Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis.

Foxo1 upregulation is linked to defective fracture healing under diabetic conditions. Previous studies demonstrated that diabetes upregulates Foxo1 expression and activation and diabetes impairs ciliogenesis resulting in defective fracture repair. However, the mechanism by which diabetes causes cilia loss during fracture healing remains elusive. We report here that streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) dramatically increased Foxo1 expression in femoral fracture calluses, which thereby caused a significant decrease in the expression of IFT80 and primary cilia number. Ablation of Foxo1 in osteoblasts in OSXcretTAFoxo1f/f mice rescued IFT80 expression and ciliogenesis and restored bone formation and mechanical strength in diabetic fracture calluses. In vitro, advanced glycation end products (AGEs) impaired cilia formation in osteoblasts and reduced the production of a mineralizing matrix, which were rescued by Foxo1 deletion. Mechanistically, AGEs increased Foxo1 expression and transcriptional activity to inhibit IFT80 expression causing impaired cilia formation. Thus, our findings demonstrate that diabetes impairs fracture healing through Foxo1 mediated inhibition of ciliary IFT80 expression and primary cilia formation, resulting in impaired osteogenesis. Inhibition of Foxo1 and/or restoration of cilia formation has the potential to promote diabetes-impaired fracture healing.

Regulation of LL-37 in Bone and Periodontium Regeneration.

The goal of regenerative therapy is to restore the structure and function of the lost tissues in the fields of medicine and dentistry. However, there are some challenges in regeneration therapy such as the delivery of oxygen and nutrition, and the risk of infection in conditions such as periodontitis, osteomyelitis, etc. Leucine leucine-37 (LL-37) is a 37-residue, amphipathic, and helical peptide found only in humans and is expressed throughout the body. It has been shown to induce neovascularization and vascular endothelial growth factor (VEGF) expression. LL-37 also stimulates the migration and differentiation of mesenchymal stem cells (MSCs). Recent studies have shown that LL-37 plays an important role in the innate defense system through the elimination of pathogenic microbes and the modulation of the host immune response. LL-37 also manifests other functions such as promoting wound healing, angiogenesis, cell differentiation, and modulating apoptosis. This review summarizes the current studies on the structure, expression, and function of LL-37 and highlights the contributions of LL-37 to oral cavity, periodontium, and bone regeneration.

SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency.

Inactivation mutations in the Indian hedgehog (Ihh) gene in humans cause numerous skeletal chondrodysplasias, including acrocapitofemoral dysplasia, brachydactyly type A1, and human short stature. The lack of an appropriate human-relevant model to accurately represent these chondrodysplasias has hampered the identification of clinically effective treatments. Here, we established a mouse model of human skeletal dysplasia induced by Ihh gene mutations via ablation of Ihh in Aggrecan-positive (Acan+) cells using Aggrecan (Acan)-creERT transgenic mice. Smoothen agonist (SAG) promoted Hh activity and rescued chondrocyte proliferation and differentiation by stimulating smoothened trafficking to the cilium in Ihh-silenced cells. SAG treatment corrected mouse stature and significantly decreased mortality without evidence of toxicity. Moreover, Ihh ablation in Acan+ cells produced enchondroma-like tissues near the growth plates that were significantly reduced by SAG treatment. These results demonstrated that SAG effectively treats skeletal dysplasia caused by Ihh gene mutations in a mouse model, suggesting that SAG may represent a potential drug for the treatment of these diseases and/or enchondromas.

Diabetes impairs fracture healing through disruption of cilia formation in osteoblasts.

Diabetes-associated fracture risk and impaired fracture healing represents a serious health threat. It is well known that type 1 diabetes mellitus (T1DM) impairs fracture healing due to its effect on osteoblasts and their progenitor cells. Previous studies have showed that primary cilia and intraflagellar transport protein 80 (IFT80) are critical for bone formation. However, whether TIDM impairs fracture healing due to influencing ciliary gene expression and cilia formation is unknown. Here, we investigated the effect of T1DM on primary cilia in a streptozotocin induced diabetes mouse model and examined the impact of cilia on fracture healing in osteoblasts by deletion of IFT80 in osteoblast linage using osterix (OSX)-cre (OSXcretTAIFT80f/f). The results showed that diabetes inhibited ciliary gene expression and primary cilia formation to an extent that was similar to normoglycemic mice with IFT80 deletion. Moreover, diabetic mice and normoglycemic mice with cilia loss in osteoblasts (OSXcretTAIFT80f/f) both exhibited delayed fracture healing with significantly reduced bone density and mechanical strength as well as with reduced expression of osteoblast markers, decreased angiogenesis and proliferation of bone lining cells at the fracture sites. In vitro studies showed that advanced glycation end products (AGEs) downregulated IFT80 expression in osteoblast progenitors. Moreover, AGEs and IFT80 deletion significantly reduced cilia number and length which inhibited differentiation of primary osteoblast precursors. Thus, this study for the first time report that primary cilia are essential for bone regeneration during fracture healing and loss of cilia caused by diabetes in osteoblasts resulted in defective diabetic fracture healing.

