Yu-Shu Huang

Common variants in P2RY11 are associated with narcolepsy

Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African Americans). We identify a SNP in the 3′ untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10−10, odds ratio = 1.28, 95% CI 1.19–1.39, n = 5689). The disease-associated allele is correlated with reduced expression of P2RY11 in CD8+ T lymphocytes (72% reduced, P = 0.003) and natural killer (NK) cells (70% reduced, P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases.

Adenotonsillectomy and obstructive sleep apnea in children: A prospective survey

Objective Prospective survey of children up to 14 years of age with OSA submitted to adenotonsillectomy. Methods Clinical evaluation, with questionnaires and clinical scales evaluating facial structures including tonsils and Mallampati scales and otolaryngologic evaluation; nocturnal polysomnography and repeat evaluation three to five months postsurgery. Results Of 207 successively seen children, 199 had follow-up polysomnography, and 94 had still abnormal sleep recording. Multivariate analysis indicates that Mallampati scale score 3 and 4, retro-position of mandible, enlargement of nasal inferior turbinates at +3 (subjective scale 1 to 3), and deviated septum were significantly associated with persistence of abnormal polysomnography (with high 95% CI for Mallampati scale and deviated septum). Conclusion Mallampati scale scores are resultant of several facial factors involving maxilla, mandible, and oral versus oral breathing but add information on risk of partial response to adenotonsillectomy. Significance Adenotonsillectomy may not resolve obstructive sleep apnea in children.

Sleep disorders in Taiwanese children with attention deficit/hyperactivity disorder

To assess obstructive sleep apnea syndrome (OSAS) and periodic limb movement disorder (PLMD) in children with attention deficit/hyperactivity disorder (ADHD) compared with a control group. The ADHD was diagnosed based on Diagnostic and Statistical Manual, version IV (DSM‐IV) criteria on successively seen elementary school children aged 6–12 years referred to a psychiatric clinic for suspected ADHD. A standardized interview (Kiddie‐SADS‐E), parents and teacher questionnaires, neuropsychological testing, and nocturnal polysomnography were completed for each child. Eighty‐eight children (77 boys) with ADHD and 27 controls were involved in the study. Fifty children with ADHD (56.8%) had an apnea–hypopnea index (AHI) >1 event h−1 and 17 (19.3%) had an AHI >5 event h−1. Nine children (10.2%) had a periodic limb movement index (PLMI) >5 events h−1. There is one child with AHI >1 and none with a PLMI > 5 in the control group. In the test of variables of attention (TOVA), the response time was significantly worse in ADHD with sleep disorders than those without them. The child behavior checklist (CBCL) showed a significant difference between groups in the hyperactivity subscale. The diagnostic criteria for ADHD based on DSM‐IV do not differentiate between children with or without sleep disorders. Evaluation of sleep disorders should be considered before starting drug treatment for ADHD.

Impact of Adenotonsillectomy on Behavior in Children With Sleep-Disordered Breathing†

Objectives/Hypothesis: Children with sleep‐disordered breathing may experience behavioral and learning problems such as inattentiveness and hyperactivity. The aim of this study was to measure the impact of adenotonsillectomy on sleep‐related adverse events and behavioral problems in children with sleep‐disordered breathing.

Si-containing crystalline carbon nitride derived from microwave plasma-enhanced chemical vapor deposition

Carbon nitride thin films have been grown by the microwave plasma-enhanced chemical vapor deposition (MW-PECVD) technique. Gas mixtures containing CH4, H2 and NH3 at various ratios were tested as precursors, and Si (100) wafers were used as substrates. X-ray photoelectron spectroscopy (XPS), Auger electron spectroscopy (AES), electron microscopy (both SEM and TEM), and Raman spectroscopy have been employed to characterize the resultant films. The phase contents in the films were found to be strongly dependent on the substrate temperature. The incorporation of significant amounts of Si into the film was observed when the substrate temperature exceeded 1000°C. However, the presence of Si along with a high substrate temperature also promotes the formation of large crystallites. XPS analyses of C(1s) and N(1s) core levels suggest a multiple bonding structure between carbon and nitrogen atoms. Microscopic investigations of the films reveal the coexistence of large grain (> 10 μm) and fine grain (< 1 μm) crystals. Preliminary structural studies suggest the presence of a crystalline carbon nitride compound corresponding to a hypothetical α-C3N4 phase (isomorphic to α-Si3N4), which may also be a stable hard material. Furthermore, we propose that some of the Si has been incorporated as a substitutional element for the C site in the new phase. The Raman spectra exhibit many sharp lines, of which the most distinct ones mimic those of the α-Si3N4 structure.

