Thyroid-Associated Orbitopathy: Evaluating Microstructural Changes of Extraocular Muscles and Optic Nerves Using Readout-Segmented Echo-Planar Imaging-Based Diffusion Tensor Imaging

OBJECTIVE: We aimed to investigate the ability of readout-segmented echo-planar imaging (rs-EPI)-based diffusion tensor imaging (DTI) in assessing the microstructural change of extraocular muscles (EOMs) and optic nerves in patients with thyroid-associated orbitopathy (TAO) as well as in evaluating disease activity.MATERIALS AND METHODS: We enrolled 35 TAO patients and 22 healthy controls (HCs) who underwent pre-treatment rs-EPI-based DTI. Mean, axial, and radial diffusivity (MD, AD, and RD) and fractional anisotropy (FA) of the medial and lateral EOMs and optic nerve for each orbit were calculated and compared between TAO and HC groups and between active and inactive TAO groups. Factors such as age, sex, disease duration, mediation, and smoking history between groups were also compared. Logistic regression analysis was used to evaluate the predictive value of significant variables for disease activity.RESULTS: Disease duration was significantly shorter in active TAOs than in inactive ones (p < 0.001). TAO patients showed significantly lower FA and higher MD, AD, and RD than HCs for both medial and lateral EOMs (p < 0.001), but not the AD value of lateral EOMs (p = 0.619). Active patients had significantly higher FA, MD, and AD than inactive patients for medial EOMs (p < 0.005), whereas only FA differed significantly in the lateral EOMs (p = 0.018). The MD, AD, and RD of optic nerves were significantly lower in TAO patients than HCs (p < 0.05), except for FA (p = 0.129). Multivariate analysis showed that the MD of medial EOMs and disease duration were significant predictors for disease activity. The combination of these two parameters showed optimal diagnostic efficiency for disease activity (area under the curve, 0.855; sensitivity, 68.4%; specificity, 96.9%).CONCLUSION: rs-EPI-based DTI is promising in assessing microstructural changes of EOMs and optic nerves and can help to indicate the disease activity of TAO, especially through the MD of medial EOMs.

Comparison of Intraocular Pressure via Goldmann-applanation Tonometry and TonoPen in Thyroid-associated Ophthalmopathy Accompanying Restrictive Strabismus

PURPOSE: To compare the intraocular pressure (IOP) measured using Goldmann-applanation tonometry (GAT) and Tonopen® tonometry and to evaluate the factors influencing the measurement difference in patients with thyroid-associated ophthalmopathy (TAO)-related restrictive strabismus. METHODS: In 50 eyes of 50 patients who were diagnosed with TAO, IOP measurements were taken using both GAT and a Tonopen® and were subsequently compared between the devices. Factors influencing the measurement difference between the devices were determined, including the restriction of eyeball movement, eyeball deviation, exophthalmometry, central corneal thickness, refractive errors, and blood thyroid hormone levels. RESULTS: In the TAO patients, the GAT-measured IOP was higher than for Tonopen® (16.1 ± 4.7 vs. 13.8 ± 4.5 mmHg, respectively, p < 0.001). As the restriction of vertical eyeball movement increased, the IOP difference between the devices also increased (p = 0.037). The absolute IOP difference between the devices was positively correlated with restrictions in vertical eyeball movement (p = 0.027), degree of vertical strabismus (p = 0.021), and central corneal thickness (p ≤ 0.031). CONCLUSIONS: In patients with TAO accompanying vertical eyeball movement restriction, potential errors in IOP measurements should be considered between the different IOP-measuring devices.

Choroidal Thickness in Thyroid-associated Ophthalmopathy between Normal Tension Glaucoma Using Optical Coherence Tomography

