Mandibular Torus as a New Index of Success for Mandibular Advancement Devices.

BACKGROUND: In obstructive sleep apnoea (OSA), treatment with mandibular advancement devices (MADs) reduces patients' Apnoea-Hypopnoea index (AHI) scores and improves their sleepiness and quality of life. MADs are non-invasive alternatives for patients who cannot tolerate traditional continuous positive airway pressure (CPAP) therapy. The variability of responses to these devices makes it necessary to search for predictors of success. The aim of our study was to evaluate the presence of mandibular torus as a predictor of MAD efficacy in OSA and to identify other potential cephalometric factors that could influence the response to treatment. METHODS: This was a retrospective cohort study. The study included 103 patients diagnosed of OSA who met the criteria for initiation of treatment with MAD. Structural variables were collected (cephalometric and the presence or absence of mandibular torus). Statistical analysis was performed to evaluate the existence of predictive factors for the efficacy of MADs. RESULTS: A total of 103 patients who were consecutively referred for treatment with MAD were included (89.3% men); the mean age of the participants was 46.3 years, and the mean AHI before MAD was 31.4 (SD 16.2) and post- MAD 11.3 (SD 9.2). Thirty-three percent of patients had mandibular torus. Torus was associated with a better response (odds ratio (OR) = 2.854 (p = 0.035)) after adjustment for sex, age, body mass index (BMI; kg/m2), the angle formed by the occlusal plane to the sella-nasion plane (OCC plane to SN), overinjection, and smoking. No cephalometric predictors of efficacy were found that were predictive of MAD treatment success. CONCLUSIONS: The presence of a mandibular torus practically triples the probability of MAD success. This is the simplest examination with the greatest benefits in terms of the efficacy of MAD treatment for OSA.

Tridimensional upper airway assessment in male patients with OSA using oral advancement devices modifying their vertical dimension.

STUDY OBJECTIVES: Mandibular advancement devices (MADs) constitute an alternative treatment in selected patients with OSA. A mandibular advanced position has been suggested to be beneficial, whereas its combination with an increased bite-raise may increase its adverse effects. The objective of this study was to assess upper airway (UA) volume and inspiratory pressure gradient variations in a group of 17 patients with OSA. The study was performed under 3 mandibular positions: intercuspal position (P1), MAD position in closed mouth (P2), and MAD position with an increased bite-raise (P3). METHODS: We conducted a 3-dimensional reconstruction of the pharynx using the finite element method via a computed tomography scan and the subsequent calculation using fluid-dynamic analysis. RESULTS: One hundred percent of the patients showed an increase in UA volume in both P2 and the MAD position with an increased bite-raise, P2 being the position where 76.47% of the patients showed the largest UA volume. P2/velopharynx was the position/region where the largest UA volume increase was achieved (4.73 mm³). A better gradient in P2 (mean = 0.62) in 58.82% of the patients and a better gradient in P3 (mean = 0.74) in 41.18% of patients respect P1 was observed. In 82.35% of patients, a better volume-pressure gradient match was also found. CONCLUSIONS: The best efficiency scores for both volume increase and better inspiratory pressure gradient were obtained in P2. This study findings suggest that in a MAD, the minimal bite opening position necessary for mandibular protrusion is more effective in increasing airway volume and inspiratory gradient compared to a larger bite-raising (15 mm).

Dental implant surgery in patients in treatment by dabigatran.

OBJECTIVES: The aim of this study was to evaluate the incidence of bleeding complications after dental implant placement in patients in treatment by the oral anticoagulant dabigatran following a specific protocol. MATERIAL AND METHODS: Seventy-one patients were divided into two groups: 29 had been taking dabigatran for over 6 months (150 mg orally every 12 h) before implant surgery (dabigatran group) and a control group consisting of 42 healthy subjects. Patients were treated in an outpatient setting. All subjects received dental implants in different positions, dabigatran group patients 12 h after the last dose of dabigatran. Nonabsorbable sutures were used and patients were given gauzes impregnated with tranexamic acid 5% to bite on for 30-60 min. Dabigatran patients resumed medication 8 h after the procedure, resuming usual dosage (every 12 h) the day after surgery. RESULTS: Two dabigatran patients and two control patients presented slight bleeding the day after surgery. Bleeding was managed with gauzes impregnated with tranexamic acid. No statistically significant differences (P = 0.542) were found in relation to bleeding episodes between the groups, with a relative risk of 0.675 based on the pooled groups and a 95% confidence interval of 0.090-5.088. CONCLUSIONS: Dental implant surgery in patients taking dabigatran can be performed safely providing 12 h have passed since the last dose and local hemostatic measures are applied. Normal dosage can be resumed 8 h after implant surgery.

