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To characterize the clinical features of patients with medication-overuse headache (MOH) according to the class of acute medications being overused.MOH is a common global health problem, severely disabling the majority of the patients affected. Although various medications can cause MOH, whether clinical features differ according to the overused medication type remains unclear.We analyzed data from a multicenter cross-sectional study in neurology clinics in Korea from April 2020 to June 2021.Among 229 eligible patients, MOH was documented in patients who overused multiple drug classes (69/229, 30.1%; most frequent occurrence), triptans (50/229, 21.8%), non-opioid analgesics (48/229, 21.0%), and combination-analgesics (40/229, 17.4%). Patients who overused multiple drug classes reported more frequent use of acute medications (median [25th-75th percentiles]: 25.0 [15.0-30.0] vs. 17.5 [10.0-25.5] days/month, p = 0.029) and fewer crystal-clear days (0.0 [0.0-9.5] vs. 9.0 [0.0-10.0] days/month, p = 0.048) than those who overused triptans. Patients who overused multiple drug classes also reported shorter intervals from chronic daily headache to the onset of MOH than patients who overused combination-analgesics (0.6 [0.2-1.9] vs. 2.4 [0.7-5.4] years, p = 0.001) or non-opioid analgesics (1.5 [0.6-4.3] years, p = 0.004). Patients who overused multiple drug classes reported more emergency room visits (1.0 [0.0-1.0] visits/year) than those who overused combination-analgesics (0.0 [0.0-1.0], p = 0.024) or non-opioid analgesics (0.0 [0.0-1.0], p = 0.030). Patients who overused triptans reported fewer headache days (21.0 [20.0-30.0] vs. 30.0 [20.5-30.0] days/month, p = 0.008) and fewer severe headache days (7.0 [4.0-10.0] vs. 10.0 [5.0-15.0] days/month, p = 0.017) than those who overused non-opioid analgesics.Some clinical characteristics of MOH significantly differed according to the class of overused medications. The findings from this study may contribute to the understanding of the clinical characteristics and pathophysiology of MOH.

Background Characteristics, disabilities, and optimal management of medication overuse headache remain uncertain. This study aimed to elucidate the clinical characteristics of patients with medication overuse headache enrolled in a medication overuse headache registry in Korea. Methods The Registry for Load and Management of MEdicAtion OveruSE Headache (RELEASE), a cross-sectional prospective observational study including seven referral headache centers in Korea, started enrolling adult patients with medication overuse headache in April 2020. Data included information on headache characteristics, burden on daily function, depression, anxiety, history of acute and preventive medications, and treatment strategies. Results A total of 229 patients (85.6% females; mean age, 45.5 ± 13.5 years) were enrolled by June 2021. The average durations of chronic headaches and medication overuse were 6.5 and 4.3 years, respectively. In the past month before enrollment, patients had headaches for 25 days and severe headaches for 12 days, and used acute medications for 20 days. Patients were disabled in 66.8 days in the past 3 months and had moderate/severe depression and anxiety in 56% and 35%, respectively. The proportion of patients on preventive treatments increased from 38% to 93% during the study period. Conclusions RELEASE study reflects the current management status and opportunities to improve the quality of care in patients with medication overuse headache.

This study aimed to identify factors influencing self-management in patients with Parkinson's disease (PD) based on social cognitive theory. A cross-sectional design was used; data were collected at three tertiary medical centers in Korea from a convenience sample of 356 PD patients. Higher self-management scores were associated with higher education level, having a religion, and higher family income. Self-management score was positively correlated with activities of daily living, self-efficacy, and social support, and negatively correlated with non-motor symptoms. Hierarchical regression analysis revealed that demographic factors and non-motor symptoms explained 26.2% of the variance in self-management in PD. The explanatory power increased by 7.5% when self-efficacy was added, and by 6.7% when social support was added. Assessment of self-management in patients with PD should consider self-efficacy and social support, along with demographic factors and non-motor symptoms. Self-management programs that reflect these factors may be useful for improving self-management in PD patients.

We aimed to compare seroprevalence of anti-myelin oligodendrocyte glycoprotein (MOG) and anti-aquaporin-4 (AQP4) antibodies in Korean adults with inflammatory demyelinating diseases (IDDs) of the central nervous system (CNS), based on a multicenter nationwide database. Sera were analyzed using a live cell–based assay for MOG and AQP4 antibodies. Of 586 Korean adults with IDDs of the CNS, 36 (6.1%) and 185 (31.6%) tested positive for MOG and AQP4 antibodies, respectively. No participant showed double positivity. Seroprevalence of MOG antibodies was about five times lower than that of AQP4 antibodies in a large cohort of Korean adults with IDDs of the CNS.

Objectives: Likelihood of clinical events occurring within the same anatomical location in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) was retrospectively investigated. Methods: A total of 236 clinical events in 90 patients with MOGAD from nine referral hospitals were analyzed via logistic regression, and odds ratios (ORs) were calculated. Anatomical lesion location was divided into four groups; optic nerve, spinal cord, cerebral hemisphere, and brainstem/cerebellum. Results: At all locations, there was an increased likelihood of a second attack occurring at the same location as the initial event (cerebral hemisphere OR = 22.14, brainstem/cerebellum OR = 18.4, spinal cord OR = 9.1, and optic nerve OR = 7.8). There was an increased likelihood of a third attack occurring at the same location as the initial event in the optic nerve (OR = 14.9), cerebral hemisphere (OR = 11.7), and spinal cord (OR = 6.7). There were positive trends toward a third clinical event occurring at the same location as the first and/or second events if the event was in the optic nerve (OR = 13.5), cerebral hemisphere (OR = 6.9), or spinal cord (OR = 5.7). Conclusions: The current study suggests that clinical relapses of MOGAD during early stage tend to recur at the same anatomical locations in the central nervous system.

Multisensory convergence and sensorimotor integration are important aspects for the mediation of higher vestibular cognitive functions at the cortical level. In contrast to the integration of vestibulo-visual or vestibulo-tactile perception, much less is known about the neural mechanism that mediates the integration of vestibular-otolith (linear acceleration/translation/gravity detection) and auditory processing. Vestibular-otolith and auditory afferents can be simultaneously activated using loud sound pressure stimulation, which is routinely used for testing cervical and ocular vestibular evoked myogenic potentials (VEMPs) in clinical neurotological testing. Due to the simultaneous activation of afferents there is always an auditory confound problem in fMRI studies of the neural topology of these systems. Here, we demonstrate that the auditory confounding problem can be overcome in a novel way that does not require the assumption of simple subtraction and additionally allows detection of non-linear changes in the response due to vestibular-otolith interference. We used a parametric sound pressure stimulation design that took each subject's vestibular stimulation threshold into account and analyzed for changes in BOLD-response below and above vestibular-otolith threshold. This approach helped to investigate the functional neuroanatomy of sound-induced auditory and vestibular integration using functional magnetic resonance imaging (fMRI). Results revealed that auditory and vestibular convergence are contained in overlapping regions of the caudal part of the superior temporal gyrus (STG) and the posterior insula. In addition, there are regions that were responsive only to suprathreshold stimulations, suggesting vestibular (otolith) signal processing in these areas. Based on these parametric analyses, we suggest that the caudal part of the STG and posterior insula could contain areas of vestibular contribution to auditory processing, i.e., higher vestibular cortices that provide multisensory integration that is important for tasks such as spatial localization of sound.