PURPOSE: To compare the macular choroidal thickness in patients with thyroid-associated ophthalmopathy (TAO) with those with normal tension glaucoma (NTG). METHODS: A total of 70 normal eyes, 74 eyes with TAO and 60 eyes with NTG were enrolled in this study. All patients underwent spectral-domain optical coherence tomography (SD-OCT) (Cirrus HD-OCT, Carl Zeiss Meditec Inc., Dublin, CA, USA). Macular choroidal thickness was assessed using enhanced depth imaging. The average macular choroidal thickness was defined as the average value of three measurements: at the fovea and at the points located 1.5 mm in the nasal and temporal directions from the fovea. Generalized estimating equations were used to uncover factors affecting the average macular choroidal thickness. RESULTS: The average, superior and inferior quadrant retinal nerve fiber layer thicknesses were significantly thinner in the NTG group compared with the TAO and control groups (p < 0.001). The average macular choroidal thickness of the TAO group, NTG group and controls was 281.01 ± 60.06 µm, 241.66 ± 55.00 µm and 252.07 ± 55.05 µm, respectively, which were significantly different (p = 0.013). The subfoveal, nasal and temporal side choroidal thicknesses were significantly thinner in the NTG group compared with the TAO group (p = 0.014, 0.012 and 0.034, respectively). Subjects with TAO were associated with a thicker average macular choroidal thickness compared with the NTG group after adjusting for age, sex, spherical equivalent and intraocular pressure (β = 32.61, p = 0.017). CONCLUSIONS: Macular choroidal thickness was significantly thicker in patients with TAO compared with those with NTG. Further evaluation is required to determine if a thick choroid in subjects with TAO has any role in glaucomatous optic neuropathy.

Identification and Functional Characterization of ST3GAL5 and ST8SIA1 Variants in Patients with Thyroid-Associated Ophthalmopathy

PURPOSE: This study was conducted to identify and to functionally characterize genetic variants in ST3GAL5 and ST8SIA1 in Korean patients with thyroid-associated ophthalmopathy (TAO). MATERIALS AND METHODS: Genetic analyses were conducted using DNA samples from TAO patients (n=50) and healthy subjects (n=48) to identify TAO-specific genetic variants of ST3GAL5 or ST8SIA1. The effect of each genetic variant on the transcription or expression of these genes was examined. Additionally, correlations between functional haplotypes of ST3GAL5 or ST8SIA1 and clinical characteristics of the patients were investigated. RESULTS: Six promoter variants and one nonsynonymous variant of ST3GAL5 were identified, and four major promoter haplotypes were assembled. Additionally, three promoter variants and two major haplotypes of ST8SIA1 were identified. All ST3GAL5 and ST8SIA1 variants identified in TAO patients were also found in healthy controls. Promoter activity was significantly decreased in three promoter haplotypes of ST3GAL5 and increased in one promoter haplotype of ST8SIA1. Transcription factors activating protein-1, NKX3.1, and specificity protein 1 were revealed as having roles in transcriptional regulation of these haplotypes. The nonsynonymous variant of ST3GAL5, H104R, did not alter the expression of ST3GAL5. While no differences in clinical characteristics were detected in patients possessing the functional promoter haplotypes of ST3GAL5, exophthalmic values were significantly lower in patients with the ST8SIA1 haplotype, which showed a significant increase in promoter activity. CONCLUSION: These results from genotype-phenotype analysis might suggest a possible link between the ST8SIA1 functional promoter haplotype and the clinical severity of TAO. However, further studies with larger sample sizes are warranted.

Clinical Features of Dry Eye in Thyroid-Associated Ophthalmopathy According to Disease Activity

PURPOSE: To evaluate the clinical features of dry eye in thyroid-associated ophthalmopathy (TAO) according to disease activity and analyze the related factors. METHODS: This study included 157 patients diagnosed with TAO and dry eye between March 2009 and March 2015. According to the clinical activity score (CAS), TAO patients were divided into inactive (CAS < 3) and active (CAS ≥ 3) groups. Clinical features included age, sex, visual acuity, proptosis, palpebral fissure width, orbital computed tomography (CT) findings, thyroid hormones, and ocular surface parameters including tear film break-up time (TFBUT), Schirmer tests, keratoepitheliopathy scores, and ocular surface disease index (OSDI) were obtained and compared between the groups. In addition, correlations between clinical features and ocular surface parameters were analyzed in both groups. RESULTS: In the inactive and active TAO groups, CAS was 1.24 ± 0.69 and 4.23 ± 1.13, respectively (p = 0.001). Thyrotropin-binding inhibitory immunoglobulin was significantly higher in the active TAO group than in the inactive TAO group (p = 0.048). On orbital CT, extraocular muscle hypertrophy was more common in the active TAO group than the inactive TAO group (p = 0.020). No significant difference was found in age, sex, visual acuity, free T4, and thyroid-stimulating hormone between the two groups. During analysis of the tear film and ocular surface parameters, TFBUT (p = 0.006) was shorter and OSDI score (p = 0.028) was higher in the active TAO group than the inactive TAO group. TFBUT was negatively correlated with proptosis (r = -0.432, p = 0.001; r = -0.308, p = 0.032) and palpebral fissure width (r = -0.367 p = 0.012; r = -0.312, p = 0.031) in both groups. OSDI was positively correlated with proptosis in the active TAO group (r = 0.301, p = 0.033). CONCLUSIONS: TFBUT was shorter and OSDI score higher in dry eye patients with active TAO than in patients with inactive TAO. The TFBUT was negatively correlated with proptosis and palpebral fissure width in both groups.

