggest that the 970 nm LLLT increases the rate of OTM in a dose-sensitive and frequency-dependent manner. Further animal and human studies are needed to determine the optimal timing and dosage of LLLT for OTM acceleration.

Hyperglycemia Augments the Adipogenic Transdifferentiation Potential of Tenocytes and Is Alleviated by Cyclic Mechanical Stretch.

Diabetes mellitus is associated with damage to tendons, which may result from cellular dysfunction in response to a hyperglycemic environment. Tenocytes express diminished levels of tendon-associated genes under hyperglycemic conditions. In contrast, mechanical stretch enhances tenogenic differentiation. However, whether hyperglycemia increases the non-tenogenic differentiation potential of tenocytes and whether this can be mitigated by mechanical stretch remains elusive. We explored the in vitro effects of high glucose and mechanical stretch on rat primary tenocytes. Specifically, non-tenogenic gene expression, adipogenic potential, cell migration rate, filamentous actin expression, and the activation of signaling pathways were analyzed in tenocytes treated with high glucose, followed by the presence or absence of mechanical stretch. We analyzed tenocyte phenotype in vivo by immunohistochemistry using an STZ (streptozotocin)-induced long-term diabetic mouse model. High glucose-treated tenocytes expressed higher levels of the adipogenic transcription factors PPARγ and C/EBPs. PPARγ was also highly expressed in diabetic tendons. In addition, increased adipogenic differentiation and decreased cell migration induced by high glucose implicated a fibroblast-to-adipocyte phenotypic change. By applying mechanical stretch to tenocytes in high-glucose conditions, adipogenic differentiation was repressed, while cell motility was enhanced, and fibroblastic morphology and gene expression profiles were strengthened. In part, these effects resulted from a stretch-induced activation of ERK (extracellular signal-regulated kinases) and a concomitant inactivation of Akt. Our results show that mechanical stretch alleviates the augmented adipogenic transdifferentiation potential of high glucose-treated tenocytes and helps maintain their fibroblastic characteristics. The alterations induced by high glucose highlight possible pathological mechanisms for diabetic tendinopathy. Furthermore, the beneficial effects of mechanical stretch on tenocytes suggest that an appropriate physical load possesses therapeutic potential for diabetic tendinopathy.

Early Orthodontic Tooth Movement into Regenerative Bony Defects: A Case Report.

Early orthodontic tooth movement following regenerative surgery is controversial. In this case, during protraction of the maxillary right first premolar to substitute for the long-term missing maxillary right canine, Bio-Oss and Bio-Gide were used for lateral ridge augmentation at the area of the maxillary right lateral incisor and to cover the denuded surface at the buccal side of the first premolar. Orthodontic tooth movement (OTM) commenced 2 weeks after regenerative surgery. After 8 months, new bone formation was observed on the root surface of the first premolar during implant surgery. A cone beam computed tomography scan taken 1.5 years postsurgery revealed good maintenance of regenerative bone at the same site. This satisfactory outcome of early OTM following regenerative surgery suggests biomechanical stimulation may not jeopardize the regenerative effect.

A retrospective analysis of the failure rate of three different orthodontic skeletal anchorage systems.

OBJECTIVES: The aim of this retrospective study was to assess systematically the case distribution among three types of mini-implants and to evaluate the clinical factors that influence the failure rates of mini-implants used as an orthodontic anchorage. MATERIAL AND METHODS: Data for 359 mini-implants (miniplates, miniscrews, and microscrews) in 129 patients were collected. The factors related to mini-implant failure were evaluated using univariate analysis and multivariate stepwise logistic regression analysis. RESULTS: Among these three different types of skeletal anchorage, there was a significant difference between the failure rates of these mini-implants, with the miniscrews and microscrews showing much higher failure rates. There were no significant differences in failure rates among the mini-implants for the following variables: gender, type of malocclusion, local or full-arch treatment, whether on the buccal or lingual side, length of the screw, loading pattern, or the duration of the healing phase. Greater risks for failure were found in younger patients, when an implant was placed for retraction/protraction, when it was placed on the mandibular arch, when it was placed anterior to the second premolars, or when using the miniscrew/microscrew systems. After adjusting for potential confounding effects, only three factors (type of mini-implant, placement on the mandibular arch, and age) were found to be statistically significant in predicting mini-implant failures (P<0.05) with an R2 value of 85.2%. CONCLUSIONS: Mini-implants placed in younger patients or placed on the mandibular arch are at a greater risk of failing. The miniplate system has greater stability compared with miniscrews or microscrews. However, it requires flap surgery for insertion and removal, which usually causes swelling and discomfort. Therefore, selection of the proper type of skeletal anchorage should be based on the specific treatment needs of each individual patient.

The effects of distraction osteogenesis on mandibular growth in growing minipigs: a report on three-dimensional morphologic changes.

BACKGROUND: The purpose of the study was to investigate the morphologic changes of distraction osteogenesis performed on the mandible in growing minipigs. METHODS: Eighteen piglets were divided into four groups. In group A (n = 6), animals received unilateral osteotomy and the distractor device was activated for 2 weeks after a 1-week latency period. In group B (n = 6), animals underwent the osteotomy procedure and distractor placement. In group C (n = 3), animals received the distractor, and in group D (n = 3), only four reference pins were placed. After completion of distraction, the head portions were sent for computed tomography scanning. The coordinates of each selected mandibular landmark were recorded on three-dimensional computed tomographic reconstruction images for further mathematical linear and angular measurements to quantify morphologic changes. RESULTS: The sagittal length related to gonial region was increased in group A but decreased in group B. Although all groups had the tendency of increased ramus width, it was only significant in group B. The distraction also reduced the gonial angle and elevated the ramus inclination to the Frankfort horizontal plane at the operated side. On the contrary, osteotomy alone opened the gonial angle and flattened the ramus inclination. CONCLUSIONS: Distraction could lengthen the mandibles in growing minipigs by reducing the gonial angle and displacing the mandible posteriorly. This effect, which allows for developing a prominent gonial angle, could be further explored in treating syndromic patients with the deficiency in the gonial region. A greater amount of overcorrection should be considered while treating growing patients because the mandibular osteotomy procedure itself seems to retard the growth.

Nonsurgical correction of skeletal deep overbite and class II division 2 malocclusion in an adult patient.

Treatment modalities for Class II Division 2 malocclusion include growth modification, dental compensation, and surgical-orthodontic therapy; which treatment is chosen depends on the patient's age and growth potential. Deep overbite can be corrected by intrusion of anterior teeth, extrusion of posterior teeth, or a combination of both. Treatment considerations include the patient's facial profile, skeletal pattern, growth potential, and severity of dental malocclusion. Here, we present the nonsurgical orthodontic treatment of an adult patient with deep overbite and underlying skeletal Class II discrepancy. He had a hypodivergent facial pattern, Class II Division 2 malocclusion, and traumatic deep overbite due to supereruption of the mandibular anterior teeth. He refused orthognathic surgery but would accept orthodontic treatment alone, with the understanding that the treatment results could be compromised. We corrected the deep overbite by proclining the mandibular incisors; this helped to level the exaggerated curve of Spee. The posttreatment occlusion was significantly improved, both functionally and esthetically, with stable interincisal contacts. However, the improvement in occlusion and esthetics was achieved at the expense of reduced periodontal support for the mandibular anterior teeth.