Association between dental extraction after radiotherapy and osteoradionecrosis: A multi-centre retrospective study.

OBJECTIVE: Radiotherapy (RT) carries a substantial risk for the development of osteoradionecrosis (ORN) of the jaw. This study was performed to investigate the relationship between dental extractions after RT and the development of ORN. MATERIAL AND METHODS: Thirty-two patients with head and neck cancer who underwent tooth extraction after RT were investigated for correlations between the development of ORN and various factors. RESULTS: Postextraction ORN was diagnosed in 12 (12.1%) teeth of 9 patients. The RT dose against the site of tooth extraction was 62.0 and 37.4 Gy in the ORN and Non-ORN groups, respectively (p < .001). The duration from RT to tooth extraction was 41.2 and 28.2 months in the ORN and Non-ORN groups, respectively (p = .025). Tooth extraction was significantly associated with ORN in patients with a high RT dose against the site (odds ratio = 1.231) and a longer duration of time from RT (odds ratio = 1.084). CONCLUSIONS: Extraction of non-restorable teeth and those with a poor prognosis should not necessarily be postponed even when patients are undergoing RT. However, clinicians should pay special attention to postoperative management after tooth extraction in patients with a high RT dose and longer time from RT.

Oral dysfunctions and cognitive impairment/dementia.

With global increases in the aging population, the number of patients with dementia is greatly increasing, which has become a big social problem. Many studies have shown strong associations between oral disorders and systemic disorders, such as diabetes, arthritis, sepsis, aspiration pneumonia, arteriosclerosis, bacterial endocarditis, and other cardiovascular diseases. Similarly, numerous cross-sectional studies showed that patients with dementia usually have poor oral conditions and tooth loss. These have long been considered as a result of difficulty with oral care due to impaired cognitive function, memory, and physical ability in patients with dementia. Indeed, even in patients with mild cognitive impairment, oral care becomes insufficient owing to decreases in spontaneity of grooming and finger dexterity. However, recent studies have shown that tooth loss and occlusal dysfunction may affect brain function and trigger the onset of dementia found in neurodegenerative diseases including Alzheimer's disease. In this review, we highlight the relationships among aging, oral dysfunction, and the development of dementia. Increasing evidence suggests that oral dysfunction is not only a result of dementia in the elderly people, but could also be a causative factor for the onset of dementia.

Secondary endpoints analysis in patients with estrogen receptor-positive metastatic breast cancer treated with everolimus and exemestane enrolled in Oral Care-BC.

BACKGROUND: The Oral Care BC-trial reported that professional oral care (POC) reduces the incidence and severity of oral mucositis in patients receiving everolimus (EVE) and exemestane (EXE). However, the effect of POC on clinical response among patients receiving EVE and EXE was not established. We compared outcomes for estrogen receptor-positive metastatic breast cancer patients who received POC to those who had not, and evaluated clinical prognostic factors. All patients simultaneously received EVE and EXE. METHODS: Between May 2015 and Dec 2017, 174 eligible patients were enrolled in the Oral Care-BC trial. The primary endpoint was the comparative incidence of grade 1 or worse oral mucositis, as evaluated for both the groups over 8 weeks by an oncologist. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collected after a follow-up period of 13.9 months. RESULTS: There were no significant differences in PFS between the POC and Control Groups (P = 0.801). A BMI <  25 mg/m2 and non-visceral metastasis were associated with longer PFS (P = 0.018 and P = 0.003, respectively) and the use of bone modifying agents (BMA) was associated with shorter PFS (P = 0.028). The PFS and OS between the POC and control groups were not significantly different in the Oral-Care BC trial. CONCLUSIONS: POC did not influence the prognosis of estrogen receptor-positive metastatic breast cancer patients. Patients with non-visceral metastasis, a BMI <  25 mg/m2, and who did not receive BMA while receiving EVE and EXE may have better prognoses. TRIAL REGISTRATION: The study protocol was registered online at the University Hospital Medical Information Network (UMIN), Japan (protocol ID 000016109), on January 5, 2015 and at ClinicalTrials.gov ( NCT02376985 ).

Oral Care Evaluation to Prevent Oral Mucositis in Estrogen Receptor-Positive Metastatic Breast Cancer Patients Treated with Everolimus (Oral Care-BC): A Randomized Controlled Phase III Trial.

