Mechanisms of tissue factor induction by Porphyromonas gingivalis in human endothelial cells

Associations between periodontal infection and cardiovascular disease have been documented. Porphyromonas gingivalis is a well-established periodontal pathogen, and tissue factor (TF) is a key initiator of the coagulation cascade. In this context, P. gingivalis has been reported to enhance TF expression in human endothelial cells. The present study investigated the underlying mechanisms of TF induction by P. gingivalis in human umbilical vein endothelial cells. P. gingivalis increased TF expression in a dose- and time-dependent manner. Not only live bacteria but also glutaraldehyde-fixed bacteria increased TF expression to the same extent. However, sonicates of P. gingivalis did not induce TF expression. Cytochalasin D and SMIFH2, which are inhibitors of actin polymerization and actin nucleation, respectively, inhibited the TF expression induced by P. gingivalis. Finally, TF production was decreased or increased in the presence of various signaling inhibitors, including mitogen-activated protein kinases. These results suggest that P. gingivalis induces endothelial TF expression by a bacterial internalization-dependent mechanism and through diverse signal transduction mechanisms.

Mechanisms of tissue factor induction by Porphyromonas gingivalis in human endothelial cells

Associations between periodontal infection and cardiovascular disease have been documented. Porphyromonas gingivalis is a well-established periodontal pathogen, and tissue factor (TF) is a key initiator of the coagulation cascade. In this context, P. gingivalis has been reported to enhance TF expression in human endothelial cells. The present study investigated the underlying mechanisms of TF induction by P. gingivalis in human umbilical vein endothelial cells. P. gingivalis increased TF expression in a dose- and time-dependent manner. Not only live bacteria but also glutaraldehyde-fixed bacteria increased TF expression to the same extent. However, sonicates of P. gingivalis did not induce TF expression. Cytochalasin D and SMIFH2, which are inhibitors of actin polymerization and actin nucleation, respectively, inhibited the TF expression induced by P. gingivalis. Finally, TF production was decreased or increased in the presence of various signaling inhibitors, including mitogen-activated protein kinases. These results suggest that P. gingivalis induces endothelial TF expression by a bacterial internalization-dependent mechanism and through diverse signal transduction mechanisms.

Green tea polyphenol (–)-epigallocatechin-3-gallate prevents ultraviolet-induced apoptosis in PC12 cells

Green tea polyphenol (–)-epigallocatechin-3-gallate (EGCG) is a potent antioxidant with protective effects against neurotoxicity. However, it is currently unclear whether EGCG protects neuronal cells against radiation-induced damage. Therefore, the objective of this study was to investigate the effects of EGCG on ultraviolet (UV)-induced oxidative stress and apoptosis in PC12 cells. The effects of UV irradiation included apoptotic cell death, which was associated with DNA fragmentation, reactive oxygen species (ROS) production, enhanced caspase-3 and caspase-9 activity, and poly (ADP-ribose) polymerase cleavage. UV irradiation also increased the Bax/Bcl-2 ratio and mitochondrial pathway-associated cytochrome c expression. However, pretreatment with EGCG before UV exposure markedly decreased UV-induced DNA fragmentation and ROS production. Furthermore, the UV irradiationinduced increase in Bax/Bcl-2 ratio, cytochrome c upregulation, and caspase-3 and caspase-9 activation were each ameliorated by EGCG pretreatment. Additionally, EGCG suppressed UV-induced phosphorylation of p38 and rescued UV-downregulated phosphorylation of ERK. Taken together, these results suggest that EGCG prevents UV irradiationinduced apoptosis in PC12 cells by scavenging ROS and inhibiting the mitochondrial pathways known to play a crucial role in apoptosis. In addition, EGCG inhibits UV-induced apoptosis via JNK inactivation and ERK activation in PC12 cells. Thus, EGCG represents a potential neuroprotective agent that could be applied to prevent neuronal cell death induced by UV irradiation.