To determine the efficacy of prophylactic medications for migraine in reducing associated dizziness and motion sickness.Multicenter prospective observational study.Nationwide 9 Dizziness Clinics in South Korea.One hundred thirty-eight patients who required a preventive medication for migraine accompanied by dizziness and motion sickness.At least one of the prophylactic medications was prescribed among the beta-blockers, calcium channel blockers, tricyclic antidepressants, and antiepileptic drugs.For 3 months from the index visit, the patients had monthly assessments of the headache (frequency and duration), dizziness handicap inventory, University of California Los Angeles dizziness questionnaire, vertigo symptom scale, and motion sickness score.The prophylactic medications significantly improved the headache profiles, all three parameters of dizziness (dizziness handicap inventory, University of California Los Angeles dizziness questionnaire, and vertigo symptom scale), and severity of motion sickness (p 0.001).The prophylactic medication for migraine also improves associated dizziness and motion sickness as well as the headaches.

Cyclosporine A (CsA) is a widely used immunosuppressive agent that may provoke unexpected neurologic complications. The mechanism is unclear and variable intervals have been reported between CsA administration and onset of the related side effects. Here, we describe a case of delayed-onset CsA neurotoxicity presenting as opsoclonus-myoclonus syndrome (OMS).A 37-year-old woman with a two-week period of opsoclonus and upper extremity myoclonus was admitted to our hospital. The patient had been taking CsA for 17 years after receiving a kidney transplant. Further evaluation did not reveal any other abnormalities. Seven days after switching from CsA to tacrolimus, in the absence of additional immune-modulating therapy, her neurologic symptoms improved considerably.This is the case of delayed, long-term complications of CsA presenting as OMS. Symptoms resolved by substituting CsA with another immunomodulating drug. The etiology of the neurologic complications may involve paradoxically-enhanced delayed-type hypersensitivity.

Introduction Several clinical studies using tacrolimus revealed reasonable therapeutic mechanisms and efficacy in patients with myasthenia gravis (MG). However, long-period studies in a large number of patients with MG are limited; therefore, the aim of this study was to investigate the therapeutic efficacies and safety of tacrolimus in patients with MG during a 12-month follow-up period. Methods Tacrolimus was administered to 150 patients with MG who were recruited based on the inclusion criteria. Fifteen medical centers in Korea participated in this study. The efficacy of tacrolimus was assessed using MG composite scales (MGCS) and the prednisolone-sparing effect. And the adverse drug reactions (ADRs) of tacrolimus were monitored in each patient from the beginning of tacrolimus treatment to the end of the follow-up period. Results After starting tacrolimus, the 32 patients were affected by ADRs, and consequentially 134 patients of the enrolled patients were followed up for 12 months. They showed that the mean prednisolone dosage significantly decreased (6.1 ± 7.6 mg/day), compared to that in the baseline (11.3 ± 9.5 mg/day), and MGCS significantly improved after 12 months of tacrolimus treatment, compared to that at the baseline. Conclusions Our study showed that tacrolimus would be an effective immunosuppressant as an initial therapeutic agent in patients with MG; in addition, it showed tolerable safety profiles during the 12-month follow-up evaluation.

ObjectiveTo assess the effect of vitamin D and calcium supplementation in preventing recurrences of benign paroxysmal positional vertigo (BPPV).MethodsWe performed an investigator-initiated, blinded-outcome assessor, parallel, multicenter, randomized controlled trial in 8 hospitals between December 2013 and May 2017. Patients with confirmed BPPV were randomly assigned to the intervention (n = 518) or the observation (n = 532) group after successful treatment with canalith repositioning maneuvers. The primary outcome was the annual recurrence rate (ARR). Patients in the intervention group had taken vitamin D 400 IU and 500 mg of calcium carbonate twice a day for 1 year when serum vitamin D level was lower than 20 ng/mL. Patients in the observation group were assigned to follow-ups without further vitamin D evaluation or supplementation.ResultsThe intervention group showed a reduction in the ARR (0.83 [95% confidence interval (CI), 0.74–0.92] vs 1.10 [95% CI, 1.00–1.19] recurrences per 1 person-year) with an incidence rate ratio of 0.76 (95% CI, 0.66–0.87, p < 0.001) and an absolute rate ratio of −0.27 (−0.40 to −0.14) from intention-to-treat analysis. The number needed to treat was 3.70 (95% CI, 2.50–7.14). The proportion of patients with recurrence was also lower in the intervention than in the observation group (37.8 vs 46.7%, p = 0.005).ConclusionsSupplementation of vitamin D and calcium may be considered in patients with frequent attacks of BPPV, especially when serum vitamin D is subnormal.Classification of evidenceThis study provides Class III evidence that for patients with BPPV, vitamin D and calcium supplementation reduces recurrences of BPPV.

BACKGROUND AND PURPOSE The patterns of head-shaking nystagmus (HSN) aid in differentiation between central and peripheral vestibular disorders, and perverted HSN (pHSN) has been considered a central sign. The aim was to determine the characteristics of HSN in a large number of patients with either peripheral or central vestibular disorders in a dizziness clinic of a university hospital. METHODS The medical records of 7544 dizzy patients were reviewed during a year and 822 patients with a clinical diagnosis of vestibular disorders were recruited. The findings of spontaneous nystagmus (SN) and HSN in these patients were compared with those of healthy controls (n = 48). RESULTS A total of 217 of the 822 patients (26.4%) were classified as having a central vestibular disorder, whilst 397 (48.3%) had a peripheral vestibular disorder. In the peripheral vestibular disorder group, SN was observed in 14.1% and HSN in 40.8%, amongst whom 24.1% were the pHSN form. In the central group, SN was observed in 17.5% and HSN in 24.0% of whom 57.7% was pHSN. HSN was more frequently observed in the peripheral vestibular disorder group than in the central group (40.8% vs. 24.0%, P

Background The environmental risks of multiple sclerosis (MS), including adolescent obesity and vitamin D deficiency, are increasing in Korea. We aimed to determine whether the patterns and/or severity of MS in Korea can change according to the year of birth or disease onset. Methods Two hundred and sixty-six patients with adult-onset MS, including 164 with an available baseline magnetic resonance imaging (MRI), were retrospectively included from 17 nationwide referral hospitals in Korea. The demographics, MRI T2 lesion burden at disease onset, cerebrospinal fluid markers, and prognosis were assessed. Results The birth year, time from disease onset to first MRI, and female sex were associated with a higher number of baseline MRI T2 lesions. The birth year was also associated with the presence of oligoclonal band in the cerebrospinal fluid and high immunoglobin G index. An increased female/male ratio was observed among those with a more recent year of birth and/or disease onset. Conclusions In Korea, the disease pattern of adult-onset MS may be changing toward a more baseline T2 MRI lesions, intrathecal humoral immune responses, and also higher female ratio.