BACKGROUND: The incidence of oral mucositis (any grade) after everolimus treatment is 58% in the general population and 81% in Asian patients. This study hypothesized that professional oral care (POC) before everolimus treatment could reduce the incidence of everolimus-induced oral mucositis. MATERIALS AND METHODS: This randomized, multicenter, open-label, phase III study evaluated the efficacy of POC in preventing everolimus-induced mucositis. Patients were randomized into POC and control groups (1:1 ratio) and received everolimus with exemestane. Patients in the POC group underwent teeth surface cleaning, scaling, and tongue cleaning before everolimus initiation and continued to receive weekly POC throughout the 8-week treatment period. Patients in the control group brushed their own teeth and gargled with 0.9% sodium chloride solution or water. The primary endpoint was the incidence of all grades of oral mucositis. We targeted acquisition of 200 patients with a 2-sided type I error rate of 5% and 80% power to detect 25% risk reduction. RESULTS: Between March 2015 and December 2017, we enrolled 175 women from 31 institutions, of which five did not receive the protocol treatment and were excluded. Over the 8 weeks, the incidence of grade 1 oral mucositis was significantly different between the POC group (76.5%, 62 of 82 patients) and control group (89.7%, 78 of 87 patients; p = .034). The incidence of grade 2 (severe) oral mucositis was also significantly different between the POC group (34.6%, 28 of 82 patients) and control group (54%, 47 of 87 patients; p = .015). As a result of oral mucositis, 18 (22.0%) patients in the POC group and 28 (32.2%) in the control group had to undergo everolimus dose reduction. CONCLUSION: POC reduced the incidence and severity of oral mucositis in patients receiving everolimus and exemestane. This might be considered as a treatment option of oral care for patients undergoing this treatment. Clinical trial identification number: NCT02069093. IMPLICATIONS FOR PRACTICE: The Oral Care-BC trial that prophylactically used professional oral care (POC), available worldwide, did not show a greater than 25% difference in mucositis. The 12% difference in grade 1 or higher mucositis and especially the ∼20% difference in grade 2 mucositis are likely clinically meaningful to patients. POC before treatment should be considered as a treatment option of oral care for postmenopausal patients who are receiving everolimus and exemestane for treatment of hormone receptor-positive, HER2-negative advanced breast cancer and metastatic breast cancer. However, POC was not adequate for prophylactic oral mucositis in these patients, and dexamethasone mouthwash prophylaxis is standard treatment before everolimus.

Clinicopathological significance of EGFR pathway gene mutations and CRTC1/3-MAML2 fusions in salivary gland mucoepidermoid carcinoma.

AIMS: Mucoepidermoid carcinoma (MEC) is one of the most common salivary gland carcinomas. Epidermal growth factor receptor (EGFR) signalling pathway gene mutations are important in predicting a patient's prognosis, selecting molecularly targeted drugs and estimating the efficacy of a molecular therapy. However, their significance in MEC have been poorly clarified. CRTC1/3-MAML2 fusions are specific to MEC and may be associated with favourable characteristics in these patients. METHODS AND RESULTS: We looked for CRTC1/3-MAML2 fusions and gene alterations in the EGFR, RAS family (KRAS, HRAS and NRAS), PIK3CA, BRAF and AKT1 in 101 MEC cases. We also examined mutations in TP53. CRTC1/3-MAML2 fusions were found in 62.4% of the cases. KRAS, HRAS and PIK3CA mutations were detected in 6.9%, 2.0% and 6.9%, respectively, but other EGFR pathway genes were not mutated. In total, gene mutations (RAS/PIK3CA) in the EGFR pathway were detected in 14.9% of the cases. TP53 mutations were found in 20.8%. CRTC1/3-MAML2 fusions were associated with a better prognosis and RAS/PIK3CA mutations a worse prognosis of the patients, respectively, and both were selected as independent prognostic factors for the overall survival of the patients. TP53 mutations had no prognostic impact. CRTC1/3-MAML2 fusion-positive rates were inversely associated with the patients' age and the fusions were found in 82% of patients aged < 30 years. CONCLUSIONS: RAS/PIK3CA mutations were frequently detected, and may be a biomarker for a poorer prognosis in MEC patients. CTRC1/3-MAML2 fusions were positive in most of the young MEC patients.