Green tea polyphenol (–)-epigallocatechin-3-gallate prevents ultraviolet-induced apoptosis in PC12 cells

Green tea polyphenol (–)-epigallocatechin-3-gallate (EGCG) is a potent antioxidant with protective effects against neurotoxicity. However, it is currently unclear whether EGCG protects neuronal cells against radiation-induced damage. Therefore, the objective of this study was to investigate the effects of EGCG on ultraviolet (UV)-induced oxidative stress and apoptosis in PC12 cells. The effects of UV irradiation included apoptotic cell death, which was associated with DNA fragmentation, reactive oxygen species (ROS) production, enhanced caspase-3 and caspase-9 activity, and poly (ADP-ribose) polymerase cleavage. UV irradiation also increased the Bax/Bcl-2 ratio and mitochondrial pathway-associated cytochrome c expression. However, pretreatment with EGCG before UV exposure markedly decreased UV-induced DNA fragmentation and ROS production. Furthermore, the UV irradiationinduced increase in Bax/Bcl-2 ratio, cytochrome c upregulation, and caspase-3 and caspase-9 activation were each ameliorated by EGCG pretreatment. Additionally, EGCG suppressed UV-induced phosphorylation of p38 and rescued UV-downregulated phosphorylation of ERK. Taken together, these results suggest that EGCG prevents UV irradiationinduced apoptosis in PC12 cells by scavenging ROS and inhibiting the mitochondrial pathways known to play a crucial role in apoptosis. In addition, EGCG inhibits UV-induced apoptosis via JNK inactivation and ERK activation in PC12 cells. Thus, EGCG represents a potential neuroprotective agent that could be applied to prevent neuronal cell death induced by UV irradiation.

Medical hypnotic management associated with drug dependence in patients with insomnia and neurological disorders

@#Objectives: We aimed to investigate the demographics and medical management factors associated with dependence on hypnotics among outpatients with neurological disorders and insomnia. Methods: We reviewed electronic medical records of patients who received an initial hypnotic prescription between January 2014 and January 2016 and had later visited a neurological outpatient clinic before January 2018. We assessed patient demographics, the effectiveness of hypnotics, prescription periods, and hypnotic intake methods during the follow-up period. Results: Of 242 patients diagnosed with insomnia, we enrolled 114 patients (more women than men, at 61.4 versus 38.6%) who visited outpatient clinics regularly during the follow-up period. The mean age at onset was 65.8 ± 14.4 years. The most frequent neurological disorder was cerebrovascular disease, followed by neurodegenerative disease. During the 2-year period, 35.9% of participants remained hypnotics-free. Patients on zolpidem showed significantly greater insomnia improvement with hypnotic discontinuation than those on benzodiazepines and combination therapy (p=0.004). However, the type of hypnotics and demographic factors were not found to be independent risk factors. Multivariable analysis showed that longer periods between regular visits and a lower ratio of receiving number of pills to the time interval (days) between regular visits were independent risk factors for dependence on hypnotics. Conclusions: We found that low-dose and/or intermittent intake of hypnotics as well as frequent doctor visits could prevent dependence on hypnotics. It is important to establish the best practical guidelines for medical hypnotics management in outpatient primary care settings, including neurological clinics.