Identification of Cilia in Different Mouse Tissues.

Cilia are microtubule-based hair-like organelles that extend from the cell surface. However, the existence and distribution of cilia in each organ and tissue at the postnatal stage in vivo remain largely unknown. In this study, we defined cilia distribution and arrangement and measured the ciliary lengths and the percentage of ciliated cells in different organs and tissues in vivo by using cilium dual reporter-expressing transgenic mice. Cilia were identified by the presence of ARL13B with an mCherry+ signal, and the cilium basal body was identified by the presence of Centrin2 with a GFP+ signal. Here, we provide in vivo evidence that chondrocytes and cells throughout bones have cilia. Most importantly, we reveal that: 1. primary cilia are present in hepatocytes; 2. no cilia but many centrioles are distributed on the apical cell surface in the gallbladder, intestine, and thyroid epithelia; 3. cilia on the cerebral cortex are well oriented, pointing to the center of the brain; 4. ARL13B+ inclusion is evident in the thyroid and islets of Langerhans; and 5. approximately 2% of cilia show irregular movement in nucleus pulposus extracellular fluid. This study reveals the existence and distribution of cilia and centrioles in different tissues and organs, and provides new insights for further comprehensive study of ciliary function in these organs and tissues.

Effect of Various Laser Wavelengths on Temperature Changes During Periimplantitis Treatment: An in vitro Study.

PURPOSE: This study aimed to investigate and compare temperature change during implant decontamination with different laser types (carbon dioxide [Co2]/diode/neodymium-doped yttrium aluminum garnet [Nd:YAG]/erbium-doped yttrium aluminum garnet [Er:YAG]/antimicrobial photodynamic therapy [aPDT]). MATERIAL AND METHODS: Sixty implants were inserted into a bone block cut from a sheep's mandible. A 3 × 8 mm vertical lesion was made at the buccal of each implant. The bone block was placed into a 37°C water bath to simulate the in vivo oral condition. A K-type thermocouple was placed in contact with the implant to register temperature changes at 3 points (apical/middle/coronal). RESULTS: In the entire laser irradiations, the mean of temperature changes remains below 10°C. The apical temperature rise was higher than the coronal and middle regions (P < 0.05), and the apical temperature took longer time to reach the initial temperature (37°C) (P < 0.001). Temperature changes over 10°C occurred at the apical point of the implants with the Co2, Nd:YAG, and diode laser irradiations; however, only the Co2 laser reached the statistical significance in this regard (P < 0.05). CONCLUSION: Our findings indicate the promising results of Er:YAG laser and aPDT in implant decontamination. Precaution should be taken in the application of Nd:YAG, diode, and especially Co2 lasers.

Performance of Preschoolers' Mothers and Senior Dental Students After Receiving Training on Fluoride Varnish Administration.

OBJECTIVES: Fluoride varnish application is an effective way to prevent caries in children. We aimed to educate preschool children's mothers on how to apply fluoride varnish and compare their performance with dental students and to assess their self-reported competency six months later. MATERIALS AND METHODS: Eighty-eight 4-6-year-old children presenting to toy houses of six randomly selected health centers in a non-affluent district of Tehran in 2014 were divided into two groups to receive fluoride varnish by their mothers and students. Mothers and senior dental students participated in a session consisting of lecture, discussion, and demonstration of fluoride varnish application for a child. Then, in three centers, mothers and in others, students applied fluoride varnish for preschoolers and their performance was evaluated. Six months later, mothers were asked to apply fluoride varnish again. Mann-Whitney U test, t-test, one-way ANOVA and logistic regression model were used for statistical analyses. RESULTS: The mean performance score was 9.74±0.22 (out of 10) for mothers and 9.71±0.15 for students (P=0.89). After six months, the mean performance score was 9.58 for mothers, which was not significantly different from that in the first session. The age and educational level of mothers were conversely correlated to their performance (P<0.05). Of mothers, 96% believed that they were competent to repeat fluoride varnish application for their children. CONCLUSIONS: Mothers' high performance score and the point that the majority of them felt competent to apply varnish for their children casts light on their potential key role in oral health promotion.