Drug holiday clinical relevance verification for antiresorptive agents in medication-related osteonecrosis cases of the jaw.

Treatment strategies of medication-related osteonecrosis of the jaw (MRONJ) are controversial. Recently, surgical treatment has been reported as superior to nonsurgical treatment, but the contribution discontinued antiresorptive agent use during MRONJ treatment remains unclear. This study aimed to evaluate the efficacy of drug holidays and treatment strategies in MRONJ cases. Four-hundred and twenty-seven patients with MRONJ treated at nine hospitals from 2009 to 2017 were included in this multicenter retrospective study. Multivariate Cox regression analysis showed that the primary disease (osteoporosis or malignant tumor), diabetes, serum albumin, and treatment method (surgical or nonsurgical) were significantly correlated with the cure rate. The cumulative 1-year cure rates in the surgical and nonsurgical treatment groups were 64.7% and 18.2%, respectively. However, discontinuing antiresorptive agents did not influence the treatment outcome in the cohort overall, or in 230 patients after performing propensity score matching among the discontinuation and continuation groups. When stratifying by treatment method, antiresorptive agent discontinuation significantly increased the cure rate in patients with osteoporosis who underwent nonsurgical treatment. In patients with malignant tumors undergoing nonsurgical therapy, discontinuing the antiresorptive agent was associated with a better treatment outcome, but not with statistical significance. In contrast, drug holidays showed no effect on improving outcomes in patients with both osteoporosis and malignant tumors who underwent surgical therapy. Thus, regardless of the primary disease, discontinuing antiresorptive agents during treatment for MRONJ may not be necessary and may be helpful in some cases. Future prospective trials should examine this question further.

Prevalence of and risk factors for postoperative hemorrhage after lower third molar extraction on warfarin therapy: a multicenter retrospective study in Japan.

Postoperative hemorrhage after tooth extraction is a critical and clinically important issue for clinicians and patients receiving anticoagulants. The purpose of the present study was to investigate the prevalence of and risk factors for postoperative hemorrhage after lower third molar extraction in Japanese patients receiving warfarin therapy. A total of 142 patients who underwent lower third molar extraction between January 2010 and December 2016 were included, and their medical records were retrospectively reviewed. The prevalence of and risk factors for postoperative hemorrhage were investigated. The prevalence of postoperative hemorrhage after lower third molar extraction was significantly higher in patients receiving warfarin than in healthy subjects (21.8% vs 0.7%, P < 0.001). The cutoff value for PT-INR was 2.11 based on a receiver-operating characteristic analysis. A multivariate analysis indicated that an elevated PT-INR value [hazard ratio (HR) 3.798, 95% confidence interval (CI) 1.400-10.467, P < 0.01], preoperative antibiotic administration (HR 4.434, 95% CI 1.591-14.775, P < 0.01), difficulties with intraoperative hemostasis (HR 16.298, 95% CI 2.986-110.677, P < 0.01), and higher serum creatinine levels (HR 7.465, 95% CI 1.616-39.576, P < 0.05) are significant predictors of postoperative hemorrhage after lower third molar extraction. Multivariate correlations were observed between risk factors including an elevated PT-INR value, preoperative antibiotic administration, and higher serum creatinine levels, and postoperative hemorrhage after lower third molar extraction in patients receiving warfarin therapy. Clinicians need to consider these risk factors for postoperative hemorrhage after the lower third molar extraction and monitor PT-INR in patients receiving warfarin therapy.

The isoflavone fraction from soybean presents mRNA maturation inhibition activity.

Recent findings indicate that mRNA splicing inhibitors can be potential anticancer candidates. We have previously established a screening system which monitors mRNA processing in order to identify mRNA processing inhibitors. Among a number of dietary resources, isoflavone fractions showed an inhibitory effect of mRNA processing. These findings demonstrate that a variety of dietary sources have an impact on mRNA biogenesis.

Multicenter Retrospective Study of the Risk Factors of Hemorrhage After Tooth Extraction in Patients Receiving Antiplatelet Therapy.

