An interim oral appliance as a screening tool during drug-induced sleep endoscopy to predict treatment success with a mandibular advancement device for obstructive sleep apnea.

PURPOSE: Previous studies have shown a wide range of efficacy (29 to 71%) of a mandibular advancement device (MAD) in the treatment of obstructive sleep apnea (OSA). Currently, the ability to preselect suitable patients for MAD therapy based on individual characteristics related to upper airway collapsibility is limited. We investigated if the use of non-custom interim MAD during drug-induced sleep endoscopy (DISE) could be a valuable screening tool to predict MAD treatment outcome. METHODS: In a single-center prospective study including a consecutive series of patients with OSA, we compared DISE outcomes with a MAD in situ with polysomnography results after 3 months of using the same MAD that was used during DISE. RESULTS: Of 41 patients who completed the study, the median apnea-hypopnea index (AHI) was 16.0 events/h [IQR 7.4-23.4]. Respiratory outcomes on polysomnography, including apnea index (AI), total AHI, AHI in supine position, and oxygen desaturation index, all significantly improved after 3 months of MAD treatment. With complete improvement of the upper airway obstruction with the MAD in situ during DISE in supine position, patients were 6.3 times more likely to be a responder to MAD treatment compared to patients with a persisting complete obstruction, although not statistically significant (OR 6.3; 95%CI 0.9-42.7; p = 0.060). CONCLUSION: The potential predictive value with regard to MAD therapy outcomes of the use of an interim MAD during DISE would be an important finding, since the prediction of MAD therapy outcome is of great clinical and scientific interest. A study with a larger cohort should be performed to further investigate our findings.

Stability of fixation methods in large mandibular advancements after sagittal split ramus osteotomy: an in vitro biomechanical study.

Sagittal split ramus osteotomy (SSRO) with large mandibular advancements is a common surgical procedure and could be indicated for patients with sleep apnoea. As a large variety of fixation methods is used for the stabilisation of SSRO, a biomechanical test model was used to analyse which fixation technique was most stable. For this in vitro study, 80 polyurethane hemimandibles with a prefabricated SSRO were used as substrates. Loads in Newtons were recorded at displacements of the mandibular incisive edge at 1mm, 3mm and 5mm. The samples were divided into two groups: mandibular advancements of 10mm and 15mm. In both groups, four fixation techniques were used: (A) one four-hole miniplate; (B) two four-hole miniplates; (C) one four-hole miniplate plus one bicortical screw; and (D) three bicortical screws in an inverted-L arrangement. In group 1, three bicortical screws resulted in the best stability, and in group 2, two miniplates resulted in the best stability. The use of two miniplates did not show significant differences between both groups. Other fixation methods showed more stability with 10mm advancements. This study therefore suggests that in SSRO with advancements exceeding 10mm, the use of two miniplates is the optimal means of providing rigid fixation.

Fixation methods in sagittal split ramus osteotomy: a systematic review on in vitro biomechanical assessments.

The aim of this systematic review was to assess the stability of rigid internal fixation (RIF) techniques in sagittal split ramus osteotomy (SSRO) based on in vitro biomechanical assessments, with particular interest in large mandibular advancements. In general, RIF methods can be divided into three groups: bicortical screws, miniplates, and a combination of the two. An electronic search of the PubMed, CINAHL, and Embase databases was performed, and studies published between January 2003 and March 2018 were screened for inclusion. Comparative studies with an in vitro experimental design, using biomechanical assessments to measure the stability of RIF methods in SSRO, were included. Of 104 unique studies identified in the initial search, 24 were included. Twenty-two of these 24 studies analyzed an advancement of the mandible of 7mm or less. The use of a single four-hole or six-hole miniplate was less stable than the use of bicortical screws, hybrid techniques, double miniplates, or grid plates. Two studies analyzed advancements of 10mm, for which two miniplates placed in parallel and a grid plate showed most stability. Although there was agreement between studies with regard to results, more biomechanical studies are required to quantify the stability of fixation methods in larger mandibular advancements.

Long-term oral appliance therapy in obstructive sleep apnea syndrome: a controlled study on dental side effects.