Treatment Outcomes of Adenotonsillectomy for Children with Obstructive Sleep Apnea: A Prospective Longitudinal Study

OBJECTIVE To evaluate the efficacy of adenotonsillectomy (AT) in the treatment of children with obstructive sleep apnea (OSA) in a 3-y prospective, longitudinal study with analysis of risk factors of recurrence of OSA. STUDY DESIGN An investigation of children (6 to 12 y old) with OSA documented at entry and followed posttreatment at 6, 12, 24, and 36 mo with examination, questionnaires, and polysomnography. Multivariate generalized linear modeling and hierarchical linear models analysis were used to determine contributors to suboptimal long-term resolution of OSA, and Generalized Linear Models were used for analysis of risk factors of recurrence. RESULTS Of the 135 children, 88 terminated the study at 36 months post-AT. These 88 children (boys = 72, mean age = 8.9 ± 2.7 yersus boys 8.9 ± 2.04 y, girls: 8.8 ± 2.07 y; body mass index [BMI] = 19.5 ± 4.6 kg/m(2)) had a preoperative mean apnea-hypopnea index (AHI0) of 13.54 ± 7.23 and a mean postoperative AHI at 6 mo (AHI6) of 3.47 ± 8.41 events/h (with AHI6 > 1 = 53.4% of 88 children). A progressive increase in AHI was noted with a mean AHI36 = 6.48 ± 5.57 events/h and AHI36 > 1 = 68% of the studied group. Change in AHI was associated with changes in the OSA-18 questionnaire. The residual pediatric OSA after AT was significantly associated with BMI, AHI, enuresis, and allergic rhinitis before surgery. From 6 to 36 mo after AT, recurrence of pediatric OSA was significantly associated with enuresis, age (for the 24- to 36-mo period), postsurgery AHI6 (severity), and the rate of change in BMI and body weight. CONCLUSIONS Adenotonsillectomy leads to significant improvement in apnea-hypopnea index, though generally with incomplete resolution, but a worsening over time was observed in 68% of our cases.

Narcolepsy: Action of Two γ-Aminobutyric Acid Type B Agonists, Baclofen and Sodium Oxybate

This study was performed to evaluate the actions of baclofen and sodium oxybate, two medications with gamma-aminobutyric acid type B (GABA(B)) receptor agonist properties, on symptoms of narcolepsy in drug-naïve teenagers. Twenty-six narcoleptic teenagers with recent onset of narcolepsy-cataplexy syndrome who were human leukocyte antigen DQB1 0602 positive were matched for age and sex and received either baclofen or sodium oxybate. If deemed necessary to combat excessive daytime sleepiness, the alerting agent modafinil was also prescribed. Clinical evaluation was performed weekly, and visual analog sleepiness score and cataplexy logs were collected weekly. The Epworth Sleepiness Scale or the Pediatric Daytime Sleepiness Scale, polysomnography, and the Multiple Sleep Latency Test were recorded at baseline and after 3 months of drug intake. The dose of baclofen demonstrating an effect on nocturnal sleep without negative side effects was determined and maintained. Both drugs increased total sleep time and delta waves during sleep, but only sodium oxybate had an effect on daytime sleepiness and cataplexy at 3 months. Improvement of total nocturnal sleep time had no beneficial effect on daytime sleepiness. The mechanism by which sodium oxybate improves cataplexy and sleepiness is inferred to be due to properties beyond direct GABA(B) agonist action.

