Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

A multicenter retrospective study of the risk factors associated with medication-related osteonecrosis of the jaw after tooth extraction in patients receiving oral bisphosphonate therapy: can primary wound closure and a drug holiday really prevent MRONJ?

Root amputation, extraction of a single tooth, bone loss or severe tooth mobility, and an unclosed wound were significantly associated with increased risk of developing medication-related osteonecrosis of the jaw (MRONJ). We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. INTRODUCTION: Osteonecrosis of the jaws can occur following tooth extraction in patients receiving bisphosphonate drugs. Various strategies for minimizing the risk of MRONJ have been advanced, but no studies have comprehensively analyzed the efficacy of factors such as primary wound closure, demographics, and drug holidays in reducing its incidence. The purpose of this study was to retrospectively investigate the relationships between these various risk factors after tooth extraction in patients receiving oral bisphosphonate therapy. METHODS: Risk factors for MRONJ after tooth extraction were evaluated using univariate and multivariate analysis. All patients were investigated with regard to demographics; type and duration of oral bisphosphonate use; whether they underwent a discontinuation of oral bisphosphonates before tooth extraction (drug holiday), and the duration of such discontinuation; and whether any additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 6.64), extraction of a single tooth (OR = 3.70), bone loss or severe tooth mobility (OR = 3.60), and an unclosed wound (OR = 2.51) were significantly associated with increased risk of developing MRONJ. CONCLUSIONS: We recommend a minimally traumatic extraction technique, removal of any bone edges, and mucosal wound closure as standard procedures in patients receiving bisphosphonates. We find no evidence supporting the efficacy of a pre-extraction short-term drug holiday from oral bisphosphonates in reducing the risk of MRONJ.

Development of an improved method for quantitative analysis of skin blotting: increasing reliability and applicability for skin assessment.

OBJECTIVE: A novel skin assessment tool named 'skin blotting' has been recently developed, which can easily predict the skin status to avoid its deterioration. The aim of this study was to propose a normalization method for skin blotting to compensate for individual differences that can hamper the quantitative comparisons and clinical applications. METHODS: To normalize individual differences, we utilized a total protein as a 'normalizer' with calibration curves. For evaluation, we performed a simple simulation experiment, in which the same concentration of a protein of interest [tumour necrosis factor (TNF)-α] was applied at different volumes as a virtual individual difference. Moreover, to demonstrate the applicability of this normalization, male volunteers were recruited for skin blotting followed by the estimation of TNF-α with normalization. RESULTS: We obtained good calibration curves for total protein (R(2)  = 0.995) and TNF-α (R(2)  = 0.997), both of which were necessary for an exact quantification. In the simulation experiment, we estimated the exact concentration of TNF-α regardless of the applied volume, demonstrating the applicability of this normalization method in skin blotting. Further, skin blotting on human subjects showed a wide range of variation in the total protein content, although the normalization was thought to reduce such individual variations. CONCLUSION: This study has proposed total protein normalization for skin blotting with calibration curves. This method may strengthen the quantitative performance of skin blotting, which may expand the applicability of this method as a skin assessment tool in broader fields, such as nursing and cosmetology.

Evaluation of masticatory function after maxillectomy using a colour-changing chewing gum.

The purpose of this study was to identify the risk factors associated with the masticatory dysfunction after maxillectomy using a colour-changing chewing gum. Thirty-nine patients who underwent maxillectomy between January 2002 and May 2010 in the Department of Kobe University Hospital were recruited for this study. There were 20 male and 19 female subjects, with a median age of 73·3 years (range of 44-90) at the time of surgery. The intra-oral conditions after maxillectomy were classified by HS classification, and the masticatory function was evaluated by a colour-changing chewing gum and the results of a modified Sato's questionnaire. The scores of the colour-changing gum were closely correlated with the scores of the modified Sato's questionnaire (r = 0·661, P < 0·01). A logistic regression analysis with the outcome variable of the gum test <4 demonstrated that significant predictors for the masticatory dysfunction were the number of anchor teeth ≤2 and a soft palate defect. A colour-changing gum was found to be useful for evaluating the post-operative masticatory function, and it was important to conserve the anchor teeth and the soft palate to avoid masticatory dysfunction.

Evaluating the masticatory function after mandibulectomy with colour-changing chewing gum.

