Early diagnosis of Alzheimer's disease from elevated olfactory mucosal miR-206 level.

MicroRNA-206, which suppresses the expression of brain-derived neurotrophic factor, is known to be elevated in the brains of Alzheimer's disease (AD) patients. We performed intranasal biopsy of the olfactory epithelia of early dementia patients (n = 24) and cognitively healthy controls (n = 9). Patients with significant depression (n = 8) were analyzed separately, as their cognitive impairments were thought to be caused by their depression. Real-time PCR was performed on the biopsied tissues. The relative microRNA-206 level exhibited a 7.8-fold increase (P = 0.004) in the mild cognitive impairment group (CDR 0.5; n = 13) and a 41.5-fold increase (P < 0.001) in the CDR 1 group (n = 11). However, this level was not increased in the depression group, even in those with cognitive decline. Using the optimal cutoff value, the sensitivity/specificity for diagnosing CDR 0.5 and CDR 1 dementia were 87.5%/94.1% and 90.9%/93.3%, respectively. In ROC analysis, the AUCs were 0.942 and 0.976 in the CDR 0.5 and CDR 1 groups, respectively. The olfactory mucosal microRNA-206 level and cognitive assessment scores were significantly correlated in the non-depressed subjects with cognitive impairment. In conclusion, the olfactory mucosal microRNA-206 level can be easily measured, and it can be utilized as an excellent biomarker for the diagnosis of early AD, including mild cognitive impairment.

Seasonal Variation, Cranial Autonomic Symptoms, and Functional Disability in Migraine: A Questionnaire-Based Study in Tertiary Care.

OBJECTIVE/BACKGROUND: Seasonal variation of migraine attack frequency has been described as a phenomenon. We aimed to compare functional disability and the occurrence of cranial autonomic symptoms (CASs) in patients who reported a seasonal variation in their migraine attack frequency with those who did not. METHODS: We conducted a questionnaire-based observational study on patients with migraine without aura who visited our institution from January 2005 to December 2013. Patient demographics, headache characteristics, and accompanying symptoms were recorded, and functional disability was evaluated by Migraine Disability Assessment (MIDAS) Questionnaire. RESULTS: Of 4423 patients screened, 769 were eligible for analysis, and 104 (13.5%) of them reported seasonal variation. Several CAS features such as conjunctival injection (25.0% vs 14.0%), lacrimation (20.2% vs 10.8%), eyelid edema (20.2% vs 10.2%), forehead and facial sweating (22.1% vs 11.4%), and ptosis (23.1% vs 11.4%) were more prominent in this subset of patients. They showed higher MIDAS scores (15.4 ± 23.5) than the other migraineurs (10.4 ± 16.9), with a 1.77-fold increased risk (95% confidence interval 1.06-2.96) of severe functional disability (MIDAS score ≥21) after adjustment for age group, sex, headache frequency, intensity, and duration. The higher the number of CASs, the greater also was the proportion of patients with severe functional disability. CONCLUSIONS: Patients who reported seasonal variation in migraine also reported more CASs and had more severe functional disability. The profound functional disability in the migraineurs reporting seasonal variation or CAS also provides direction for proactive clinical management in these patients.

The First Case of Successful Transcatheter Aortic Valve Implantation Using CoreValve in Korea.

Surgical replacement of the aortic valve is the standard therapy for severe aortic valve stenosis. However, it is generally associated with increased mortality and morbidities in older individuals. Transcatheter aortic valve implantation (TAVI) is a less invasive procedure and has shown similar clinical outcomes as surgical treatment in elderly patients at high risk for conventional surgery. In this report, we describe the first case of TAVI using a CoreValve in Korea. An 84-year-old man with symptomatic severe aortic valve stenosis was successfully treated by transfemoral TAVI. The patient was discharged without any significant complications and remained free of adverse clinical event for a follow-up duration of 6 months.

The first korean patient with severe aortic stenosis and bilateral iliofemoral artery disease treated with transcatheter aortic valve implantation by transsubclavian approach.

Transcatheter aortic valve implantation (TAVI) is indicated as an alternative treatment modality to surgical aortic valve replacement for high risk patients. The standard retrograde approach through the femoral artery is not feasible in the case of unfavorable iliofemoral anatomy or severe peripheral arterial disease (PAD). However, patients with aortic stenosis (AS) have a higher prevalence of for PAD because both diseases are consequences of atherosclerotic degenerative changes. Transsubclavian, transapical, and direct access to the ascending aorta by thoracotomy are alternative routes for the TAVI procedure. In this report, we present the first Korean patient with symptomatic severe AS and bilateral iliofemoral artery disease who was successfully treated with TAVI using a CoreValve (Medtronic, Minneapolis, MN, USA) by transsubclavian approach.

Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.