Association of MicroRNA Biogenesis Genes Polymorphisms with Ischemic Stroke Susceptibility and Post-Stroke Mortality / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: MicroRNA (miRNA) expression has been examined in multiple conditions, including various cancers, neurological diseases, and cerebrovascular diseases, particularly stroke. Existing evidence indicates that miRNA biosynthesis and function play crucial roles in ischemic stroke physiology and pathology. In this study, we selected six known polymorphisms in miRNA-biogenesis genes; DICER rs13078A>T, rs3742330A>G; DROSHA rs10719T>C, rs6877842G>C; Ran GTPase (RAN) rs14035C>T; exportin 5 (XPO5) rs11077A>C. METHODS: We analyzed the associations between these polymorphisms and disease status and clinical factors in 585 ischemic stroke patients and 403 controls. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The DICER rs3742330A>G (AA vs. AG+GG: adjusted odds ratio [AOR], 1.360; 95% confidence interval [CI], 1.024 to 1.807; P=0.034) and DROSHA rs10719T>C polymorphisms (TT vs. CC: AOR, 2.038; 95% CI, 1.113 to 3.730; P=0.021) were associated with ischemic stroke prevalence. During a mean follow-up of 4.80±2.11 years, 99 (5.91%) of the stroke patients died. In multivariate Cox proportional hazard regression models, a significant association was found between RAN rs14035 and survival of large artery disease patients with ischemic stroke (CC vs. TT: adjusted hazard ratio, 5.978; P=0.015). CONCLUSIONS: An association was identified between the DICER and DROSHA polymorphisms and ischemic stroke. Specifically, polymorphisms (rs3742330 and rs10719) were more common in stroke patients, suggesting that they may be associated with an increased risk of ischemic stroke.

The Effect of Pulsatility Index on Infarct Volume in Acute Lacunar Stroke

PURPOSE: Lacunar stroke, in the context of small vessel disease, is a type of cerebral infarction caused by occlusion of a penetrating artery. Pulsatility index (PI) is an easily measurable parameter in Transcranial Doppler ultrasound (TCD) study. PI reflects distal cerebral vascular resistance and has been interpreted as a surrogate marker of small vessel disease. We hypothesized that an increased PI, a marker of small vessel disease, might be associated with a larger infarct volume in acute lacunar stroke. MATERIALS AND METHODS: This study included 64 patients with acute lacunar stroke who underwent TCD and brain MRI. We evaluated the association between the mean PI value of bilateral middle cerebral arteries and infarct volume on diffusion-weighted MRI using univariate and multivariate linear regression. RESULTS: The mean infarct volume and PI were 482.18±406.40 mm3 and 0.86±0.18, respectively. On univariate linear regression, there was a significant positive association between PI and infarct volume (p=0.001). In the multivariate model, a single standard deviation increase of PI (per 0.18) was associated with an increase of 139.05 mm3 in infarct volume (95% confidence interval, 21.25 to 256.85; p=0.022). CONCLUSION: We demonstrated that PI was an independent determinant of infarct volume in acute lacunar stroke. The PI value measured in acute stroke may be a surrogate marker of the extent of ischemic injury.

Plasma Total Homocysteine Level Is Associated with the Pulsatility Index of Cerebral Arteries in Lacunar Infarction

PURPOSE: The pulsatility index (PI), measured by transcranial Doppler (TCD), is a surrogate marker for distal vascular resistance in cerebral arteries, and elevated plasma total homocysteine (tHcyt) is regarded as a cause of ischemic stroke, including lacunar infarction. We investigated the relationship between the PI of cerebral arteries and plasma tHcyt in patients with lacunar infarction. MATERIALS AND METHODS: Plasma tHcyt level and TCD examination were performed in 94 patients with lacunar infarction. Mean flow velocity (MFV) and PI were assessed at the ipsilateral middle cerebral artery (MCA) and contralateral MCA, relative to the infarction, and the basilar artery (BA). Multivariate regression analysis was conducted between log-transformed tHcyt levels (logHcyt) and the PI of individual arteries. RESULTS: There was a significant correlation between logHcyt and the PI in all tested arteries (ipsilateral MCA: r=0.21, p=0.03; contralateral MCA: r=0.21, p=0.04; BA: r=0.35, p=0.01). In multivariate regression analysis, this significance remained unchanged after adjusting for vascular risk factors, creatinine, hematocrit and platelet count (ipsilateral MCA: beta=0.26, p=0.01; contralateral MCA: beta=0.21, p=0.04; BA: beta=0.39, p=0.001). There was no significant association between logHcyt and MFV of individual arteries. CONCLUSION: A significant association between plasma tHcyt and the PI of cerebral arteries indicates that homocysteine plays a role in the increase of distal arterial resistance in lacunar infarction.