OBJECTIVES: This study aimed to assess possible dental side effects associated with long-term use of an adjustable oral appliance compared with continuous positive airway pressure (CPAP) in patients with the obstructive sleep apnea syndrome and to study the relationship between these possible side effects and the degree of mandibular protrusion associated with oral appliance therapy. MATERIALS AND METHODS: As part of a previously conducted RCT, 51 patients were randomized to oral appliance therapy and 52 patients to CPAP therapy. At baseline and after a 2-year follow-up, dental plaster study models in full occlusion were obtained which were thereupon analyzed with respect to relevant variables. RESULTS: Long-term use of an oral appliance resulted in small but significant dental changes compared with CPAP. In the oral appliance group, overbite and overjet decreased 1.2 (±1.1) mm and 1.5 (±1.5) mm, respectively. Furthermore, we found a significantly larger anterior-posterior change in the occlusion (-1.3 ± 1.5 mm) in the oral appliance group compared to the CPAP group (-0.1 ± 0.6 mm). Moreover, both groups showed a significant decrease in number of occlusal contact points in the (pre)molar region. Linear regression analysis revealed that the decrease in overbite was associated with the mean mandibular protrusion during follow-up [regression coefficient (ß) = -0.02, 95 % confidence interval (-0.04 to -0.00)]. CONCLUSIONS: Oral appliance therapy should be considered as a lifelong treatment, and there is a risk of dental side effects to occur. CLINICAL RELEVANCE: Patients treated with the oral appliance need a thorough follow-up by a dentist or dental-specialist experienced in the field of dental sleep medicine.

[A rare complication during the surgical removal of an impacted maxillary third molar]. / Een zeldzame complicatie bij verwijdering van een geïmpacteerde derde molaar in de bovenkaak.

A 12-year-old boy was referred by his orthodontist due to the dysmorphic condition of the impacted teeth 18 and 28. Because teeth 17 and 27 were close related to the third molars, the decision was made to remove the impacted teeth under general anaesthesia. During luxation of tooth 28, it was accidentally displaced deeper into the socket. The tooth could still not be localized after the use of radiographs, an antrostomy, and surgical exploration. It was decided to leave the 28 in its place and to perform cone beam computertomography. This showed that tooth 28 was displaced into the infratemporal fossa. Since the patient was free of symptoms, a period of watchful waiting was initiated. A control visit and cone beam computertomography 9 months postoperatively revealed no signs or symptoms or changes in the position of the displaced tooth. It was therefore decided to leave the third molar in its displaced position. Displacement of a maxillary third molar into the infratemporal fossa is considered a rare complication.

Long-term oral-appliance therapy in obstructive sleep apnea: a cephalometric study of craniofacial changes.

OBJECTIVES: The aim of this randomized controlled study was to cephalometrically assess possible changes in craniofacial morphology associated with long-term use of an adjustable oral-appliance compared with continuous positive airway pressure (CPAP) in patients with the obstructive sleep apnea/hypopnea syndrome (OSAHS). In addition, we wanted to study the relationship between these possible changes and the degree of mandibular protrusion associated with oral-appliance therapy. METHODS: Fifty-one patients were randomized to oral-appliance therapy and 52 patients to CPAP therapy. At baseline and after follow-up (2.3±0.2 years), a lateral cephalogram of all patients was made in maximum intercuspation to determine relevant cephalometric variables. Both baseline and follow-up cephalograms were traced digitally whereupon cephalometric variables were compared. Changes in craniofacial morphology between the oral-appliance- and CPAP group were evaluated with a linear regression analysis. RESULTS: Compared with CPAP, long-term use of an oral-appliance resulted in small but significant (dental) changes. Overbite and overjet decreased, 1.0 (±1.5)mm and 1.7 (±1.6)mm, respectively. Furthermore we found a retroclination (-2.0 (±2.8)°) of the upper incisors and a proclination (3.7 (±5.4)°) of the lower incisors. Moreover, the lower- and total anterior facial height increased significantly, 0.8 (±1.5)mm and 0.9 (±1.4)mm, respectively. No changes in skeletal variables were found. Linear regression analysis revealed that the decrease in overbite was associated with the mean mandibular protrusion during follow-up (B=-0.029, SE=0.014, p<0.05). CONCLUSIONS: Oral-appliance therapy should be considered as a life long treatment, and there is a risk of craniofacial changes to occur. Therefore, patients treated with an oral-appliance, need a thorough follow-up by a dentist or dental-specialist experienced in the field of dental sleep medicine.

Effects of a mandibular advancement device on the upper airway morphology: a cephalometric analysis.

