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Background: Apixaban is commonly used to prevent stroke in older adults with nonvalvular atrial fibrillation (AF). Although its package insert has specific dose reduction criteria, providers may dose reduce outside of these parameters based on clinical scenarios., Objective: The primary objective was to determine the incidence of apixaban off-label reduced dosing, while secondarily determining the safety and efficacy outcomes associated with such dosing., Methods: A retrospective analysis of patients aged 65 and older with orders for apixaban for AF was institutional review board (IRB)-approved and conducted across 3 academic medical centers. Patients receiving off-label reduced-dose apixaban (ie, "underdosed") were matched to a cohort of patients dosed according to the package insert at the standard dosing (5 mg twice daily) using stratified random sampling. Secondary outcomes included 1-year incidence of major bleeding, clinically relevant non-major bleeding (CRNMB), stroke or transient ischemic attack (TIA), and mortality. The Fisher exact tests were used to compare between-group differences., Results: Of the 1172 patients meeting initial inclusion criteria, 201 (17%) were dosed off-label, with 175 (15%) "underdosed." The 147 "underdosed" patients with documented follow-up were matched with 139 patients receiving standard Food and Drug Administration (FDA)-labeled dosing. There were no significant differences in incidence of stroke (2.7% vs 2.2%), major bleeding (0% vs 0.7%), and CRNMB (2.7% vs 1.4%) in the off-label reduced dosing versus standard dosing groups. All-cause mortality was higher in the off-label reduced-dose group (16 [10.9%] vs 2 [1.4%], P < 0.05)., Conclusion and Relevance: Older adults with nonvalvular AF are commonly prescribed lower-than-recommended doses of apixaban. However, no significant association was found between empiric off-label reduced dosing and stroke or bleeding outcomes., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

N-alpha-tosyl-L-phenylalanyl chloromethyl ketone (TPCK) has anti-tumorigenic properties, but its direct cellular targets are unknown. Previously, we showed TPCK inhibited the PDKl-dependent AGC kinases RSK, Akt and S6K1 without inhibiting PKA, ERK1/2, PI3K, and PDK1 itself. Here we show TPCK-inhibition of the RSK-related kinases MSK1 and 2, which can be activated independently of PDK1. Mass spectrometry analysis of RSK1, Aktl, S6K1 and MSK1 immunopurified from TPCK-treated cells identified TPCK adducts on cysteines located in conserved activation loop Phenylalanine-Cysteine (Phe-Cys) motifs. Mutational analysis of the Phe-Cys residues conferred partial TPCK resistance. These studies elucidate a primary mechanism by which TPCK inhibits several AGC kinases, inviting consideration of TPCK-like compounds in chemotherapy given their potential for broad control of cellular growth, proliferation and survival., (Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I-restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals' HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I-restricted antigen presentation and vaccine development.

Immunodominance is variably used to describe either the most frequently detectable response among tested individuals or the strongest response within a single individual, yet factors determining either inter- or intraindividual immunodominance are still poorly understood. More than 90 individuals were tested against 184 HIV- and 92 EBV-derived, previously defined CTL epitopes. The data show that HLA-B-restricted epitopes were significantly more frequently recognized than HLA-A- or HLA-C-restricted epitopes. HLA-B-restricted epitopes also induced responses of higher magnitude than did either HLA-A- or HLA-C-restricted epitopes, although this comparison only reached statistical significance for EBV epitopes. For both viruses, the magnitude and frequency of recognition were correlated with each other, but not with the epitope binding affinity to the restricting HLA allele. The presence or absence of HIV coinfection did not impact EBV epitope immunodominance patterns significantly. Peptide titration studies showed that the magnitude of responses was associated with high functional avidity, requiring low concentration of cognate peptide to respond in in vitro assays. The data support the important role of HLA-B alleles in antiviral immunity and afford a better understanding of the factors contributing to inter- and intraindividual immunodominance.

Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.

Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection.

Virus-specific CD8(+) T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon gamma assays presently used. Here, we demonstrate that HIV-1-specific CD8(+) T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4(+) T cells or addition of interleukin 2-neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4(+) T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1-specific CD4(+) T helper cell responses. These data demonstrate a loss of HIV-1-specific CD8(+) T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1-specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions.

CD8(+) T cells play a crucial role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. Recent data suggest that HIV-1-specific CD8(+) T cell subsets may differ in their ability to exert these effector functions. Here, we directly compared the cytokine secretion patterns and cytotoxic capacity of HIV-1-specific CD8(+) T cells, using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells. These experiments revealed considerable intraindividual and interindividual differences among epitope-specific T-cell effector functions: while the frequency of HIV-1-specific CD8(+) T cells secreting interferon-gamma but no tumor necrosis factor-alpha (TNF-alpha) following antigenic stimulation was only weakly correlated to their cytotoxic activity (R = 0.05, P =.57), a subset of CD8(+) T cells secreting both inter-feron-gamma and TNF-alpha was substantially more strongly associated with cytotoxicity (R = 0.67, P <.001). This subset of CD8(+) T cells also exhibited stronger intracellular perforin expression and more pronounced direct ex vivo HIV-1-specific cytoxicity than CD8(+) T cells secreting solely interferon-gamma following sorting of these subpopulations according to their cytokine profile. These results suggest that HIV-1-specific cytotoxicity of CD8(+) T cells is preferentially mediated by a subset of CD8(+) T cells secreting both interferon-gamma and TNF-alpha.

Objective: To compare the magnitude, breadth and protein specificity of HIV-1-specific CD8 T-cell responses against the clade B consensus sequence during primary and chronic HIV-1 infection and to analyze the impact of viral diversity on the localization of detected responses., Methods: HIV-1-specific CD8 T-cell responses against the clade B consensus sequence in individuals with acute (n = 10), early (n = 19) and chronic (n = 10) infection were longitudinally assessed using an interferon-gamma EliSpot assay., Results: CD8 T-cell responses against clade B consensus sequences were preferentially directed against central regions of Nef during primary HIV-1 infection, despite a relatively higher degree of genetic diversity compared with other subsequently targeted regions. In subjects with acute and early infection, Nef-specific CD8 T-cell responses against the consensus Nef sequence represented 94 and 46% of the total magnitude of HIV-1-specific CD8 T-cell responses, respectively. Subjects with untreated chronic infection exhibited broadly diversified CD8 T-cell responses against more conserved viral regions, with only 17% of virus-specific T-cell responses targeting Nef. The initial immunodominance of Nef persisted in individuals with treated acute infection, but shifted rapidly to Gag, Env and Pol in subjects with continuous antigen exposure., Conclusion: These data show that despite relatively high sequence variability, viral regions within the clade B consensus sequence of Nef are preferentially recognized during primary HIV-1 infection. Later diversification of responses to other proteins during prolonged antigen exposure provides evidence of the initial preferential immunogenicity of Nef epitopes compared to similarly conserved regions within other viral proteins.

