Ji-Hoon Kang

Arsenic trioxide-induced apoptosis is independent of stress-responsive signaling pathways but sensitive to inhibition of inducible nitric oxide synthase in HepG2 cells.

Arsenic trioxide (As2O3) has been found to be remarkably effective in the treatment of patients with acute promyelocytic leukemia (APL). Although evidences for the proapoptotic activity of As2O3 have been suggested in leukemic and other solid cancer cells, the nature of intracellular mechanisms is far from clear. In the present study, we investigated As2O3 affect on the stress-responsive signaling pathways and pretreatment with antioxidants using HepG2 cells. When treated with micromolar concentrations of As2O3, HepG2 cells became highly apoptotic paralleled with activation of caspase-3 and members of mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) but not p38 MAP kinase. However, inhibition of each kinase activity failed to inhibit apoptosis by As2O3. Addition of n-acetyl cysteine (NAC) or diphenyleneiodonium (DPI) effectively protected cells from apoptosis and significantly lowered As2O3-induced activation of caspase-3. However, neither NAC nor DPI was able to effect ERK or JNK activation induced by As2O3. Guanidinoethyldisulfide dihydrochloride (GED) and 2-ethyl- 2-thiopseudourea (ETU), known inhibitors of the inducible nitric oxide synthase (iNOS), also suppressed the apoptotic activity of As2O3. These results suggest that As2O3 induces caspase-mediated apoptosis involving a mechanism generating oxidative stress. However, activation of some stress- responsive signaling pathways by As2O3 may not be the major determinant in the course of apoptotic processes.

Family history and risk for ischemic stroke: sibling history is more strongly correlated with the disease than parental history.

Current data concerning the association between family history and the risk for developing stroke have been controversial. There has been very little data on the influence of family history on intracranial atherosclerosis (ICAS), stroke severity, and recovery, especially among Asian populations. We evaluated the association between family history and the risk for stroke and investigated the relationships between family history and ICAS, stroke severity, and short-term stroke outcome in Korean stroke patients. In this case-control study, we recruited 400 patients with acute ischemic stroke, along with the same number of age- and gender-matched control subjects. Assessments of first-degree family history of stroke, myocardial infarction, hypertension and diabetes mellitus were obtained by structured questionnaires, followed by reviews of the clinical and neuro-radiological findings of the stroke patients. A family history of stroke was associated with an increased risk of ischemic stroke (OR, 2.65; 95% CI, 1.75 to 4.01), and the correlation remained significant after multivariate analysis. The odds ratios of paternal, maternal, and sibling history were 2.07, 2.16, and 4.21, respectively. The risk of stroke did not differ significantly with the presence of ICAS, stroke severity, and stroke outcome. Family history of stroke was an independent risk factor for ischemic stroke. A positive sibling history was more strongly correlated with the incidence of stroke than a positive parental history, and this finding may indicate the possible role of environmental factors in a shared household in addition to the genetic factors involved in family medical history.

Diversity of Stroke Presentation in CADASIL: Study from Patients Harboring the Predominant NOTCH3 Mutation R544C

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of the cerebral small blood vessels caused by mutations in the NOTCH3 gene. Several characteristic population-specific clinical phenotypes and neuroimaging features have been reported in CADASIL. This study investigated the clinical stroke presentation and cranial magnetic resonance imaging (MRI) findings in a group of patients with CADASIL. We reviewed the clinical stroke presentation and brain MRI findings in 73 consecutive Korean patients aged >18 years diagnosed with CADASIL between May 2004 and April 2009. Brain MRI images were also scored for lacunar infarction and cerebral microbleeds. Intracranial atherosclerosis (ICAS) was assessed by magnetic resonance angiography. Disability was measured with the modified Rankin scale (mRS) and classified as good (mRS score 0-2) or poor (mRS score 3-5). In this study, 65 of the 73 patients (90.3%) had the same R544C genotype. A total of 40 episodes of cerebral infarction were confirmed in 31 patients, with a mean age at onset of 58.8 ± 11.4 years (range, 38-76 years). Twelve patients (16.9%) had ICAS, and 5 of these patients had symptomatic stenoses. Intracerebral hemorrhage occurred in 9 patients (12.3%). Both intracerebral hemorrhage and ICAS were associated with poor clinical outcome. Our data demonstrate the diversity of clinical stroke presentation according to ethnicity and vascular risk factors.

6-Hydroxydopamine-Induced PC12 Cell Death is Mediated by MEF2D Down-regulation

Recently, it was reported that in a 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model, neuronal cell death is associated with the cdk5-mediated hyperphosphorylation of myocyte enhancer factor 2 (MEF2), a transcription factor that is critically required for neuronal survival. In the present study, we investigated the possible involvement of cdk5-mediated MEF2D down-regulation on 6-hydroxydopamine (6-OHDA)-induced PC12 cell death. 6-OHDA was found to significantly increase nitric oxide (NO) production and to induce apoptosis in a time-dependent manner in PC12 cells. Furthermore, 6-OHDA was found to markedly reduce MEF2D levels under conditions that could induce PC12 cell apoptosis. In addition, PC12 cell death and MEF2D degradation by 6-OHDA were prevented by the cdk5 inhibitor roscovitine, but roscovitine could not restore the 6-OHDA-induced inactivation of Akt. These results suggest that the cell death and MEF2D degradation caused by 6-OHDA are dependent on cdk5 activity. On the other hand, roscovitine enhanced the 6-OHDA-induced activations of ERK1/2 and JNK, but reduced the 6-OHDA-induced activation of p38. These results suggest that PC12 cell death by 6-OHDA appears to be regulated by the down-regulation of MEF2D via some interaction between cdk5 and MAP kinase.

