Association between PAI-1 Polymorphisms and Ischemic Stroke in a South Korean Case-Control Cohort.

Stroke is the second leading cause of death in the world. Approximately 80% of strokes are ischemic in origin. Many risk factors have been linked to stroke, including an increased level of plasminogen activator inhibitor-1 (PAI-1). PAI-1 levels increase and remain elevated in blood during the acute phase of ischemic stroke, which can impair fibrinolytic activity, leading to coronary artery disease and arterial thrombotic disorders. Here, we present a case-control study of 574 stroke patients and 425 controls seen for routine health examination or treatment for nonspecific dizziness, nonorganic headache, or anxiety for positive family history of stroke at the Bundang Medical Center in South Korea. Polymorphisms in PAI-1 were identified by polymerase chain reaction/restriction fragment length polymorphism analysis using genomic DNA. Specifically, three variations (-675 4G>5G, 10692T>C, and 12068G>A) were linked to a higher overall prevalence of stroke as well as a higher prevalence of certain stroke subtypes. Haplotype analyses also revealed combinations of these variations (-844G>A, -675 4G>5G, 43G>A, 9785A>G, 10692T>C, 11053T>G, and 12068G>A) that were significantly associated with a higher prevalence of ischemic stroke. To the best of our knowledge, this is the first strong evidence that polymorphic sites in PAI-1 promoter and 3'-UTR regions are associated with higher ischemic stroke risk. Furthermore, the PAI-1 genotypes and haplotypes identified here have potential as clinical biomarkers of ischemic stroke and could improve the prognosis and future management of stroke patients.

Gender differences in seizure recurrence and antiepileptic drug polytherapy predicting health-related quality of life of persons 1 year after diagnosis of epilepsy.

PURPOSE: The aim of this study was to determine whether gender influences the prediction of health-related quality of life (HRQoL) in persons with newly diagnosed epilepsy (NDE). METHODS: This was a 1-year longitudinal study. Persons with NDE were assessed with the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), the Hospital Anxiety Depression Scale (HADS), the Stigma Scale, and the Rosenberg Self-esteem Scale. An analysis of covariance (ANCOVA) with interaction terms was used. RESULTS: Among 134 adults with NDE, there were no gender differences in the scores of the QOLIE-31 and its subscales. A multivariate linear regression analysis showed that the HADS-anxiety scores at diagnosis (p = 0.005) and seizure recurrence after diagnosis (p = 0.050) negatively predicted QOLIE-31 scores in persons with NDE. There were significant effects of the gender interaction with seizure recurrence (F = 8.745, p = 0.004, partial eta2 = 0.066) and antiepileptic drug (AED) polytherapy (F = 6.320, p = 0.013, partial eta2 = 0.049) in the adjusted model. Specifically, seizure recurrence negatively predicted the QOLIE-31 scores only in men. By contrast, AED polytherapy negatively predicted the QOLIE-31 scores only in women. CONCLUSIONS: There are gender differences in certain epilepsy-related factors predicting HRQoL at 1 year in persons with NDE.

Enhancing the Therapeutic Potential of CCL2-Overexpressing Mesenchymal Stem Cells in Acute Stroke.

Although intravenous administration of mesenchymal stem cells (MSCs) is effective for experimental stroke, low engraftment and the limited functional capacity of transplanted cells are critical hurdles for clinical applications. C-C motif chemokine ligand 2 (CCL2) is associated with neurological repair after stroke and delivery of various cells into the brain via CCL2/CCR2 (CCL2 receptor) interaction. In this study, after CCL2-overexpressing human umbilical cord-derived MSCs (hUC-MSCs) were intravenously transplanted with mannitol in rats with middle cerebral arterial occlusion, we compared the differences between four different treatment groups: mannitol + CCL2-overexpressing hUC-MSCs (CCL2-MSC), mannitol + naïve hUC-MSCs (M-MSC), mannitol only, and control. At four-weeks post-transplantation, the CCL2-MSC group showed significantly better functional recovery and smaller stroke volume relative to the other groups. Additionally, we observed upregulated levels of CCR2 in acute ischemic brain and the increase of migrated stem cells into these areas in the CCL2-MSC group relative to the M-MSC. Moreover, the CCL2-MSC group displayed increased angiogenesis and endogenous neurogenesis, decreased neuro-inflammation but with increased healing-process inflammatory cells relative to other groups. These findings indicated that CCL2-overexpressing hUC-MSCs showed better functional recovery relative to naïve hUC-MSCs according to the increased migration of these cells into brain areas of higher CCR2 expression, thereby promoting subsequent endogenous brain repair.