Opsoclonus-myoclonus syndrome in adults is a rare and heterogeneous disorder with the clinical features of opsoclonus, myoclonus, ataxia, and behavioral and sleep disturbances. The pathophysiology is thought to be immunological on the basis of paraneoplastic or infectious etiologies. Immunomodulatory therapies should be performed although the response may be incomplete. A number of autoantibodies have been identified against a variety of antigens, but no diagnostic immunological marker has yet been identified. This review focuses on underlying mechanisms of opsoclonus-myoclonus syndrome, including findings that have been identified recently, and provides an update on the clinical features and treatments of this condition.

To evaluate the clinical and imaging characteristics of patients with visually equivocal amyloid PET images, patients from the Alzheimer's Disease Neuroimaging Initiative cohort who had fluorine-18-florbetapir PET scans both at baseline and 24 months were selected. Five nuclear medicine physicians visually assessed the PET images and classified them as either positive or negative. Images not reaching a majority agreement were classified as equivocal. Among a total of 379 patients, the number of patients in each fluorine-18-florbetapir PET negative/equivocal/positive categories was 218 (57.5%), 32 (8.4%), and 129 (34.0%). Eight to 9% of patients with normal cognition (N=12/141), mild cognitive impairment (N=20/214), and no Alzheimer's disease (N=0/24) showed equivocal PET finding for each. In negative/equivocal/positive groups, positive cerebrospinal fluid Aβ1-42 was observed in 25.7, 81.5, and 98.3%, respectively. Baseline standardized uptake value ratios of fluorine-18-florbetapir PET were 0.75±0.05, 0.86±0.09, and 1.01±0.09, respectively [F(2, 376)=603.547; P

To evaluate utricular and saccular function during the acute and resolved phases of BPPV, ocular and cervical vestibular evoked myogenic potentials (VEMPs) were studied in 112 patients with BPPV and 50 normal controls in a referral-based University Hospital. Ocular (oVEMPs) and cervical VEMPs (cVEMPs) were induced using air-conducted sound (1000Hz tone burst, 100dB normal hearing level) at the time of initial diagnosis and 2 months after successful repositioning in patients with BPPV, and the results were compared with those of the controls. Abnormalities of cVEMPs and oVEMPs in patients with BPPV were prevalent and significantly higher compare to the healthy control group (p

Vestibular-evoked myogenic potentials (VEMPs) are short latency manifestations of vestibulo-ocular and vestibulocollic reflexes that originate from the utricle and saccule. Although cervical and ocular VEMPs have mostly been applied to peripheral vestibular disorders, the characteristics and the diagnostic values of VEMPs have been expanded to assess the function of the central otolithic pathways. In the central nervous system, the cervical VEMPs (cVEMPs) are mediated by the vestibular nuclei and uncrossed medial vestibulospinal tract descending in the lower brainstem and spinal cord. In contrast, the ocular VEMPs (oVEMPs) reflect the function of the vestibular nuclei and the crossed vestibulo-ocular reflex (VOR) pathways, mostly contained in the medial longitudinal fasciculus (MLF). Therefore, lesions involving the vestibular nuclei can present abnormalities of both cVEMPs and oVEMPs. The medullary lesions involving the descending MLF or the spinal accessory nucleus impair cVEMPs. In contrast, the lesions involving the MLF, the crossed ventral tegmental tract, oculomotor nuclei and the interstitial nucleus of Cajal can impair oVEMPs. Patients with unilateral cerebellar infarctions may show abnormal VEMPs especially when they have the ocular tilt reaction. Delayed responses of VEMPs are characteristic of multiple sclerosis (MS). Reduced VEMP responses can be observed in patients with vestibular migraine. VEMPs are useful in evaluating central as well as peripheral otolithic function that are not readily defined by conventional vestibular function tests, and can aid in detecting and localizing central lesions, especially silent brainstem lesions such as tiny infarctions or MS plaques.

A variant of Guillain-Barré syndrome (GBS) with predominant manifestation of facial diplegia (FD) has been described recently. This study aimed to characterize and determine the incidence of this FD-predominant GBS variant. The clinical and serological information of 900 consecutive patients were reviewed. In total, eight patients were identified between January 2007 and December 2010 as having FD accompanied by some features of GBS. These features were subjective sensory symptoms such as distal paresthesia (7/8, 88%), albumin-cytological (A/C) dissociation (7/8, 88%), antecedent infection (6/8, 75%), and minor nerve conduction study (NCS) abnormalities (5/7, 71%). One patient presented with the typical NCS feature of demyelinating neuropathy. Only two patients exhibited areflexia (2/8, 25%). None of the patients possessed any anti-ganglioside antibodies; however, the serum of two patients was positive for anti-mycoplasma antibody (2/6, 33%). FD variant of GBS occurred in less than 1% of our dataset. FD can be a regional variant of GBS when it is accompanied by supporting features, such as subjective tingling, A/C dissociation, and minor NCS abnormalities.

Objective This study attempts to clarify the clinical characteristics of chronic dizziness and its relationships with specific vestibular, oculomotor, autonomic and psychiatric dysfunctions. Methods 73 Patients with idiopathic chronic dizziness were recruited and classified based on history taking and clinical examination into the following four clinical subgroups; vestibular migraine (VM), dysautonomia, psychogenic, and unspecified groups. They were also evaluated using oculomotor, otolithic and autonomic function tests, and psychologic investigation. Results Patients in the VM group showed a high proportion of abnormality on smooth pursuit and otolithic function testing compared to the other groups. The dysautonomia group revealed significant abnormalities in sympathetic and cardiovagal autonomic function, while the psychogenic group had a high frequency of abnormality in sympathetic autonomic testing and in Beck’s anxiety inventory scale. The unspecified group showed abnormalities on saccade, smooth pursuit and autonomic function testing. Conclusions Clinical classification of patients with chronic dizziness was relevant and they showed a correlation with disease-specific abnormal results in oculomotor, otolithic, autonomic function and psychology testing. Significance Appropriate diagnostic investigation based on precise clinical diagnosis of chronic dizziness reduces the need for extensive laboratory testing, neuroimaging, and other low-yield tests.

Aim Deep pontine lacunar infarction (DPLI) not involving the basal pial surface of the medial part of the pons, is known to be a small vessel disease in the territory of the basilar artery (BA). In the present study, we examined whether morphological features of the BA differ in individuals with an advanced age and may be associated with DPLI. Methods This study included 338 healthy subjects and 78 patients with DPLI treated at the stroke centers of three university hospitals in Korea. Time-Of-Flight magnetic resonance angiographic images were transported to a central lab and analyzed blind to obtain the clinical data. For the quantitative analysis, the BA was projected two-dimensionally in the anteroposterior and lateral views and perceived as triangles of the vertebrobasilar junction, angulation point and BA division. The angles and triangular areas were summated into angulation indexes and used to quantify the degree of BA tortuosity. Results The BA showed a more acute angle at the angulation point in the elderly patients than in the healthy subjects. Compared to the healthy subjects, the DPLI patients exhibited significantly larger angles at the vertebrobasilar junction, in addition to the acute angles noted at the angulation point. A unit increase in the BA angle indexes at the vertebrobasilar junction and angulation points for DPLI was found to have an odds ratio of 1.15 (95% confidence interval, 1.05-1.26) and 0.95 (95% CI, 0.91-0.99), respectively, even after adjusting for potential confounders. Conclusions The angulation point of the BA becomes more acute in elderly individuals. In this study, the vertebrobasilar junction showed a larger angle in the patients with DPLI than in the healthy controls.

