Sung-Pil Lee

Narcolepsy is strongly associated with the T-cell receptor alpha locus

Narcolepsy with cataplexy, characterized by sleepiness and rapid onset into REM sleep, affects 1 in 2,000 individuals. Narcolepsy was first shown to be tightly associated with HLA-DR2 (ref. 3) and later sublocalized to DQB1*0602 (ref. 4). Following studies in dogs and mice, a 95% loss of hypocretin-producing cells in postmortem hypothalami from narcoleptic individuals was reported. Using genome-wide association (GWA) in Caucasians with replication in three ethnic groups, we found association between narcolepsy and polymorphisms in the TRA@ (T-cell receptor alpha) locus, with highest significance at rs1154155 (average allelic odds ratio 1.69, genotypic odds ratios 1.94 and 2.55, P < 10−21, 1,830 cases, 2,164 controls). This is the first documented genetic involvement of the TRA@ locus, encoding the major receptor for HLA-peptide presentation, in any disease. It is still unclear how specific HLA alleles confer susceptibility to over 100 HLA-associated disorders; thus, narcolepsy will provide new insights on how HLA–TCR interactions contribute to organ-specific autoimmune targeting and may serve as a model for over 100 other HLA-associated disorders.

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.

Pattern analysis of sleep-deprived human EEG

Progress during the past decade in non‐linear dynamics and instability theory has provided useful tools for understanding spatio‐temporal pattern formation. Procedures which apply principle component analysis (using the Karhunen–Loeve decomposition technique) to the multichannel electroencephalograph (EEG) time series have been developed. This technique shows localized changes of cortical functioning; it identifies increases and decreases of the activity of localized cortical regions over time while the subject performs a simple task or test. It can be used to demonstrate the change in cortical dynamics in response to a continuous challenge. Using 16 EEG electrodes, the technique provides spatio‐temporal information not obtained with power spectrum analysis, and includes the weighted information given with omega complexity. As an application, we performed a pattern analysis of sleep‐deprived human EEG data in 20 healthy young men. Electroencephalograph recordings were performed on subjects for <2 min, with eyes closed after normal sleep and after 24 h of experimentally‐induced sleep deprivation. The significant changes in the eigenvector components indicated the relative changes of local activity in the brain with progressive sleep deprivation. A sleep deprivation effect was observed, which was hemispherically correlated but with opposite directional dynamics. These changes were seen in the temporo‐parietal regions bilaterally. The application of the technique showed that the simple test task was performed with a limited unilateral hemispheric involvement at baseline, but needed a much larger cortical participation with decreased frontal activity and increased coherence and bilateral hemispheric involvement. The calculations performed demonstrated that the same weighted changes as those obtained with omega complexity were shown, but the technique had the added advantage of showing the localized directional changes of the principle eigenvector at each studied electrode, pointing out the cortical localized region affected by the sleep deprivation and toward which direction the environmental challenge induced the spatial change. This methodology may allow the evaluation of changes in local dynamics in brain activity in normal and pathological conditions.

A Case of a Patient with Both Chorea and Restless Legs Syndrome

The patient was a 44-yr-old man with end-stage renal disease who had developed chorea as a result of hypoglycemic injury to the basal ganglia and thalamus and who was subsequently diagnosed with depression and restless legs syndrome (RLS). For proper management, the presence of a complex medical condition including two contrasting diseases, chorea and RLS, had to be considered. Tramadol improved the pain and dysesthetic restlessness in his feet and legs, and this was gradually followed by improvements in his depressed mood, insomnia, lethargy, and feelings of hopelessness. This case suggests that the dopaminergic system participates intricately with the opioid, serotoninergic, and noradrenergic systems in the pathophysiology of RLS and pain and indirectly of depression and insomnia.

SU-F-T-314: Estimation of Dose Distributions with Different Types of Breast Implants in Various Radiation Treatment Techniques for Breast Cancer

PURPOSE This study investigates the effects of different kinds and designs of commercialized breast implants on the dose distributions in breast cancer radiotherapy under a variety of conditions. METHODS The dose for the clinical conventional tangential irradiation, Intensity Modulated Radiation Therapy (IMRT), volumetric modulated arc therapy (VMAT) breast plans was measured using radiochromic films and stimulated luminescence dosimeter (OSLD). The radiochromic film was used as an integrating dosimeter, while the OSLDs were used for real-time dosimetry to isolate the contribution of dose from individual segment. The films were placed at various slices in the Rando phantom and between the body and breast surface OSLDs were used to measure skin dose at 18 positions spaced on the two (right/left) breast. The implant breast was placed on the left side and the phantom breast was remained on the right side. Each treatment technique was performed on different size of the breasts and different shape of the breast implant. The PTV dose was prescribed 50.4 Gy and V47.88≥95%. RESULTS In different shapes of the breast implant, because of the shadow formed extensive around the breast implant, dose variation was relatively higher that of prescribed dose. As the PTV was delineated on the whole breast, maximum 5% dose error and average 3% difference was observed averagely. VMAT techniques largely decrease the contiguous hot spot in the skin by an average of 25% compared with IMRT. The both IMRT and VMAT techniques resulted in lower doses to normal critical structures than tangential plans for nearly all dose analyzation. CONCLUSION Compared to the other technique, IMRT reduced radiation dose exposure to normal tissues and maintained reasonable target homogeneity and for the same target coverage, VMAT can reduce the skin dose in all the regions of the body.