Are there differences in treatment effects between labial and lingual fixed orthodontic appliances? A systematic review and meta-analysis.

BACKGROUND: An evaluation is made of possible differences in treatment effects between labial and lingual fixed appliances. METHODS: A comprehensive search was made of the PubMed-Medline, Cochrane Library and LILACS databases, with an additional manual search covering the period up until April 2017. There were no restrictions in terms of year of publication or language. Agreement between the authors was quantified by the Cohen kappa statistic. A random-effect model was applied to calculate weighted mean differences with 95% confidence intervals. RESULTS: A total of 249 patients corresponding to four eligible studies were included in the systematic review. Among the six angles and distances entered in the meta-analysis, a tendency was observed in lingual appliances to increase the interincisal angle (95% CI -0.80-8.99; p = 0.101) and reduce the angle between the major axis of upper central incisor and the sellar-nasion plane - though statistical significance was not reached (95% CI -5.75-0.32; p = 0.079). CONCLUSION: The results obtained indicate that treatment with lingual appliances favors incisor tipping by exerting lingual crown torque, but there are no differences in cephalometric values between labial and lingual fixed appliances. Because of the small number of included studies, the results of this meta-analysis should be interpreted with caution. Future research should focus on the generation of a consensus document allowing selection of the type of orthodontic approach not only conditioned to the esthetic requirements of the patient but also considering the characteristics of the malocclusion. On the other hand, standardized international guidelines are lacking; the measurements of angles and distances therefore have to be unified with a view to future investigations.

Can treatment with statins have a negative influence on the tolerance of mandibular advancement devices?

BACKGROUND: Statins are considered the most effective drugs used in the treatment of dyslipidemias. Some of their adverse effects are related to muscle problems. Myalgias produced by statins appear more often during exercise. Mandibular advancement devices (MAD) force the propulsory and elevatory musculature of the mandible to exercise by making the jaw move forward. The aim of this study is to evaluate the incidence of muscular side effects (referred, spontaneous, or under palpation pain, myofascial pain, mandibular rigidity and fatigue, tension and sensitivity of the masticatory muscles) in a group of patients with a diagnosis of obstructive sleep apnea being treated with MAD. METHODS: This was a prospective study, involving consecutively 104 patients with a diagnosis of OSAS, and who had begun treatment with a custom made oral device. Muscular side effects were collected by anamnesis (verbal request and questionnaires), psychological status and clinical assessment (manual muscle palpation in the masticatory and cervical muscle groups), before and during MAD treatment. RESULTS: Of the total sample, 22.1 % presented muscular side effects with the oral device. However, in patients taking statins, this percentage was 57.1 %, as opposed to 16.7 % of the non-statins patients (p < 0.001). The risk of suffering muscular alterations during oral device treatment is higher in statin patients (odds ratio 6.67, p = 0.002). CONCLUSION: Treatment with statins can give rise to the appearance of undesirable side effects among patients being treated with oral devices.

Adverse effects of lingual and buccal orthodontic techniques: A systematic review and meta-analysis.

INTRODUCTION: The aim of this systematic review was to assess the prevalence of adverse effects associated with lingual and buccal fixed orthodontic techniques. METHODS: Two authors searched the PubMed, EMBASE, Cochrane Library, and LILACS databases up to October 2014. Agreement between the authors was quantified by the Cohen kappa statistic. The following variables were analyzed: pain, caries, eating and speech difficulties, and oral hygiene. The Newcastle-Ottawa scale was used to assess risk of bias in nonrandomized studies, and the Cochrane Collaboration's tool for assessing risk of bias was used for randomized controlled trials. RESULTS: Eight articles were included in this systematic review. Meta-analysis showed a statistically greater risk of pain of the tongue (odds ratio [OR], 28.32; 95% confidence interval [95% CI], 8.60-93.28; P <0.001), cheeks (OR, 0.087; 95% CI, 0.036-0.213; P <0.0010), and lips (OR, 0.13; 95% CI, 0.04-0.39; P <0.001), as well as for the variables of speech difficulties (OR, 9.39; 95% CI, 3.78-23.33; P <0.001) and oral hygiene (OR, 3.49; 95% CI, 1.02-11.95; P = 0.047) with lingual orthodontics. However, no statistical difference was found with respect to eating difficulties (OR, 3.74; 95% CI, 0.86-16.28; P = 0.079) and caries (OR, 1.15; 95% CI, 0.17-7.69; P = 0.814 [Streptococcus mutans] and OR, 0.67; 95% CI, 0.20-2.23; P = 0.515 [Lactobacillus]). CONCLUSIONS: This systematic review suggests that patients wearing lingual appliances have more pain, speech difficulties, and problems in maintaining adequate oral hygiene, although no differences for eating and caries risk were identified. Further prospective studies involving larger sample sizes and longer follow-up periods are needed to confirm these results.