Clinical Features of Dry Eye in Thyroid-Associated Ophthalmopathy According to Disease Activity

PURPOSE: To evaluate the clinical features of dry eye in thyroid-associated ophthalmopathy (TAO) according to disease activity and analyze the related factors. METHODS: This study included 157 patients diagnosed with TAO and dry eye between March 2009 and March 2015. According to the clinical activity score (CAS), TAO patients were divided into inactive (CAS < 3) and active (CAS ≥ 3) groups. Clinical features included age, sex, visual acuity, proptosis, palpebral fissure width, orbital computed tomography (CT) findings, thyroid hormones, and ocular surface parameters including tear film break-up time (TFBUT), Schirmer tests, keratoepitheliopathy scores, and ocular surface disease index (OSDI) were obtained and compared between the groups. In addition, correlations between clinical features and ocular surface parameters were analyzed in both groups. RESULTS: In the inactive and active TAO groups, CAS was 1.24 ± 0.69 and 4.23 ± 1.13, respectively (p = 0.001). Thyrotropin-binding inhibitory immunoglobulin was significantly higher in the active TAO group than in the inactive TAO group (p = 0.048). On orbital CT, extraocular muscle hypertrophy was more common in the active TAO group than the inactive TAO group (p = 0.020). No significant difference was found in age, sex, visual acuity, free T4, and thyroid-stimulating hormone between the two groups. During analysis of the tear film and ocular surface parameters, TFBUT (p = 0.006) was shorter and OSDI score (p = 0.028) was higher in the active TAO group than the inactive TAO group. TFBUT was negatively correlated with proptosis (r = -0.432, p = 0.001; r = -0.308, p = 0.032) and palpebral fissure width (r = -0.367 p = 0.012; r = -0.312, p = 0.031) in both groups. OSDI was positively correlated with proptosis in the active TAO group (r = 0.301, p = 0.033). CONCLUSIONS: TFBUT was shorter and OSDI score higher in dry eye patients with active TAO than in patients with inactive TAO. The TFBUT was negatively correlated with proptosis and palpebral fissure width in both groups.

Surgical Outcomes of Balanced Deep Lateral and Medial Orbital Wall Decompression in Korean Population: Clinical and Computed Tomography-based Analysis

PURPOSE: To evaluate the clinical outcomes of balanced deep lateral and medial orbital wall decompression and to estimate surgical effects using computed tomography (CT) images in Korean patients with thyroid-associated ophthalmopathy (TAO). METHODS: Retrospective chart review was conducted in TAO patients with exophthalmos who underwent balanced deep lateral and medial orbital wall decompression. Exophthalmos was measured preoperatively and postoperatively at 1 and 3 months. Postoperative complications were evaluated in all study periods. In addition, decompressed bone volume was estimated using CT images. Thereafter, decompression volume in each decompressed orbital wall was analyzed to evaluate the surgical effect and predictability. RESULTS: Twenty-four patients (48 orbits) with an average age of 34.08 ± 7.03 years were evaluated. The mean preoperative and postoperative exophthalmos at 1 and 3 months was 18.91 ± 1.43, 15.10 ± 1.53, and 14.91 ± 1.49 mm, respectively. Bony decompression volume was 0.80 ± 0.29 cm3 at the medial wall and 0.68 ± 0.23 cm3 at the deep lateral wall. Postoperative complications included strabismus (one patient, 2.08%), upper eyelid fold change (four patients, 8.33%), and dysesthesia (four patients, 8.33%). Postsurgical exophthalmos reduction was more highly correlated with the deep lateral wall than the medial wall. CONCLUSIONS: In TAO patients with exophthalmos, balanced deep lateral and medial orbital wall decompression is a good surgical method with a low-risk of complications. In addition, deep lateral wall decompression has higher surgical predictability than medial wall decompression, as seen with CT analysis.