Posterior reversible encephalopathy syndrome in a patient with acute intermittent porphyria

Sirs: Acute intermittent porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis that can affect the autonomic, peripheral and central nervous system [6]. Posterior reversible encephalopathy syndrome (PRES) is a clinical entity characterized by headache, seizure, conscious disturbance and visual disorder associated with neuroradiological findings, predominantly white matter abnormalities of the parieto-occipital lobes [5]. It has been recognized in a wide variety of conditions, including hypertensive encephalopathy, organ transplantation, uremia, eclampsia and connective tissue disease [1, 3]. However, few reports have described PRES in AIP [2, 4, 7, 8]. A 24-year-old woman presented with abdominal pain, seizure and quadriparesis. The diagnosis of porphyria was confirmed by increased urinary porphobilinogen (78.5 mg/ 24 h; normal 0–2 mg). The urinary and fecal porphyrin profiles were suggestive of AIP. Nerve conduction study demonstrated severe sensorimotor axonal neuropathy. The patient was treated with a high-carbohydrate diet and hematin, which was given intravenously at a dose of 3 mg/ kg of body weight. On the fifth day the patient complained of bilateral visual disturbance. The patient’s visual acuity was decreased to light perception only. The light reflex was preserved. The patient had mildly increased blood pressure (systolic 140–160 mmHg; diastolic 90– 100 mmHg) and tachycardia. Laboratory findings showed a mild increase in liver enzymes and creatinine. Serum electrolytes and osmolarity were normal. Brain MRI demonstrated multifocal high signal intensities in the bilateral occipitoparietal lobe, pons, midbrain, thalamus, basal ganglia, left corona radiata and right frontal lobe on T2-weighted and FLAIR images (Fig. 1a, c). These lesions showed low signal intensity on T1and diffusion-weighed images (DWI). The apparent diffusion coefficient value was increased with 15.1 9 10 mm/s. There was no contrast enhancement. The results of cerebrospinal fluid examination were normal. Tests for connective tissue disorders, paraneoplastic antibodies, viral infections, thyroid function, antithyroid antibodies and antiphospholipid antibodies were all negative. An EEG revealed a generalized slowing in both hemispheres and no epileptiform discharge. The diagnosis of PRES was made on the basis of clinical features and MRI findings. The patient was treated with hematin and strict blood pressure control therapy. Three days after developing visual disturbance, the patient’s visual acuity began to improve and fully recovered. A new MRI performed 2 weeks after the initiation of treatment showed complete disappearance of the lesions (Fig. 1d, f). Cerebral manifestations are unusual in porphyria. Transient and permanent MRI abnormalities have rarely been described in cases of CNS involvement. These lesions are nonspecific with cortical, subcortical and multifocal findings, and can show mild enhancement [7–9]. The pattern of the lesion in our patient was similar to those described as PRES. Typical lesions are usually hypointense or isointense on DWI, with an increase of the apparent diffusion coefficient map, indicating vasogenic edema. The lesions of vasogenic edema in PRES would switch to cytotoxic edema if the precipitating factors were not removed promptly [8]. In our patient, the lesions regressed on the subsequent MRI, and visual acuity fully recovered. S.-Y. Kang (&) J.-H. Kang J. C. Choi J. S. Lee Department of Neurology, College of Medicine, Jeju National University, 1 Ara 1-dong, Jeju-si, Jeju 690-756, South Korea e-mail: neurokang@jejunu.ac.kr

Ocular motor characteristics of different subtypes of spinocerebellar ataxia: Distinguishing features

Because of frequent involvement of the cerebellum and brainstem, ocular motor abnormalities are key features of spinocerebellar ataxias and may aid in differential diagnosis. Our objective for this study was to distinguish the subtypes by ophthalmologic features after head‐shaking and positional maneuvers, which are not yet recognized as differential diagnostic tools in most common forms of spinocerebellar ataxias. Of the 302 patients with a diagnosis of cerebellar ataxia in 3 Korean University Hospitals from June 2011 to June 2012, 48 patients with spinocerebellar ataxia types 1, 2, 3, 6, 7, or 8 or with undetermined spinocerebellar ataxias were enrolled. All patients underwent a video‐oculographic recording of fixation abnormalities, gaze‐evoked nystagmus, positional and head‐shaking nystagmus, and dysmetric saccades. Logistic regression analysis controlling for disease duration revealed that spontaneous and positional downbeat nystagmus and perverted head‐shaking nystagmus were strong predictors for spinocerebellar ataxia 6, whereas saccadic intrusions and oscillations were identified as positive indicators of spinocerebellar ataxia 3. In contrast, the presence of gaze‐evoked nystagmus and dysmetric saccades was a negative predictor of spinocerebellar ataxia 2. Positional maneuvers and horizontal head shaking occasionally induced or augmented saccadic intrusions/oscillations in patients with spinocerebellar ataxia types 1, 2, and 3 and undetermined spinocerebellar ataxia. The results indicated that perverted head‐shaking nystagmus may be the most sensitive parameter for SCA6, whereas saccadic intrusions/oscillations are the most sensitive for spinocerebellar ataxia 3. In contrast, a paucity of gaze‐evoked nystagmus and dysmetric saccades is more indicative of spinocerebellar ataxia 2. Head‐shaking and positional maneuvers aid in defining ocular motor characteristics in spinocerebellar ataxias.

