Oleanolic Acid Provides Neuroprotection against Ischemic Stroke through the Inhibition of Microglial Activation and NLRP3 Inflammasome Activation

Oleanolic acid (OA), a natural pentacyclic triterpenoid, has been reported to exert protective effects against several neurological diseases through its anti-oxidative and anti-inflammatory activities. The goal of the present study was to evaluate the therapeutic potential of OA against acute and chronic brain injuries after ischemic stroke using a mouse model of transient middle cerebral artery occlusion (tMCAO, MCAO/reperfusion). OA administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, functional neurological deficits, and neuronal apoptosis. Moreover, delayed administration of OA (at 3 h after reperfusion) attenuated brain infarction and improved functional neurological deficits during the acute phase. Such neuroprotective effects were associated with attenuation of microglial activation and lipid peroxidation in the injured brain after the tMCAO challenge. OA also attenuated NLRP3 inflammasome activation in activated microglia during the acute phase. In addition, daily administration of OA for 7 days starting from either immediately after reperfusion or 1 day after reperfusion significantly improved functional neurological deficits and attenuated brain tissue loss up to 21 days after the tMCAO challenge; these findings supported therapeutic effects of OA against ischemic stroke-induced chronic brain injury. Together, these findings showed that OA exerted neuroprotective effects against both acute and chronic brain injuries after tMCAO challenge, suggesting that OA is a potential therapeutic agent to treat ischemic stroke.

Impaired Hand Dexterity Function in a Non-human Primate Model with Chronic Parkinson’s Disease

ymptoms of Parkinson’s disease (PD) caused by loss of dopaminergic neurons are accompanied by movement disorders, including tremors, rigidity, bradykinesia, and akinesia. Non-human primate (NHP) models with PD play an essential role in the analysis of PD pathophysiology and behavior symptoms. As impairments of hand dexterity function can affect activities of daily living in patients with PD, research on hand dexterity function in NHP models with chronic PD is essential. Traditional rating scales previously used in the evaluation of animal spontaneous behavior were insufficient due to factors related to subjectivity and passivity. Thus, experimentally designed applications for an appropriate apparatus are necessary. In this study, we aimed to longitudinally assess hand dexterity function using hand dexterity task (HDT) in NHP-PD models. To validate this assessment, we analyzed the alteration in Parkinsonian tremor signs and the functionality of presynaptic dopaminergic neuron using positron emission tomography imaging of dopamine transporters in these models. In addition, a significant inverse correlation between HDT and DAT level was identified, but no local bias was found. The correlation with intention tremor signs was lower than the resting tremor. In conclusion, the evaluation of HDT may reflect behavioral symptoms of NHP-PD models. Furthermore, HDT was effectively used to experimentally distinguish intention tremors from other tremors.

Inhibition of LPA5 Activity Provides Long-Term Neuroprotection in Mice with Brain Ischemic Stroke

Stroke is a leading cause of long-term disability in ischemic survivors who are suffering from motor, cognitive, and memory impairment. Previously, we have reported suppressing LPA5 activity with its specific antagonist can attenuate acute brain injuries after ischemic stroke. However, it is unclear whether suppressing LPA5 activity can also attenuate chronic brain injuries after ischemic stroke. Here, we explored whether effects of LPA5 antagonist, TCLPA5, could persist a longer time after brain ischemic stroke using a mouse model challenged with tMCAO. TCLPA5 was administered to mice every day for 3 days, starting from the time immediately after reperfusion. TCLPA5 administration improved neurological function up to 21 days after tMCAO challenge. It also reduced brain tissue loss and cell apoptosis in mice at 21 days after tMCAO challenge. Such long-term neuroprotection of TCLPA5 was associated with enhanced neurogenesis and angiogenesis in post-ischemic brain, along with upregulated expression levels of vascular endothelial growth factor. Collectively, results of the current study indicates that suppressing LPA5 activity can provide long-term neuroprotection to mice with brain ischemic stroke.