Change in Quality of Life after Orbital Decompression Surgery in Patients with Dysthyroid Ophthalmopathy

PURPOSE: To evaluate the effect of orbital decompression surgery on quality of life in thyroid-associated ophthalmopathy (TAO) patients. METHODS: From August 2014 to December 2015, 80 patients diagnosed with TAO at our clinic were retrospectively analyzed. The patients were divided into 2 groups: 30 patients who underwent orbital decompression surgery and 50 patients who did not receive surgery. The Korean version of the Grave's ophthalmopathy specific quality of life (GO-QoL) questionnaire was completed by all patients. We compared questionnaire scores between groups and analyzed demographic and clinical factors affecting change in GO-QoL. RESULTS: The patients who underwent orbital decompression had lower mean GO-QoL score for appearance in comparison with patients without orbital decompression (p < 0.001). The mean GO-QoL score for appearance was increased from 28.8 ± 17.1 to 51.5 ± 18.8 after orbital decompression (p = 0.024). The mean GO-QoL score for visual function was not different between the patients who did not receive surgery and the orbital decompression group. The mean GO-QoL score for visual function was not changed after orbital decompression. There was a significant relation between postoperative proptosis degree and change in GO-QoL score for appearance after orbital decompression. CONCLUSIONS: GO-QoL score for appearance was significantly improved after orbital decompression surgery, and psychological interventions should be considered to enhance the quality of life outcomes.

The Change of Lacrimal Gland Volume in Korean Patients with Thyroid-associated Ophthalmopathy

PURPOSE: To describe the change of lacrimal gland volumes in Korean patients with thyroid-associated ophthalmopathy (TAO) via computed tomography (CT). METHODS: A retrospective review of CT images from 217 TAO patients and 135 control subjects was performed. The TAO patients were diagnosed between May 2005 and May 2014 and had a CT performed on initial presentation (330 orbital CT scans). These images were compared with 270 orbital CT scans from the control group, obtained between May 2013 and May 2014. An open source DICOM viewer was used to calculate the volume of the lacrimal gland. RESULTS: The mean volume of the lacrimal gland in TAO patients was 0.816 cm³ in the right orbit (standard deviation [SD], 0.048) and 0.811 cm3 in the left orbit (SD, 0.051), with no significant difference between right and left (p = 0.192). However, significant differences were observed between TAO patients and healthy individuals (p < 0.001). There was no significant difference between mean lacrimal gland volumes of males (0.812 cm³; SD, 0.037) and females (0.816 cm³; SD, 0.029) (p = 0.513). There was a negative correlation between gland volume and age in TAO patients (Pearson r = -0.479, p = 0.00). The subjective tearing (right: r = 0.244, p = 0.018; left: r = 0.226, p = 0.024), corneal superficial punctate keratopathy (right: r = 0.192, p = 0.040; left: r = 0.206, p = 0.036), and exophthalmometry (right: r = 0.182, p = 0.032; left: r = 0.180, p = 0.046) correlated with lacrimal gland volume. CONCLUSIONS: This study is the first to use CT images to calculate the lacrimal gland volume of Korean TAO patients. In TAO patients, the lacrimal gland volume was notably increased compared to control subjects. The lacrimal gland volume decreased with age, but there was no difference between gender and no difference between left and right. The lacrimal gland volume correlated with subjective tearing, corneal superficial punctate keratopathy and exophthalmometry.

Comparison of Patient Characteristics in Thyroid-Associated Ophthalmopathy with and without Strabismus

PURPOSE: To determine immunochemical and clinical differences in thyroid-associated ophthalmopathy (TAO) patients with restrictive strabismus and without strabismus. METHODS: A retrospective chart review of 15 TAO patients with strabismus (25 eyes) and 24 TAO patients without strabismus (39 eyes) who presented to the Ophthalmology Clinic between August 2011 and December 2013 was performed. Visual acuity, intraocular pressure (IOP), Hertel exophthalmometry, soft tissue score, and enlargement of extraocular muscles on computed tomography (CT) were obtained and compared in each group. Thyroid related autoantibody (thyroid-stimulating hormone receptor antibody, TRAb; thyroid peroxidase antibody, TPOAb; anti-thyroglobulin antibody, TgAb) titers and positive rates were obtained at the time of diagnosis or before treatment and analyzed. RESULTS: The gender and smoking proportion were not significantly different between the 2 groups. The mean age of TAO patients with strabismus was 52.53 years and of TAO patients without strabismus 40.33 years (p = 0.004). The differences in visual acuity and IOP between the 2 groups were not significant. Hertel exophthalmometry showed less proptotis in the TAO with strabismus group than the TAO without strabismus group (16.84 mm versus 18.67 mm). The soft tissue score was not significantly different. The extraocular muscle enlargement rate of TAO with strabismus was significantly higher than in TAO without strabismus group. In the TAO with strabismus group, TRAb level was higher than in the TAO without strabismus group (p = 0.021). CONCLUSIONS: The TAO with strabismus group was older and had higher positive rate, level of TRAb, and extraocular muscle enlargement rate on CT than the TAO without strabismus group. Furthermore, proptosis was less definite in the TAO with strabismus group.