Pediatric obstructive sleep apnea and the critical role of oral-facial growth: evidences

Aims: Review of evidence in support of an oral-facial growth impairment in the development of pediatric sleep apnea in non-obese children. Method: Review of experimental data from infant monkeys with experimentally induced nasal resistance. Review of early historical data in the orthodontic literature indicating the abnormal oral-facial development associated with mouth breathing and nasal resistance. Review of the progressive demonstration of sleep-disordered-breathing (SDB) in children who underwent incomplete treatment of OSA with adenotonsillectomy, and demonstration of abnormal oral-facial anatomy that must often be treated in order for the resolution of OSA. Review of data of long-term recurrence of OSA and indication of oral-facial myofunctional dysfunction in association with the recurrence of OSA. Results: Presentation of prospective data on premature infants and SDB-treated children, supporting the concept of oral-facial hypotonia. Presentation of evidence supporting hypotonia as a primary element in the development of oral-facial anatomic abnormalities leading to abnormal breathing during sleep. Continuous interaction between oral-facial muscle tone, maxillary-mandibular growth and development of SDB. Role of myofunctional reeducation with orthodontics and elimination of upper airway soft tissue in the treatment of non-obese SDB children. Conclusion: Pediatric OSA in non-obese children is a disorder of oral-facial growth.

An epidemiologic study of sleep problems among adolescents in North Taiwan

BACKGROUND AND PURPOSE To investigate the prevalence of sleep problems and their association with daytime sleepiness among Taiwanese adolescents by use of a validated questionnaire. PATIENTS AND METHODS This is a cross-sectional, community based study with self-reported sleep questionnaires. Completed questionnaires from 1939 adolescent subjects from schools in Lin-Kou district (Taipei, Taiwan) (96.7% responded); 1906 valid questionnaires (62.3% girls) were analyzed. The randomly selected classes included elementary grade 6 (age range: 12-13 years), junior high school (age range: 14-16 years) and senior high school students (age range: 17-18 years). RESULT The mean sleep duration on weekdays was 7.35±1.23 h and on weekends 9.38±1.62 h. Weeknight sleep decreased significantly with increasing school grade (6.87±1.14 h for high school seniors). There was a trend towards increased daytime sleepiness for students in higher school grade levels. Daytime sleepiness directly correlated with shorter total sleep time (TST) on weekdays, longer TST on weekends, snoring, insomnia and nightmares. Coffee intake, smoking, periodic leg movement/restless legs syndrome, body mass index (BMI), mouth breathing and breathing problems were indirect factors that induced daytime sleepiness. Pearson correlation showed no significant correlation between the TST during the weekday and BMI (-0.047, p=0.079) or body weight (BW) (-0.048, p=0.072). But it showed significant negative correlation (-0.103, p=0.0001) for increasing total sleep time on the weekend and decreasing BMI. CONCLUSIONS Daytime sleepiness correlated with the shorter TST on weekdays, longer TST on weekends, snoring, insomnia and nightmares. There is no significant correlation between the weekday TST and BMI or BW. Meals and food intake of children are still traditional and have not changed as much in Taiwan as in some other western countries, and compared to a similar survey performed 12 years ago in Taiwan among junior high school students, sleep duration was not significantly different but reduced due to school demands.

Is obstructive sleep apnea syndrome a neurological disorder? A continuous positive airway pressure follow‐up study

Abnormal sensory responses have been found in the upper airway of obstructive sleep apnea patients, but no long‐term study has been published previously regarding the evolution of obstructive sleep apnea syndrome and persistence of abnormal pharyngeal sensory evaluation in response to continuous positive airway pressure (CPAP) treatment. Over 5 years, we managed healthy, nonobese subjects compliant with nasal CPAP. Only 47 subjects completed this prospective study, due to protocol requirements. They underwent regular clinical evaluation, subjective scales, four polysomnographies without nasal CPAP, recalibration of nasal CPAP with polysomnography, regular downloading of home data, and a palatal two‐point discrimination study. None of the subjects presented normal results at any checkpoint when they had been without CPAP for two or three nights. By the completion of the study, all subjects required an increase in nasal CPAP (1–7cm H2O) and demonstrated abnormal two‐point palatal discrimination compared with control subjects. Despite initial control of clinical symptoms with regular usage of nasal CPAP in subjects without weight change, abnormal sensory palatal evaluation was present at the conclusion of the study. Obstructive sleep apnea syndrome involves abnormal upper airway sensory input, which may be responsible for the development of apneas and hypopneas. These neurological lesions are persistent despite nasal CPAP treatment. Ann Neurol 2006