Erratum: Comparison between Clinical Disabilities and Electrophysiological Values in Charcot-Marie-Tooth 1A Patients with PMP22 Duplication

The publisher wishes to apologize for incorrectly displaying the author (Seok Beom Gwon) name. We correct his name from Seok Beom Gwon to Seok Beom Kwon.

Comparison between Clinical Disabilities and Electrophysiological Values in Charcot-Marie-Tooth 1A Patients with PMP22 Duplication

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) type 1A (CMT1A) is the demyelinating form of CMT that is significantly associated with PMP22 duplication. Some studies have found that the disease-related disabilities of these patients are correlated with their compound muscle action potentials (CMAPs), while others have suggested that they are related to the nerve conduction velocities. In the present study, we investigated the correlations between the disease-related disabilities and the electrophysiological values in a large cohort of Korean CMT1A patients. METHODS: We analyzed 167 CMT1A patients of Korean origin with PMP22 duplication using clinical and electrophysiological assessments, including the CMT neuropathy score and the functional disability scale. RESULTS: Clinical motor disabilities were significantly correlated with the CMAPs but not the motor nerve conduction velocities (MNCVs). Moreover, the observed sensory impairments matched the corresponding reductions in the sensory nerve action potentials (SNAPs) but not with slowing of the sensory nerve conduction velocities (SNCVs). In addition, CMAPs were strongly correlated with the disease duration but not with the age at onset. The terminal latency index did not differ between CMT1A patients and healthy controls. CONCLUSIONS: In CMT1A patients, disease-related disabilities such as muscle wasting and sensory impairment were strongly correlated with CMAPs and SNAPs but not with the MNCVs or SNCVs. Therefore, we suggest that the clinical disabilities of CMT patients are determined by the extent of axonal dysfunction.

Analysis of an Association between Single Nucleotide Polymorphisms of Vascular Endothelial Growth Factor Gene and Risk of Cerebral White Matter Lesion

BACKGROUND: Endothelial dysfunction is suggested to be one of the pathogenesis of cerebral white matter lesion (cWML). Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and integrity of vascular endothelial cell, and altered expression of VEGF gene induces vascular diseases including cerebrovascular diseases. The objective of this study is to investigate whether single nucleotide polymorphism (SNP) of VEGF gene confers an increased risk of cWML. METHODS: Total 337 study subjects without history of stroke were included. The presence and severity of cWML were measured on fluid-attenuated inversion recovery image. Genotypes of VEGF -2578G>A, -1154G>A, -634G>C and +936C>T were analyzed. RESULTS: Among 337 study subjects, cWML was found in 208 patients (62%), and fifty-eight cases (17%) of them had overt cWML. In univariate analysis, age, female sex and plasma total homocysteine level (tHcyt) were higher in the mild and overt cWML group than no cWML group (p<0.05). The percentage of previous history of hypertension and the value of systolic blood pressure were higher in overt cWML group than no cWML group. In univariate and logistic regression analysis, none of four tested VEGF SNPs was significantly different between control group, mild and overt cWML groups. There was no difference between plasma tHcyt levels and each VEGF SNPs in control group and cWML groups. CONCLUSIONS: In this study, old age, female sex, hypertension and plasma tHcyt were associated with cWML. However, we failed to find an association between cWML and VEGF gene polymorphism, which may indicate that genetic polymorphism of VEGF does not play a direct role in the pathogenesis of cWML.

Odontogenic Keratocyst Associated with an Ectopic Tooth in the Maxillary Sinus: A Report of Two Cases and a Review of the Literature

Odontogenic keratocysts are benign intraosseous tumors of odontogenic origin that occur most commonly in the jaw. In particular, they have a predilection for the angle and ascending ramus of the mandible. In contrast, odontogenic keratocysts arising in the maxillary sinus are relatively rare. Two such cases are reported herein. In addition, the English literature that concerns odontogenic keratocysts of the maxillary sinus is reviewed.