The Clinical Features of Ocular Myasthenia Gravis in Thyroid-Associated Ophthalmopathy

PURPOSE: There are some challenges to accurate diagnosis of ocular myasthenia gravis (MG) in thyroid-associated ophthalmopathy (TAO) patients because the clinical features of these diseases are similar. The aim of this study was to discuss the clinical features and treatment options that may help differentiate these 2 diseases. METHODS: We performed a retrospective analysis using the medical records of patients who visited our clinic and were diagnosed with ocular MG and TAO, from January 2002 to December 2012. The diagnosis of Ocular MG was made on the basis of clinical symptoms and signs with laboratory evaluation, including assays for antithyroid and antiacetylcholine receptor (AchRAb) antibodies, and the Ice, neostigmine, and electromyography tests. RESULTS: Of the 9 ocular MG patients with associated ophthalmopathy, 5 were male and 4 were female. The mean age was 36 +/- 16.0 years and the follow-up period was 45.6 +/- 36.6 months. Graves' disease (8 patients) was predominant and all patients showed abnormal thyroid function. Atypical symptoms and/or mild clinical features were predominant in ocular MG patients with TAO. Positive test results were obtained as follows: Neostigmine test 33.3%, electromyography 44.4%, ice test 77.8% and anti-AchR titer test 77.8%. Thyroid function test results were abnormal in all patients. In 3 patients who were first diagnosed with TAO, symptoms remained persistent despite steroid therapy then improved dramatically by administration of an anti-acetylcholinesterase agent. These patients were diagnosed with ocular MG in conjunction with TAO. CONCLUSIONS: Patients with thyroid disease who show atypical features, symptomatic changes with fatigue, odd appearing ptosis, and who, do not exhibit good response to treatment of TAO need to be examined for ocular MG with additional tests and treatment.

A Phase I Study of Human Cord Blood-Derived Mesenchymal Stem Cell Therapy in Patients with Peripheral Arterial Occlusive Disease

BACKGROUND AND OBJECTIVES: Half of patients with critical limb ischemia (CLI) are ineligible for revascularization at diagnosis. The aim of this study was to assess the safety and feasibility of intramuscular human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) therapy in patients with CLI due to atherosclerosis obliterans (ASO) or thromboangiitis obliterans (TAO). METHODS AND RESULTS: A total of eight patients (all male, median age 52 years, range 31~77) with CLI were enrolled in this phase I trial. All patients were considered ineligible for further revascularization to improve CLI. We injected 1x10(7) hUCB-MSCs per single dose intramuscularly into the affected limb. The primary end points of safety were occurrence of adverse events (procedure-related complication, allergic reaction to hUCB-MSCs, graft-versus-host disease, cardiovascular and cerebrovascular events) and improvement of symptoms/clinical parameters (healing of foot ulcer, ankle-brachial index, and pain-free walking distance). Angiogenesis was measured with conventional angiography and scored by an independent reviewer. There were four adverse events in three patients. One patient, developed whole body urticaria after injection on treatment day, which disappeared after one day of antihistamine treatment. The other adverse events included diarrhea, oral ulceration, and elevation of serum creatinine level; all conditions improved without treatment. Abnormal results of laboratory parameters were not detected in any patients. Three of four ulcerations (75%) healed completely. Angiographic scores increased in three of eight patients. CONCLUSIONS: This phase I study demonstrates that intramuscular hUCB-MSC injection is a safe and well tolerated treatment for patients with end-stage CLI due to ASO and TAO.