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms.

Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14-4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11-2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.

Adalimumab improves cognitive impairment, exerts neuroprotective effects and attenuates neuroinflammation in an Aß1-40-injected mouse model of Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) is associated with an increased inflammatory response via activated microglia and astrocytes. In the present study, we investigated whether treatment with the anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody adalimumab can improve cognitive function and reduce AD pathology in Aß1-40-injected animal models of AD, as well as the mechanisms underlying the effects of treatment. Aß1-40-injected mice treated with adalimumab exhibited significant improvements in memory relative to mice injected with Aß1-40 alone, as well as decreases in beta secretase-1 (BACE1) protein expression and Aß1-40 plaques. In addition, adalimumab treatment significantly attenuated neuronal damage and neuroinflammation in Aß1-40-injected mice. Aß1-40-induced decreases in brain-derived neurotrophic factor (BDNF) expression were also attenuated by treatment with adalimumab. Our experiments further verified that the effects of adalimumab are mediated by nuclear factor kappa B (NF-κB) p65 signalling. Serine 536 residues of NF-κB p65, which is phosphorylated by TNF-α, increased along with the degradation of inhibitor of κB (IκB) in the hippocampus of Aß-injected mice, although these effects were again attenuated by adalimumab. Furthermore, Aß1-40-induced increases in TNF-α and interleukin (IL)-6 expression were decreased by treatment with adalimumab. Our results indicate that adalimumab may be clinically useful in human patients with AD.

Association study of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with venous thromboembolism in a Korean population.

Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in Asian patients, remains limited. This case-control study sought to determine the correlation between the presence of polymorphisms in the genes encoding the miRNAs miR-146a, miR-149, miR-196a2, miR-499, and VTE in Korean patients. We observed no statistically significant differences in the genotype frequency of miRNA polymorphisms between 300 control individuals and 203 VTE patients. However, we observed a significant association between three allelic combinations of miRNA polymorphisms and VTE risk. Overall, our findings suggest that specific miRNA polymorphisms are associated with the risk of VTE in a Korean population.

The Protective Role of Feruloylserotonin in LPS-Induced HaCaT Cells.

Epidermal inflammation is caused by various bacterial infectious diseases that impair the skin health. Feruloylserotonin (FS) belongs to the hydroxycinnamic acid amides of serotonin, which mainly exists in safflower seeds and has been proven to have anti-inflammatory and antioxidant activities. Human epidermis mainly comprises keratinocytes whose inflammation causes skin problems. This study investigated the protective effects of FS on the keratinocyte with lipopolysaccharides (LPS)-induced human HaCaT cells and elucidated its underlying mechanisms of action. The mechanism was investigated by analyzing cell viability, PGE2 levels, cell apoptosis, nuclear factor erythroid 2-related factor 2 (Nrf2) translocation, and TLR4/NF-κB pathway. The anti-inflammatory effects of FS were assessed by inhibiting the inflammation via down-regulating the TLR4/NF-κB pathway. Additionally, FS promoted Nrf2 translocation to the nucleus, indicating that FS showed anti-oxidative activities. Furthermore, the antioxidative and anti-inflammatory effects of FS were found to benefit each other, but were independent. Thus, FS can be used as a component to manage epidermal inflammation due to its anti-inflammatory and anti-oxidative properties.

Additional increased effects of mannitol-temozolomide combined treatment on blood-brain barrier permeability.