ObjectiveTo increase clinical application of vestibular-evoked myogenic potentials (VEMPs) by reducing the testing time by evaluating whether a simultaneous recording of ocular and cervical VEMPs can be achieved without a loss in diagnostic sensitivity and specificity.MethodsSimultaneous recording of ocular and cervical VEMPs on each side during monaural stimulation, bilateral simultaneous recording of ocular VEMPs and cervical VEMPs during binaural stimulation, and conventional sequential recording of ocular and cervical VEMPs on each side using air-conducted sound (500 Hz, 5-millisecond tone burst) were compared in 40 healthy participants (HPs) and 20 patients with acute vestibular neuritis.ResultsEither simultaneous recording during monaural and binaural stimulation effectively reduced the recording time by ≈55% of that for conventional sequential recordings in both the HP and patient groups. The simultaneous recording with monaural stimulation resulted in latencies and thresholds of both VEMPs and the amplitude of cervical VEMPs similar to those found during the conventional recordings but larger ocular VEMP amplitudes (156%) in both groups. In contrast, compared to the conventional recording, simultaneous recording of each VEMP during binaural stimulation showed reduced amplitudes (31%) and increased thresholds for cervical VEMPs in both groups.ConclusionsThe results of simultaneous recording of cervical and ocular VEMPs during monaural stimulation were comparable to those obtained from the conventional recording while reducing the time to record both VEMPs on each side.ClinicalTrials.gov identifierNCT03049683.

Objective: We aimed to determine the topology of anatomical pathways for verticality perception in the brainstem. Methods: We measured the subjective visual vertical (SVV) in 82 patients with acute unilateral infarction of the brainstem alone. The topology of the brainstem lesions responsible for pathologic SVV tilt were determined using MRI-based voxel-wise lesion-behavior mapping, from which probabilistic lesion maps were constructed. Results: Fifty percent of patients (41/82) with acute unilateral brainstem infarcts had abnormal SVV tilt, of which 76% (31/41) had ipsiversive tilt and 24% (10/41) had contraversive tilt. Patients with contraversive SVV tilt exhibited overlapping lesions of the rostral medial vestibular nucleus, medial longitudinal fasciculus, rostral interstitial medial longitudinal fasciculus, and interstitial nucleus of Cajal. In contrast, patients with ipsiversive SVV tilt and oculomotor disturbances exhibited lesions of the medial and inferior vestibular nuclei in the caudal medulla, while those with isolated vertical perceptual changes had injury to the medial side of the medial lemniscus. Conclusions: Our findings provide evidence of a pathway transmitting ipsiversive otolithic signals that bypass the oculomotor system at the medial side of the medial lemniscus, called the ipsilateral vestibulothalamic tract.

Background Leukoaraiosis (LA) is associated with structural and functional vascular changes that correlate with motor and gait disturbances, depressive symptoms, urinary disturbances, and dementia. The blood–brain barrier (BBB) plays a key role in development of lacunar stroke, leukoaraiosis, and other feature of cerebral small-vessel disease, and there are numerous studies examining changes in the BBB with normal aging and in dementia and LA. Aquaporin-4 (AQP-4), the primary water channel protein in the central nervous system, is involved in BBB development, function, and integrity, and its dysfunction induces several neurologic diseases. The aim of our study was to evaluate whether genetic variations in AQP-4 gene are associated with the development of LA. Methods DNA was amplified and the single-nucleotide polymorphisms in AQP-4 gene were investigated by melting curve analysis using real-time polymerase chain reaction. Results The frequency of both T allele and CT/TT genotypes of rs2075575 was significantly higher in LA group than in control group (C versus T, P = .0145; CC versus CT/TT, P = .038). However, no significant difference was observed between LA group and control group in rs9951307 . Interestingly, the rs9951307 AG + GG genotype may confer a synergistic effect in odds ratio (OR) values when combined with the rs2075575 CT + TT genotypes (OR = 1.65 → 2.51). The C-A haplotype was significantly different between LA group and the control group ( P = .005). By stratified analysis, rs2075575 and rs9951307 polymorphisms were statistically significant in the subjects with hypertension and hemoglobin A1c ( P rs2075575 polymorphism was associated with high serum cholesterol ( P rs9951307 polymorphism was associated with low serum homocysteine ( P Conclusions Our results indicate that AQP-4 genetic variations and haplotypes might contribute to the risk factors for LA.

It remains controversial whether APOE E4 polymorphism is related to cognitive function in general population. We aimed to evaluate an association between the APOE E4 genotype and cognitive function, and whether this association may differ by age. Cognitive function was assessed using the Korean version of modified Mini-Mental State Examination (K-mMMSE) in 10,371 Koreans aged 45-74 years in Namwon City. According to the APOE E4 status, all participants were classified as non-carriers, heterozygotes, or homozygotes. Multiple linear and logistic regression models were used to evaluate the association between APOE genotypes and cognition. The frequency of APOE genotypes in the study population was 0.4, 10.1, 1.1, 72.9, 14.7 and 0.8 % for E2E2, E2E3, E2E4, E3E3, E3E4, and E4E4, respectively. Compared to the APOE E4 non-carriers, the heterozygotes and homozygotes showed 1.3 and 7.3 % lower K-mMMSE scores at 65-74 years and 0.8 and 4.6 % higher scores at 45-55 years, respectively. Educational attainment modified the effect of APOE E4 on cognitive function in the 45-54 age group (p for interaction =0.003), showing that the E4 carriers with no-formal education showed significantly higher cognitive function than those with formal education. The present study demonstrates that the effect of APOE E4 on cognitive function depends on age and education.

To clarify the changes of cervical (cVEMP) and ocular (oVEMP) vestibular evoked myogenic potentials induced by air-conducted sound (ACS) and bone-conducted vibration (BCV) in patients with vestibular neuritis (VN), patients with VN (n = 30) and normal controls (n = 45) underwent recording of cVEMP and oVEMP in response to ACS (1,000 Hz, 5 ms, tone bursts) and BCV (500 Hz, short tone burst). Patients with VN showed a high proportion of oVEMP abnormalities in response to both ACS (80.0 %) and BCV at the forehead (Fz, 73.3 %) or the mastoid (76.7 %). In contrast, cVEMPs were mostly normal with both ACS and BCV in the patients. The dissociations in the abnormalities of cVEMP and oVEMP induced by ACS and BCV at the mastoids and at the forehead in patients with VN suggest that oVEMP reflects functions of the superior vestibular nerve and most likely the utricular function. The results of our study suggest that oVEMP induced by either ACS or BCV appears to depend on integrity of the superior vestibular nerve, possibly due to the utricular afferents travelling in it. In contrast, cVEMP elicited by either ACS or BCV may reflect function of the saccular afferents running in the inferior vestibular nerve.

