Addition of Ipragliflozin to Metformin Treatment in Korean Patients with Type 2 Diabetes Mellitus: Subgroup Analysis of a Phase 3 Trial

BACKGROUND: This is a subgroup analysis of Korean patients from a phase 3 clinical trial investigating the efficacy and safety of ipragliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin. METHODS: This multicenter, placebo-controlled, double-blind, parallel-group study was carried out between November 2011 and January 2013. Patients entered a 2-week placebo pretreatment period, followed by a 24-week treatment period with either ipragliflozin (50 mg/day) or placebo, while continuing metformin. Efficacy outcomes (glycosylated hemoglobin [HbA1c], fasting plasma glucose [FPG], and body weight) and safety outcomes (treatment-emergent adverse events [TEAEs]) were measured and compared between the two treatment groups for patients enrolled in all 18 study sites in Korea. RESULTS: Eighty-two Korean patients received ipragliflozin (n=43) or placebo (n=39) during the study period. Mean changes in HbA1c levels from baseline to the end of treatment were –0.97% in the ipragliflozin group and –0.31% in the placebo group, with an adjusted between-group difference of –0.60% (P<0.001). Compared to placebo, FPG and body weight also decreased significantly (both P<0.001) from baseline after treatment in the ipragliflozin group, with between-group differences of –21.4 mg/dL and –1.53 kg, respectively. Decreased weight was the most common TEAE in the ipragliflozin group (7.0%); there were no reports of genital and urinary tract infection. CONCLUSION: Ipragliflozin treatment in addition to metformin led to significant improvement in glycemic outcomes and reduction in body weight in Korean patients with type 2 diabetes mellitus, compared with metformin treatment alone; the safety profile was comparable in both groups.

Spontaneous Subclavian Artery Dissection Presenting as Posterior Circulation Infarction

BACKGROUND: Spontaneous subclavian artery dissection (SAD) is rare. Moreover, there are very few case reports which document spontaneous SAD accompanied by symptomatic neurological deficits related with ischemic stroke. CASE REPORT: A 71-year-old man without any reported history of trauma presented with left facial hypesthesia, left arm ataxia and gait disturbance, subsequently diagnosed as posterior circulation infarction affecting medulla and cerebellum. The computed tomography angiography revealed spontaneous left SAD with left vertebral artery occlusion, atherosclerotic plaque surrounding the origin of left subclavian artery and normal aortic vasculature. His neurological status did not deteriorate further after dual anti-platelet therapy, and intravenous hydration with volume expander were applied. CONCLUSIONS: This is an unusual case of spontaneous SAD with lateral medullary infarction as well as cerebellar infarction. Although spontaneous SAD is a distinctly rare disease entity, it should be considered in the differential diagnosis when multiple posterior circulation infarctions are observed.

Long-term Treatment with Oriental Medicinal Herb Artemisia princeps Alters Neuroplasticity in a Rat Model of Ovarian Hormone Deficiency

Artemisia princeps (AP) is a flowering perennial used as a traditional medicine and dietary supplement across East Asia. No study has yet assessed its effects on synaptic plasticity in hippocampus and much less in a model of ovarian hormone deficiency. We examined the influence of chronic oral AP ethanol extract treatment in ovariectomized rats on the induction of long-term depression in a representative synapse (CA3-CA1) of the hippocampus. Ovariectomized rats demonstrated lower trabecular mean bone mineral densities than sham, validating the establishment of pathology. Against this background of pathology, AP-treated ovariectomized rats exhibited attenuated long-term depression (LTD) in CA1 relative to water-treated controls as measured by increased field excitatory post-synaptic potentials (fEPSP) activation averages over the post-stimulation period. While pathological significance of long-term depression (LTD) in ovariectomized rats is conflicting, that AP treatment significantly affected its induction offers justification for further study of its influences on plasticity and its related disorders.