PURPOSE: To identify the risk factors affecting hemorrhage after tooth extraction in patients receiving antiplatelet therapy, this study investigated the relation between various factors and hemorrhage events after tooth extraction. PATIENTS AND METHODS: The records of 264 patients receiving antiplatelet therapy who underwent tooth extraction were retrospectively reviewed from 6 institutions belonging to the Japanese Study Group of Cooperative Dentistry with Medicine. Demographic information, hemorrhage events after tooth extraction, the presence or absence of comorbidities, antiplatelet agent, the use of preoperative antibiotics or nonsteroidal anti-inflammatory drugs, number of teeth extracted, serum creatinine level, estimated glomerular filtration rate, and alanine transaminase level were assessed. Risk factors for hemorrhage after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: The study population of 264 patients consisted of 153 men and 111 women with a mean age of 73.6 years (range, 24 to 96 yr). Six hundred ninety-four teeth were extracted (mean, 2.6 ± 2.3 teeth per patient). In patients receiving antiplatelet therapy, the frequency of hemorrhage after tooth extraction, including mild and self-controlled hemorrhages, was 17.4%. Univariate analysis showed that serum creatinine level and dual antiplatelet therapy were correlated with hemorrhage after tooth extraction (P = .001 and P = .049, respectively). Only serum creatinine was identified as an independent risk factor for hemorrhage after tooth extraction in patients receiving antiplatelet therapy (P = .037). CONCLUSIONS: The risk of hemorrhage after tooth extraction is increased in patients receiving dual antiplatelet therapy with or without chronic kidney disease. Local hemostatic treatments, such as at least suturing, are recommended.

Crestal Approach to Sinus Floor Elevation for Atrophic Maxilla Using Platelet-Rich Fibrin as the Only Grafting Material: A 1-Year Prospective Study.

PURPOSE: Platelet-rich fibrin (PRF) has been recently used as the sole grafting material in sinus floor elevation procedures. The aim of this prospective study was to measure the bone gain around the dental implant after using the crestal approach to sinus floor elevation using platelet-rich fibrin as the only grafting material in atrophic posterior maxillae with residual bone height <5 mm. MATERIALS AND METHODS: Two different types of implants were used: hydroxyapatite (HA) and sandblasted acid-etched (SA) implants. Panoramic radiography and computed tomography were used to measure the endosinus bone gain. RESULTS: Twenty-seven patients with 39 implants (19 HA and 20 SA) were included in this study. The mean residual bone measurements before surgery in the SA and HA groups were 2.85 and 2.68 mm, respectively. The mean average bone gains for 1 year in the SA and HA groups were 4.38 and 4.00 mm, respectively. CONCLUSION: This prospective study showed that platelet-rich fibrin promoted endosinus bone gain when used as the grafting material in the crestal approach to sinus floor elevation.

Postradiotherapy Dental Implant Insertion Into Bone Grafts Harvested From Nonirradiated Tissue: Case Reports.

BACKGROUND: Prostheses and dental implants are often used to aid oral rehabilitation after surgery (with/without radiotherapy) for oral cancer. However, some studies have reported that the insertion of dental implants into irradiated bone results in a higher frequency of implant failure than the insertion of such implants in nonirradiated bone. MATERIALS AND METHODS: This report describes the cases of 4 patients with oral cancer who underwent surgery and radiotherapy (total dose: 50-86 Gy) and then had dental implants inserted within the irradiated area. In each case, an ilium bone graft or a latissimus dorsi myocutaneous flap containing scapular bone was transferred to the dental implant site before the insertion of the implants. RESULTS: Twenty-three implants were inserted. After loading, 2 implants were lost, and 21 remained stable. CONCLUSION: In patients who have undergone radiotherapy for oral cancer, transferring bone grafts harvested from nonirradiated tissue to the irradiated site before implant insertion might help to improve dental implant survival rates.

CT Evaluation of Morphology of Transferred Fibula for Implant Placement in Reconstructed Mandible.

BACKGROUND: Dental rehabilitation with osseointegrated implants in reconstructed mandibles remains one of the most challenging procedures for oral and maxillofacial surgeons. Satisfactory outcome requires appropriate assessment of graft morphology. There are few analyses of the morphology of fibulae in reconstructed mandibles, although cadaver studies on fibular shape have been performed. MATERIALS AND METHODS: In this study, we used postoperative computed tomography to retrospectively evaluate the shape, height, and orientation of fibulae transferred after mandibulectomy in 19 patients. RESULTS: The average height of transferred fibulae was 14.3 mm (range, 10.8-20.5 mm). The cross-sectional morphology of transferred fibulae could be classified into 2 types: apex and nonapex. The former type included knife-edged and triangular shapes; the latter included square and circular shapes. CONCLUSION: When implant insertion is planned in a reconstructed mandible, the orientation of the apex of transferred fibula should be evaluated preoperatively to allow for adjustments in implant procedure because the ridge at the apex of the fibula is narrow.