OBJECTIVES: Ginseng has been reported to improve cognitive function in animals and in healthy and cognitively impaired individuals. In this study, we investigated the efficacy of a heat-processed form of ginseng that contains more potent ginsenosides than raw ginseng in the treatment of cognitive impairment in patients with moderately severe Alzheimer's disease (AD). METHODS: Forty patients with AD were randomized into one of three different dose groups or the control group as follows: 1.5 g/day (n = 10), 3 g/day (n = 10), and 4.5 g/day (n = 10) groups, or control (n = 10). The Alzheimer's Disease Assessment Scale (ADAS) and Mini-Mental State Examination (MMSE) were used to assess cognitive function for 24 weeks. RESULTS: The treatment groups showed significant improvement on the MMSE and ADAS. Patients with higher dose group (4.5 g/day) showed improvements in ADAS cognitive, ADAS non-cognitive, and MMSE score as early as at 12 weeks, which sustained for 24-week follow-up. DISCUSSION: These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.

Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with korean red ginseng.

A 24-week randomized open-label study with Korean red ginseng (KRG) showed cognitive benefits in patients with Alzheimer's disease. To further determine long-term effect of KRG, the subjects were recruited to be followed up to 2 yr. Cognitive function was evaluated every 12 wk using the Alzheimer's Disease Assessment Scale (ADAS) and the Korean version of the Mini Mental Status Examination (K-MMSE) with the maintaining dose of 4.5 g or 9.0 g KRG per d. At 24 wk, there had been a significant improvement in KRG-treated groups. In the long-term evaluation of the efficacy of KRG after 24 wk, the improved MMSE score remained without significant decline at the 48th and 96th wk. ADAS-cog showed similar findings. Maximum improvement was found around week 24. In conclusion, the effect of KRG on cognitive functions was sustained for 2 yr follow-up, indicating feasible efficacies of long-term follow-up for Alzheimer's disease.

Protective action of the immunomodulator ginsan against carbon tetrachloride-induced liver injury via control of oxidative stress and the inflammatory response.

The aim of the present study was to evaluate immunomodulator ginsan, a polysaccharide extracted from Panax ginseng, on carbon tetrachloride (CCl(4))-induced liver injury. BALB/c mice were injected i.p. with ginsan 24 h prior to CCl(4) administration. Serum liver enzyme levels, histology, expression of antioxidant enzymes, and several cytokines/chemokines were subsequently evaluated. Ginsan treatment markedly suppressed the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and hepatic histological necrosis increased by CCl(4) treatment. Ginsan inhibited CCl(4) induced lipid peroxidation through the cytochrome P450 2E1 (CYP2E1) downregulation. The hepatoprotective effect of ginsan was attributed to induction of anti-oxidant protein contents, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) as well as restoration of the hepatic glutathione (GSH) concentration. The marked increase of proinflammatory cytokines (IL-1beta, IFN-gamma) and chemokines (MCP-1, MIP-2beta, KC) in CCl(4) treated mice was additionally attenuated by ginsan, thereby preventing leukocyte infiltration and local inflammation. Our results suggest that ginsan effectively prevent liver injury, mainly through downregulation of oxidative stress and inflammatory response.

White matter hyperintensities and cognitive dysfunction in Alzheimer disease.

The effect of white matter lesions in magnetic resonance imaging or vascular atherosclerosis on cognitive function is not fully understood in Alzheimer disease (AD). In this investigation, we examined the influence of white matter lesions on cognitive decline in AD. A total of 142 patients with AD (44 men, mean age 65.7 + 7.6 years; mean education period 7.8 + 5.0 years) were included. Patients were divided into 4 groups based on the severities of white matter hyperintensities (WMH) in brain magnetic resonance images (MRI) using Fazekas scale. Cognitive functions were determined using the Korean version of the Mini-Mental State Examination (K-MMSE) and the Clinical Dementia Rating (CDR) scale before acetylcholinesterase inhibitors were administered. Of the 142 patients, 30% (43/142) had no white matter signal abnormality (grade 0). Fourteen percentage (20/142) were grade 1, 42% (59/142) grade 2, and 14% (20/142) were grade 3. Mean K-MMSE scores declined as MRI grades increased to grade 2 and 3 compared to grade 0 (P < .01). Clinical Dementia Ratings were also aggravated by MRI grade. These results remained significant after adjusting for compounding factors affecting cognitive functions; sex, age, number of years in full-time education, hypertension, diabetes, hypercholesterolemia, smoking, and atrial fibrillation. The presence of WMHs were associated with score of MMSE and CDR impairment in patients with AD. These features could be a correctable factor hastening cognitive decline in AD.

N-acetylphytosphingosine enhances the radiosensitivity of lung cancer cell line NCI-H460.