Association between Single Nucleotide Polymorphisms of alpha2A-, alpha2B-, and alpha2C-Adrenergic Receptor Genes and Risk of Cerebral White Matter Lesion / 대한뇌졸중학회지

BACKGROUND: An alpha2-adrenergic receptor (alpha2-AR, ADRA2) mediates induction of hypotension and inhibition of lipolysis and insulin secretion. We evaluated whether single nucleotide polymorphisms (SNPs) of alpha2A (ADRA2A), alpha2B (ADRA2B), and alpha2C (ADRA2C) adrenergic receptors are associated with cerebral white matter lesion (cWML). METHODS: Total 336 study subjects who had no stroke were enrolled in this study. The Indices of cWML include total WML (TWML), periventricular WML (PVWML), and subcortical WML (SCWML) on brain fluid-attenuated inversion recovery (FLAIR) image. Common genetic variants of ADRA2A (1780G>A), ADRA2B (Ins/Del301-303), and ADRA2C (Ins/Del322-325) were examined. RESULTS: Among 336 study subjects, cWML was found in 66 patients (20%). In multivariate analysis, there were no significant effects of all tested ADRA2 polymorphisms on TWML. Significant association of ADRA2A 1780 AA genotype was found in PVWML (OR: 3.368, 95% CIs: 1.280-8.865, adjusted p-value after false discovery rate (FDR) correction=0.014) but not SCWML. CONCLUSION: Although SNPs of three ADRA2 subtypes failed to reach a significance in overall risk for cWML, the ADRA2A 1780G>A polymorphism may be associated with development of PVWML.

Association of Methylenetetrahydrofolate Reductase (MTHFR 677C>T and 1298A>C) Polymorphisms and Haplotypes with Silent Brain Infarction and Homocysteine Levels in a Korean Population

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is the main regulatory enzyme for homocysteine metabolism. In the present study, we evaluated whether the MTHFR 677C>T and 1298A>C gene polymorphisms are associated with SBI and plasma homocysteine concentration in a Korean population. MATERIALS AND METHODS: We enrolled 264 patients with SBI and 234 healthy controls in South Korea. Fasting plasma total homocysteine (tHcy) concentrations were measured, and genotype analysis of the MTHFR gene was carried out. RESULTS: The plasma tHcy levels were significantly higher in patients with SBI than in healthy controls. Despite a significant association between the MTHFR 677TT genotype and hyperhomocysteinemia, the MTHFR 677C>T genotypes did not appear to influence susceptibility to SBI. However, odds ratios of the 1298AC and 1298AC + CC genotypes for the 1298AA genotype were significantly different between SBI patients and normal controls. The frequencies of 677C-1298A and 677C-1298C haplotypes were significantly higher in the SBI group than in the control group. CONCLUSION: This study demonstrates that the MTHFR 1298A>C polymorphism is a risk factor for SBI in a Korean population. The genotypes of 677C>T and 1298A>C polymorphisms interact additively, and increase the risk of SBI in Korean subjects.

Antioxidant profile of whole saliva after scaling and root planing in periodontal disease

PURPOSE: This study compared the total antioxidant status (TAS) and superoxide dismutase (SOD) activity in the saliva of periodontally compromised patients before and after scaling and root planing (SRP) to assess their diagnostic utility. METHODS: Severe chronic periodontitis patient (test group) and subjects with no attachment loss, sites showing a 3 mm or more probing depth and a sulcus bleeding index < 10% (control group) were enrolled in this study. Saliva sampling and clinical examination were performed at one week, one month and 3 months after SRP. The TAS and SOD activity in each patient's saliva was measured for the comparative analysis between the groups. RESULTS: In the test group, the TAS decreased directly after SRP. With time, it increased slightly and was relatively unchanged compared to the baseline. In the control group, the TAS also decreased immediately after SRP but increased gradually with time until 3 months. The SOD activity in the test and control subjects decreased immediately after SRP until 1 month. At 3 months, the SOD activity had increased. Both groups had a similar profile of SOD activity. However, the SOD activity of the control group was significantly higher than that of the test group at each point in time (P < 0.05). CONCLUSIONS: There was a significant difference in the total salivary antioxidant level between the periodontitis and healthy or gingivitis (control) group during the experiment period. The total antioxidant level in the saliva was higher in the patients with severe chronic periodontitis than the healthy or gingivitis control before SRP. The SOD activity of the periodontitis patients was lower than the control at each time point. These findings conclusively reveal the possible use of saliva as a diagnostic tool for periodontal health.