Enterohemorrhagic Escherichia coli cause approximately 1.5 million infections globally with 176,000 cases occurring in the United States annually from ingesting contaminated food, most frequently E. coli O157:H7 in ground beef or fresh produce. In severe cases, the painful prodromal hemorrhagic colitis is complicated by potentially lethal hemolytic uremic syndrome (HUS), particularly in children. Bacterial Shiga-like toxins (Stx1, Stx2) are primarily responsible for HUS and the kidney and neurologic damage that ensue. Small animal models are hampered by the inability to reproduce HUS with thrombotic microangiopathy, hemolytic anemia, and acute kidney injury. Earlier, we showed that nonhuman primates (Papio) recapitulated clinical HUS after Stx challenge and that novel therapeutic intervention rescued the animals. Here, we present detailed light and electron microscopic pathology examination of the kidneys from these Stx studies. Stx1 challenge resulted in more severe glomerular endothelial injury, whereas the glomerular injury after Stx2 also included prominent mesangiolysis and an eosinophilic inflammatory infiltration. Both toxins induced glomerular platelet-rich thrombi, interstitial hemorrhage, and tubular injury. Analysis of kidney and other organs for inflammation biomarkers showed a striking chemotactic profile, with extremely high mRNA levels for IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1α and elevated urine chemokines at 48 hours after challenge. These observations give unique insight into the pathologic consequences of each toxin in a near human setting and present potential pathways for therapeutic intervention.

To investigate structural, metabolic, and functional connectivity changes in visual and oculomotor structures in a patient with paraneoplastic opsoclonus-myoclonus syndrome, serial resting-state functional and structural MRI, and FDG-PET data were collected during the acute stage and later on when the opsoclonus had resolved. In the acute stage, an FDG-PET scan demonstrated a substantially increased metabolism in structures around the deep cerebellar nuclei [e.g., fastigial nucleus (FN)] and a relatively reduced metabolism in the bilateral occipital lobes which normalized over 12 months. Functional connectivity increased initially between the seeds of the oculomotor and visual systems, including the primary and motion-sensitive visual cortex, frontal eye fields, superior colliculus, and cerebellar oculomotor vermis (OMV), and then decreased in the chronic stage as the symptoms resolved. The functional connectivity between the OMV and FN showed a positive correlation during the acute stage, which decreased later on. We provide a descriptive presentation of the changes of abnormal functional connectivity throughout visuo-oculomotor brain areas during opsoclonus and suggest directions for further research on the pathogenesis of opsoclonus.

Objectives To clarify the origin and afferent pathways of short-latency ocular vestibular-evoked myogenic potential (oVEMP) in response to air-conducted sound (ACS), we evaluated cervical (cVEMP) and ocular VEMPs in patients with vestibular neuritis (VN). Methods In response to air-conducted tone burst, the oVEMP and cVEMP were measured in 60 healthy controls and in 41 patients with acute VN. The VN selectively involved the superior vestibular nerve (superior VN) in 30 patients, affected the inferior vestibular nerve only (inferior VN) in three and damaged both superior and inferior vestibular nerve branches in eight. Results All 30 patients with superior VN presented normal cVEMPs, indicating preservation of the saccular receptors and their afferents in the inferior vestibular nerve. However, the oVEMP was abnormal in all patients with superior VN. By contrast, the patients with inferior VN showed normal oVEMP and abnormal cVEMP. Conclusion These dissociations in the abnormalities of cVEMP and oVEMP in patients with VN selectively involving the superior or inferior vestibular nerve suggest that the origin of the vestibular nerve afferents of oVEMP differ from those of cVEMP. Significance The oVEMP in response to ACS may be mediated by the superior vestibular nerve, probably due to an activation of the utricular receptors.

Background There has been no systematic study that carefully investigates the characteristic features of abnormal cervical vestibular-evoked myogenic potential (cVEMP) response associated with the AICA territory infarction. Objectives To investigate the frequency, the characteristic patterns of abnormal cVEMP associated with AICA territory infarction, and the crucial site for producing abnormal cVEMP response in the AICA territory infarction. Methods We studied 16 consecutive cases of unilateral AICA territory infarction diagnosed by brain MRI. VEMP was induced by a short click sound and was recorded in contracting sternocleidomastoid muscle. Each patient underwent a quantitative audiovestibular evaluation, including bithermal caloric test and pure tone audiogram. Results Eight patients (50%) exhibited abnormal cVEMP response on the side of the AICA territory infarction. All patients with abnormal cVEMP showed an absent or decreased response in amplitude but no difference in latency. Patients with abnormal VEMP were significantly more likely to have canal paresis (CP), sensorineural hearing loss, or both compared with patients who had normal cVEMP. Conversely, abnormal cVEMP was more frequently observed among patients with CP than among those without CP. There was no difference in lesion sites according to brain MRI among patients with or without abnormal cVEMP response. Conclusions Our findings suggest that the peripheral vestibular structure with the inner ear probably plays a crucial role in producing abnormal cVEMP response associated with AICA territory infarction.

We report a patient who showed a selective deficit of voluntary saccades and quick phases of nystagmus after cardiac surgery. Voluntary saccades in the horizontal plane were very slow, while vertical saccades, vestibular and optokinetic nystagmus, were absent. However, smooth pursuit, the vestibulo-ocular reflex, and the ability to hold steady eccentric gaze were preserved.

Transforming growth factor beta (TGF-beta) superfamily ligands have important roles in regulating cellular homeostasis, embryonic development, differentiation, proliferation, immune surveillance, angiogenesis, motility, and apoptosis in a cell type and context specific manner. TGF-beta superfamily signaling pathways also have diverse roles in human cancer, functioning to either suppress or promote cancer progression. The TGF-beta superfamily co-receptor, the type III TGF-beta receptor (TbetaRIII, also known as betaglycan) mediates TGF-beta superfamily ligand dependent as well as ligand independent signaling to both Smad and non-Smad signaling pathways. Loss of TbetaRIII expression during cancer progression and direct effects of TbetaRIII on regulating cell migration, invasion, proliferation, and angiogenesis support a role for TbetaRIII as a suppressor of cancer progression and/or as a metastasis suppressor. Defining the physiological function and mechanism of TbetaRIII action and alterations in TbetaRIII function during cancer progression should enable more effective targeting of TbetaRIII and TbetaRIII mediated functions for the diagnosis and treatment of human cancer.

Protein tyrosine phosphatase SHP-1 is an essential regulatory molecule in many different signaling pathways. The biological importance of SHP-1 is underscored by the motheaten mutant mouse strains with immunological disorders involving multiple organs and by the close association of aberrant SHP-1 expression with several human diseases. Recent studies provided some compelling evidence that supports a role of SHP-1 in regulating mast cell development and function and also in regulating type 2 allergic inflammatory responses in both innate and adaptive immune responses. In this article, we summarize the recent advancement of our understanding of this interesting phosphatase in the important area of allergic inflammation.