Neuroprotective Effects of 6-Shogaol and Its Metabolite, 6-Paradol, in a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by progressive neuronal loss, neuroinflammation, axonal degeneration, and demyelination. Previous studies have reported that 6-shogaol, a major constituent of ginger (Zingiber officinale rhizome), and its biological metabolite, 6-paradol, have anti-inflammatory and anti-oxidative properties in the central nervous system (CNS). In the present study, we investigated whether 6-shogaol and 6-paradol could ameliorate against experimental autoimmune encephalomyelitis (EAE), a mouse model of MS elicited by myelin oligodendrocyte glycoprotein (MOG35-55) peptide immunization with injection of pertussis toxin. Once-daily administration of 6-shogaol and 6-paradol (5 mg/kg/day, p.o.) to symptomatic EAE mice significantly alleviated clinical signs of the disease along with remyelination and reduced cell accumulation in the white matter of spinal cord. Administration of 6-shogaol and 6-paradol into EAE mice markedly reduced astrogliosis and microglial activation as key features of immune responses inside the CNS. Furthermore, administration of these two molecules significantly suppressed expression level of tumor necrosis factor-α, a major proinflammatory cytokine, in EAE spinal cord. Collectively, these results demonstrate therapeutic efficacy of 6-shogaol or 6-paradol for EAE by reducing neuroinflammatory responses, further indicating the therapeutic potential of these two active ingredients of ginger for MS.

S1P₁ Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia

M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 (S1P₁) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between S1P₁ and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of S1P₁ is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether S1P₁ was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing S1P₁ activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing S1P₁ activity with AUY954 administration inhibited M1-polarizatioin-relevant NF-κB activation in post-ischemic brain. Particularly, NF-κB activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through S1P₁ in post-ischemic brain mainly occurred in activated microglia. Suppressing S1P₁ activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that S1P₁ could also influence M2 polarization in post-ischemic brain. Finally, suppressing S1P₁ activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following S1P₁ activation. Overall, these results revealed S1P₁-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

Usefulness of Anterior Cervical Interbody Fusion Using Locally Harvested Bone: Minimum 5-Year Follow-Up / 대한정형외과학회잡지

PURPOSE: The purpose of this study is to determine the usefulness of locally harvested autobone as a filling material for fusion. MATERIALS AND METHODS: Retrospective study was conducted for 21 patients diagnosed as cervical disc herniation with cervical myelopathy or radiculopathy who underwent anterior cervical fusion using locally harvested autobone and polyetheretherketone solis cage from June 2006 to September 2009, with a follow-up period of longer than 5 years. Radiologic outcomes were evaluated by the rate of bone union, the change of intervertebral height, and the subsidence of the cage. RESULTS: In clinical results, visual analogue scale score was 5.8±0.71/7.7±0.78 at preoperative, 1.6±0.58/2.3±0.97 at 1-year follow-up, 1.8±0.81/2.7±1.28 at 5-year follow-up, and neck disability index score was 34.3±6.2 in preoperative stage, 6.25±3.21 at 1-year follow-up, and 6.51±4.05 at 5-year follow-up. Radiologically intervertebral height was reduced from average 6.31±0.93 mm in 1-year follow-up to average 6.22±0.85 mm in 5-year follow-up. Subsidence of cage was average 1.28±0.41 mm at 1-year follow-up and average 1.31±0.43 mm at 5-year follow-up, with no statistically significant difference (p>0.05). Average subsidence of cage in these cases was 3.25 mm. In postoperative complication, screw breakage occurred in 1 case, screw pull out occurred in 1 case, and there was no postoperative infection. CONCLUSION: Using locally harvested autobone as filling material for fusion resulted in outstanding bone union and improvement of clinical results. In long term follow-up, there was no significant difference in union rate and complication incidence. Therefore use of locally harvested autobone as a filling material for fusion is considered an effective method.