Acute Spinal Subdural Hematoma Presenting with Spontaneously Resolving Hemiplegia

Although prompt diagnosis and emergent surgical intervention are important in acute spinal subdural hematoma (SSDH), some cases with spontaneous remission of symptom and hematoma without surgery have been reported. We present a case of acute nontraumatic SSDH presenting with transient left hemiplegia for 4 hours. A magnetic resonance imaging study of cervical spine confirmed SSDH with C3-6 cervical cord compression at the left side. The patient had conservative management without recurrence. Although hemiplegia is an unusual clinical manifestation of SSDH, it should be differentiated from that of cerebrovascular origin promptly. Conservative management may be an alternative therapeutic option for selective cases with transient neurological deficits.

Multiple Fusiform Cerebral Aneurysms and Highly Elevated Serum Interleukin-6 in Cardiac Myxoma

Cerebral embolic infarction is the most common neurologic complication of cardiac myxoma (CM). Development of cerebral aneurysms in CM is very rare. We present a 64-year-old woman with acute cerebral infarction and multiple cerebral aneurysms complicated by CM. The aneurysms were multiple, fusiform-shaped, and located in distal branch of major cerebral arteries. The serum interleukin (IL)-6 was highly elevated, which was normalized after surgical resection of CM. There was no regression of aneurysms on follow-up neuroimaging. Multiple cerebral aneurysms in CM are rare condition. Highly elevated serum IL-6 may be associated with increased risk of cerebral aneurysmal formation.

Prevalence of Oral Microbes in the Saliva of Oncological Patients

This study examined the prevalence of oral microbes in the saliva of oncological patients and healthy subjects. PCR was used to assess the frequency of oral microbes including 3 cariogenic bacteria, 5 periodontopathic bacteria and 4 Candida species in the saliva of 104 oncological patients and 52 healthy subjects. Among these microorganims, Streptococcus mutans, Fusobacterium nucleatum and Candida albicans were most frequently detected in both groups. There were no significant differences in the prevalence of cariogenic bacteria between the patient and healthy groups, whereas significant differences in the frequency of Porphyromonas gingivalis and Tannerella forsythia were observed between the two groups (p < 0.05). The prevalence of all five periodontopathogens was higher in the healthy group than in the patient group. The prevalence of C. albicans in patients was significantly higher than that of healthy group (p < 0.05). In conclusion, there were significant differences in the prevalence of P. gingivalis, T. forsythia and C. albicans between the oncological patient group and healthy group.

A Case of Dementia with Transient Splenial lesion on MRI after Hypoglycemia

We report a rare case having dementia with transient splenial lesion on MRI after hypoglycemia. A 75-year-old woman with type 2 diabetes was admitted with mental change after medication of a hypoglycemic agent. Initial serum glucose was 22 mg/dL. High signal intensity in the splenium on diffusion-weighted MRI was shown. After conservative management, she was gradually improved and splenial lesion was disappeared, but her cognitive impairment remained.

A Case of Hypokalemic Paralysis Provoked after Trigger Point Injection with Dexamethasone and Lidocaine

Acute hypokalemic paralysis is characterized by acute systemic weakness and low serum potassium. Trigger point injection (TPI) is frequently performed for myofacial pain relief with rare complications. 34-year-old male was admitted with quadriparesis after TPI with dexamethasone and lidocaine before 24 hours. Hypokalemia was found with compatible findings on nerve conduction studies and electromyography. Hypokalemia and weakness were fully recovered after potassium replacement. Steroid and lidocaine can provoke iatrogenic hypokalemic paralysis, therefore, TPI with these medications should be cautiously performed.