The aims of this study were to assess changes in the upper airway morphology associated with an oral appliance in situ in patients suffering from the obstructive sleep apnoea-hypopnoea syndrome and to relate these changes to treatment response. Changes in upper airway morphology as a result of an oral appliance were assessed in 52 patients with obstructive sleep apnoea-hypopnoea syndrome by means of cephalometric analysis. Lateral cephalograms were taken at baseline and after 2-3 months of treatment. Baseline and follow-up cephalograms were traced twice and cephalometric variables were compared. The predictive value of changes in upper airway morphology for the treatment response was evaluated in univariate and multivariate regression analyses. Oral appliance therapy resulted in an increased posterior airway space at the level of the second vertebra, the uvular tip and the base of the tongue. The increase of the posterior airway space at the level of the second vertebra and the uvular tip were the best predictors for relative improvement of the apnoea-hypopnoea index. However, the predictive value for treatment response of these cephalometric upper airway changes should be interpreted with caution.

[Treatment of the obstructive sleep apnea syndrome. Side effects of a mandibular advancement device]. / Behandeling van het obstructief slaapapneusyndroom. Neveneffecten van een mandibulair repositieapparaat.

The obstructive sleep apnea syndrome is characterised by repeatedly occurring complete or partial obstructions of the upper airway during sleep, which can be accompanied by serious oxygen desaturations. This can result in cardiovascular co-morbidity and excessive daytime sleepiness, with an increased chance of motor vehicle accidents and diminished performance at work. The use of a mandibular advancement device appears to be an effective therapy. In the long term, however, the possibility of dental side effects should be taken into consideration. Development of a relative mesio-occlusion has frequently been observed. Side effects are usually mild and transient. To objectively evaluate whether the side effects are stable or progressive, a thorough follow-up is needed. It is therefore desirable that treatments with a mandibular advancement device are carried out by dentists or specialists with experience and special expertise in this area.

Obstructive sleep apnea therapy.

In clinical practice, oral appliances are used primarily for obstructive sleep apnea patients who do not respond to continuous positive airway pressure (CPAP) therapy. We hypothesized that an oral appliance is not inferior to CPAP in treating obstructive sleep apnea effectively. We randomly assigned 103 individuals to oral-appliance or CPAP therapy. Polysomnography after 8-12 weeks indicated that treatment was effective for 39 of 51 persons using the oral appliance (76.5%) and for 43 of 52 persons using CPAP (82.7%). For the difference in effectiveness, a 95% two-sided confidence interval was calculated. Non-inferiority of oral-appliance therapy was considered to be established when the lower boundary of this interval exceeded -25%. The lower boundary of the confidence interval was -21.7%, indicating that oral-appliance therapy was not inferior to CPAP for effective treatment of obstructive sleep apnea. However, subgroup analysis revealed that oral-appliance therapy was less effective in individuals with severe disease (apnea-hypopnea index > 30). Since these people could be at particular cardiovascular risk, primary oral-appliance therapy appears to be supported only for those with non-severe apnea.

Predictors of obstructive sleep apnea-hypopnea treatment outcome.

Oral appliance therapy is an alternative to continuous positive airway pressure (CPAP) for treating the obstructive sleep apnea-hypopnea syndrome. However, the ability to pre-select suitable candidates for either treatment is limited. The aim of this study was to assess the value of relevant variables that can predict the outcome of oral appliance and CPAP therapy. Fifty-one patients treated with oral appliance therapy and 52 patients treated with CPAP were included. Relevant clinical, polysomnographic, and cephalometric variables were determined at baseline. The predictive value of variables for treatment outcome was evaluated in univariate and multivariate analyses. The outcome of oral appliance therapy was favorable, especially in less obese patients with milder sleep apnea and with certain craniofacial characteristics (mandibular retrognathism in particular). Neither univariate nor multivariate analyses yielded variables that reliably predicted the outcome of CPAP. We conclude that the variables found in this study are valuable for pre-selecting suitable candidates for oral-appliance therapy.

[Management of the obstructive sleep apnoea syndrome: more knowledge required for an optimal choice of treatment modality]. / Behandeling van het obstructief slaapapneusyndroom: meer kennis nodig voor optimale indicatiestelling.