Texture Analysis of Food Samples Used for the Evaluation of Masticatory Function.

Introduction Food questionnaire surveys are often used to evaluate masticatory function. In daily clinical practice in Japan, a survey is performed using a list of food groups suitable for the Japanese diet. The foods on the list were categorized into five food groups based on their mastication index. The patient's masticatory function is determined by the food groups that can be eaten. The masticatory index, which indicates chewability, was defined based on the percentage of 110 denture wearers who responded that they could eat food normally. A survey with this list is useful because of its simplicity; however, there is a lack of objective data on the physical properties of food samples. Consequently, to make the results of the food questionnaire survey more objective indicators, we performed a texture analysis of the food samples on the list. Methods We performed a texture analysis of 93 samples from 77 food items on the list. Compression tests were performed using a texture analyzer, and hardness, cohesiveness, adhesiveness, viscosity, and gumminess were calculated by a texture profile analysis. Results Even with the same ingredients, the results differed depending on the presence or absence of food skin, the direction of pressing (vertical or horizontal), cooking methods, and temperature differences. However, the masticatory index was negatively correlated with hardness (-0.4157, p<0.001) and gumminess which is determined as the product of hardness×cohesiveness (-0.4980, p<0.001). Conclusion This study suggests that the masticatory index indicating chewability may be related to the hardness and cohesiveness of food samples. Even for foods with the same hardness, the degree of difficulty in forming a food mass is expected to vary depending on differences in cohesiveness. Moreover, the presence or absence of food skin, the direction of food fibers, cooking methods, and temperature differences change the physical properties of the food. Therefore, the composition and structure of the foods or eating habits of patients should be taken into consideration when conducting a food questionnaire survey.

Efficacy of perioperative oral care management in the prevention of surgical complications in 503 patients after pancreaticoduodenectomy for resectable malignant tumor: A multicenter retrospective analysis using propensity score matching.

BACKGROUND: Pancreaticoduodenectomy has been associated with a high mortality rate and significant postoperative morbidity. Recently, perioperative oral care management has been reported to be effective in preventing postoperative pneumonia and surgical site infection. In this study, we examined the effect of perioperative oral care management in reducing complications after pancreaticoduodenectomy, including surgical site infection. METHODS: This retrospective multicenter study included 503 patients who underwent pancreaticoduodenectomy at 8 facilities between January 2014 and December 2016. Among these, 144 received perioperative oral management by dentists and dental hygienists (oral management group), whereas the remaining 359 did not (control group). The oral care management program included oral health instructions, removal of dental calculus, professional mechanical tooth cleaning, removal of tongue coating, denture cleaning, instructions for gargling, and tooth extraction. The participants were matched using propensity scores to reduce background bias. Various factors were examined for correlation with the development of complications. RESULTS: The incidence of organ/space surgical site infection was significantly lower in the oral management group than in the control group (8.0% vs 19.6%, P = .005). Multivariable logistic regression analysis revealed that hypertension and lack of perioperative oral management were independent risk factors for organ/space surgical site infection. Lack of perioperative oral management had an odds ratio of 2.847 (95% confidence interval 1.335-6.071, P = .007). CONCLUSION: Perioperative oral care management reduces the occurrence of surgical site infections after pancreaticoduodenectomy and should be recommended as a strategy to prevent infections in addition to antibiotic use.

Oral squamous cell carcinoma with multiple neck metastases--cases with more than ten pathologically positive lymph nodes in the unilateral side.