The aim of this study was to clarify the usefulness of colour-changing gum in evaluating masticatory performance after mandibulectomy. Thirty-nine patients who underwent mandibulectomy between 1982 and 2010 at Kobe University Hospital were recruited in this study. There were 21 male and 18 female subjects with a mean age of 64·7 years (range: 12-89 years) at the time of surgery. The participants included six patients who underwent marginal mandibulectomy, 21 patients who underwent segmental mandibulectomy and 12 patients who underwent hemimandibulectomy. The masticatory function was evaluated using colour-changing chewing gum, gummy jelly and a modified Sato's questionnaire. In all cases, the data were obtained more than 3 months after completing the patient's final prosthesis. The colour-changing gum scores correlated with both the gummy jelly scores (r = 0·634, P < 0·001) and the total scores of the modified Sato's questionnaire (r = 0·537, P < 0·001). In conclusion, colour-changing gum is a useful item for evaluating masticatory performance after mandibulectomy.

Influence of the Crystallization Firing Process on Marginal and Internal Adaptation of Silicate-based Glass-ceramic Inlays Fabricated With a CAD/CAM Chairside System.

OBJECTIVE: Computer-aided design/computer-aided manufacturing (CAD/CAM) systems are widely used in dental treatment. Clinicians can use chairside CAD/CAM technology, which has the advantage of being able to fabricate inlays on the same day. We aimed to evaluate the effects of crystallization firing processes, fabrication methods (one-step and two-step), and materials on marginal and internal adaptations of silicate-based glass-ceramic all-ceramic inlays fabricated with CAD/CAM chairside systems. METHODS: Ten artificial mandibular left first molars were prepared with standardized ceramic class II mesialocclusal (MO) inlay cavities. Optical impressions were obtained using CEREC Omnicam Ban. IPS e-max CAD (IE), (Ivoclar Vivadent, Schaan, Liechtenstein), Initial LiSi Block (LS) (Hongo, Bunkyoku, Tokyo, Japan), VITA Suprinity (SP), (Vita Zahnfabrick, Bad Säckingen, Germany), and Celtra Duo (CD) (Ivoclar Vivadent, Schaan, Liechtenstein) (n=10) were milled using CEREC MC XL (Bensheim, Germany). IE and SP were crystallization-fired using CEREC Speed Fire. The silicone replica technique was used for the measurement of internal (axial and pulpal walls) and marginal (cervical and occlusal edge) adaptations. The adaptations were measured using a thin layer of light-body polyvinyl siloxane impression material placed between the master tooth inlay preparation and restoration. Marginal and internal adaptations of IE, LS, SP, and CD were measured using a stereomicroscope (500×). For IE and SP, marginal and internal adaptations were measured before and after the crystallization firing process. Data analyses were conducted using one-way ANOVA and the Tukey test. For IE and SP, marginal and internal adaptations before and after the crystallization firing process were analyzed using the t-test. The significance level was set at α=0.05. RESULTS: One-way ANOVA revealed statistically significant differences in occlusal and cervical edge marginal adaptations among the material groups (p<0.001). The Tukey HSD test revealed a significant difference in marginal occlusal and cervical edge adaptations between LS and CD groups and IE and SP groups (p≤0.05). For IE and SP inlays, the t-test revealed a significant difference between occlusal and cervical edge adaptations before the crystallization firing process and those after the crystallization firing process, with the latter group showing a more significant discrepancy in adaptation than the former group (p≤0.05). CONCLUSIONS: Fabrication methods (one- and two-step) affected the marginal adaptation compatibility but not internal compatibility of MO inlays. The crystallization firing process affected the marginal adaptation of inlays using lithium silicate or lithium disilicate glass-ceramics. However, adaptation to the cavity was considered clinically acceptable for all materials.

Difference in dental arch size between obese and non-obese patients with obstructive sleep apnoea.

A large tongue is recognised as a factor that increases the collapsibility of the upper airway in obstructive sleep apnoea (OSA) patients. We hypothesised that the propensity to develop severe OSA could be minimised if the dental arches were enlarged in obese OSA people who are thought to have a large tongue. We therefore compared the size of the dental arches in obese and non-obese OSA patients. Using a lateral cephalogram and study models, we compared the sizes of the tongue and dental arches in 23 obese and 23 non-obese Japanese male OSA patients, who were matched for age, apnoea hypopnea index (AHI) and maxillomandibular size. The median age (years) and AHI (events per hour) for the obese and non-obese groups were 36·5 and 39·0, and 13·4 and 14·3, respectively. The maxillomandibular size was matched with regard to SNA, SNB and lower face cage obtained from cephalometric measurements. The parameters that were measured for the study model included dental arch width, dental arch length, overjet and overbite. Tongue size (P < 0·05) and both upper (P < 0·01) and lower (P < 0·05) dental arch widths were significantly larger in obese than in non-obese OSA patients, and there was no difference in the severity of OSA between the two groups. These findings suggest that the tongue was larger and dental arches were enlarged in obese patients compared with non-obese patients under the same disease severity. Wider dental arches in obese OSA patients may help to offset the impact of the enlarged tongue on upper airway patency.