Low-Density-Lipoprotein Particle Size Predicts a Poor Outcome in Patients with Atherothrombotic Stroke

BACKGROUND AND PURPOSE: Low-density lipoprotein (LDL) particle size is considered to be one of the more important cardiovascular risk factors, and small LDL particles are known to have atherogenic potential. The aim of this study was to determine whether LDL particle size is associated with stroke severity and functional outcome in patients with atherothrombotic stroke. METHODS: Between January 2009 and May 2011, 248 patients with first-episode cerebral infarction who were admitted to our hospital within 7 days after symptom onset were prospectively enrolled. LDL particle size was measured using the nondenaturing polyacrylamide gradient gel electrophoresis assay. Stroke severity was assessed by applying the National Institutes of Health Stroke Scale (NIHSS) at admission. Functional outcome was investigated at 3 months after the index stroke using the modified Rankin Scale (mRS), and poor functional outcome was defined as an mRS score of > or =3. RESULTS: The LDL particle size in the 248 patients was 25.9+/-0.9 nm (mean+/-SD). LDL particle size was inversely correlated with the degree of cerebral artery stenosis (p=0.010). Multinomial multivariate logistic analysis revealed that after adjustment for age, sex, and variables with p or =5; reference, NIHSS score 0-2; odds ratio=0.38, p=0.028) and poor functional outcome (odds ratio=0.44, p=0.038). CONCLUSIONS: The results of this study demonstrate that small LDL particles are independently correlated with stroke outcomes. LDL particle size is thus a potential biomarker for the prognosis of atherothrombotic stroke.

Low Plasma Proportion of Omega 3-Polyunsaturated Fatty Acids Predicts Poor Outcome in Acute Non-Cardiogenic Ischemic Stroke Patients / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: Alterations in blood fatty acid (FA) composition are associated with cardiovascular diseases. We investigated whether plasma FA composition was related to stroke severity and functional outcome in acute ischemic stroke patients. METHODS: We prospectively enrolled 156 patients with first-episode cerebral infarction, within 7 days of symptom onset. The proportion of FAs was analyzed using gas chromatography, and the summation of the omega-3 polyunsaturated fatty acids (omega3-PUFA), 18:3 omega3 alpha-linolenic acid, 20:3 omega3 eicosatrienoic acid, 20:5 omega3 eicosapentaenoic acid (EPA), and 22:6 omega3 docosahexaenoic acid (DHA) was reported as Sigmaomega3-PUFAs. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score on admission. Poor functional outcome was defined by modified Rankin scale (mRS) > or =3 at three months after the index stroke. RESULTS: Lower proportions of EPA (beta=-0.751), DHA (beta=-0.610), and Sigmaomega3-PUFAs (beta=-0.462) were independently associated with higher NIHSS score, after adjusting for stroke subtype, hemoglobin, high density lipoprotein, high sensitivity C-reactive protein, fasting glucose, 16:0 palmitic acid, and Sigmasaturated fatty acids. Moreover, a lower proportion of DHA (odds ratio [OR]: 0.20, 95% confidence interval [CI]: 0.04-0.88), and Sigmaomega3-PUFAs (OR: 0.22, 95% CI: 0.05-0.84) showed an independent relationship with poor functional outcome after adjusting for age, sex, smoking status, NIHSS score, stroke subtype, and 16:0 palmitic acid. CONCLUSIONS: Our results demonstrate that omega3-PUFAs correlated with stroke severity on admission and functional outcomes at 3 months. omega3-PUFAs are potential blood biomarkers for prognosis of acute non-cardiogenic ischemic stroke patients.

Can Silent Ischemic Cerebral Lesions Affect Cognition of Parkinson's Disease Dementia?

BACKGROUND: Several studies have shown that the presence of cerebrovascular lesions may play an important role for determining the severity of the clinical symptoms of dementia. But no study to date has explored the clinical effect of cerebrovascular disease in Parkinson's disease with dementia (PDD), although cerebrovascular disease is common causes of dementia in elderly population. Therefore we conducted this study to evaluate the relationship between silent cerebrovascular lesions and cognitive decline in PDD. METHODS: Only 27 patients with PDD were chosen; 17 patients had PDD with silent cerebral ischemic lesions (PDDI) and 10 patients had PDD without silent cerebral ischemic lesions (pure PDD). These subjects received the global cognitive function testing and were all evaluated with detailed neuropsychological tests including attention, memory, language, and also the visuospatial and frontal function. RESULTS: There were no significant differences between pure PDD and PDDI group on general cognitive functions tests. Regard to mean time duration of suffering from Parkinson motor symptoms and motor function scale, pure PDD group showed more long duration than PDDI group but there was no significant difference between two groups. Furthermore, there were not any significant differences between the two groups on detailed neuropsychological tests. CONCLUSIONS: We concluded that silent cerebrovascular lesions do not contribute to neuropsychological severity of PDD, although vascular disease is a common cause of cognitive impairment in the elderly. Thus the results of the present study suggest that factors other than cerebrovascular disease contribute to severity of PDD.