The blood-brain barrier (BBB) is major obstacle in drug or stem cell treatment in chronic stroke. We hypothesized that adding mannitol to temozolomide (TMZ) is a practically applicable method for resolving the low efficacy of intravenous mannitol therapy. In this study, we investigated whether BBB permeability could be increased by this combined treatment. First, we established a chronic ischemic stroke rat model and examined changes in leakage of Evans blue dye within a lesion site, and in expression of tight junction proteins (TJPs), by this combined treatment. Additionally, in an in vitro BBB model using trans-wells, we analyzed changes in diffusion of a fluorescent tracer and in expression of TJPs. Mannitol-TMZ combined treatment not only increased the amount of Evans blue dye within the stroke lesion site, but also reduced occludin expression in rat brain microvessels. The in vitro study also showed that combined treatment increased the permeability for two different-sized fluorescent tracers, especially large size, and decreased expression of TJPs, such as occludin and ZO-1. Increased BBB permeability effects were more prominent with combined than with single treatments. Mannitol-TMZ combined treatment induced a decrease of TJPs with a consequent increase in BBB permeability. This combined treatment is clinically useful and might provide new therapeutic options by enabling efficient intracerebral delivery of various drugs that could not otherwise be used to treat many CNS diseases due to their inability to penetrate the BBB.

The combination of mannitol and temozolomide increases the effectiveness of stem cell treatment in a chronic stroke model.

BACKGROUND: The blood-brain barrier (BBB) presents a significant challenge to the therapeutic efficacy of stem cells in chronic stroke. Various methods have been developed to increase BBB permeability, but these are associated with adverse effects and are, therefore, not clinically applicable. We recently identified that combination drug treatment of mannitol and temozolomide improved BBB permeability in vitro. Here, we investigated whether this combination could increase the effectiveness of stem cell treatment in an animal model of chronic ischemic stroke. METHODS: Chronic stroke was induced in rats by middle cerebral artery occlusion (MCAo). After then, rats were administered human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) by intravenous injection with or without combination drug treatment of mannitol and temozolomide. To evaluate the therapeutic efficacy, behavioral and immunohistochemical tests were performed, and the differences among control, stem cell only, combination drug only and stem cell with combination drug treatment were analyzed. RESULTS: Although no hUC-MSCs were detected in any group, treatment with stem cells and combination drug of mannitol and temozolomide increased the intracerebral delivery of hCD63-positive microvesicles compared with stem cell only treatment. Furthermore, treatment with stem cells and drug combination ameliorated behavioral deficits and increased bromodeoxyuridine-, doublecortin- and Reca-1-positive cells in the perilesional area as compared with other groups. DISCUSSION: The combination drug treatment of mannitol and temozolomide allowed for the efficient delivery of hUC-MSC-derived microvesicles into the brain in a chronic stroke rat model. This attenuated behavioral deficits, likely by improving neural regeneration and angiogenesis. Thus, combination drug treatment of mannitol and temozolomide could be a novel therapeutic option for patients with chronic ischemic stroke.

Factors contributing to anxiety and depressive symptoms in adults with new-onset epilepsy.

PURPOSE: We investigated factors contributing to anxiety and depressive symptoms over a 1-year period in Korean adults with new-onset epilepsy. METHODS: This longitudinal multicenter study included adults diagnosed with epilepsy within 12 months of a first seizure. Using stepwise regression analyses, we determined whether Hospital Anxiety Depression Scale (HADS) scores could be predicted by demographic, clinical, and psychosocial variables at baseline and at 12 months. RESULTS: Of 141 patients included at baseline, 63 (44.7%) and 60 (42.6%) had Hospital Anxiety Depression Scale-Anxiety (HADS-A) and Hospital Anxiety Depression Scale-Depression (HADS-D) scores >7, respectively. Of 98 patients who completed the 12-month study, the corresponding figures decreased to 32.7% and 36.7%, respectively. Higher HADS-A scores both at baseline and 12 months were predicted by higher neuroticism, stigma, and lower self-esteem (p < 0.05). Higher HADS-D scores at baseline were predicted by higher neuroticism, lower self-esteem, marital status, and lower extroversion (p < 0.05) whereas those at 12 months were predicted by self-esteem, seizure recurrence, and age at epilepsy onset (p < 0.05). Neuroticism or self-esteem was the strongest predictor of psychological distress. CONCLUSIONS: Anxiety and depressive symptoms are common at the time of diagnosis in Korean adults with new-onset epilepsy. While these decrease over time, they remained high 12 months after epilepsy diagnosis. Psychological factors, particularly neuroticism and self-esteem, may be the most important risk factors. Epilepsy variables, such as seizure recurrence and age at onset, may also be important factors for depressed mood at 12 months.