In Vivo Ca2+ Imaging of the Insular Cortex during Experimental Tooth Movement.

Pain and discomfort are common problems for patients undergoing orthodontic treatment. We have demonstrated that cortical excitation propagation in the somatosensory and insular cortices (IC) induced by electrical stimulation of the periodontal ligament (PDL) is facilitated 1 d after experimental tooth movement (ETM). However, it is necessary to examine ETM-induced changes in neural responses at a single-cell level to understand the mechanisms of cortical plastic changes, in which excitatory glutamatergic and inhibitory GABAergic neurons are intermingled to form cortical local circuits. We performed in vivo 2-photon Ca2+ imaging by loading the Ca2+ indicator Oregon Green BAPTA with the astrocyte marker sulforhodamine. We focused on the IC region that exhibited the largest neural response to maxillary PDL (mxPDL) stimulation using a VGAT-Venus transgenic rat that expresses venus fluorescent protein in GABAergic neurons and discerned changes in the neural activities of each cortical neuronal subtype before and during ETM treatment of the maxillary incisor and first molar. Notably, 1 d after ETM treatment (1d-ETM), the number of neurons responding to mxPDL stimulation increased from 47.6% to 64.2% in excitatory neurons and from 44.5% to 66.2% in inhibitory neurons. On the other hand, only 3% to 4% of excitatory and inhibitory neurons responded to mandibular molar PDL (mbPDL) stimulation in control rats, and the 1d-ETM group showed significant increases in excitatory (14.0%) and inhibitory neurons (22.5%) responding to mbPDL stimulation. Interestingly, most mbPDL-responding neurons also responded to mxPDL stimulation. The population of excitatory and inhibitory neurons that responded only to mxPDL stimulation was comparable between the control and 1d-ETM groups. The facilitative responses in the 1d-ETM group had almost recovered 7 d after ETM treatment. These results suggest that ETM induces parallel increases in PDL-responding neurons and changes some insensitive neurons to respond to both mxPDL and mbPDL stimulation.

Optimal positive airway pressure predicts oral appliance response to sleep apnoea.

Patients with less severe obstructive sleep apnoea (OSA) are usually prescribed oral appliances and/or smaller optimal nasal continuous positive airway pressure (P(nCPAP)) in nCPAP therapy. We hypothesised that OSA patients with greater P(nCPAP) would not respond favourably to oral appliances. Oral appliances were inserted in nCPAP users after washing-out the nCPAP effect. Follow-up polysomnography was undertaken with the adjusted oral appliance in place. The predictability of P(nCPAP) was evaluated with receiver-operating characteristic (ROC) curves. The median baseline apnoea/hypopnoea index (AHI) was reduced with the oral appliance from 36 to 12 events.h(-1) in 35 patients. When responders were defined as patients showing a follow-up AHI of <5 events.h(-1) with >50% reduction in baseline AHI, the area under the ROC curve for P(nCPAP) was 0.76. The best cut-off value of P(nCPAP) turned out to be 10.5 cmH(2)O with a high negative predictive value (0.93) and a low negative likelihood ratio (0.18). OSA patients with a P(nCPAP) of >10.5 cmH( 2)O are unlikely to respond to oral appliance therapy. This prediction is clinically helpful to both OSA patients and medical personnel in discussing oral appliances as a temporary substitute and/or alternative for nCPAP.

Silicone-induced foreign-body reaction after first metatarsophalangeal joint arthroplasty for Jaccoud's arthropathy.

We report a case of Jaccoud's arthropathy with forefoot plantar callosity. The lesser toe metatarsal heads were resected and Swanson's double-stemmed flexible-hinge implant arthroplasty of the first metatarsophalangeal joint was performed. An osteolytic defect had formed around the implant after 2 years. Surgical revision comprised implant removal and synovectomy. Histology revealed a foreign-body reaction with birefringent material in multinucleated giant cells. Because the capsuloligamentous system is fragile in Jaccoud's arthropathy, we recommend resection arthroplasty or arthrodesis of the first MP joint as an initial operative approach.

Actinobacillus actinomycetemcomitans lipopolysaccharide stimulates collagen phagocytosis by human gingival fibroblasts.