Clinical Significance of Hyperhomocysteinemia Between Alzheimer's Disease and Vascular Dementia

BACKGROUND: Recent research has shown that risk factors for cerebrovascular disorders are also causes of dementia. Of these risk factors, hyperhomocysteinemia is well known to be positively correlated with all types of dementias including Alzheimer's disease (AD) and vascular dementia (VaD). But it is not know if there is a difference in the concentration of homocysteine in AD and VaD. We analyzed the homocysteine concentrations in AD and VaD and investigated the relationship between homocysteine and the progression of these two dementias. METHODS: A total of 193 patients to the dementia clinic at our hospital were enrolled. Fifty-four patients had AD and 48 patients had VaD. The remaining patients were the healthy control. Data for analysis consisted of the results of neuropsychological tests and homocysteine levels. RESULTS: Homocysteine levels were higher in AD and VaD patients than in healthy subjects, and no statistical difference was seen between AD and VaD. With lower mini-mental state examination scores, the homocysteine concentration increased significantly in VaD, but not in AD. The homocysteine concentration and the sum of box of clinical dementia rating were positively correlated in both AD and VaD. Other neuropsychological tests had no correlation with the homocysteine level. CONCLUSION: This study suggests that hyperhomocysteinemia, resulting in inflammation of vessel walls and oxidative stress, is a risk factor for both AD and VaD. However, our results did not clarify if hyperhomocysteinemia is related to the progression of dementia symptoms.

Is There the Preventive Effect of COMT-inhibitor on Parkinson's Disease Associated with Dementia?

BACKGROUND: Elevated homocysteine (hcy) levels are associated with dementia, which is a frequent non-motor symptom of Parkinson's disease (PD). High levels of hcy in PD patients treated with levodopa are thought to result from increased synthesis during the metabolism of levodopa by COMT, and that use of a COMT-inhibitor may reduce hcy levels. In this study, we sought to clarify the effects of COMT-inhibitors on dementia in PD patients. METHODS: Thirty-eight PD patients without dementia (PDwoD), 35 PD patients with dementia (PDD), and 48 controls were enrolled in this study. All subjects underwent neuropsychological testing and a neurological examination. The hcy levels were measured in all subjects, and the relationship between hcy levels and dementia was evaluated in two PD groups (those that underwent treatment with levodopa-alone versus treatment with levodopa plus a COMT-inhibitor). RESULTS: Patients in the PDD group showed higher hcy levels than patients in the PDwoD group, though there was no significant difference in the hcy level between PDwoD patients and healthy controls. Regarding the effects of a COMT-inhibitor, there was no correlation between hcy levels in the 2 PD subgroups, indicating that there were no significant effects of the COMT-inhibitor on PDD. In addition, the odds ratio for PDD with the use of a COMT-inhibitor was 0.864 (95% CI=0.342-2.180). CONCLUSIONS: These results are in agreement with previous studies in that levodopa treatment in PD patients leads to elevated hcy concentrations. COMT-inhibitors, on the other hand, had no preventive effect on cognitive impairment in PD patients.

Two Cases of Cerebral Infarctions from Vertebral Artery Dissection Induced by Severe Coughing / 대한뇌졸중학회지

Vertebral artery dissection (VAD) is a rare cause of young age stroke. This risky condition can be caused by even minor head or neck trauma. None of the previous studies has reported cough-related intracranial vertebral arterial dissection in Korea. We present two cases of cerebral infarctions from VAD induced by severe coughing. We should be alert to clinical manifestations of VAD to make proper diagnosis and to recognize coughing as a potential cause of VAD.