PURPOSE: The purpose of this study is to know an outcome of the treatment for oral squamous cell carcinoma having more than 10 unilateral pathologically positive lymph nodes (pN)s. PATIENTS AND METHODS: We reviewed 212 primary cases of oral squamous cell carcinoma that visited our hospital from January 1999 to December 2011 and underwent resection of the primary tumor with neck dissection. The patients were classified into 3 categories of pN0, pN1-9, and pN ≥ 10 cases, and an outcome of pN ≥ 10 was studied specifically in comparison with the other categories. RESULTS: Of the patients studied, 103 cases (48.6%) were pN0, 103 cases (48.6%) were pN1-9, and 6 cases (2.8%) were pN ≥ 10. The pN ≥ 10 group, which had positive nodes of 10 to 30 on the ipsilateral side, was predominantly male and had no cases of well-differentiated squamous cell carcinoma. Extracapsular spread (ECS) was found in all pN ≥ 10 cases, and postoperative distant metastasis occurred in cases with ECS, which was localized in levels higher than III. The proportion of distant metastasis was 0% (0 cases) in pN0, 8.7% (9 cases) in pN1-9, and 66.7% (4 cases) in pN10. Overall survival rate in pN ≥ 10 was 20.8%, whereas it was 89.0% in pN0, and 34.9% in pN1-9. CONCLUSION: Oral squamous cell carcinoma having multiple neck metastases (pN ≥ 10) had a poor prognosis because the proportion of distant metastasis was higher in comparison with the other groups of pN0 and pN1-9.

Observation of osseous healing after intraoral vertical ramus osteotomy: focus on computed tomography values.

PURPOSE: The purpose of this study was to observe long-term osseous healing of the cleavage space between bone fragments after intraoral vertical ramus osteotomy using computed tomographic (CT) values. PATIENTS AND METHODS: CT examinations were performed to observe long-term osseous healing immediately after intraoral vertical ramus osteotomy and at 6 months, 1 year, and 2 years postoperatively. Bone fragments were observed on the interior and lateral sides. CT values between bone fragments were used to measure the range of each point within a 1.7- × 1.7-mm square, and the mean of the measurements was calculated. RESULTS: CT values between bone fragments increased significantly over time at 1 month, 6 months, 1 year, and 2 years after surgery. CONCLUSIONS: Osseous healing in the cleavage between bone fragments after intraoral vertical ramus osteotomy was successful according to CT values.

Myelosuppression grading of chemotherapies for hematologic malignancies to facilitate communication between medical and dental staff: lessons from two cases experienced odontogenic septicemia.

BACKGROUND: Odontogenic diseases can be a risk factor for life-threatening infection in patients with hematologic malignancies during chemotherapy that induces myelosuppression of variable severity. Previous studies noted the necessity of the elimination of all odontogenic foci before hematopoietic stem cell transplantation. To enable planning for the adequate dental intervention, the oral medicine team must understand the general status of patient and the intensity of the chemotherapy, which is sometimes difficult to be fully appreciated by dental staff. Therefore, a simplified grading would facilitate the sharing of information between hematologists, dentists and oral hygienists. This study aimed to introduce our myelosuppression grading of chemotherapies for hematologic malignancies and analyze the timing of occurrence of severe odontogenic infection. METHODS: 37 patients having received various chemotherapies for hematologic malignancies were enrolled. The chemotherapy regimens were classified into four grades based on the persistency of myelosuppression induced by chemotherapy. Mild myelosuppressive chemotherapies were classified as grade A, moderate ones as grade B, severe ones as grade C, and chemotherapies that caused severe myelosuppression and persistent immunodeficiency (known as conditioning regimens for transplant) as grade D. The timing of occurrence of severe odontogenic infection was retrospectively investigated. RESULTS: Two patients (5.4%) had severe odontogenic infections after grade B or C chemotherapy. One occurred after extraction of non-salvageable teeth; the other resulted from advanced periodontitis in a tooth that could not be extracted because of thrombocytopenia. Both were de novo hematologic malignancy patients. During grade D chemotherapy, no patients had severe odontogenic infections. CONCLUSIONS: The simplified grading introduced in this study is considered a useful tool for understanding the myelosuppressive state caused by chemotherapy and facilitating communication between medical and dental staff. During the period around the primary chemotherapy, especially for de novo hematologic malignancy patients who often received grade B to C myelosuppression chemotherapy, caution should be exercised for severe odontogenic infection by the oral medicine team, irrespective of whether invasive treatment is to be performed.

Aß42 treatment of the brain side reduced the level of flotillin from endothelial cells on the blood side via FGF-2 signaling in a blood-brain barrier model.