INTRODUCTION: Collagen phagocytosis by fibroblasts is involved in the intracellular pathway related to collagen breakdown in soft connective tissues. The possible role of lipopolysaccharide (LPS) in regulating this fibroblast function has not been elucidated so we investigated the effect of LPS from Actinobacillus actinomycetemcomitans, a periodontopathic bacterium, on collagen phagocytic activity in human gingival fibroblasts and associated regulatory mechanisms. METHODS: LPS pretreatment stimulated binding of collagen-coated beads to cells and, subsequently, their internalization. RESULTS: The LPS-activated collagen phagocytic process was enhanced in the presence of the soluble form of CD14 (sCD14) or LPS-binding protein (LBP), while the LPS/LBP treatment activated Akt and induced actin reorganization. Furthermore, these LPS/LBP-induced effects were partially suppressed by adding phosphatidyl-inositol-3 kinase (PI3K) inhibitors. CONCLUSION: These results suggest that A. actinomycetemcomitans LPS disturbs the homeostasis of collagen metabolism within gingival tissue by facilitating collagen phagocytosis by gingival fibroblasts, and serum sCD14 and LBP positively regulate the action of LPS. In addition, the PI3K/Akt signaling is thought to partially mediate the LPS/LBP-stimulated collagen phagocytic pathway, which may be dependent on actin cytoskeletal rearrangement.

Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency.

HAX1 deficiency has recently been identified as a cause of severe congenital neutropenia (SCN), but little is known about the phenotype. We described an SCN patient with a homozygous 256C-to-T transition causing an R86X mutation in the HAX1 gene. Notably, the patient has been complicated by epilepsy and severe delay of motor, cognitive, and intellectual development; each developmental quotient was 21-26 at 7 years old. Growth failure and dental development delay were also noted. Neurodevelopmental delay in this patient expands the clinical phenotype of HAX1 deficiency and suggests an important role of HAX1 on neural development as well as myelopoiesis.

Metalloenzyme nitrile hydratase: structure, regulation, and application to biotechnology.

Nitrile hydratase (NHase), which catalyzes the hydration of nitriles to amides, has been used in the industrial production of acrylamide and nicotinamide. Recent studies on NHases, which are roughly classified into iron and cobalt types according to the metal involved, have clarified the photoactivation mechanism, the novel ligand structure of the metal-binding sites, the unique mechanism of the enzyme hyper-induction, and the occurrence of an accessory gene involved in cobalt-containing NHase formation. These detailed analyses have led to the development of biotechnological applications of NHase, including biotransformation and bioremediation.

Initial Experience with a Novel Low-Dose Micro-CT System.

PURPOSE: Investigation of the hardware and image characteristics of a novel micro-CT system and evaluation of its potential to image animals and tissue samples. MATERIALS AND METHODS: The scanner was characterized by phantom studies regarding image homogeneity, CT number stability, soft-tissue contrast, spatial resolution and X-ray dose. The phantoms used were specially designed to evaluate the imaging of mice and rats. Scans of hearts with coronary stents were performed and the tissue morphology and vascularization of tumor-bearing rodents were studied with dynamic contrast-enhanced (DCE) CT. RESULTS: The CT numbers of the acrylic phantoms were reproducible with a 4 HU deviation. The inter-pixel deviation was low but depended on the scan mode. The correlation coefficient between CT number and iodine concentration (0 - 6000 HU) was 0.99. Single wires, lumen and endo-luminal plaques of heart stents were distinguishable. The density-time courses were reliably recorded and made it possible to distinguish the tumor and muscle tissue in DCE micro-CT scans CONCLUSION: The novel micro-CT scanner is suitable for studying tissue densities and contrast agent kinetics.

Effect of bubble flow velocity on drag-force and shear stress working on submerged hollow fibre membrane.

This study is aimed at elucidating the mechanism by which rising air bubbles induce shear stress on hollow fibre membrane surfaces. Shear stress on hollow fibre membrane surfaces (laterally-set and vertically-set) caused by aeration was measured directly using a two-direction load sensor. In the laterally-set hollow fibre module, time-averaged upward-direction shear stress on the membrane surface was compared to theoretical shear stress values considering the effect of water flow on membrane surface. Measured time-average shear stress values were almost 200 times larger than theoretical values implying strong interactions between bubbles and solid surface. In the vertically-set membrane module, velocity measurement of bubble flow using laser Doppler velocimeter revealed that drag force working on membrane surface was closely related to upward-direction water velocity. Also fluctuation of drag force and shear force on membrane surface was found to be related to velocity fluctuation (turbulence).

Distinct Excitation to Pulpal Stimuli between Somatosensory and Insular Cortices.