Ceramides are well-known second messengers that induce apoptosis in various kinds of cancer cells, and their effects are closely related to radiation sensitivity. Phytoceramides, the yeast counterparts of the mammalian ceramides, are also reported to induce apoptosis. We investigated the effect of a novel ceramide derivative, N-acetylphytosphingosine (NAPS), on the radiosensitivity of NCI-H460 human lung carcinoma cells and its differential cytotoxicity in tumor and normal cells. The combination of NAPS with radiation significantly increased clonogenic cell death and caspase-dependent apoptosis. The combined treatment greatly increased Bax expression and Bid cleavage, but not Bcl-2 expression. However, there was no effect on radiosensitivity and apoptosis in BEAS2B cells, which derive from normal human bronchial epithelium. Cell proliferation and DNA synthesis were significantly inhibited by NAPS in both NCI-H460 and BEAS2B cells, but only the BEAS2B cells recovered by 48h after removal of the NAPS. Furthermore, the NCI-H460 cells underwent more DNA fragmentation than the BEAS2B cells in response to NAPS. Our results indicate that NAPS may be a potential radiosensitizing agent with differential effects on tumor vs. normal cells.

The Effect of Paroxetine on the Reduction of Migraine Frequency is Independent of Its Anxiolytic Effect.

BACKGROUND AND PURPOSE: Anxiety is the most important precipitating factor of migraine attacks, and more than half of migraineurs have coexisting anxiety disorders. Paroxetine, an antidepressant, is one of the selective serotonin reuptake inhibitors (SSRIs) that has an anxiolytic effect, and is also known to be effective for migraine prophylaxis. The aim of this study was to determine the role of the anxiolytic effect of paroxetine on the prevention of migraine. METHODS: This study investigated migraineurs with a general anxiety disorder who visited the neurological clinic. The following efficacy variables were assessed at baseline and after taking paroxetine (20 for 12 weeks: headache frequency, Hamilton Anxiety Rating Scale (HAM-A), Headache Management Self-Efficacy Scale (HMSE), and Headache Disability Inventory (HDI). The correlation between the headache responsiveness to paroxetine and improvement in anxiety levels was analyzed. RESULTS: Twenty-four patients (aged 54.96+/-12.09 years, mean+/-SD) were included in this study. Paroxetine reduced headache frequency by 49.1% within 12 weeks (p<0.05 vs baseline). HAM-A and HMSE scores also showed an improvement, whereas there was no significant change in HDI score. The baseline HAM-A scores did not differ between paroxetine responders and nonresponders. In addition, the improvement in HAM-A score was not correlated with the reduction in headache frequency. CONCLUSIONS: Paroxetine decreased the headache frequency and reduced anxiety levels. However, the anxiolytic effect of paroxetine was not correlated with the migraine prevention effect. These observation indicate that the anxiolytic effect of paroxetine does not contribute strongly to its prophylactic effect on migraine frequency in migraineurs with anxiety disorder.

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll-like receptor-mediated inflammatory signals.

Ginsan, a polysaccharide extracted from Panax ginseng, has multiple immunomodulatory effects. In this study, we show that pretreatment of ginsan (25 mug/kg) protected mice from lethality induced by Staphylococcus aureus challenge. This survival benefit was associated with enhanced bacterial clearance from circulation, spleen and kidney. The phagocytic activity of macrophages treated with ginsan was significantly enhanced against S. aureus. However, the production of proinflammatory cytokines, such as TNF-alpha, IL-1beta, IL-6, IFN-gamma, IL-12, and IL-18, was markedly down-regulated in ginsan-treated mice compared with those of control-infected mice. The expression of Toll-like receptor (TLR) 2 and the adaptor molecule MyD88, which was greatly increased in septic macrophages, was significantly reduced by ginsan treatment in vitro. Similarly, the expression of phospho-JNK1/2, phospho-p38 MAPK, and NF-kappaB was decreased in the same culture system. These results illustrate that the antiseptic activity of ginsan can be attributed to enhanced bacterial clearance, and reduced proinflammatory cytokines via the TLR signaling pathway.

Radiation protective effect of an extract from Chelidonium majus.

We earlier reported that CM-AIa isolated from Chelidonium majus had mitogenic activity, generated lymphokine-activated killer cells, and increased the number of granulocyte-macrophage colony-forming cells (GM-CFC). In an extended effort to search for other immunostimulatory effects, we evaluated the protective effects of in vivo injected CM-AIa against irradiation. CM-AIa was found to increase the number of bone marrow cells, spleen cells, GM-CFC, and platelets in irradiated mice. In addition, this agent induced endogenous production of cytokines such as interleukin 1 and tumor necrosis factor alpha, which are required for hematopoietic recovery. We also demonstrated that CM-AIa treatment 24 hours before irradiation protected mice with 80% survival at lethal dose 100/15. These findings indicate that CM-AIa may be a useful agent for reducing the time needed for reconstitution of hematopoietic cells after irradiation treatment.