Comparison of the Efficacy and Safety Profiles of a Pelubi Sustained Release Tab Versus a Pelubi Tab in Patients with Chronic Back Pain: A Randomized, Double-Blind, Multi-Institution Phase III Study

STUDY DESIGN: A randomized, double-blind, multi-institution, phase III study. OBJECTIVES: To evaluate the efficacy and safety of the Pelubi Sustained Release (SR) Tab in patients with chronic back pain, in comparison with the Pelubi Tab, whose efficacy has already been approved, a phase 3 clinical trial was conducted. SUMMARY OF LITERATURE REVIEW: The Pelubi Tab Has shown clinical efficacy in patients with back pain. MATERIALS AND METHODS: From April 11, 2014 to July 24, 2014, 166 chronic back pain patients were recruited as subjects through a multi-institution, double-blind, random sample. We compared the experimental and control groups' clinical efficacy, which was estimated by the 100-mm Pain Visual Analog Scale (VAS) after 28 days of medication. We also compared the treatment efficacy of both drugs by using a variation of the Oswestry Disability Index (ODI) and Physician Global Assessment (PGA), with the total usage of relief medicine. The side effects and clinical pathology were also noted. RESULTS: Neither group showed a significant difference in 100-mm Pain VAS or ODI variation (p=0.1702, p=0.9041). There was no statistically significant difference between the experimental group and the control group in PGA or total usage of relief medicine. The ODI and PGA variation were not worse in the experimental group than the control group. The two groups showed no significant differences in side effects (p=0.9708). CONCLUSIONS: This study found that the Pelubi SR Tab applied to back pain patients was not inferior to the Pelubi Tab and did not show any significant difference in terms of safety. The Pelubi SR Tab can be used with the same expectation of safety as the Pelubi Tab.

How Serious Is Erectile Dysfunction in Men's Lives? Comparative Data From Korean Adults

PURPOSE: Whereas sexual function has long been assumed to be an important component of adult men's lives, the impact of sexual dysfunction has not been estimated in parallel to other modern disease entities. We compared the seriousness of erectile dysfunction (ED) with that of other diseases by use of self-administered questionnaires. MATERIALS AND METHODS: Between January 2012 and July 2012, 434 healthy male volunteers (group 1) and 263 ED patients (group 2) were enrolled. The questionnaire consisted of the following: "If you must undergo only one disease in all your life, which disease could you select among these items or ED?" The comparative disease entities included hypertension, diabetes mellitus (oral hypoglycemic agent/insulin injection), hemodialysis, myocardial infarction, herpes zoster, chronic sinusitis, chronic otitis media, gastric cancer (early/late), lung cancer (early/late), liver cancer (early/late), and dementia. RESULTS: Group 1 recognized ED as being a more serious disease than hypertension, diabetes mellitus (oral hypoglycemic agent), herpes zoster, chronic sinusitis, and chronic otitis media. In comparison, group 2 recognized ED as being a more serious condition than diabetes mellitus (insulin injection) and dementia (p<0.001 and p<0.001, respectively). In particular, ED was deemed to be more serious than hemodialysis, gastric cancer (early), lung cancer (early), and liver cancer (early) by men in group 2 in their 30s to 40s, and these results were statistically significant compared with the same age subgroups in group 1 (p<0.001, p<0.007, p<0.02, and p<0.007, respectively). CONCLUSIONS: In contrast with their healthy counterparts, Korean men with ED recognized ED as being as serious as hemodialysis, dementia, and early stage cancer, which reflects the severe bother of ED in Korean patients.

Predictive Factors of the Outcome of Extracorporeal Shockwave Lithotripsy for Ureteral Stones

PURPOSE: Extracorporeal Shock Wave Lithotripsy (ESWL) has shown successful outcomes for ureteral stones. We investigated predictive factors for failure of ESWL for treating ureteral stones. MATERIALS AND METHODS: A total of 153 patients who underwent ESWL between July 2006 and July 2009 for ureteral stones diagnosed by non-enhanced spiral computed tomography were divided into two groups: (group A, stone size 10 mm). The failure was defined as remnant stones >4 mm. We assessed age, sex, body mass index, stone size, laterality, location, skin-to-stone distance (SSD), Hounsfield unit, and the presence of secondary signs (hydronephrosis, renal enlargement, perinephric fat stranding, and tissue rim sign). We analyzed predictive factors by using logistic regression in each group. RESULTS: The success rates were 90.2% and 68.6% in group A and B, respectively. In the univariate analysis of each group, stone size, SSD, and all secondary signs showed statistically significant differences in terms of the outcome of ESWL (p10 mm), the presence of perinephric fat stranding is also an independent predictive factor.