Role of Periostin in Adhesion and Migration of Bone Remodeling Cells.

Periostin is an extracellular matrix protein highly expressed in collagen-rich tissues subjected to continuous mechanical stress. Functionally, periostin is involved in tissue remodeling and its altered function is associated to numerous pathological processes. In orthodontics, periostin plays key roles in the maintenance of dental tissues and it is mainly expressed in those areas where tension or pressing forces are taking place. In this regard, high expression of periostin is essential to promote migration and proliferation of periodontal ligament fibroblasts. However little is known about the participation of periostin in migration and adhesion processes of bone remodeling cells. In this work we employ the mouse pre-osteoblastic MC3T3-E1 and the macrophage-like RAW 264.7 cell lines to overexpress periostin and perform different cell-based assays to study changes in cell behavior. Our data indicate that periostin overexpression not only increases adhesion capacity of MC3T3-E1 cells to different matrix proteins but also hampers their migratory capacity. Changes on RNA expression profile of MC3T3-E1 cells upon periostin overexpression have been also analyzed, highlighting the alteration of genes implicated in processes such as cell migration, adhesion or bone metabolism but not in bone differentiation. Overall, our work provides new evidence on the impact of periostin in osteoblasts physiology.

Recombinant osteoprotegerin effects during orthodontic movement in a rat model.

BACKGROUND AND OBJECTIVES: Anchorage is one of the most challenging sides in orthodontics. The use of biological modulators that inhibit osteoclasts could be a solution to address these problems and provide new adjunctive approaches. The aim of this study was to assess the effectiveness of recombinant osteoprotegerin fusion protein (OPG-Fc) in orthodontic anchorage. MATERIALS AND METHODS: Two groups of male Sprague-Dawley rats were utilized. The animals in the experimental group received twice-weekly injections with high dose of OPG-Fc (5.0mg/kg) in mesial and distal mucosa of the first molars, and those in the control group received no drugs. Right first maxillary molars were mesialized using a calibrated nickel-titanium spring connected to an anterior mini-screw. Tooth movement was measured by two blinded observers using scanned and magnified stone casts. Receptor activator of nuclear factor κB (RANK), run-related transcription factor 2 (Runx2), type I collagen, vimentin, matrix metalloproteinases 2 and 9, S100 protein and the putative mechanoproteins acid-sensing ion channel (ASIC2) and transient receptor potential vainilloid 4 (TRPV4) were evaluated using immunohistochemistry. RESULTS: OPG-Fc group showed an important decreased in mesial molar movement with only 52%, 31%, and 22% of the total mesial molar movement compared with control group at Days 7, 14, and 21, respectively (P < 0.001). RANK ligand and Runx2 positive cells were severely reduced after OPG-Fc treatment. Periodontal ligament architecture, cell arrangement, and immunohistochemical patter for vimentin, type I collagen and the mechanoproteins TRPV4 and ASIC2 were altered by tooth movement and all these parameters altered by the applied treatment. CONCLUSIONS: OPG-Fc effectively inhibits osteoclastogenesis resulting in improved bone quantity and orthodontic anchorage. Based on present results, OPG-Fc could have clinical utility in preventing undesired tooth movements.

Reduced innervation in the human pharynx in patients with obstructive sleep apnea.

Obstructive sleep apnea is a disease characterized by repetitive breathing during sleep that lead to reduced oxygen saturation and sleep disturbance among other symptoms. Obstructive sleep apnea is caused by blockade of the upper respiratory airway, although the pathogenic mechanism underlying this occlusion remains unknown. In these studies we explored the hypothesis that alterations in the innervation, especially mechanosensory innervation, of the pharynx may contribute to obstructive sleep apnea. We tested this hypothesis by analyzing the innervation of the human pharynx in normal individuals and in subjects clinically diagnosed with obstructive sleep apnea. Using immunohistochemistry for axon and Schwann cells, as well as for two putative mechanoproteins (ASIC2 and TRPV4), we observed a significant reduction in the density of nerve fibers in the submucosa of patients with obstructive sleep apnea as well as morphological abnormalities in mechanosensory corpuscles. Importantly, while ASIC2 and TRPV4 expression was regularly found in the axons of mechanosensory corpuscles distributed throughout the muscular layer in the control subjects, it was absent in patients with obstructive sleep apnea. These findings support that neurological alterations are important contributors to the pathogenesis of obstructive sleep apnea.

Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response.

Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and Lmna(G609G/G609G) mice). Causal involvement of NF-κB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-κB pathway to slow down the progression of physiological and pathological aging.

Rodlet cells development in the intestine of sea bass (Dicentrarchus labrax).

The enigmatic rodlet cells (RCs) are characterized by conspicuous inclusions named "rodlets". They were discovered over 100 years ago and were considered as parasites but shortly afterward interpreted as endogenous cells. The RCs have been described in different tissues of marine and freshwater teleosts, but their origin and function remain unknown. This work was designed to an ultrastructural study on RCs development and distribution in intestinal epithelium of Dicentrarchus labrax. Three different stages of RCs development from early precursor cells to mature phase were observed, as well as a migration and finally an extrusion of their contents. In this study, the immature cells were found near the basal epithelium membrane. They were mainly identified by a rough endoplasmic reticulum with dilated cisternae, by developing rodlets and a thin fibrillar coat. The maturing RCs, localized in the middle zone of the epithelium, appeared to be undergoing a reorganization of the cell organelles. The mature RCs, placed near the free surface, showed a thick subplasmalemmar fibrillar coat. Most of the organelles were aggregated at the cell apex with a basally located nucleus. A cellular polarity was more evident. One of the most conspicuous features was the occurrence of mature rodlets club-sac in shape orientated toward the cell apex. Adhesive junctions between surface epithelial cells and RCs, while discharging their contents, were seen. We have connected morphological figures and distribution to different stages of development in RCs, supporting the hypothesis of their secretory function.

Morphology of the European sea bass (Dicentrarchus labrax) tongue.

The European sea bass, a member of the Moronidae family, is a food fish, considered one of the first models for the intensive breeding in salt water. It has nowadays an important and increasing presence in the international fishing markets. Sea basses are carnivorous, feeding on little fishes and invertebrates. Considering the important role of the tongue during the intraoral transport and the swallowing of food, scarce data are present in literature about its morphology. The aim of this study was to analyze the morphology of the tongue by means of scanning electron and light microscopy. Adult sea basses were obtained from the aquarium of the Sicilian Center of Experimental Ichthyiopathology of the University of Messina. The fishes were anaesthetized with MS 222 and the heads were then quickly removed and processed for the paraffin embedding and SEM processing. Three different tongue regions could be distinguished: an apex, a body, and a root. Scanning electron and light microscopy showed the presence of numerous canine-like teeth, surrounded by taste buds and numerous fungiform and conical papillae. The teeth were curved and their tips were posteriorly oriented. The results confirm, in teleosts too, the fundamental role of the tongue in the mechanics of food ingestion. Moreover, the presence of taste buds demonstrates the interaction of food processing and taste. These data could be a potential source to identify new and better methods of nutrition in the breeding of this fish.

Rhodopsin expression in the zebrafish pineal gland from larval to adult stage.

The zebrafish pineal gland plays an important role in different physiological functions including the regulation of the circadian clock. In the fish pineal gland the pinealocytes are made up of different segments: outer segment, inner segment and basal pole. Particularly, in the outer segment the rhodopsin participates in the external environment light reception that represents the first biochemical step in the melatonin production. It is well known that the rhodopsin in the adult zebrafish is well expressed in the pineal gland but both the expression and the cellular localization of this protein during development remain still unclear. In this study using qRT-PCR, sequencing and immunohistochemistry the expression as well as the protein localization of the rhodopsin in the zebrafish from larval (10 dpf) to adult stage (90 dpf) were demonstrated. The rhodopsin mRNA expression presents a peak of expression at 10 dpf, a further reduction to 50 dpf before increasing again in the adult stage. Moreover, the cellular localization of the rhodopsin-like protein was always localized in the pinealocyte at all ages examined. Our results demonstrated the involvement of the rhodopsin in the zebrafish pineal gland physiology particularly in the light capture during the zebrafish lifespan.

The photoreceptive cells of the pineal gland in adult zebrafish (Danio rerio).