Effect of Pretreatment with the NADPH Oxidase Inhibitor Apocynin on the Therapeutic Efficacy of Human Placenta-Derived Mesenchymal Stem Cells in Intracerebral Hemorrhage.

Several studies have demonstrated the beneficial effect of mesenchymal stem cells (MSCs) on intracerebral hemorrhage (ICH). Enhancement of the therapeutic efficacy of MSCs in ICH is necessary, considering the diseases high association with mortality and morbidity. Various preconditioning methods to enhance the beneficial properties of MSCs have been introduced. We suggested apocynin, a well-known nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, as a novel preconditioning regimen to enhance the therapeutic efficacy of MSCs in ICH. Rat ICH models were made using bacterial collagenase. 24 h after ICH induction, the rats were randomly divided into apocynin-preconditioned MSC-treated (Apo-MSC), naïve MSC-treated and control groups. Hematoma volume, brain edema, and degenerating neuron count were compared at 48 h after the ICH induction. The expression of tight junction proteins (occludin, zona occludens [ZO]-1) were also compared. Hematoma size, hemispheric enlargement and degenerating neuron count were significantly lower in the Apo-MSC group than in the naïve MSC group (p = 0.004, 0.013 and 0.043, respectively), while the expression of occludin was higher (p = 0.024). Apocynin treatment enhances the therapeutic efficacy of MSCs in ICH in the acute stage, through the improvement of the beneficial properties of MSCs, such as neuroprotection and the reinforcement of endovascular integrity of cerebral vasculature.

Predictors of disclosure management behavior at the end of 1-year follow-up in Korean adults with newly diagnosed epilepsy.

PURPOSE: Epilepsy is a concealable stigmatizing condition. We investigated the factors predicting disclosure management behavior in Korean adults with newly diagnosed epilepsy. METHODS: This longitudinal multicenter study included Korean adults with newly diagnosed epilepsy. Using statistical analyses, we determined at the end of a 1-year follow-up whether Disclosure Management Scale (DMS) scores were predicted by demographic, clinical, and psychosocial variables, including felt stigma, stress coping style, personality traits, social support, and experienced discrimination from society. RESULTS: Of a total of 121 participants, 69% reported that they often or sometimes kept their diagnosis a secret from others and rarely or never talked to others about their epilepsy. The average DMS score was 5.8 (SD=2.9, range 0-11). In univariate analyses, DMS scores were significantly associated with an emotion-focused coping style (r=0.320, p<0.001), social support (r=-0.185, p<0.05), and experienced discrimination (p<0.05). Emotion-focused coping was the only independent predictor of a higher DMS score. Felt stigma, personality traits, and seizure freedom were not related to the DMS score. CONCLUSIONS: Two-thirds of Korean adults with newly diagnosed epilepsy often or sometimes keep their epilepsy a secret. Emotion-focused coping is the most important predictor of concealment of epilepsy diagnosis at the end of a 1-year follow-up, although social support and episodes of experienced discrimination are also associated with disclosure management strategies.

The Role of RNF213 4810G>A and 4950G>A Variants in Patients with Moyamoya Disease in Korea.

Although a founder variant of RNF213 4810G>A is a major genetic risk factor for moyamoya disease (MMD) in East Asians, the frequency and disease susceptibility of RNF213 variants remain largely unknown. This study investigated the mutation analysis of RNF213 (4448, 4810, 4863, and 4950) between Korean MMD and healthy controls. We performed a polymerase chain reaction-restriction fragment length polymorphism analysis. To identify the association between RNF213 gene polymorphisms and MMD disease, we performed statistical analyses such as multivariable logistic regression and Fisher's exact test. Genetic data from 117 MMD patients were analyzed and compared with 253 healthy controls. We assessed and compared single nucleotide polymorphisms of RNF213 (4448, 4810, 4863, and 4950) between MMD and control groups. We performed genome-wide association studies to investigate the genetic pathophysiology of MMD. Among the RNF213 variants (4448G>A, 4810G>A, 4863G>A, and 4950G>A), RNF213 4810G>A and 4950G>A variants were more frequent in MMD patients. In a subgroup analysis, the RNF213 4810G>A was more frequent in moyamoya disease, and the comparison with GG+AA genotype was also significantly different in moyamoya patients. These results confirm that RNF213 4810G>A and RNF213 4950G>A were more frequent in MMD patients. We have confirmed that RNF213 4810G>A and 4950G>A are strongly associated with Korean MMD in children and adults as well as for the ischemic and hemorrhagic types.