The mechanisms of vestibular migraine and motion sickness remain unknown. The aims of this study were to determine interictal vestibular dysfunction in migraineurs according to associated dizziness/vertigo and motion sickness, and to find out whether impaired uvulonodular inhibition over the vestibular system underlies the vestibular symptoms and signs by measuring tilt suppression of the vestibulo-ocular reflex (VOR). One hundred and thirty-one patients with migraine [65 with vestibular migraine (MV), 41 with migrainous dizziness (MD), and 25 with migraine only (MO)] and 50 normal controls underwent evaluation of vestibular function. Motion sickness was assessed using the motion sickness susceptibility questionnaire (MSSQ) and subjective scale. Compared with normal controls and MO group, patients with MV/MD showed increased VOR time constant (TC) and greater suppression of the post-rotatory nystagmus with forward head tilt. The mean MSSQ score and subjective scale were highest in MV group, followed by MD, MO, and controls (p = 0.002, p < 0.001). Multiple linear regression model analyses revealed that motion sickness is an independent factor of TC prolongation (p = 0.024). Twenty-eight (21.4%) patients with migraine also showed perverted head shaking nystagmus and 12 (9.2%) had positional nystagmus. In view of the increased tilt suppression of the VOR, we speculate that dysfunction of the nodulus/uvula may not account for the prolonged TCs in MD/MV. Instead, innate hypersensitivity of the vestibular system may be an underlying mechanism of motion sickness and increased TC in MD/MV. The increased tilt suppression may be an adaptive cerebellar mechanism to suppress the hyperactive vestibular system in migraineurs.

Background and Purpose— Isolated nodular infarction has rarely been described in human. The purpose of this study is to report clinical and laboratory findings of isolated nodular infarction. Methods— Eight patients with isolated nodular infarction were recruited from 6 hospitals in Korea. All patients underwent a complete and standardized neurotological evaluation including ocular torsion, bithermal caloric tests, and rotatory chair test in addition to MRI and MR angiography. Results— All patients presented with isolated vertigo and moderate to severe imbalance. The most common manifestation was unilateral nystagmus and falling in the opposite direction, which mimicked peripheral vestibulopathy. Six patients had unilateral lesion, and 2 showed bilateral lesions. The direction of the spontaneous nystagmus was all ipsilesional in the unilateral lesion. However, head impulse and bithermal caloric tests were normal. Other findings include periodic alternating nystagmus, perverted head shaking nystagmus, paroxysmal positional nystagmus, and impaired tilt suppression of the postrotatory nystagmus. Hypoplasia of the ipsilesional vertebral artery was the only abnormal finding on MR angiography in 3 patients. The prognosis was excellent. Conclusions— Isolated nodular infarction mostly presents with isolated vertigo mimicking acute peripheral vestibulopathy. However, severe imbalance and a negative head impulse test are important clinical discriminants between nodular infarcts and peripheral vestibular dysfunction. The findings of isolated nodular infarctions are consistent with impaired gravito-inertial processing of the vestibular signals and disrupted nodular inhibition on the vestibular secondary neurons and the velocity storage mechanism.

Background: Anti-GQ1b antibody has been found in Miller Fisher syndrome (MFS), Guillain-Barre syndrome (GBS) with ophthalmoplegia, Bickerstaff brainstem encephalitis (BBE), and acute ophthalmoplegia without ataxia (AO). The aim of this study was to determine the clinical features of AO associated with anti-GQ1b antibody. Methods: We retrospectively collected 34 patients with anti-GQ1b antibody syndrome. Of these patients, 31 patients had ophthalmoplegia. The patients with ophthalmoplegia were classified into MFS (n = 13), AO (n = 11), GBS with ophthalmoplegia (n = 6), and BBE (n = 1). We analyzed clinical features and patterns of external and internal ophthalmoplegia of AO, and neuro-ophthalmologic findings were compared with those of other anti-GQ1b syndromes with ophthalmoplegia. Results: AO was observed in 11 (32.4%) of the 34 patients with anti-GQ1b antibody. External ophthalmoparesis was present in all the patients and included mixed horizontal-vertical (n = 7), pure horizontal (n = 3), and pure vertical gaze palsy (n = 1). Binocular involvement was common, but unilateral ophthalmoparesis was also observed in 27.3%. Other findings included ptosis (n = 5, 45.5%) and internal ophthalmoplegia (n = 6, 54.5%). Other anti-GQ1b antibody syndromes had prominent neurologic signs including ataxia, weakness, and facial palsy in addition to ophthalmoplegia. The patterns of neuro-ophthalmologic findings did not differ between AO and other anti-GQ1b antibody syndromes with ophthalmoplegia. Conclusions: Acute ophthalmoplegia (AO) commonly occurs in anti-GQ1b antibody syndrome and manifests as various combinations of external and internal ophthalmoplegia. Internal ophthalmoplegia is fairly common and unilateral involvement may occur in AO.

Background: Chronic cough is associated with increased sensitivity to inhaled capsaicin, and both tachykinins and their receptors play important roles in the cough reflex. However, associations between polymorphisms of the tachykinin receptor genes and cough sensitivity in patients with non-productive chronic cough have not been reported. Methods: Direct sequencing was used to identify single nucleotide polymorphisms (SNPs) in the genes for the neurokinin-1 and neurokinin-2 receptors (NK-1R and NK-2R, respectively). Informative non-synonymous SNPs were scored using the single base extension method for 312 patients with chronic cough and for 100 age matched healthy controls. The cough response to capsaicin was recorded for 312 patients with chronic cough, and the potential genetic association between cough sensitivity to capsaicin and the NK-1R and NK-2R genotypes was evaluated. Results: Two informative SNPs were identified in NK-2R (Gly231Glu and Arg375His), whereas no informative SNP was found in NK-1R . After adjusting for atopy, sex, age, and smoking, the prevalence of enhanced cough sensitivity to capsaicin was higher in the chronic cough patients with the 231Glu allele (p = 0.004; OR 1.69 (95% CI 1.18 to 2.42)) and the 231Glu_375Arg haplotype (p = 0.003; OR 1.71 (95% CI 1.20 to 2.24)]. Moreover, the lowest capsaicin concentration to cause five consecutive coughs (C5) was significantly lower in patients with 231Glu (mean (SD) 44.1 (53.2) v 60.9 (55.8) μM/l, p = 0.04) and those with 231Glu_375Arg (43.2 (52.7) v 69.6 (52.0) μM/l, p = 0.03). Conclusions: The results of this study suggest that NK-2R gene polymorphisms are involved in the enhanced cough sensitivity to capsaicin of patients with chronic cough.

Background Vascular endothelial growth factor (VEGF) has been suggested to be a key mediator in the development of atopy and T H 2 inflammation. Objective We sought to evaluate the effects of variations in the gene coding VEGF receptor (VEGFR) 2 on intermediate phenotypes of asthma in the Korean population. Methods A cohort of 2055 children and adolescents responded to a questionnaire concerning asthma symptoms and risk factors and underwent methacholine bronchial challenge and skin tests. The VEGFR2 gene, including the promoter area, was sequenced on 24 healthy subjects to discover informative single nucleotide polymorphisms (SNPs; minor allele frequency >2%). After haplotype reconstruction, 4 tagging SNPs (IVS6+54A>G, +889G>A, +1416T>A, and IVS25-92G>A) were scored. These SNPs were also scored in 480 adult asthmatic patients to verify the above genetic association study. Results The prevalence of atopy was associated with a single SNP (+889G>A) of VEGFR2 with borderline significance ( P = .048; relative risk, 1.13; 95% CI, 1.00-1.28). However, haplotype analysis showed that the atopy prevalence was strongly associated with a haplotype (AGAG) of VEGFR2 ( P = .002; relative risk, 1.25; 95% CI, 1.09-1.42). As for airway hyperresponsiveness, neither individual SNPs nor haplotypes were found to be associated. Interestingly, the significant association was also found between atopy and the AGAG haplotype among adult asthmatic patients ( P = .008; odds ratio, 1.66; 95% CI, 1.14-2.44). Conclusions The present study demonstrated that genetic variations of VEGFR2 are significantly associated with atopy in the Korean population.