To assess the role of lateral cephalometric films in the evaluation of orthodontic patients, 16 certified orthodontists examined 80 sets of dental casts and lateral cephalograms. The patients included 5 subgroups: Class I with mild crowding, Class II Division 2, Class III, open bites, and bimaxillary protrusion. A 5-point Visual Analogue Scale was used to assess the degree of severity and difficulty of each case. Severity was defined as the degree of deviation from ideal occlusion, while difficulty was defined as the probability of attaining an ideal occlusion when all treatment options were available. The examiner then chose one or more of the following treatment options: growth modification, extraction, nonextraction, and surgery. All examiners scored the degree of severity and difficulty of each case with casts only at Time 1 (T1), then with casts and cephalograms at Time 2 (T2). The observed ratings from the Visual Analogue Scale were scored by using the Rasch model, which transforms the nonlinear ordinal ratings to a linear interval scale. Intersubgroup differences and differences between T1 and T2 difficulty and severity were assessed by using a 5 x 2 repeated measures analysis of variance. A paired t test examined the amount and direction of the differences between T1 and T2 of each subgroup. Multiple contingency tables were used to compare treatment option changes between all subgroups at each time. Severity and difficulty scores highly correlated. Analysis of variance showed significant differences among subgroups for both severity and difficulty; however, there were significant time differences for severity only. Paired t tests revealed a small increase in severity for the bimaxillary protrusive group and small but significant decreases for the subgroups Class II Division 2 and Class III when cephalograms were added. The multicontingency table analysis demonstrated that a significant number of examiners did change their treatment options at T2 for bimaxillary protrusive, nonextraction, and Class II Division 2 patients. It was concluded that lateral cephalometric films showed a significant influence on a clinician's determination on severity of some types of orthodontic malocclusions.

The anti-tumorigenic and anti-proliferative effects of N-alpha-tosyl-l-phenylalanyl chloromethyl ketone (TPCK) have been known for more than three decades. Yet little is known about the discrete cellular targets of TPCK controlling these effects. Previous work from our laboratory showed TPCK, like the immunosuppressant rapamycin, to be a potent inhibitor of the 70-kilodalton ribosomal S6 kinase 1 (S6K1), which mediates events involved in cell growth and proliferation. We show here that rapamycin and TPCK display distinct inhibitory mechanisms on S6K1 as a rapamycin-resistant form of S6K1 was TPCK-sensitive. Additionally, we show that TPCK inhibited the activation of the related kinase and proto-oncogene Akt. Upstream regulators of S6K1 and Akt include phosphoinositide 3-kinase (PI 3-K) and 3-phosphoinositide-dependent kinase 1 (PDK1). Whereas TPCK had no effect on either mitogen-regulated PI 3-K activity or total cellular PDK1 activity, TPCK prevented phosphorylation of the PDK1 regulatory sites in S6K1 and Akt. Furthermore, whereas both PDK1 and the mitogen-activated protein kinase (MAPK) are required for full activation of the 90-kilodalton ribosomal S6 kinase (RSK), TPCK inhibited RSK activation without inhibiting MAPK activation. Consistent with the capacity of RSK and Akt to mediate a cell survival signal, in part through phosphorylation of the pro-apoptotic protein BAD, TPCK reduced BAD phosphorylation and led to cell death in interleukin-3-dependent 32D cells. Finally, in agreement with results seen in embryonic stem cells lacking PDK1, protein kinase A activation was not inhibited by TPCK showing TPCK specificity for mitogen-regulated PDK1 signaling. TPCK inhibition of PDK1 signaling thus disables central kinase cascades governing diverse cellular processes including proliferation and survival and provides an explanation for its striking biological effects.

Increased resistance in the upper airway is known to be a contributing factor to deviant facial growth patterns. These patterns are the result of a prolonged presence of unbalanced oropharyngeal muscle activity. We hypothesized that mechanically increasing airway resistance would enhance the activity of the muscles facilitating respiration, and we attempted to demonstrate that the increased muscle activity is modulated by mechanoreceptors in the pharyngeal airway. The response of oropharyngeal muscles to increased airway resistance during spontaneous breathing was observed in 11 rabbits. Electromyographic signals from the ala nasi, orbicularis oris superior, genioglossus, mylohyoid muscles, and the diaphragm were recorded by fine-wire electrodes. Pressure changes were monitored by pressure transducers at the side branch of the cannule close to openings for the nose and the trachea. The study consisted of 2 experimental sessions. First, to evoke the response of muscles to the inspiratory resistance, increasing stepwise polyethylene tubes of various diameters were attached to the nasal and tracheal opening and the diameter of the tubes was gradually reduced. Muscle activity changes in response to the increased resistance were recorded during spontaneous nasal or tracheal breathing. Second, to examine muscle responses to negative pressure to the pharyngeal airway, irrespective of breathing activity, the pharynx was isolated as a closed circuit by a stoma constructed at a more caudal side in the trachea. Muscle responses to the negative pressure generated by a syringe in the pharyngeal segment were measured. Nasal breathing induced a greater muscle activity than did tracheal breathing, in general, at P <.05. When resistance was gradually increased, nasal breathing resulted in a greater increase in muscle activity than did tracheal breathing (P <.05), except in the diaphragm. Application of negative pressure to the isolated pharyngeal airway segment increased the muscle activity significantly (P <.05). We conclude that an increased airway resistance may facilitate oropharyngeal muscle activity through mechanoreceptors in the oropharyngeal airway.