Factors contributing to the development of perceived stigma in people with newly diagnosed epilepsy: A one-year longitudinal study.

PURPOSE: We evaluated the course of perceived stigma and the factors associated with perceived stigma over the first year in newly diagnosed people with epilepsy (PWE). METHODS: We recruited newly diagnosed PWE from 12 tertiary hospitals in Korea. The perceived stigma of epilepsy was assessed using the Stigma Scale at baseline and one year later. At the time of diagnosis, demographic, clinical seizure-related, and psychological data were collected. The predictive factors for perceived stigma over one year were analyzed using logistic regression analyses. RESULTS: Two hundred eighteen newly diagnosed PWE were included at baseline, and 153 completed the study. The percentage of participants who felt stigmatized decreased from 30.7% at the time of diagnosis to 17.6% at the end of follow-up. Introverted personality and a high level of anxiety were independent factors contributing to stigma at the time of epilepsy diagnosis. At the one-year follow-up, introverted personality and lower economic status were predictive of the development of perceived stigma. CONCLUSION: Introverted personality was an important factor contributing to the development of perceived stigma at the time of diagnosis and at one year after diagnosis. In addition, a high level of anxiety and a low economic status were independently related to feelings of stigma at baseline and at one year after diagnosis, respectively. There may be a decrease in the perception of stigma over one year in newly diagnosed PWE.

Digital panoramic radiographs are useful for diagnosis of osteoporosis in Korean postmenopausal women.

OBJECTIVE: The purpose of this study was to determine whether digital panoramic radiographs could be used for the diagnosis of osteoporosis through evaluation of the radiographs based on the correlation with bone mineral density (BMD). METHODS: One hundred and ninety-four post-menopausal women were selected from participants who had participated in the Dong-gu study. Panoramic radiographic indices measured are mental index (MI), mandibular cortical index (MCI) and simple visual estimation (SVE). BMD at the lumbar spine and proximal femur was measured by dual-energy X-ray absorptiometry (DXA). The Pearson's correlation test was performed to analyse the correlation between MI and age and BMD at the lumbar spine, femoral neck and total hip. Multiple linear regression analysis was performed to analyse the association of MI, MCI and SVE with BMD after adjusting for age, height and weight. To determine the optimal cut-off point of MI for the diagnosis of osteoporosis, the receiver operating characteristic analysis was performed. RESULTS: The MI was positively correlated with BMDs: lumbar spine: r = 0.36, femoral neck: r = 0.59 and total hip: r = 0.58 (p < 0.001). As age increased, MI decreased (r = -0.46). BMD at the lumbar spine and total hip were significantly lower in participants with reduction of mandibular width, thinning and resorption of mandibular cortex by the MI, SVE and MCI, respectively. The optimal cut-off value of MI for the diagnosis of spinal osteoporosis was 2.22 mm. CONCLUSION: Thickness and morphological changes of mandibular inferior cortical bone are associated with BMD, independent of age, height and weight. These results suggest that MI, MCI and SVE may be useful indices for the diagnosis of osteoporosis in a Korean population.

The effect of recurrent seizures on cognitive, behavioral, and quality-of-life outcomes after 12 months of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy.