Background: C1 esterase inhibitor (C1INH) plays a key role in the classical pathway of the complement cascade. Mutations in this gene cause a decreased level of antigenic (type I hereditary angioedema, HAE) or functional (type II HAE) C1INH. Objective: To find novel mutations in C1INH and evaluate the expression of C1INH gene in HAE patients. Methods: Direct sequencing mutation analysis was performed for genomic DNA from three unrelated families (14 HAE patients and 18 family members). Genomic DNA from one family was also analyzed for larger genomic rearrangements, using Southern blotting analysis. We used real-time quantitative polymerase chain reaction (PCR) to evaluate C1INH mRNA expression level. Results: Four mutations in exons (2311 T fi C, 14 034 G fi A, 16 830 G fi A, and 16 979–16 980 G insertion) and four in introns (738 G fi A, 8531 A fi G, 14 254 A fi G, and 14 337–14 378 TT deletion) were found. Interestingly, all of the nine patients in one family share the same mutation of Gly345Arg (14 034 G fi A) in the seventh exon. In another family, a single base mutation near the splice site (14 254 A fi G) was found in all of the three patients. In the last family, although a significant mutation was not found by direct sequencing, patients showed an abnormal 16 kb fragment in addition to the normal allele (21 kb Bcl I fragment). The C1INH mRNA expression of HAE patients in two families was not significantly different compared with that of normal controls. Conclusion: The two novel exonal mutations (G fi A and A fi G) and one large gene deletion were associated with the clinical phenotypes of HAE. Considering the normal C1INH mRNA levels but below normal protein levels in two families, their phenotypes would be associated with the post-translational defect.

A key mediator in cold-sensation is the protein transient receptor potential melastatin 8 (TRPM8), which is expressed on sensory nerves and cutaneous blood vessels. These receptors are activated by cold temperatures and play a key role in body thermoregulation. Cold sensitivity and Raynaud's phenomenon are frequent clinical features in scleroderma, and are thought to be secondary to a local defect in cutaneous thermoregulation. We investigated whether autoantibodies targeting TRPM8 were present in the sera of patients with scleroderma as evidence for a possible mechanism for an acquired immune mediated defect in thermoregulation.Sera from 50 well-characterised scleroderma patients with Raynaud's phenomenon were studied. TRPM8 autoantibodies were assayed as follows: 1. immunoprecipitation with 35S-methionine-labelled TRPM8 generated by in vitro transcription and translation, 2. immunoblotting lysates made from cells transiently transfected with TRPM8 cDNA, 3. Immunoprecipitation of TRPM8 transfected lysates with detection by blotting and 4. flow cytometry.Fifty scleroderma patients with Raynaud's phenomenon (41 female, 39 Caucasian, 23 with limited scleroderma, and 20 with history of cancer) were studied. Four different methods to assay for TRPM8 antibodies were set up, optimised and validated using commercial antibodies. All 50 scleroderma patients' sera were assayed using each of the above methods, and all were negative for TRPM8 autoantibodies.Antibodies against TRPM8 are not found in scleroderma patient sera, suggesting that the abnormal cold sensitivity and associated abnormal vascular reactivity in scleroderma patients is not the result of an immune process targeting TRPM8.

Background Ciguatera-fish poisoning (or ciguatera) is a common but underdiagnosed food-borne illness related to fish consumption that is characterized by nausea, vomiting and neurologic symptoms such as tingling in the fingers or toes. Objective We describe the case of a young man who suffered from diarrhea and abdominal pain after eating raw fish and who also developed severe ataxia with spontaneous downbeat and perverted head-shaking nystagmus. Case report The patient experienced visual fixation suppression failure during the bithermal caloric test and bilateral smooth-pursuit impairment. Oculomotor findings suggested dysfunction of the vestibulocerebellum, especially the flocculus. Conclusion These findings suggest that both the peripheral and the central nervous systems can be involved in ciguatera.

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism. The WD gene codes for a copper transporting P-type ATPase (ATP7B) are located on chromosome 13q14.3. Mutation of this gene disrupts copper homeostasis, resulting in the accumulation of copper in the liver, brain, kidneys and corneas and copper toxication at these sites. Since the detection of the WD gene in 1993, approximately 300 disease-specific muations have been identified. We recently evaluated a Korean family with WD. The proband, a 17-year-old boy, visited our hospital due to abnormal behaviors including generalized slow movement, dysphagia, drooling and ataxia. Laboratory results revealed decreases in serum copper and ceruloplasmin and an increase in urinary excretion of copper. He had liver cirrhosis, brain lesions and Kayser–Fleischer corenal rings. Molecular genetic analysis of the ATP7B gene demonstrated that he was heterozygous for deletion mutation c.2697_2723del27 in exon 11. Further study of family members revealed that his father and younger brother had the same mutation. The c.2697_2723del27 deletion mutation in exon 11 has not yet been reported as a causative muation of WD and is an in-frame deletion not expected to lead to a frame shift. Therefore, we report a novel mutation of the ATP7B gene in a family with WD.

Background and Objective Human leukocyte antigen (HLA) class II gene products are involved in the antigen presentation of exogenous antigens. The aim of this study was to evaluate whether specific immunoglobulin (Ig)E responses to purified major allergens of Dermatophagoides pteronyssinus (Der p 1 and Der p 2) were associated with genotypes of HLA-DRB1 alleles. Subjects and Methods Peripheral venous blood samples were collected from two groups of unrelated Korean adolescents: 168 subjects with positive skin response (wheal ≥3 mm) to crude D. pteronyssinus allergens and 94 age-matched controls with negative skin response and low serum-specific IgE to crude D. pteronyssinus allergens. The former group was found to contain 104 with high serum-specific IgE to crude D. pteronyssinus allergens, 100 with high serum-specific IgE to Der p 1, and 122 with high serum-specific IgE to Der p 2. Genotypes of the HLA-DRB1 alleles were determined using polymerase chain reaction-sequence specific oligonucleotide probes. Results HLA-DRB1*07 was significantly higher in subjects with a high serum-specific IgE response to crude D. pteronyssinus allergens than the controls (16.3% vs 3.2%, odds ratio [OR] = 5.93, corrected P [ Pc ] = 0.02). The excess of DRB1*07 was more marked in those with high serum-specific IgE responses to Der p 1 or Der p 2 than the controls (20.0% vs 3.2%, OR=7.58, Pc = 0.004; 18.9% vs 3.2%, OR=7.05, Pc = 0.006). Among subjects with high serum IgE to Der p 1, DRB1*13 significantly increased than the controls (32.0% vs 13.8%, OR=2.93, Pc = 0.03). Conclusions We clearly observed the association between HLA-DRB1 alleles and specific IgE responsiveness to D. pteronyssinus major allergens. The molecular mechanism of HLA-DRB1*07 and DRB1*13 involvement in D. pteronyssinus -specific IgE responsiveness awaits further investigation.