Following Surgically Assisted Rapid Palatal Expansion, Do Tooth-Borne or Bone-Borne Appliances Provide More Skeletal Expansion and Dental Expansion?

PURPOSE: The aim of this study was to compare outcome measurements of skeletal and dental expansion with bone-borne (BB) versus tooth-borne (TB) appliances after surgically assisted rapid palatal expansion (SARPE). This study was performed to provide quantitative measurements that will help the oral surgeon and orthodontist in selecting the appliance with, on average, the greatest amount of skeletal expansion and the least amount of dental expansion. MATERIALS AND METHODS: A computerized database search was performed using PubMed, EBSCO, Cochrane, Scopus, Web of Science, and Google Scholar on publications in reputable oral surgery and orthodontic journals. A systematic review and meta-analysis was completed with the predictor variable of expansion appliance (TB vs BB) and outcome measurement of expansion (in millimeters). RESULTS: Of 487 articles retrieved from the 6 databases, 5 articles were included, 4 with cone-beam computed tomographic (CBCT) data and 1 with non-CBCT 3-dimensional cast data. There was a significant difference in skeletal expansion (standardized mean difference [SMD], 0.92; 95% confidence interval [CI], 0.54-1.30; P < .001) in favor of BB rather than TB appliances. However, there was no significant difference in dental expansion (SMD, 0.05; 95% CI, -0.24 to 0.34; P = .03). CONCLUSION: According to the literature, to achieve more effective skeletal expansion and minimize dental expansion after SARPE, a BB appliance should be favored.

Intra- and Postoperative Complications of Lateral Maxillary Sinus Augmentation in Smokers vs Nonsmokers: A Systematic Review and Meta-Analysis.

PURPOSE: This meta-analysis and systematic review focused on the following question: Does tobacco smoking increase the risk of intra- or postoperative complications of lateral maxillary sinus floor elevation? MATERIALS AND METHODS: The following electronic databases were searched up to and including November 2015 without language restriction: CENTRAL, MEDLINE, Google Scholar, Scopus, Sirous, and Doaj. Studies were included if rates of intra-or postoperative complications of sinus floor elevation in smokers and nonsmokers were recorded separately. The following complications were assessed: sinus membrane perforation, bleeding, wound dehiscence, wound infection, sinusitis, hematoma, and oroantral fistula. The Critical Appraisal Skills Programme was used to assess the risk of bias in included studies. Random-effects meta-analyses were used to assess the number of each complication in smokers and nonsmokers. RESULTS: Out of 929 eligible publications, 11 articles were included. Meta-analysis of the studies revealed a significantly increased risk of developing wound dehiscence after sinus floor elevation among smokers compared with nonsmokers (Risk Ratio [RR]: 7.82; 95% confidence interval [CI]: 2.38, 25.74; P = .0007). Moreover, risk of developing wound infection was greater in smokers when prospective studies were included in the meta-analysis (RR: 5.33; 95% CI: 1.34, 21.25; P = .02). However, the meta-analysis of included studies did not show significant differences between smokers and nonsmokers concerning risk of sinus membrane perforation and bleeding during sinus floor elevation (P = .46 and P = .33, respectively). CONCLUSION: Considering the lack of randomized controlled trials and the small number of included studies, the results indicate that smoking seems to be associated with increased risk of wound dehiscence and infection after the sinus augmentation procedure.

Antimicrobial photodynamic therapy using diode laser activated indocyanine green as an adjunct in the treatment of chronic periodontitis: A randomized clinical trial.

INTRODUCTION: Clinical studies have shown the usefulness of antimicrobial photodynamic therapy (aPDT) as an adjunctive in periodontal therapy. These studies did not utilize indocyanine green (ICG) as a recently introduced photosensitizer. The aim of this study was to perform a full-mouth double-blind randomized controlled clinical study to test the efficacy of adjunctive aPDT with ICG compared with scaling and root planing (SRP) alone in chronic periodontitis treatment. MATERIALS AND METHODS: Fifty patients were selected for this study. All patients received SRP. Then, each patient was randomly assigned to either the test group (aPDT+SRP) or the control group (SRP). aPDT was performed with a diode laser (wavelength: 810nm, power: 200mW) and ICG as photosensitizer. The adjunctive procedure was repeated after 7, 17 and 27 days. The clinical parameters including bleeding on probing (BOP), clinical attachment loss (CAL), plaque index (PI), probing pocket depth (PPD), full mouth plaque score (FMPS) and full mouth bleeding score (FMBS) were measured at baseline and after 1 and 3 months. RESULTS: There were no significant differences between two groups at baseline. BOP, PPD and FMBS showed significant improvements in the test group (P≤0.001). In terms of PI, FMPS and CAL, no significant differences were observed between both groups (P≥0.05). CONCLUSION: aPDT as an adjunctive approach yielded complete resolution of inflammation and significant reduction in periodontal pocket depth. However, aPDT had no additional advantages in clinical attachment gain and plaque score.