To achieve predictable and physiologic orthodontic tooth movement, estimating the axis of rotation of a tooth and the level and location of maximum stress distributed in the periodontal ligament is essential. An extracted upper canine was scanned into a computer 2-dimensionally and divided into 80 nodes along the long axis of the tooth. A mathematical formula was derived, and stress was calculated on each node. The purpose of this study was to reveal the center of resistance, axis of rotation, and an ideal force magnitude associated with various periodontal conditions, such as potential root resorption, alveolar bone loss, and varying anatomic root shape by analyzing the stress distribution in the periodontal ligament. The study demonstrates that the location of center of resistance changes significantly with variation of shape and length of the root embedded in alveolar bone. In contrast, in response to alveolar bone loss, the relative location of the center of resistance to total root length remains constant. Analysis of the stress distribution pattern in our 2-dimensional model reveals that the relationship between location of force and axis of rotation is determined by s(2) (that is) a constant depends on shape and length of a root in alveolar bone. Tapered and short roots that result from alveolar bone loss or apical root resorption are prone to tipping. The optimal orthodontic force may vary depending on the maximum stress in the periodontal ligament.

The purpose of this study was to determine the facial characteristics of nonobese patients with obstructive sleep apnea (OSA). Observational data on a cohort of patients was analyzed retrospectively. The subjects were classified into four groups: nonobese mild, obese mild, nonobese severe, and obese severe. The nonobese mild group included patients with a body mass index (BMI = kilogram/meter2) <25 and an apnea-hypopnea index (AHI) >5 and <15; the obese mild patients had a BMI >35 and an AHI >5 and <15; the nonobese severe patients had a BMI <25 and an AHI >40; the obese severe group had a BMI >35 and AHI >40. Thirty-three male patients referred for overnight polysomnography and lateral cephalometry who met the selection criteria were included. Between-group differences were examined pairwise by analysis of variance (ANOVA) with Bonferroni correction. Only two variables--lower facial height and overbite--were significantly different at p<0.05 between the nonobese severe group and the obese mild group. A discriminant analysis on the cephalometric measurements revealed that patients in the nonobese severe group could be distinguished from patients in other groups by their facial characteristics. OSA patients do not have a homogenous bony structure of the face. In particular, OSA severity in nonobese severe patients may be associated with a vertical skeletal disharmony.

Clinicians have long suspected that tongue shape differs between obstructive sleep apnea (OSA) patients and normal subjects. The purpose of this study was to determine whether such differences exist. Because of the difficulty in specifying reproducible homologous landmarks for the tongue, a morphometric technique-the eigenshape analysis-was used. The eigenshape analysis transforms an outline contour into a set of discrete numbers that are tangent angles of the curvature along the outline at each digitized point on the outline. Pairs of cephalograms were taken of 80 male patients in upright and supine positions. The subjects were subgrouped into four categories according to severity of symptoms. The contour of the tongue was traced, digitized, and subgrouped. When the major portion of the tongue shape variations in the supine position were graphically compared between subgroups, variations in the nonapneic group were distinguished from those in the apneic groups. The results suggest that the eigenshape analysis on cephalograms in the supine position may be a useful tool to distinguish OSA subjects from nonapneic subjects.