Radiographic Analysis of Extraocular Muscle Volumetric Changes Following Orbital Decompression in Thyroid-Associated Orbitopathy: Comparison of Nunery Types 1 and 2

PURPOSE: To evaluate the radiographic volume change in extraocular muscles (EOM) following orbital wall decompression for Nunery type 1 and type 2 thyroid-associated orbitopathy (TAO). METHODS: Medical records of 31 orbits in 20 patients undergoing postoperative orbital CT after orbital decompression for TAO were retrospectively reviewed. The patients were divided according to Nunery classifications. A type 1 classification was assigned to patients who had no diplopia and essentially normal versions. A type 2 classification was assigned to patients with restrictive motility loss and diplopia within 20 degrees of the primary position. EOM volumes were determined by the summation of each EOM's cross-sectional areas in the coronal plane of the CT scans and multiplying the sum by the slice thickness. Main outcome measure was a comparison of EOM volume changes between types 1 and 2 TAO and a relationship between EOM volume and change in proptosis. RESULTS: In type 2 TAO, a significant increase in the volume of the medial rectus muscle, lateral rectus, and total EOM was detected postoperatively (p = 0.044, 0.022, 0.049), whereas no significant changes were found in the EOM's volume changes in type 1 TAO. The reduction of proptosis after orbital decompression in type 1 TAO was significantly greater than in type 2 TAO (p = 0.025). A significant positive association was observed between the preoperative EOM volumes and the reduction of proptosis following orbital wall decompression (r = 0.505). CONCLUSIONS: The postoperative EOM volumes following orbital wall decompression was significantly increased in Nunery type 2 patients who had restrictive myopathy.

On Textual and Contextual Position of The Ophthalmological Treatise of Bodhisattva Nagarjuna / 의사학

Medical knowledge in India began to be introduced to China in earliest from the Later Han Dynasty period to the times of Wei-Qin and South & North Dynasties. This is proved by many Buddhist medical books appeared in those days. Of the contents of Indian medicine, the theory of four major elements affected Chinese medicine more than did the theory of body fluids. Based on the theory of four major elements that was began to be introduced in Fu shuo fu yi jing, an attempt to establish a new medical system was made in Zhou hou bai yifang written by Tao Hong-jing and Sun Si-miao who tried to develop etiology further but could not achieve any great outcomes. Unlike the foregoing situation, Indian medicine aroused a large echo in China in the field of ophthalmology with ophthalmological knowledge mentioned in Susrutasamhita and 'Jin-zhen-shu'(cataract couching) introduced as a surgical treatment of cataract. The Susrutasamhita which is one of the three major texts of Indian medicine contains additional information on surgical operations not introduced in the Carakasamhita. The technique of cataract surgery was particularly popular in the Tang and Song dynasty periods in China under the name Long shu pu sa yan lun(The Ophthalmological Treatise of Bodhisattva Nagarjuna) or Long shu lun and was even designated as a subject to educate medical officers. While the original text of Long shu pu sa yan lun was not handed down, the first testimony that show the trace of the introduction of this text into China was the Tian zhu jing lun yan mentioned in Wai tai mi yao(Arcane Essential from the Imperial Library) written by Wang Tao. Long shang dao ren who was mentioned as the compiler of the book is assumed to be Long shu. Although Tian zhu jing lun yan introduced anatomical knowledge about the eyeball that could have not been in the traditional Chinese medicine, this book has only limited quantity of information in this regard. Thereafter, Tai ping sheng hui fang(Holy Prescriptions for Universal Relief) compiled by a national agency at the beginning of the Song Dynasty period introduced Long shu pu sa yan lun without clear indication of the reference. Contemporary with this book, many ophthalmological books such as Mi chuan yan ke long mu lun(Longmu's Ophthalmology Secretly Handed Down) were published. As Chinese culture was spreading out into surrounding countries, medical knowledge was also introduced to Korean peninsula and Japan. The ophthalmological knowledge contained in Long shu pu sa yan lun was also reflected and some parts of it were introduced in I shin bo in Japan. Based on the policy decision of King Sejong, the fourth king of Joseon Dynasty, large scaled promoting projects of medical knowledge was established. It is notable that the Ui bang ryu chwi compiled as a result of the synthesis of the medical treatises available at that time initiated by King Sejong contained a considerable part of Long shu pu sa yan lun in reedited form that had already passed into oblivion in China. The intellectuals in Joseon Dynasty who participated in the compilation of Ui bang ryu chwi not only indicated that Long shu pu sa yan lun was a medical text published in the times of Wei-Qin and South & North Dynasties in China but also clearly indicated the textual reference and left the original text for later generation without modifying the contents. According to the Ui bang ryu chwi, the Long shu pu sa yan lun indicated that the core causes of eye diseases were heat, winds, and three body fluids(tridosa) and contained the analyses of symptoms, related treatments, and several analyses of wrong treatments. In addition, Long shu pu sa yan lun explained diverse eye diseases through more than 30 medical treatments. In particular, this book accurately described golden needle acupuncture for treatment of a Nei-zhang understood to be cataract. Therefore, this book is a significant textual record in the history of ophthalmological medicine in East Asia. Along with the golden needle acupuncture which is a method of removing the crystalline lens in which white turbidity occurred by stabbing the eyeball with a needle, traces of Indian medicine that had been already lost in China were clearly indicated in Long shu pu sa yan lun kept in the Ui bang ryu chwi. In particular, the book indicates that the eyes were directly correlated with the brain and that to treat the internal disorder, treating the brain that lost stability due to heat and bodily wind was indispensable; these are the traces of Indian influence. This textual source demonstrates a case of knowledge exchange in field of medicine with concrete cases of the encounter and clash between the standpoints of understanding human body.