Intravenous t-PA Thrombolysis in an Acute Ischemic Stroke Patient With Takayasu's Arteritis

The usefulness of intravenous tissue plasminogen activator (IVT) in patients with acute ischemic stroke related to Takayasu's arteritis (TA) has not been documented; it is not recommended due to the risk of hemorrhage. We experienced a 43-year-old female with acute ischemic stroke as an initial manifestation of TA, who was treated with IVT without subsequent complication. Typical occlusion of the abdominal aorta and common carotid artery in angiography led to the delayed diagnosis of TA. Follow-up conventional angiography performed 3 years later showed a stable vascular lesion.

Takotsubo Cardiomyopathy Following Cerebral Infarction Involving the Insular Cortex

BACKGROUND: Takotsubo cardiomyopathy is characterized by clinical features similar to those of acute myocardial ischemia, but without angiographic evidence of obstructive coronary artery disease. We present a patient with takotsubo cardiomyopathy following acute infarction involving the left insular cortex. CASE REPORT: A 52-year-old man was admitted with acute infarction of the left middle cerebral artery territory and acute chest pain. Acute myocardial infarction was suspected because of elevated serum troponin levels and hypokinesia of the left ventricle on echocardiography. However, a subsequent coronary angiography revealed no stenosis within the coronary arteries or ballooning of the apical left ventricle. CONCLUSIONS: We postulated that catecholamine imbalance due to the insular lesion could be responsible for these interesting features.

Increasing Frequency and Burden of Cerebral Artery Atherosclerosis in Korean Stroke Patients

PURPOSE: Koreans have been undergoing rapid lifestyle changes that may have an effect on patterns of cerebral artery atherosclerosis. This study was aimed at determining the frequency and distribution of atherosclerosis in the cerebral arteries and associated temporal changes over the past eight-year period among Korean stroke patients. MATERIALS AND METHODS: By using stroke registry data registered between April 1999 and March 2007, we investigated the presence, severity, and location of cerebral artery atherosclerosis as determined by angiographic findings. Their annual patterns and association with vascular risk factors were investigated. RESULTS: Of 1,955 patients, 1,517 patients (77.6%) demonstrated atherosclerosis in one or more arteries. A significantly increasing trend of atherosclerosis was observed during the past eight years, which was ascribed to an increase of combined extracranial (EC) and intracranial (IC) atherosclerosis. The number of atherosclerotic arteries increased as the number of risk factors increased. In the multivariate analysis, the year and vascular risk factors were independent predictors of the presence of atherosclerosis. CONCLUSION: We found that the atherosclerotic burden has been increasing for the past eight years in Korean stroke patients, particularly the combined EC and IC subtype. Lifestyle changes and increase in vascular risk factors may be contributing factors.

Increasing Frequency and Burden of Cerebral Artery Atherosclerosis in Korean Stroke Patients

PURPOSE: Koreans have been undergoing rapid lifestyle changes that may have an effect on patterns of cerebral artery atherosclerosis. This study was aimed at determining the frequency and distribution of atherosclerosis in the cerebral arteries and associated temporal changes over the past eight-year period among Korean stroke patients. MATERIALS AND METHODS: By using stroke registry data registered between April 1999 and March 2007, we investigated the presence, severity, and location of cerebral artery atherosclerosis as determined by angiographic findings. Their annual patterns and association with vascular risk factors were investigated. RESULTS: Of 1,955 patients, 1,517 patients (77.6%) demonstrated atherosclerosis in one or more arteries. A significantly increasing trend of atherosclerosis was observed during the past eight years, which was ascribed to an increase of combined extracranial (EC) and intracranial (IC) atherosclerosis. The number of atherosclerotic arteries increased as the number of risk factors increased. In the multivariate analysis, the year and vascular risk factors were independent predictors of the presence of atherosclerosis. CONCLUSION: We found that the atherosclerotic burden has been increasing for the past eight years in Korean stroke patients, particularly the combined EC and IC subtype. Lifestyle changes and increase in vascular risk factors may be contributing factors.