Objectives: To determine the shape difference of the face and tongue of obstructive sleep apnea (OSA) patients, in comparison to those of non-apneic patients., Design: Retrospective analysis of observational data on a cohort of patients., Setting: A university teaching hospital and sleep referral center. SAMPLE POPULATION AND METHOD: Eighty patients referred for overnight polysomnography and lateral cephalometry and who met the selection criteria were included. Upright and supine cephalograms were obtained and subgrouped based on the severity of clinical symptoms. Shape differences between the groups were assessed by a multiple analysis of variance and a Hotelling's T2., Measurements and Results: A set of anatomical landmarks were selected for outlines of the face and the tongue on cephalograms. X and Y coordinates of each landmark were utilized as variables. As symptoms become severe, the hyoid bone and the submental area positioned inferiorly and the fourth vertebra relocated posteriorly with respect to the lower mandibular border. When subjects changed their body position from the upright to the supine, the posterior part of the tongue appeared to sink down. The hyoid bone position to epiglottis-retrognathion line in the supine position distinguishes OSA patients from non-apneic subjects., Conclusion: Despite many limitations, we demonstrate that the supine cepahlometrics during wakefulness can be a useful adjunctive diagnostic tool for OSA, when cephalograms are analyzed in a coordinate data form.

The shape characteristics of the face and tongue in obstructive sleep apnea (OSA) patients were investigated using thin-plate (TP) splines. A relatively new analytic tool, the TP spline method, provides a means of size normalization and image analysis. When shape is one's main concern, various sizes of a biologic structure may be a source of statistical noise. More seriously, the strong size effect could mask underlying, actual attributes of the disease. A set of size normalized data in the form of coordinates was generated from cephalograms of 80 male subjects. The TP spline method envisioned the differences in the shape of the face and tongue between OSA patients and nonapneic subjects and those between the upright and supine body positions. In accordance with OSA severity, the hyoid bone and the submental region positioned inferiorly and the fourth vertebra relocated posteriorly with respect to the mandible. This caused a fanlike configuration of the lower part of the face and neck in the sagittal plane in both upright and supine body positions. TP splines revealed tongue deformations caused by a body position change. Overall, the new morphometric tool adopted here was found to be viable in the analysis of morphologic changes.

Anterior open bites may be localized dental manifestations, which are caused by habits or skeletal disharmony, with or without functional aberration. Previous studies suggest various associations between open bites and underlying etiologic factors. We hypothesize that respiratory efficiency may be associated with anterior open bites. Under the assumption that breathing efficiency of the oropharynx and hypopharynx may be related to pharyngeal airway length, a cephalometric variable, vertical airway length (VAL), was measured on lateral cephalograms obtained from a total of 58 subjects with, so called, "open bite tendencies" (hereafter, open bite tendency). By means of the variable VAL, the association between pharyngeal length and open bite was investigated. In addition, the difference between actual open bite and open bite tendencies was also examined. The samples were randomly collected under stringent selection criteria from an existing database. A series of statistical analyses, such as unpaired t test, multiple regression, and discriminant analysis, was used to test the proposed hypothesis. The study found that none of the open bite tendency indicators used can segregate open bite subjects from nonopen bite subjects. The obtained discriminant function clearly divides the samples into two groups, i.e., open bite group and nonopen bite group, which were based on VAL and lower facial height. The study concludes that, first, an open bite tendency may be a different entity from an actual open bite or may be a misconceptualized term. Second, pharyngeal length may be a convenient indicator to diagnose open bite. We speculate that open bite may be different from an open bite tendency in pharyngeal length.