The Versatility of 980 nm Diode Laser in Dentistry: A Case Series.

Introduction: Laser surgery has been considered a popular alternative over conventional modalities in dentistry during the last few years. Among different types of lasers, diode lasers have gained special attention in oral soft tissue surgery. Case Reports: Five patients were referred to a private office. After careful evaluation of medical history and oral examination, oral diagnosis and treatment plan of each patient was established as follows: (1) A 21-year-old female with ankyloglossia (tongue-tie); (2) A 65-year-old female with a poor denture fit needing vestibuloplasty and frenectomy; (3) A 10-year-old male patient with pigmented gingiva in mandible and maxilla; (4) A 14-year-old female needing exposure of maxillary right canine for bracket bonding; and (5) A 25-year-old female patient who has a gingival maxillary frenum with a nodule. The treatment plan for all the patients was laser surgery with diode laser at 980 nm, in continuous mode. Results: All the patients experienced normal healing process with no postoperative complications. Favorable outcomes of laser surgery were observed on follow-up sessions. Conclusion: Considering the versatility of the 980 nm diode laser in oral soft tissue surgeries and the advantages of laser surgery, this study suggests the use of 980 nm diode laser in this regard.

Seroepidemiology of Rubella in Women Under 25 Years Old Attending Medical Centers in Ahvaz, Iran in 2013.

BACKGROUND: Rubella is a mild viral infection affecting women of reproductive age, and the fetus in early pregnancy, leading to miscarriage, stillbirth and Congenital Rubella Syndrome. OBJECTIVES: The present study aimed to assess serum level of anti-rubella antibodies in women younger than 25 years attending medical centers in Ahvaz city. PATIENTS AND METHODS: This descriptive cross-sectional study was conducted on 760 women younger than 25 years attending medical centers in Ahvaz. A sample of 3 mL of venous blood was taken from each woman and ELISA method was used to assess anti-rubella IgG levels. Antibody level more than 11 IU/mL was considered safe. Data was analyzed by SPSS software using Chi-square, ANOVA and Pearson Correlation tests. RESULTS: Of total samples, 683 women (88.9%) had immunity against rubella, 80 (10.4%) no immunity and 5 (0.7%) intermediate levels of antibody. Immunity to rubella increased significantly with aging (P = 0.001) and a significant association was found between age and antibody titer (P = 0.001, r = 0.261). CONCLUSIONS: More than 95% of 15 to 25 year-old women (main reproductive age in Iran) are within acceptable immunity range. Level of immunity to rubella in women of reproductive age in this region appears satisfactory.

Detection of IL-4, IL-6 and IL-12 serum levels in generalized aggressive periodontitis.

BACKGROUND: Periodontitis is a multifactorial chronic inflammatory disease characterized by destruction of tooth-supporting tissues. Environmental and genetic factors as well as the immune system participate in this process. Recent studies have attempted to elucidate the role of cytokine networks involved in periodontal diseases. OBJECTIVE: To assess and compare the levels of IL-4, IL-6 and IL-12 in serum samples of patients with generalized aggressive periodontitis (GAgP) and control individuals. METHODS: A total of 50 subjects were included in the study of which 25 patients had generalized aggressive periodontitis and 25 were healthy unrelated age and gender matched patients undergoing extraction and surgical crown lengthening (control group). Local blood samples of patients were collected from surgical sites of pocket reduction and from healthy individuals before tooth extraction or crown lengthening from non inflamed sites. The levels of IL-4, IL-6 and IL-12 were determined by an ELISA assay using serum samples separated from the whole blood of both groups. RESULTS: The level of IL-4 increased significantly in control group in comparison with the test group (p=0.002). The amount of IL-6 in GAgP patients increased strongly compared with control group (p<0.0001). There was no significant difference between the two groups concerning the level of IL-12. CONCLUSION: There is an association between generalized aggressive periodontitis and low level of IL-4 as an anti-inflammatory cytokine, and high level of IL-6 as a proinflammatory cytokine. No correlation between IL-12 and generalized aggressive peridontitis was found.