Cerebral Infarction During Sexual Intercourse

Paradoxical embolism after the Valsalva maneuver can cause ischemic stroke in patients with patent foramen ovale (PFO). A 27-year-old woman presented with abnormal movement of the right arm and aphasia. Brain imaging showed acute infarction in the left frontal lobe and segmental steno-occlusion in the left middle cerebral artery. A PFO study demonstrated air embolic signals in the middle cerebral artery. This case of embolic stroke occurred during sexual intercourse, probably related to the Valsalva maneuver, in a patient with PFO.

Student's Evaluation of Problem-Based Learning Curriculum in Medical School / 한국의학교육

PURPOSE: Konkuk medical school has tried to improve its problem-based learning (PBL) curriculum. In this study, we evaluated the serial changes of student satisfaction of this PBL curriculum. METHODS: Student satisfaction for the PBL curriculum was assessed using the same questionnaire for 3 years, from 2005 to 2007. Twenty individual questions were classified into five categories: individual learning, group learning, tutoring, module, and learning environment. Scores of the individual items and categories were compared. RESULTS: For the first 3 years after the introduction of a graduate medical school, scores for the individual learning, group learning, and tutoring categories were higher those for the module and learning environment categories. Satisfaction of the learning environment, however, gradually improved. CONCLUSION: In general, satisfaction of the PBL curriculum was good for the first 3 years after the introduction of the graduate medical school. However, further investment in improving the PBL module and learning environments was necessary for the success of the PBL curriculum.

Cerebral Air Embolism Following a Gastroscopy

Cerebral air embolism, the entry of air into the cerebral artery, is an iatrogenic clinical problem in most cases, which may result in seizure, severe neurologic deficits and even death. Although cerebral air embolism may result from almost all procedures that are performed in clinical specialties, occurrence following a gastroscopy is very rare. We report a patient who developed cerebral air embolism following a gastroscopy.

Clinical outcomes of first trimester discordant twins / 대한산부인과학회지

OBJECTIVE: To compare the clinical outcomes of first trimester discordant twins with second or third trimester discordant twins and concordant twins. METHODS: Pregnancy outcomes of twin pregnancies delivered from October 1994 to February 2006 were analyzed retrospectively. Subjects were categorized into following three groups: 1) group 1, first trimester discordant twins defined as intertwin CRL difference > or =5 days at 10-14 weeks of gestation (n=32), 2) group 2, second or third trimester discordant twins defined as intertwin AC difference >20 mm at 20-28 weeks of gestation or intertwin fetal weight difference >25% beyond 29 weeks of gestation (n=42), 3) group 3, concordant twins with no discordancy throughout the whole gestation (n=723). Perinatal complications analyzed for were congenital anomaly, fetal growth restriction (FGR), fetal death in utero (FDIU). RESULTS: The three groups were similar with respect to maternal characteristics and chorionicity. Overall, the group 2 had higher perinatal complications compared to the group 3. Congenital anomaly was more common in the group 1 than the group 2 (21.9% vs. 11.9%, p<0.001). However, FGR rate was higher in the group 2 than the group 1 (32.3% vs. 71.8%, p<0.01). Congenital anomaly, FGR and FDIU were more common in the group 1 compared to the group 3 (21.9% vs. 3.5%, p<0.001, 32.3% vs. 9.1%, p<0.01, 6.3% vs. 1.0%, p<0.05, respectively). CONCLUSIONS: First trimester discordant twins have an increased risk of congenital anomaly, FGR and FDIU, and therefore, they should be regarded as a high-risk pregnancy likewise second or third trimester discordant twins.