Cystic Lymphangioma of the Scrotum and Perineum / 대한남성과학회지

Cystic lymphangiomas are a benign tumor caused by lymphatic malformation. They are normally seen in the head and neck region and very rarely occur in the scrotum. We report a rare case of a 20-year-old man who presented with a gradually enlarging, painful scrotal mass which was identified ultrasonographically and histologically as a scrotal cystic lymphangioma and treated by surgical excision.

The Effects of Antiepileptic Drugs on Hematologic Parameters and Liver Enzymes According to Antiepileptics Plasma Concentrations in Epileptic Children

PURPOSE: Successful management of epileptic patients requires complete control of seizures without adverse effect. The purpose of this study is to evaluate the hematologic effect and hepatic enzyme change of antiepileptic drugs in epileptic children and compare the changes of these values according to serum drug level. METHODS: The study included 89 epileptic children with antiepileptic drugs such as phenobarbital, valproate, and carbamazepine from May 1990 to July 1999. We classified these patients into 3 groups according to the drug they had taken; group 1 : patients treated by phenobarbital, group 2 : valproate, group 3 : carbamazepine. Baseline screening tests before the start of therapy for all patients included complete blood count(CBC) and differential, platelet count, serum alanine aminotransferase(ALT), aspartate aminotransferase(AST). The tests wee repeated at follow-up visits in 2nd week, 4th week, 6th week, 12th month on the new drug. We compared their mean hematologic and liver enzyme values, which were examined before and after taken the medications, such as white blood cell counts(WBC), red blood cell(RBC), platelets, hemoglobin(Hgb), hamatocrit(Hct), mean corpuscular volume(MCA), mean corpuscular hemoglobin(MCH), mean corpuscular hemoglobin concentration(MCHC), AST, and ALT. Statistically significant change of each value was observed according to drug blood levels. RESULTS: No significant differences were found between before and after medication on AST, ALT, Hgb, MCHC in all the groups. The WBC count diminished after medication of carbamazepine, significantly. But the correlation between WBC count and serum carbamazepine level was no statistically significant. The mean platelet count diminished significantly after medication of phenobarbital and valproate, and the correlation of maximum serum valproate level with the degree of platelets count was statistically significant. Statistically significant changes were found on MCV and MCH values before and after the medication in 3rd group. But it did not depend on carbamazepine blood level. CONCLUSION: Statistically significant correlations was found between the platelet count and the plasma valproate level. Significant increase of MCV and MCH, and decrease WBC count was observed after the medication of carbamazepine.

A Case of Matemal Hemorrhage

Fetomaternal hemorrhage is very common and the commonest cause of anernia in the newborn. But, few blood cells enter the maternal circulation in most pregnancies. Occasionally large intrauterine bleeding results in severe fetal and neonatal anemia, shock, and rarely death. To identify the fetal blood in the maternal circu1ation, acid elution technique of Kleihauer-Betke test is usually used. And imrnedate neonatal blood transfusion should be done for good prognosis. We report a case of massive feto-maternal hemorrhage (>100 ml) in a preterm neonate with severe anemia at birth, which was diagnosed by Kleihauer-Betke test and was treated with blood transfusion.

Distributional patterns of phospholipase C isozymes in heart and brain of spontaneously hypertensive and normotensive rats

The phospholipase C (PLC)-mediated intracellular signal transduction pathway is considered to be involved in the regulation of blood pressure. However, little information is available concerning the distributional and functional significance of PLC in the genetic hypertensive rats. As the first step of knowing the role of PLC on hypertension, we investigated the distribution of 6 PLC isozymes (PLC-beta1, -beta3, -beta4, -gamma1, -gamma2 and -delta1) in the heart and brain, which are concerned with hypertension, in the normotensive Wistar-Kyoto rat (WKY) and spontaneously hypertensive rat (SHR) using the western blotting and immunocytochemistry. The immunoreactivities of PLC isozymes in brain were detected, but there were no distributional and quantitative differences between the WKY and SHR. In the heart, but the immunoreactivities to PLC-beta1 and -gamma2 in the SHR were higher than those in WKY. In immunocytochemistry to confirm these western blotting data, PLC-beta1 and -gamma2 were localized in cardiac myocytes and the intensities of immunoreactivity in SHR were stronger than that in WKY. These results suggest that PLC-beta1 and -gamma2 would have possibility to concern with the establishment of spontaneous hypertension.