A narrow pharyngeal pathway may be one of the most significant predisposing factors for obstructive sleep apnea (OSA). Accordingly, the objectives of many treatment modalities are focused on widening the constricted part of the pharynx. Despite the obvious limitations as a two-dimensional imaging technique, cephalometrics has been used more recently as a clinical screening tool for OSA. This study was designed to investigate whether pharyngeal variables more reliable than a single measurement of the most constricted area exist in cephalograms. A total of 80 pairs of upright and supine cephalograms were obtained and subclassified into four groups, in accordance with OSA severity. A medial axis program conveniently provided the variables for the study by transforming digitized outlines of the pharyngeal structure. The results indicate that the pharyngeal length and the pharyngeal width below the most constricted area may be the most important variables. We observed that the pharynx becomes considerably longer in the apneic group after a body position change from upright to supine. Pharyngeal length in the supine position may be more important than a one-dimensional measurement of the most constricted area in the diagnosis and treatment of OSA.

Units of length, degree, and area are used when measuring cephalograms. In particular, the measurement of angles is a conventional method of quantifying shape. Because angles do not provide information about direction, there is no way to tell how and where one part of the facial structure has moved with respect to the rest. A new landmark data system using x- and y-coordinates is proposed, and some of its advantages over conventional methods are explained.

Obstructive sleep apnea (OSA) is caused by repeated obstruction of the upper airway during sleep. The purpose of this study was to test the relative contributions of specific demographic and cephalometric measurements to OSA severity. Demographic, cephalometric, and overnight polysomnographic records of 291 male OSA patients and 49 male nonapneic snorers were evaluated. A partial least squares (PLS) analysis was used for statistical evaluation. The results revealed that the predictive powers of obesity and neck size variables for OSA severity were higher than the cephalometric variables used in this study. Compared with other cephalometric characteristics, an extended and forward natural head posture, lower hyoid bone position, increased soft palate and tongue dimensions, and decreased nasopharyngeal and velopharyngeal airway dimensions had relatively higher associations with OSA severity. The respiratory disturbance index (RDI) was the OSA outcome variable that was best explained by the demographic and cephalometric predictor variables. We conclude that the PLS analysis can successfully summarize the correlations between a large number of variables, and that obesity, neck size, and certain cephalometric measurements may be used together to evaluate OSA severity.

To investigate whether patients with obstructive sleep apnea (OSA) have abnormalities in their craniofacial and upper airway (UA) structures compared with normal subjects, cephalometric comparisons were systematically performed in both the upright and the supine positions in subjects with and without OSA, who were then grouped according to their craniofacial skeletal type and gender. A total of 347 patients with OSA and 101 control subjects were divided into male and female groups and then classified into Class I (CI), Class II, Division 1 (CII/1), Class II, Division 2 (CII/2), and Class III (CIII) skeletal subtypes. In the upright position, the most atypical craniofacial and UA structure was shown in male patients with CI OSA. In patients with OSA, the degree of UA abnormalities was less in the supine position regardless of skeletal subtype. In the supine position, the most atypical craniofacial and UA structure was also shown in male patients with CI OSA; there were no significant differences between male patients with CII/2 OSA and control subjects or between female patients with CI OSA and control subjects. With a change in body position from upright to supine, distinctive changes in the UA structure in both patients with OSA and control subjects occurred, according to skeletal subtype and gender. We conclude that there are a series of characteristics of craniofacial and UA structure that differ between patients with OSA and control subjects matched for skeletal subtype and gender. These differences may predispose to UA obstruction during sleep in patients with OSA.