Somatosensory information from the dental pulp is processed in the primary (S1) and secondary somatosensory cortex (S2) and in the insular oral region (IOR). Stimulation of maxillary incisor and molar initially induces excitation in S2/IOR, rostrodorsal to the mandibular incisor and molar pulp-responding regions. Although S1 and S2/IOR play their own roles in nociceptive information processing, the anatomical and physiological differences in the temporal activation kinetics, dependency on stimulation intensity, and additive or summative effects of simultaneous pulpal stimulation are still unknown. This information contributes not only to understanding topographical organization but also to speculating about the roles of S1 and S2/IOR in clinical aspects of pain regulation. In vivo optical imaging enables investigation of the spatiotemporal profiles of cortical excitation with high resolution. We determined the distinct features of optical responses to nociceptive stimulation of dental pulps between S1 and S2/IOR. In comparison to S1, optical signals in S2/IOR showed a larger amplitude with a shorter rise time and a longer decay time responding to maxillary molar pulp stimulation. The latency of excitation in S2/IOR was shorter than in S1. S2/IOR exhibited a lower threshold to evoke optical responses than S1, and the peak amplitude was larger in S2/IOR than in S1. Unexpectedly, the topography of S1 that responded to maxillary and mandibular incisor and molar pulps overlapped with the most ventral sites in S1 that was densely stained with cytochrome oxidase. An additive effect was observed in both S1 and S2/IOR after simultaneous stimulation of bilateral maxillary molar pulps but not after contralateral maxillary and mandibular molar pulp stimulation. These findings suggest that S2/IOR is more sensitive for detecting dental pulp sensation and codes stimulation intensity more precisely than S1. In addition, contra- and ipsilateral dental pulp nociception converges onto spatially closed sites in S1 and S2/IOR.

Sequential Changes in Cortical Excitation during Orthodontic Treatment.

Cortical excitation responding to periodontal ligament (PDL) stimulation is observed in the rat primary somatosensory (S1), secondary somatosensory, and insular oral region of the cortex (S2/IOR), which are considered to process somatosensation, including nociception. Our previous studies have demonstrated that excitatory propagation induced by PDL stimulation is facilitated in S1 and S2/IOR 1 d after experimental tooth movement (ETM), and tetanic stimulation of IOR induces long-term potentiation of cortical excitatory propagation consistently. These findings raise the possibility that ETM induces neuroplastic changes, and as a result, facilitation of cortical excitation would be sustained for weeks. However, no information is available about the temporal profiles of the facilitated cortical responses. We estimated PDL stimulation-induced cortical excitatory propagation in S1 and S2/IOR of rats by optical imaging 1 to 7 d after ETM of the maxillary first molar. ETM models showed facilitated cortical excitatory propagation in comparison with controls and sham groups 1 d after ETM, but the facilitation gradually recovered to the control level 3 to 7 d after ETM. Sham groups that received wire fixation without orthodontic force tended to enhance cortical responses, although the differences between controls and sham groups were almost insignificant. We also examined the relationship between cortical responses and expression of inflammatory cytokines, interleukin (IL)-1ß and tumor necrosis factor (TNF)-α, in PDL of the first molar. The peak amplitude of optical signals responding to PDL stimulation tended to be increased in parallel to the number of IL-1ß and TNF-α immunopositive cells, suggesting that, at least in part, the enhancement of cortical responses is induced by PDL inflammation. These findings suggest that ETM-induced facilitation of cortical excitatory propagation responding to PDL stimulation 1 d after ETM recovers to the control level within a week. The time course of the facilitated cortical responses is comparable to that of pain and discomfort induced by clinical orthodontic treatments.

A multi-centre retrospective study of mandibular fractures: do occlusal support and the mandibular third molar affect mandibular angle and condylar fractures?

This retrospective study was performed to investigate the influence of occlusal support and the presence, state, and position of mandibular third molars on the incidence of mandibular angle and condylar fractures. The following variables were investigated: age, sex, cause of fracture, presence and state (impaction, angulation, and the number of roots) of the mandibular third molars, site of the mandibular fracture, presence of occlusal support, duration of intermaxillary fixation, and postoperative complications. Various risk factors for mandibular angle and condylar fractures were investigated by univariate analysis. The risk of mandibular angle fracture was significantly higher in patients with occlusal support and mandibular third molars. The risk of condylar fracture was significantly higher in patients without occlusal support or mandibular third molars. The position and angulation of the mandibular third molars were not significant risk factors in mandibular angle and condylar fractures. This study demonstrated the influence of occlusal support and the presence of mandibular third molars on the incidence of mandibular angle and condylar fractures. The presence of occlusal support may be a more important factor affecting mandibular angle or condylar fractures than the position of the mandibular third molars.