Clinical outcome of preterm premature rupture of membranes in singleton versus twin pregnancy / 대한산부인과학회지

OBJECTIVE: To compare the latency period and perinatal outcome of singleton and twin pregnancies complicated by preterm premature rupture of the membranes (PPROM). METHODS: From January 1996 to December 2005, the medical records of women with singleton (n=345) and twin pregnancies (n=73) complicated by PPROM (24-34 weeks of gestation) were reviewed. Pregnancy and neonatal outcomes including the latency period, neonatal morbidity, and mortality were compared between the singleton and twin groups. RESULTS: No differences were noted with respect to gestational age at the time of membrane rupture and use of tocolytics, steroid and prophylactic antibiotics between the two groups. The latency period was significantly shorter in twins (median [range]; 4.0 [0-50] day vs. 1.0 [0-25] days, p<0.001), and significantly more twins were born within 48 hours and within 7 days after rupture of the membranes (within 48 hours, 33.0%vs. 65.8%, p<0.001; within 7 days, 67.5%vs. 87.7%, p<0.001). The latency period was longer when PPROM occurred before 30 weeks of gestation than after 30 weeks of gestation in both groups (median [range]; singleton, 11.5 [0-50] days vs. 3.0 [0-33] days, p<0.001; twin, 3.0 [0-25] days vs. 0 [0-6] day, p<0.001). Although gestational age at delivery was similar in singleton and twin groups, more twin infants had low birth weight, low Apgar score and neonatal morbidities. CONCLUSION: Twin pregnancy with PPROM, compared to singleton pregnancy with PPROM, had shorter latency period and worse perinatal outcome.

The effect of multiple courses of antenatal corticosteroid therapy on perinatal outcome of the preterm neonates / 대한산부인과학회지

OBJECTIVE: To investigate the effect of multiple courses of antenatal corticosteroid (ACS) therapy on perinatal outcomes, especially the respiratory distress syndrome (RDS), of the premature neonates. METHODS: We retrospectively evaluated the pregnancy and neonatal outcomes of 622 singleton pregnancies delivered at 24-34 weeks of gestation from January 1996 to December 2005. Subjects were categorized into three groups according to ACS exposure: (1) a non-user group (n=234), (2) a single-course group (n=299) and (3) a repeated-course group (n=89). Univariate and multiple logistic regression analyses were used for the incidences of RDS. RESULTS: Pregnancy outcomes including gestational age at delivery, occurrence of clinical and histological chorioamnionitis, birth weight, neonatal intensive care unit (NICU) admission rate, duration of NICU stay and neonatal mortality were similar in the three groups. The incidence of RDS was significantly lower in ACS user groups than the non-user group, with lowest incidence in multiple-course group (44.9% vs. 37.8% vs. 12.4%, p<0.001). The incidence of bronchopulmonary dysplasia and overall neonatal composite morbidity were also lowest in multiple-course group. Multivariate analysis showed that multiple courses of ACS were associated with reduced incidence of RDS (OR 0.100, 95% CI 0.042, 0.240, p<0.001) independently with gestational age at delivery, admission-to-delivery interval and premature rupture of membranes. CONCLUSION: Multiple courses of ACS administered to women with risk of preterm delivery were found to be associated with decreased incidence of RDS of the premature neonates.

Myelin Protein Zero (MPZ) Gene Analysis in Korean Patients with Charcot-Marie-Tooth: Clinical and Electrophysiological Characteristics

BACKGROUND: Mutations in the myelin protein zero (MPZ) gene, which is located on chromosome 1q21-q22, is present in Charcot-Marie-Tooth disease type 1B (CMT1B), CMT type 2, Dejerine-Sottas syndrome, and congenital hypomyelination neuropathy. It is proposed that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. In this study, we investigated to determine the clinical and electrophysiological characteristics in CMT patients with mutations in the MPZ gene. METHODS: We examined mutations of MPZ, in 62 Korean families diagnosed as having CMT disease. Mutations were confirmed by through both strands sequencing. Nerve conduction studies were carried out in CMT patients having each mutation. RESULTS: The three mutations (Asp118Asn, c.449-1G>T (3'-splice site), Lys236Glu), determined to be novel, were not detected in the 105 healthy controls. The mutation frequency of MPZ was similar as those found in several European populations. Electrophysiologically, 3'-splice site mutation (449-1G>T) showed the conduction block and moderate slowing nerve conduction velocities like that of CMT1B. However, the other mutations represented the electrophysiological features of CMT type 2. CONCLUSIONS: We report the identified three novel MPZ mutations in Korean CMT patients and the phenotype-genotype correlations based on nerve conduction studies.