Knowledge of how dental appliances alter upper airway muscle activity when they are used for the treatment of snoring and/or obstructive sleep apnea (OSA) is very limited. The purpose of this study was to define the effect of a tongue retaining device (TRD) on awake genioglossus (GG) muscle activity in 10 adult subjects with OSA and in 6 age and body mass index (BMI) matched symptom-free control subjects. The TRD is a custom-made appliance designed to allow the tongue to remain in a forward position between the anterior teeth by holding the tongue in an anterior bulb with negative pressure, during sleep. This pulls the tongue forward to enlarge the volume of the upper airway and to reduce upper airway resistance. In this study, two customized TRDs were used for each subject. The TRD-A did not have an anterior bulb but incorporated lingual surface electrodes to record the GG electromyographic (EMG) activity. The TRD-B contained an anterior bulb and two similar electrodes. The GG EMG activity was also recorded while patients used the TRD-B but were instructed to keep their tongue at rest outside the anterior bulb; this condition is hereafter referred to as TRD-X. The GG EMG activity and nasal airflow were simultaneously recorded while subjects used these customized TRDs during spontaneous awake breathing in both the upright and supine position. The following results were obtained and were consistent whether subjects were in the upright or the supine position. The GG EMG activity was greater with the TRD-B than with the TRD-A in control subjects (p < 0.05), whereas the GG EMG activity was less with the TRD-B than with the TRD-A in subjects with OSA (p < 0.01). Furthermore, there was no significant difference between the GG EMG activity of the TRD-A and the TRD-X in control subjects, whereas there was less activity with the TRD-X than with the TRD-A in subjects with OSA (p < 0.05). On the basis of these findings, it was concluded that the TRD has different effects on the awake GG muscle activity in control subjects and patients with OSA. The resultant change in the anatomic configuration of the upper airway caused by the TRD may be important in the treatment of OSA because such a change may alleviate the impaired upper airway function.

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep, usually in the supine position. To investigate the relationship between upper airway size and genioglossus (GG) muscle activity, upright and supine cephalograms were obtained in 20 OSA patients and 10 symptom-free control subjects. Tongue electromyographic (EMG) recordings were obtained with surface electrodes, and pressure transducers were placed in the 10 symptom-free controls. The tongue cross-sectional area increased 4.3% (p < 0.05), and the oropharyngeal area decreased 36.5% (p < 0.01) when the OSA patients changed their body position from upright to supine. No changes were observed in the tongue area, but soft palate thickness increased (p < 0.01) when the control subjects changed from the upright to the supine position. Furthermore, the oropharyngeal cross-sectional area decreased 28.8% (p < 0.01) despite a 34% increase (p < 0.05) in resting GG EMG activity. Posterior tongue pressure increased 17% (p < 0.05) with the change from upright to supine. On the basis of these findings, we propose that body posture has a substantial effect on upper airway structure and muscle activity. This postural effect should be taken into account when assessing upper airway size in the erect posture (conventional cephalography) and in the supine position (computed tomography). The vertical and anteroposterior position of the tongue and its relationship to airway size may be more important than soft palate size in the pathogenesis of OSA.

A sample of 84 adult male patients with obstructive sleep apnea (OSA) were classified by a cluster analysis on the basis of apnea index (AI) and body mass index (BMI). Demographic, cephalometric, tongue, soft palate, and upper airway-size data were evaluated for the two subgroups of OSA patients and for 18 control subjects. One OSA group consisted of 43 patients with a high AI and low BMI ratio, the other group was comprised of 41 patients with a low AI and high BMI ratio. The patients with a high AI and low BMI ratio had retruded mandibles with high mandibular plane angles and proclined lower incisors. The patients with a low AI and high BMI ratio had inferior hyoid bones and large soft palates. A multiple regression analysis was performed between AI (the dependent variable) and the other variables (independent variables) for each of the subgroups. In the patients with a high AI and low BMI ratio, a high AI was related to a large skeletal anteroposterior discrepancy, a steep mandibular plane, and an inferoanterior position of the hyoid bone. In the patients with a low AI and high BMI ratio, a high AI was related to a large tongue and a small upper airway. In both groups, BMI was the major contributor to AI. In conclusion, these two groups may represent distinct subgroups of OSA patients and provide some insight into the contribution of obesity to the pathogenesis of OSA. The patients with a high AI and low BMI ratio have a skeletal mismatch, whereas the patients with a low AI and high BMI have atypical soft tissue structures.