Our previous study showed that the flotillin level is decreased in the blood of patients with Alzheimer's disease (AD) when compared to that of patients with non-AD and vascular dementia; however, the molecular mechanism remains to be determined. In this study, to elucidate whether Aß accumulation in the brain has an effect on the blood flotillin level, we used our previously established blood-brain barrier (BBB) culture model using microvascular endothelial cells obtained from human induced pluripotent stem cells (iBMECs) and astrocytes prepared from rat cortex. In this BBB model with iBMECs plated on the upper compartment (blood side) and astrocytes plated on the lower compartment (brain side), the trans-endothelial electrical resistance values are high (over 1500 Ωm2) and stable during experiments. We found that the addition of Aß42 (0.5 and 2 µM) to the brain side significantly reduced the level of flotillin secreted by iBMECs on the blood side. The level of basic fibroblast growth factor (FGF-2) in the brain side was significantly reduced by Aß42 treatment, and was accompanied by a reduction in the level of phosphorylation of the fibroblast growth factor receptor in iBMECs. The brain-side Aß42 treatment-induced reduction of flotillin secretion into the blood side was restored in a dose-dependent manner by the addition of FGF-2 into the brain side. These results indicated that Aß accumulation in the brain side reduced FGF-2 release from astrocytes, which attenuated FGF-2-mediated iBMECs signaling via the FGF-2 receptor, and thereby reduced flotillin secretion from iBMECs on the blood side. Our findings revealed a novel signaling pathway crossing the BBB from the brain side to the blood side, which is different from the classical intramural periarterial drainage or lymphatic-system-to-blood pathway.

Alkali-treated titanium dioxide promotes formation of proteoglycan layer and altered calcification and immunotolerance capacity in bone marrow stem cell.

Introduction: In this study, we report that a proteoglycans (PGs)-layer between the bone and titanium dioxide (TiO2) surface after osseointegration improved the calcification capacity and immunotolerance of human bone marrow mesenchymal stem cells (hBMSCs) on TiO2. Alkaline treatment of TiO2 is a method for promoting osteogenesis in hBMSCs. We hypothesized that promotion of osteogenesis due to alkaline treatment was caused by changing PGs-layer on TiO2. Objective: This study aimed to analyze whether alkaline treatment of TiO2 affects PGs-layer formation and immunotolerance in hBMSCs. Methods: The topology and wettability of the alkaline-treated titanium (Ti-Al) and unprocessed titanium (Ti-MS) surfaces were characterized. Initial cell attachment, cell proliferation, calcification capacity, alkaline phosphatase activity, PGs-layer formation, PGs function, and the expression of osteogenic and immunotolerance-related genes were analyzed. The conditioned medium (CM) from hBMSCs grown on Ti-Al and Ti-MS was added to macrophages (hMps) and Jurkat cells, and immunotolerance gene expression in these cells was analyzed. Results: hBMSCs cultured on Ti-Al showed increased initial cell attachment, cell proliferation, PG-layer formation, and osteogenic capacity compared with hBMSCs on Ti-MS. Gene expression of indoleamine 2,3-dioxygenase (IDO) in the hBMSCs cultured on Ti-Al was higher than that in the hBMSCs on Ti-MS. CM from hBMSCs did not affect markers of M1 and M2 macrophages in hMps. CM from hBMSCs cultured on Ti-Al altered the gene expression of Foxp3 in Jurkat cells compared to that of CM from hBMSCs on Ti-MS. Significance: These results suggest that alkaline treatment of TiO2 altered PGs-layer formation, and changed the osteogenesis and immunotolerance of hBMSCs.

Prevention of lingual inclination of the transport segment in vertical distraction osteogenesis in the mandible.

Vertical distraction osteogenesis can extend not only to hard tissues but also to soft tissues. There is a tendency to cause progressive lingual inclination of the distracted segment. This study describes a method for preventing the lingual inclination of the transport segment in patients with vertical distraction osteogenesis in the anterior region of the mandible and reports the results of long-term follow-up. The subjects included 5 patients who had severely atrophic ridges in the anterior mandible. In all cases, a part of the mental protuberance was scraped out, and the distractor was placed suitably in a labioinclination beforehand. Therefore, the transport segments did not lean to the lingual side and had long-term stability.