PURPOSE: The purpose of this study was to determine whether seizure recurrence has a negative impact on cognition, psychological function, and health-related quality of life (HRQoL) over a 12-month period of monotherapy in adults with newly diagnosed or previously untreated partial epilepsy. METHODS: Seizure freedom (SF) was defined as no seizure recurrence during the 40-week maintenance period of medication. Neuropsychological tests, the Symptom Checklist-90 (SCL-90), and the Quality of Life in Epilepsy-31 (QOLIE-31) were administered at baseline and after 48 weeks of carbamazepine or lamotrigine monotherapy. Seventy-three patients successfully continued treatment until the 48-week follow-up time point. Fifty patients (68.5%) had SF, and the remaining 23 were not seizure-free (NSF). A seizure outcome group-by-time interaction was analyzed using a linear mixed model. RESULTS: A group-by-time interaction was identified for the total QOLIE-31 score (p<0.05) and score on two QOLIE-31 subscales (social function: p<0.001 and seizure worry: p<0.001), with a significant improvement over time only present in the SF group (all p<0.001). There was no significant group-by-time interaction for most cognitive function tests, with the exception of the serial clustering score (p<0.01) and number of recognition hits on the California Verbal Learning Test (p<0.05). Serial clustering did not differ between the SF and NSF groups at baseline, but was significantly more used in the NSF group than in the SF group at 48 weeks (p<0.01). There was no significant group-by-time interaction for any dimension of the SCL-90. CONCLUSION: Recurrent seizures had a significant effect on HRQoL, a subtle effect on cognitive performance, and no effect on psychological symptoms over one year in newly diagnosed or previously untreated adults with partial epilepsy.

Periodontal disease associated with blood glucose levels in urban Koreans aged 50 years and older: the Dong-gu study.

OBJECTIVE: To investigate the association of periodontal disease and the number of teeth present with the risk of prediabetes and diabetes as well as with blood glucose and HbA1c levels in adult Koreans. BACKGROUND: The relationship between periodontal disease and diabetes has not been fully elucidated. MATERIALS AND METHODS: Cross-sectional data from 5535 participants aged ≥50 years were obtained from 2008 to 2010. Periodontal status was measured as pocket depth (PD), clinical attachment loss (CAL) and bleeding on probing (BOP) recorded. The percentage of sites with a PD ≥4 mm, CAL ≥4 mm (CAL4) and BOP (BOP%) were recorded. Participants were divided into three groups according to PD4, CAL4 and BOP% measurements. Number of teeth present was divided into four groups. Participants were classified as normoglycaemic, prediabetic or diabetic based on HbA1c and fasting glucose levels. RESULTS: After full adjustment, the highest tertile of CAL4 (OR: 1.47, 95% CI: 1.18-2.02, p < 0.001), PD4 (OR: 1.58, 95% CI: 1.26-1.97, p < 0.001) and BOP% (OR: 1.37, 95% CI: 1.07-1.75, p = 0.012) had significantly increased odds of diabetes. The number of teeth present was inversely related to diabetes (p < 0.001) and prediabetes (p = 0.032) risk. Periodontal disease severity was positively associated with HbA1c and glucose levels. The number of teeth present was positively associated with HbA1c, but not glucose, levels. CONCLUSION: Periodontal disease and the number of teeth present are associated with an increased risk of diabetes and increased blood glucose and HbA1c levels in Koreans aged ≥50 years.

Cilostazol decreases cerebral arterial pulsatility in patients with mild white matter hyperintensities: subgroup analysis from the Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of Transcranial Doppler (ECLIPse) study.