Searching for Hidden, Painful Osteochondral Lesions of the Ankle in Patients with Chronic Lower Limb Pain: Two Case Reports

It is easy to overlook osteochondral lesions (OCLs) of the ankle in patients with chronic lower limb pain, such as complex regional pain syndrome (CRPS) or thromboangiitis obliterans (TAO, Buerger's disease). A 57-year-old woman diagnosed with type 1 CRPS, and a 58-year-old man, diagnosed with TAO, complained of tactile and cold allodynia in their lower legs. After neurolytic lumbar sympathethic ganglion block and titration of medications for neuropathic pain, each subject could walk without the aid of crutches. However, they both complained of constant pain on the left ankle during walking. Focal tenderness was noted; subsequent imaging studies revealed OCLs of her talus and his distal tibia, respectively. Immediately after percutaneous osteoplasties, the patients could walk without ankle pain. It is important to consider the presence of a hidden OCL in chronic pain patients that develop weight-bearing pain and complain of localized tenderness on the ankle.

The Antifibrotic Effects of alpha-Tocotrienols in Primary Cultured Orbital Fibroblasts from Thyroid-Associated Ophthalmopathy Patients

PURPOSE: To evaluate the antiproliferative and antifibrotic effects of alpha-tocotrienols in primary cultured orbital fibroblasts from thyroid-associated ophthalmopathy (TAO) patients. METHODS: Orbital fibroblasts were cultured (5 eyes from TAO patients, 5 eyes from normal patients) and classified into a control group, alpha-tocotrienol group and alpha-tocopherol group. The cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The proliferation of orbital fibroblasts was measured using the Click-iT(TM) assay. The collagen production of the control and alpha-tocotrienol groups was measured using a hydroxyproline assay. RESULTS: The alpha-tocotrienol and alpha-tocopherol groups showed no cytotoxicity up to 150 microm in orbital fibroblasts from TAO and normal patients. The proliferation of orbital fibroblasts from TAO and normal patients was significantly inhibited with alpha-tocotrienol at 80 microm and 120 microm. The collagen production of orbital fibroblasts from TAO patients was significantly inhibited with alpha-tocotrienol at 120 microm. CONCLUSIONS: The results from the present study indicate that non-toxic concentrations of alpha-tocotrienol have significant antiproliferative and antifibrotic effects on orbital fibroblasts from TAO patients.

Ophthalmopathy Induced by Bilateral Carotid Cavernous Fistula in a Patient with Graves' Disease

Graves' disease (GD) can lead to specific eye afflictions including proptosis, periorbital swelling, conjunctival injection, chemosis, and opthalmoplegia, which then become a condition called Graves' ophthalmopathy or thyroid-associated ophthalmopathy (TAO). A carotid cavernous fistula (CCF) is an abnormal vascular communication between the carotid artery and the cavernous sinus. The clinical signs of CCF are very similar to TAO and should be considered as a differential diagnosis of TAO. We would like to present an interesting case of a bilateral ophthalmopathy induced by CCF in a GD patient. A 54-year-old man with a 6-year history of GD presented with bilateral exophthalmos and conjunctival injection for two months. The orbital CT scan findings were consistent with CCF, and an angiography revealed bilateral CCF. He received a bilateral coil embolization for the CCF and his ophthalmic signs were immediately improved. We recommend orbital imaging to exclude other coexisting diseases in patients who are suspected of TAO, especially when the diagnosis is uncertain or when determining whether medical or surgical intervention is appropriate.