In the management of the obstructive sleep apnoea syndrome (OSAS), clinicians may consider various conservative, non-invasive and surgical treatment modalities. Continuous positive airway pressure (CPAP) is regarded as the treatment of choice for, especially, moderate to severe OSAS. However, due to the obtrusive nature of this conservative treatment, especially in mild manifestations ofOSAS, the effectiveness of CPAP may be compromised due to poor therapeutic acceptance and adherence. Over the last decade, oral appliance therapy has emerged as an increasingly popular treatment alternative to CPAP. However, due to the methodological limitations of most trials studying this dental treatment modality, the precise indication for oral appliance therapy is still indistinct. In addition, based on the current level of evidence, most surgical interventions in OSAS should generally be reserved for patients with failing CPAP therapy. In order to determine whether the available treatment alternatives are competitive with CPAP, methodologically sound and preferably randomised studies are indicated.

Efficacy and co-morbidity of oral appliances in the treatment of obstructive sleep apnea-hypopnea: a systematic review.

The Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a common sleep-related breathing disorder characterized by repetitive obstructions of the upper airway during sleep. Modification of pharyngeal patency by Oral Appliance (OA) therapy has been suggested as an alternative to various treatment modalities for OSAHS. To determine the evidence base with respect to the efficacy and co-morbidity of OA therapy in OSAHS, we conducted a systematic review of the available literature. Primary outcome measures were the reduction in number of upper-airway obstructions and co-morbidity related to the craniomandibular or craniofacial complex, respectively. Eligible studies regarding efficacy were independently assessed by two assessors using a quality assessment scale. Effect sizes of methodologically sound studies were calculated. In identical interventions, effect sizes were pooled with the use of a random-effects model. Given the scarcity of controlled studies related to co-morbidity, appraisal was confined to a description of eligible studies. Sixteen controlled trials related to efficacy were identified. With respect to the primary outcome measure, OA therapy was clearly more effective than control therapy (pooled effect size, -0.96; 95% confidence interval [CI], -1.49 to -0.42) and possibly more effective than uvulopalatopharyngoplasty. Although patients generally preferred OA therapy, improvement of respiratory variables, such as the number of upper-airway obstructions, was usually better in Continuous Positive Airway Pressure (CPAP) therapy (pooled effect size, 0.83; 95% CI, 0.59 to 1.06). Moreover, specific aspects related to OA design may influence patient-perceived efficacy and preference. Twelve patient-series and one controlled trial related to co-morbidity were identified. Analysis of the data suggests that OA therapy may have adverse effects on the craniomandibular and craniofacial complex. Although CPAP is apparently more effective and adverse effects of OA treatment have been described, it can be concluded that OA therapy is a viable treatment for, especially, mild to moderate OSAHS. Controlled studies addressing the specific indication and co-morbidity of OA therapy are warranted.

[Treatment of the obstructive sleep-apnea syndrome in adults]. / Behandeling van het obstructieve slaapapneusyndroom bij volwassenen.

When treating the obstructive sleep-apnoea syndrome (OSAS), conservative management and the correction of treatable stenoses in the upper airway should be considered first. If these measures are neither effective nor applicable, then continuous positive airway pressure (CPAP) is the preferred treatment. Surgical interventions should only be considered after failure of non-surgical treatment modalities. Pharmacological management of OSAS is usually only indicated as a form of supplementary treatment in specific patients. Oral-appliance therapy appears to be of value in the management of OSAS and, in specific groups of patients, seems likely to offer a good alternative to CPAP in the future.

Craniofacial morphology and obstructive sleep apnoea: a cephalometric analysis.

The craniofacial morphology of 31 male patients diagnosed with obstructive sleep apnoea syndrome (OSAS) and 37 healthy male subjects were compared using cephalometric evaluation of lateral skull radiographs. The aim was to evaluate which cephalometric variables related to craniofacial morphology discriminate between OSAS patients and non-OSAS subjects. Sixteen cephalometric measurements were determined to study the craniofacial morphology. Differences in cephalometric variables between the two groups were analysed with unpaired Student t-tests (significance level 0.05). A multiple regression analysis was used to evaluate the joint predictive value of selected variables. With regard to five variables, significant differences were observed between OSAS patients and non-OSAS subjects (P < 0.05). Data indicated a relatively anterior position of the maxilla, an increase of the mid-facial height and a more inferiorly located hyoid bone in the OSAS patient group. The multiple regression analysis yielded a model discriminating between OSAS patients and non-OSAS subjects, which included two hyoid bone variables and one related with the intermaxillary relationship. A causal relationship between cephalometric variables of craniofacial morphology and OSAS is not sufficiently supported by our data. Presumably, hyoid bone position is of predictive value in the cephalometric discrimination between OSAS patients and non-OSAS subjects.