Background. No previous study examined a disease modifying effect of APOEE4 status on the association between the urinary albumin-to-creatinine ratio (UACR) and cognition. This study aimed to investigate whether APOEE4 modified the association in Korean adults.Methods. We performed a cross-sectional study in adults aged 45 to 74 who were living in Namwon City, Republic of Korea. Cognitive function was measured with the Korean version of modified Mini-Mental State Examination (K-mMMSE) and cognitive impairment was defined as scores falling below the 25th percentile of the K-mMMSE according to age, sex, and educational attainments.Results. A total of 10,190 participants (4006 men and 6184 women) were analyzed in the present study. Of these, 1698 subjects (16.7%) were APOEE4 carriers. The UACR values were negatively associated with the K-mMMSE scores, even after adjusting for potential confounders including age, sex, education, and vascular risk factors. APOEE4 modified the association significantly, resulting in a steeper decline of cognitive function with the increase in UACR inE4 carriers (Pfor interaction = 0.021).Conclusion. Higher UACR values were significantly associated with cognitive dysfunction in the general Korean population, with cognition in APOEE4 carriers being more severely affected by increased UACR.

2H-[1,2,3]Triazolo[4,5-g]isoquinoline-4,9-diones and 2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-diones were synthesized and tested for in vitro antifungal activity against pathogenic fungi. Many of those synthesized showed potent antifungal activity. Compounds 3a, 3b, 3g, and 3h completely inhibited the growth of all fungal species tested at the MIC level of 0.8-12.5 µg/mL. The results suggest that 2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-diones could be antifungal agents.

MicroRNAs (miRNAs) are small, noncoding RNAs that have been shown to play a critical role in normal physiology and disease, such as hematopoietic development and cancer. However, their role in mast-cell function and development is poorly understood. The major objective of this study was to determine how global miRNA expression affects mast-cell physiology. The RNase III endonuclease, Dicer, is required for the processing of pre-miRNAs into mature miRNAs. To investigate the effect of global miRNA depletion on mast cells in vivo, we generated a mast-cell-specific knock out of Dicer in mice. Transgenic mice (Mcpt5-Cre) that express Cre selectively in connective tissue mast cells were crossed with mice carrying the floxed conditional Dicer allele (Dicer fl/fl). Mcpt5-Cre × Dicer fl/fl mice with homozygous Dicer gene deletion in mast cells were found to have a profound mast-cell deficiency with near complete loss of peritoneal, gastrointestinal, and skin mast cells. We examined the in vivo functional consequence of mast-cell-specific Dicer deletion using an immunoglobulin-E-dependent passive systemic anaphylaxis murine model. Immunoglobulin-E-sensitized wild type Mcpt5-Cre × Dicer +/+ and heterozygous Mcpt5-Cre × Dicer fl/+ mice show marked hypothermia with antigen; however, homozygous Mcpt5-Cre × Dicer fl/fl mice were completely unresponsive to antigen challenge. These studies suggest a critical role for Dicer and miRNA expression for establishment of tissue compartments of functional mast cells in vivo.

Central vestibular lesions may cause paroxysmal positional nystagmus (PPN) or paroxysmal positional vertigo as a result of lesions involving the brainstem dorsolateral to the fourth ventricle or the cerebellar nodulus/uvular region. PPN usually presents as persistent downbeating nystagmus during head hanging or as apogeotropic horizontal nystagmus during head turning in the supine position. Geotropic PPN during head turning in the supine position has not been previously reported. We report such a case in a patient with HIV encephalopathy.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy after hepatocellular carcinoma. ICC can be divided into 2 types according to their location: peripheral and hilar types. Intense F-FDG uptake on PET was reported in peripheral ICC. However, the usefulness of PET/CT in detecting tumors and predicting prognosis in peripheral ICC has not been fully evaluated. In this study, we evaluated the clinical role of F-FDG PET/CT to predict the recurrence after the curative resection in patients with surgically indicated peripheral ICC.Eighteen patients with ICC underwent preoperative CT and F-FDG PET/CT scans. SUVmax of tumor, tumor to normal liver SUV ratio (TNR), lymph node status evaluated by F-FDG PET/CT, tumor and lymph node size measured by CT, vascular invasion confirmed by pathology, and satellite nodules found on CT were compared between 1-year recurrence group and recurrence-free group by chi-square test.Of total 23 measurable lymph nodes, 4 nodes were positive and other 19 nodes were negative or equivocal on CT. Among those 23 nodes, 9 nodes were positive and other 14 nodes were negative on F-FDG PET/CT. The sensitivity and specificity of CT were 20.0% and 86.4%, and those of F-FDG PET/CT were 80.0% and 92.3%. In the comparison between 1-year recurrent and nonrecurrent groups, lymph node metastasis detected on F-FDG PET/CT had statistically positive correlation with the 1-year recurrence after surgical resection (P = 0.02). Other factors showed no statistically significant difference between the groups.We found that lymph node metastasis detected on F-FDG PET/CT correlated positively with 1-year recurrence after surgical resection in patients with peripheral ICC.

Two sequential homozygous mutations are demonstrated in the recently cloned proton-coupled folate transporter (PCFT) gene resulting in the absence of this protein in a 27 year old woman with hereditary folate malabsorption, who is normal in all respects and has completed higher education, following treatment with parenteral 5-formyltetrahydrofolate since infancy.

Chronic debilitating pruritus is a cardinal feature of atopic dermatitis (AD). Little is known about the underlying mechanisms. Antihistamines lack efficacy in treating itch in AD, suggesting the existence of histamine-independent itch pathways in AD. Transient receptor potential ankyrin 1 (TRPA1) is essential in the signaling pathways that promote histamine-independent itch. In this study, we tested the hypothesis that TRPA1-dependent neural pathways play a key role in chronic itch in AD using an IL-13–transgenic mouse model of AD. In these mice, IL-13 causes chronic AD characterized by intensive chronic itch associated with markedly enhanced growth of dermal neuropeptide-secreting afferent nerve fibers and enhanced expression of TRPA1 in dermal sensory nerve fibers, their dorsal root ganglia, and mast cells. Inhibition of TRPA1 with a specific antagonist in these mice selectively attenuated itch-evoked scratching. Genetic deletion of mast cells in these mice led to significantly diminished itch-scratching behaviors and reduced TRPA1 expression in dermal neuropeptide containing afferents in the AD skin. Interestingly, IL-13 strongly stimulates TRPA1 expression, which is functional in calcium mobilization in mast cells. In accordance with these observations in the AD mice, TRPA1 expression was highly enhanced in the dermal afferent nerves, mast cells, and the epidermis in the lesional skin biopsies from patients with AD, but not in the skin from healthy subjects. These studies demonstrate a novel neural mechanism underlying chronic itch in AD and highlight the complex interactions among TRPA1+ dermal afferent nerves and TRPA1+ mast cells in a Th2-dominated inflammatory environment.