Nerve conduction studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral microangiopathy linked to mutations in the Notch3 gene. The cerebral impairments of CADASIL are well-known, but peripheral nervous impairments such as polyneuropathy are less clear. Recently, peripheral neuropathy was proposed as one of the CADASIL phenotypes. We investigated peripheral nerve involvement in CADASIL patients. Forty-three CADASIL patients with confirmed Notch3 gene mutations underwent a nerve conduction studies using a conventional surface technique in 86 upper and lower extremities. Nerve conduction abnormalities were apparent in seven of the 43 patients. Of the seven patients, four displayed nerve entrapment syndromes (carpal tunnel syndrome, nxa0=xa03; ulnar neuropathy, nxa0=xa01), and three displayed sensorimotor polyneuropathy. Of the latter three, two patients had diabetes mellitus. We suggest that peripheral neuropathy may not be part of the CASASIL phenotype. However, genotype–phenotype heterogeneity can not be excluded.

Effects of lacunar infarctions on cognitive impairment in patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Background and Purpose Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. Although previous studies have shown an association between lacunar infarction and cognitive impairment, the relationship between MRI parameters and cognition remains unclear. In this study we investigated the influence of MRI parameters on cognitive impairment in CADASIL. Methods We applied a prospective protocol to 40 patients. MRI analysis included the normalized volume of white-matter hyperintensities (nWMHs), number of lacunes, and number of cerebral microbleeds. Cognition was assessed with the aid of psychometric tests [Mini-Mental State Examination (MMSE), Alzheimers Disease Assessment Scale-cognition (ADAS-cog), Trail-Making Test, and Stroop interference (Stroop IF)]. Results A multivariate regression analysis revealed that the total number of lacunes influenced the performance in the MMSE, ADAS-cog, and Stroop IF, while nWMHs had a strong univariate association with ADAS-cog and Stroop IF scores. However, this association disappeared in the multivariate analysis. Conclusions These findings demonstrate that the number of lacunes is the main predictive factor of cognitive impairment in CADASIL.

Screening for NOTCH3 gene mutations among 151 consecutive Korean patients with acute ischemic stroke.

BACKGROUNDnCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a single-gene disorder of cerebral small blood vessels caused by mutations in the NOTCH3 gene. The initial detection of CADASIL may be more difficult among Asian populations because common clinical phenotypes and neuroimaging findings are not frequently found in these populations. The purpose of this study was to screen the NOTCH3 gene for mutations among consecutive patients with acute ischemic stroke from our region in Korea.nnnMETHODSnBetween April 2008 and March 2009, 151 consecutive patients with acute ischemic stroke were screened for NOTCH3 mutations. All patients underwent a detailed clinical examination and structured interview for clinical symptoms and family history. We reviewed brain magnetic resonance imaging data from stroke patients to assess the severity of white-matter hyperintensity lesions, the number of cerebral microbleeds, and the number of lacunar infarctions. Polymerase chain reaction was used to screen exons 3, 4, 6, 11, and 18 of the NOTCH3 gene.nnnRESULTSnAmong 151 consecutive patients with acute ischemic stroke, 6 patients (4.0%; 95% confidence interval [CI] 0.9-7.1) possessed a NOTCH3 gene mutation. All patients exhibited the same R544C mutation in exon 11. Four of these 6 patients presented with large artery atherosclerosis. The prevalence of CADASIL in patients with neuroimaging features consistent with advanced small-vessel disease was 36.0% (95% CI 8.0-64.8).nnnCONCLUSIONSnIn this region, NOTCH3 gene mutations are frequently found in acute stroke patients who present with neuroimaging features consistent with advanced small-vessel disease.

Isolated posterior femoral cutaneous neuropathy following intragluteal injection

Isolated posterior femoral cutaneous nerve lesions are rarely encountered. Electrophysiological documentation has only been made in a few cases. In this study we evaluated a 22‐year‐old woman with sensory loss and pain in the lower buttock and posterior thigh after left gluteal intramuscular injection. We assessed the posterior femoral cutaneous nerve using an accepted conduction technique. The results showed a normal response on the asymptomatic side, but no response on the symptomatic side. Muscle Nerve, 2009