Stable accumulation of Aspergillus niger phytase in transgenic tobacco leaves.

Phytase from Aspergillus niger increases the availability of phosphorus from feed for monogastric animals by releasing phosphate from the substrate phytic acid. A phytase cDNA was constitutively expressed in transgenic tobacco (Nicotiana tabacum) plants. Secretion of the protein to the extracellular fluid was established by use of the signal sequence from the tobacco pathogen-related protein S. The specific phytase activity in isolated extracellular fluid was found to be approximately 90-fold higher than in total leaf extract, showing that the enzyme was secreted. This was confirmed by use of immunolocalization. Despite differences in glycosylation, specific activities of tobacco and Aspergillus phytase were identical. Phytase was found to be biologically active and to accumulate in leaves up to 14.4% of total soluble protein during plant maturation. Comparison of phytase accumulation and relative mRNA levels showed that phytase stably accumulated in transgenic leaves during plant growth.

Factors influencing transformation frequency of tomato (Lycopersicon esculentum).

We developed an efficient procedure for transformation and regeneration of L. esculentum cv. Moneymaker from cotyledon explants. The effect of two parameters on the transformation frequency was investigated in detail. The use of feeder layers during cocultivation proved to be critical. In addition, it was found that Agrobacterium strains harbouring a L,L-succinamopine type helper plasmid yielded significantly higher transformation frequencies than those with octopine or nopaline type helper plasmids. The optimized protocol was used to obtain transformation frequencies averaging 9%. Of the plants produced approximately 80% proved to be diploid, of which 67% contained the transgene(s) on a single locus.

Direct screening for high-level expression of an introduced alpha-amylase gene in plants.

A method is described for obtaining transgenic plants with a high level of expression of the introduced gene. Tobacco protoplasts were transformed with an expression construct containing a translational fusion between mature alpha-amylase from Bacillus licheniformis and the signal peptide of the tobacco PR-S protein. A total number of 5200 transformed protoplasts was cultured to microcalli and screened for alpha-amylase expression by incubation on media containing starch followed by staining with iodine. The calli were divided into four classes, based on the resulting halo sizes on the plates. The halo sizes were found to correlate with the expression levels in transgenic plants regenerated from the calli. The expression levels varied between 0 and 0.5% of soluble leaf protein in the regenerated transgenic plants. Wider implications of this method are discussed.

Production of active Bacillus licheniformis alpha-amylase in tobacco and its application in starch liquefaction.

As a first example of the feasibility of producing industrial bulk enzymes in plants, we have expressed Bacillus licheniformis alpha-amylase in transgenic tobacco, and applied the seeds directly in starch liquification. The enzyme was properly secreted into the intercellular space, and maximum expression levels of about 0.3% of total soluble protein were obtained. No apparent effect of the presence of the enzyme on plant phenotype was observed. The molecular weight of the enzyme produced in tobacco was around 64 kD. The difference, compared to 55.2 kD for the bacterial enzyme, was found to result from complex-type carbohydrate chains attached to the protein. Application studies on the liquefaction of starch were done with transgenic seeds containing the recombinant alpha-amylase. The resulting hydrolysis products were virtually identical with those obtained from degradation with alpha-amylase from Bacillus licheniformis.

Production of correctly processed human serum albumin in transgenic plants.

We have used a modified CaMV 35S promoter to direct the expression of chimaeric genes encoding human serum albumin (HSA) in transgenic potato and tobacco plants. To secrete the protein, either the human prepro-sequence or the signal sequence from the extracellular tobacco protein PR-S was used. We demonstrate secretion of HSA with both types of signal sequences in transgenic leaf tissue and in suspension cultures. HSA produced in transgenic potato plants was purified to chromatographic homogeneity. N-terminal amino acid sequence analysis revealed that the processing of the precursor protein was dependent on the type of signal sequence. Expression of the human preproHSA gene lead to partial processing of the precursor and secretion of proHSA. Fusion of HSA to the plant PR-S presequence resulted in cleavage of the presequence at its natural site and secretion of correctly processed HSA that is indistinguishable from the authentic human protein.