Predictive Factor for Therapeutic Results after Intravenous Glucocorticoid Therapy in Thyroid-Associated Ophthalmopathy / 대한갑상선학회지

BACKGROUND AND OBJECTIVES: Little has been known for factors predicting improvement of proptosis in patients with thyroid-associated ophthalmopathy (TAO) after intravenous (IV) glucocorticoid therapy. This study aimed to evaluate the efficacy of IV glucocorticoid therapy and to find factor predicting treatment outcomes in patients with TAO. MATERIALS AND METHODS: Forty-two consecutive patients with TAO treated by IV glucocorticoid from 2000 to 2009 were retrospectively analyzed. They received IV methylprednisolone of 7.0 g over 18 weeks. Before and after treatment, patients underwent orbital CT for assessment of proptosis and extraocular muscle hypertrophy, and physical examination for clinical activity score (CAS). RESULTS: Thirteen patients (31%) showed improvement in proptosis after therapy. High extraocular muscle diameter index was an independent predictor for improvement in proptosis (odds ratio=1.25, p=0.03). Smoking, age, gender and initial CAS did not predict improvement. Seven of 16 patients with initial CAS or =3 (77%) showed improvement in diplopia after treatment (p=0.002). Of patients with CAS> or =3, patients with intermittent, inconstant and constant diplopia showed improvement in diplopia in 100%, 80% and 63%, respectively. Of patients with CAS<3, patients showed improvement in 80%, 33% and 20%, respectively. CONCLUSION: Presence of extraocular muscle hypertrophy was the only factor predicting improvement in proptosis after IV glucocorticoid therapy. In patients with TAO, IV glucocorticoid therapy could be considered to improve proptosis when they present with increased extraocular muscle diameter, or to improve diplopia especially when they also have high initial CAS.

Metabolism of 3-cyanomethyl-4-methyl-DCK, a new anti-HIV candidate, in human intestinal microsomes / 药学学报

The biotransformation, CYP reaction phenotyping, the impact of CYP inhibitors and enzyme kinetics of 3-cyanomethyl-4-methyl-DCK (CMDCK), a new anti-HIV preclinical candidate belonging to DCK analogs, were investigated in human intestinal microsomes and recombinant cytochrome P450 (CYP) enzymes. CMDCK (4 micromol L(-1)) was incubated with a panel of rCYP enzymes (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The remaining parent drug in incubates was quantitatively analyzed by a LC-MS method. CYP3A4 was identified as the principal CYP isoenzyme responsible for its metabolism in intestinal microsomes. The major metabolic pathway of CMDCK was oxidation and a number of oxidative metabolites were screened with LC-MS. The Km, Vmax, CLint and T1/2 of CMDCK obtained from human intestinal microsome were 45.6 micromol L(-1), 0.33 micromol L(-1) min(-1), 12.1 mL min(-1) kg(-1) and 25.7 min, respectively. Intestinal clearance of CMDCK was estimated from in vitro data to be 3.3 mL min(-1) kg(-1), and was almost equal to the intestinal blood flow rate (4.6 mL min(-1) kg(-1)). The selective CYP3A4 inhibitors, ketoconazole, troleandomycin and ritonavir demonstrated significant inhibitory effects on CMDCK intestinal metabolism, which suggested that co-administration of CMDCK with potent CYP3A inhibitors, such as ritonavir, might decrease its intestinal metabolic clearance and subsequently improve its bioavailability in body.

Effect of CYP3A and P-glycoprotein on the absorption of buagafuran in rat intestinal lumen / 药学学报

The rat single-pass intestinal perfusion model was applied to study the effect of CYP3A and P-glycoprotein on the absorption of buagafuran in lumen of rats. Buagafuran concentrations in intestinal perfusate and blood in vena mesenterica collected at different time points after perfusion were determined by GC-MS. Permeability coefficient of buagafuran was calculated by the equation [P(lumen) = -(Q/2pirl)Ln(C(out)/C(in)) and P(blood) = (deltaM(B)/deltat)/(2pirl<C>)]. The effects of troleandomycin (TAO, CYP3A inhibitor), cyclosporin A (CYP3A/p-glycoprotein inhibitor) on the absorption of buagafuran in lumen were observed. After rat single-pass intestinal perfusion, the cumulative amount of buagafuran in mesenteric vein of rat was 73.4, 82.9, and 98.3 pmol x cm(-2) and were increased 3.9, 4.6, and 5.6 fold by addition of inhibitor of P-gp (LSN335984), CYP3A (TAO) or P-gp and CYP3A (CsA), respectively. Moreover, the metabolized fraction of buagafuran was decreased by 12%, 11% and 21% with inhibitors. The results suggested that the poor bioavailability of buagafuran was mostly due to the interplay of P-gp and CYP3A on the absorption, transport and metabolism of buagafuran in intestine of rats.