BACKGROUND: The Effect of Cilostazol in Acute Lacunar Infarction Based on Pulsatility Index of the Transcranial Doppler (ECLIPse) study showed a significant decrease in the transcranial Doppler (TCD) pulsatility index (PI) with cilostazol treatment at 90 days after acute lacunar infarction. The aim of the present study was to perform a subgroup analysis of the ECLIPse study in order to explore the effect of cilostazol in acute lacunar infarction based on cerebral white matter hyperintensities (WMH) volume. METHODS: The ECLIPse study was a multicenter, randomized, double-blind, placebo-controlled trial that evaluated the difference between the efficacy of cilostazol and a placebo to reduce the PI in patients with acute lacunar infarction using serial TCD examinations. The primary outcome was changes in the PIs of the middle cerebral artery (MCA) and basilar artery at 14 and 90 days from the baseline TCD study. For this subgroup analysis, using semi-automated computerized software, the WMH volume was measured for those subjects for whom fluid-attenuated inversion recovery (FLAIR) images were available. RESULTS: Of the 203 patients in eight hospitals in the ECLIPse study, 130 participants from six hospitals were included in this subgroup analysis. Cilostazol was given to 63 patients (48.5%) and placebo to 67 patients (51.5%). All baseline characteristics were well balanced across the two groups, and there were no significant differences in these characteristics except in the changes of PI from the baseline to the 90-day point. There was a significant decrease of TCD PIs at 90-day study from baseline in the cilostazol group (p = 0.02). The mean WMH volume was 11.57 cm(3) (0.13-68.45, median 4.86) and the mean MCA PI was 0.95 (0.62-1.50). The changes in PIs from the baseline to 14 days and to 90 days were 0.09 (-0.21 to 0.33) and 0.10 (-0.22 to 0.36). While there were no significant correlations between WMH volume and the changes in PIs, a trend of inverse correlation was observed between the WMH volume and the changes in PIs from the baseline to the 90-day point. For the subgroup analysis, the WMH volume was dichotomized based on its median value (4.90 cm(3)). Cilostazol decreased the TCD PIs significantly at the 90-day point in patients with WMH volumes ≤ 4.9 cm(3) (p = 0.002). Significant treatment effects were observed in the cilostazol group. CONCLUSIONS: This study showed that cilostazol decreased cerebral arterial pulsatility in patients with WMH. Our findings indicate the unique effect of cilostazol in small vessel disease (SVD), especially in patients with mild WMH changes. Further clinical trials focusing on WMH volume and clinical outcomes are required to assess the unique efficacy of cilostazol in SVD.

Association of the miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with ischemic stroke and silent brain infarction risk.

OBJECTIVE: MicroRNAs play a role in atherosclerosis-related diseases, such as cerebrovascular or cardiovascular disease. However, the effect of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms on stroke and silent brain infarction (SBI) susceptibility has not been reported. METHODS AND RESULTS: Using polymerase chain reaction-amplified DNA, microRNA polymorphisms were analyzed in 678 patients with ischemic stroke, 373 patients with SBI, and 553 control subjects. The miR-146aC>G polymorphism and miR-146aG/-149T/-196a2C/-499G allele combination was significantly associated with ischemic stroke prevalence. For SBI prevalence, there were no statistically significant genetic markers. However, some allele combinations were associated with increased SBI incidence (C-T-C-G and G-T-T-A of miR-146a/-149/-196a2/-499). In subgroup analyses, miR-146aC>G increased stroke risk in female, normotensive, and nondiabetic groups. There were significant combined effects between microRNA polymorphisms and homocysteine/folate levels on ischemic stroke and SBI prevalence. CONCLUSIONS: The miR-146aG allele and miR-146aG/-149T/-196a2C/-499G allele combination were associated with ischemic stroke pathogenesis. The combined effects between microRNA polymorphisms and homocysteine/folate levels may contribute to stroke and SBI prevalence.

Relationship between periodontal disease and subclinical atherosclerosis: the Dong-gu study.

AIM: We assessed the association of periodontal disease and number of missing teeth with subclinical atherosclerosis in an adult Korean population. MATERIALS AND METHODS: Cross-sectional data from 5404 individuals aged ≥50 years were obtained from the 2008-2010 Dong-gu study. Periodontal examinations were conducted to determine the number of missing teeth, pocket depth (PD), clinical attachment loss (CAL), and bleeding on probing (BOP). The percentages of sites with PD ≥ 4 mm (PD 4%), CAL ≥ 4 mm (CAL 4%), and BOP (BOP%) were recorded for each participant. B-mode ultrasound was performed to determine common carotid artery intima-media thickness (CCA IMT) and the presence of carotid plaques. Multivariate linear regression models were used to assess the associations between periodontal parameters and CCA IMT and carotid plaque. RESULTS: Number of missing teeth was associated with increased CCA IMT, and BOP% was associated with increased CCA IMT in females only. This association was robust in never smokers. CONCLUSIONS: The number of missing teeth was associated with CCA IMT, and BOP% was associated with CCA IMT in females only. These associations were robust in never smokers. Our results suggest that tooth loss due to oral disease may play a role in subclinical carotid atherosclerosis.