The zebrafish pineal gland plays a fundamental role in the regulation of the circadian rhythm through the melatonin secretion. The pinealocytes, also called photoreceptive cells, are considered the morphofunctional unit of pineal gland. In literature, the anatomical features, the cellular characteristics, and the pinealocytes morphology of zebrafish pineal gland have not been previously described in detail. Therefore, this study was undertaken to analyze the structure and ultrastructure, as well as the immunohistochemical profile of the zebrafish pineal gland with particular reference to the pinealocytes. Here, we demonstrated, using RT-PCR, immunohistochemistry and transmission electron microscopy, the expression of the mRNA for rhodopsin in the pineal gland of zebrafish, as well as its cellular localization exclusively in the pinealocytes of adult zebrafish. Moreover, the ultrastructural observations demonstrated that the pinealocytes were constituted by an outer segment with numerous lamellar membranes, an inner segment with many mitochondria, and a basal pole with the synapses. Our results taken together demonstrated a central role of zebrafish pinealocytes in the control of pineal gland functions.

Splicing-directed therapy in a new mouse model of human accelerated aging.

Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. Here, we report a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. Using this animal model, we have developed an antisense morpholino-based therapy that prevents the pathogenic Lmna splicing, markedly reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotide-based therapies for treating human diseases of accelerated aging.

Human odontoblasts express transient receptor protein and acid-sensing ion channel mechanosensor proteins.

Diverse proteins of the denegerin/epithelial sodium channel (DEG/ENa(+) C) superfamily, in particular those belonging to the acid-sensing ion channel (ASIC) family, as well as some members of the transient receptor protein (TRP) channel, function as mechanosensors or may be required for mechanosensation in a diverse range of species and cell types. Therefore, we investigated the putative mechanosensitive function of human odontoblasts using immunohistochemistry to detect ENa(+) C subunits (α, ß, and γ) and ASIC (1, 2, 3, and 4) proteins, as well as TRPV4, in these cells. Positive and specific immunoreactivity in the odontoblast soma and/or processes was detected for all proteins studied except α-ENa(+) C. The intensity of immunostaining was high for ß-ENa(+) C and ASIC2, whereas it was low for ASIC1, ASIC3, γ-ENa(+) C, and TRPV4, being absent for α-ENa(+) C and ASIC4. These results suggest that human odontoblasts in situ express proteins related to mechanosensitive channels that probably participate in the mechanisms involved in teeth sensory transmission.

Orthoimplants: an alternative treatment for SAHS?

UNLABELLED: Numerous sleep studies have been published recently regarding the use of intraoral devices (ODs) for the treatment of sleep apnea-hypopnea syndrome (SAHS). The effectiveness of these devices varies, however, according to the series studied (patient characteristics, parameters assessed, type of device, etc.). Two factors should always be assessed: the presence of an appropriate dental support and a possible temporomandibular joint pathology which can, on occasions, contraindicate the use of these devices. OBJECTIVES: To use orthoimplants as orthodontic anchorages for intermaxillary elastic bands which allow a mandibular advancement to be performed as an alternative treatment to ODs in SAHS patients without appropriate dental support. MATERIALS AND METHODS: Four orthoimplants were placed in an edentulous SAHS patient who did not tolerate continuous positive airway pressure (CPAP). The mandible is pushed forward using orthodontic elastic bands anchored to the orthoimplants. RESULTS AND CONCLUSIONS: Although more studies are still required, orthoimplants could be an alternative treatment for reducing snoring and the apnea-hypopnea index and increasing SaO2, which should be considered for patients who do not tolerate CPAP and lack appropriate dental support for attaching intraoral devices.

Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging.

Several human progerias, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by the accumulation at the nuclear envelope of farnesylated forms of truncated prelamin A, a protein that is also altered during normal aging. Previous studies in cells from individuals with HGPS have shown that farnesyltransferase inhibitors (FTIs) improve nuclear abnormalities associated with prelamin A accumulation, suggesting that these compounds could represent a therapeutic approach for this devastating progeroid syndrome. We show herein that both prelamin A and its truncated form progerin/LADelta50 undergo alternative prenylation by geranylgeranyltransferase in the setting of farnesyltransferase inhibition, which could explain the low efficiency of FTIs in ameliorating the phenotypes of progeroid mouse models. We also show that a combination of statins and aminobisphosphonates efficiently inhibits both farnesylation and geranylgeranylation of progerin and prelamin A and markedly improves the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects. Likewise, the longevity of these mice is substantially extended. These findings open a new therapeutic approach for human progeroid syndromes associated with nuclear-envelope abnormalities.