Yoshihiro Sugiura

Chemical preconditioning-induced reactive astrocytosis contributes to the reduction of post-ischemic edema through aquaporin-4 downregulation.

Aquaporins are a family of membrane proteins that promote the transmembrane diffusion of water. Aquaporin-4 (AQP4) is a predominant water channel protein in the brain and is concentrated in the end-feet of astrocytes. A critical question is what role astrocytic AQP4 plays in pathological conditions. Another matter to be elucidated is the relationship between morphological changes in astrocytes and AQP4 expression in such cases. We investigated the correlation between AQP4 expression and post-ischemic brain edema formation with astrocytic molecular markers after 3-nitropropionic acid (3NP) preconditioning. 3NP is a mitochondrial toxin, which can induce tolerance to ischemia at subtoxic levels. Rats were treated with 3NP at the tolerance-inducible and the non-tolerance-inducible stage (TS or NTS) before focal ischemia. The control group was injected with physiological saline. After ischemia, the hemispheric enlargement (HE) was volumetrically measured. Immunohistochemical and immunofluorescence analyses of AQP4, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS) were also conducted after the 3NP treatment and a vehicle was applied. HE was found to be significantly smaller in the TS group than in the vehicle group or the NTS group. The immunofluorescence analyses demonstrated that the AQP4 immunoreactivity in the cortex and striatum was significantly reduced in the TS group but not in the NTS group. In contrast, both GFAP expression and GS expression in the TS group were enhanced, with reactive astrocytosis. AQP4 downregulation in reactive astrocytosis may be one of the factors contributing to the role of 3NP preconditioning in attenuating post-ischemic edema.

Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin

The mechanisms of paradoxical aggravation of epileptic seizures induced by selected antiepileptic drugs (AEDs) remain unclear. The present study addressed this issue by determining the seizure-threshold doses of carbamazepine (CBZ) and phenytoin (PHT), as well the dose-dependent effects of CBZ, PHT, and carbonic anhydrase-inhibiting AEDs, acetazolamide (AZM), topiramate (TPM), and zonisamide (ZNS), on neurotransmitter release in rat hippocampus. The dose-dependent effects of AEDs on hippocampal extracellular levels of glutamate (Glu), GABA, norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were determined by microdialysis with high-speed and high-sensitive extreme liquid chromatography. Proconvulsive effects of AEDs were determined by telemetric-electrocorticography. Therapeutically relevant doses of AZM, CBZ, TPM, and ZNS increased hippocampal extracellular levels of GABA, NE, DA, and 5-HT, while PHT had no effect. Supratherapeutic doses of AZM, CBZ, PHT, TPM, and ZNS decreased extracellular levels of GABA, NE, DA, and 5-HT, without affecting Glu levels. Toxic doses of CBZ and PHT produced seizures (paradoxical intoxication), markedly increasing all transmitter levels, but TPM and ZNS even at toxic doses did not produce seizure. Co-administration experiments showed that therapeutically relevant doses of CBZ or PHT reduced the seizure-threshold doses of PHT or CBZ, respectively. In contrast, therapeutically relevant doses of AZM, TPM, and ZNS elevated the seizure-threshold doses of CBZ and PHT. These results suggested that blockade of high percentage of the population of voltage-dependent sodium channels by CBZ and PHT might be important in inducing paradoxical intoxication/reaction, and that inhibition of carbonic anhydrase inhibits this effect. TPM and ZNS are candidate first-choice agents in treatment of epilepsy when first-line AEDs are ineffective.

Impact of Platelet Transfusion on Survival of Patients with Intracerebral Hemorrhage after Administration of Anti-Platelet Agents at a Tertiary Emergency Center

This study examined the impact of platelet transfusion (PLT) on the survival of intracerebral hemorrhage (ICH) patients who had been administered anti-platelet agents (APA). This retrospective cohort analysis investigated 432 patients (259 men, 60%) who were newly diagnosed with ICH between January 2006 and June 2011 at the tertiary emergency center of Kitasato University Hospital. Median age on arrival was 67.0 years (range, 40–95 years). ICH was subcortical in 72 patients (16.7%), supratentorial in 233 (53.9%), and infratentorial in 133 (30.8%). PLT was performed in 16 patients (3.7%). Within 90 days after admission to the center, 178 patients (41.2%) had died due to ICH. Before the onset of ICH, 66 patients had been prescribed APA because of atherosclerotic diseases. Multivariate regression analysis indicated APA administration was an independent risk factor for death within 7 days (odds ratio, 5.12; P = 0.006) and within 90 days (hazard ratio, 1.87; P = 0.006) after arrival. Regarding the effect of a PLT in ICH patients with APA, no patient with PLT died. PLT had a survival benefit on patients with ICH, according to our analysis. Further prospective analysis is necessary to confirm the effects of PLT on survival in ICH with APA.

Lack of potassium current in W309R mutant KCNQ3 channel causing benign familial neonatal convulsions (BFNC)

BFNC is an autosomal dominant epileptic disorder caused by mutations of KCNQ2 or KCNQ3 potassium channel gene. W309R missense mutation in KCNQ3 gene was previously reported in a family with BFNC. In this study, potassium currents were recorded from HEK293 cells expressing both W309R mutant KCNQ3 and wild type KCNQ2 channels. We found a lack of potassium current in W309R mutant KCNQ3 and KCNQ2 channels, which can explain the hyper-excitability of CNS in patients with BFNC.

Different degrees of loss of function between GEFS+ and SMEI Nav1.1 missense mutants at the same residue induced by rescuable folding defects

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) differ in their clinical severity and prognosis even though mutations of the Nav1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Nav1.1 channels characterized by distinct amino acid substitutions at the same residue position: GEFS+ (A1685V) and SMEI (A1685D). Both the mutants showed complete loss of function when expressed alone. However, the function of A1685V can be partly rescued by the β1 subunit, consistently with a folding defect, whereas that of A1685D was not rescued. These electrophysiologic differences are consistent with the divergence in clinical severity between GEFS+ and SMEI.

Aconiti tuber (Bushi) improves microcirculatory disturbances induced by endotoxin in rats.

The present study investigated the effects of processed Aconiti tuber (TJ‐3022, Tsumura‐shuchi‐bushi), a traditional herbal medicine (Kampo), on microcirculatory disturbances induced by endotoxin in the rat mesentery. The changes in arteriolar diameter, the velocity of red blood cells in arterioles and the venular microcirculation after endotoxin injection (6 mg/kg, iv) were observed using videomicroscopy. The mean arterial pressure and heart rate were monitored continuously during the experiments. TJ‐3022 prevented significantly the decrease of mean arterial pressure, controlled the reduced velocity and apparently also inhibited leukocyte extravasation across venules. However, there were no significant changes in the arteriolar diameter and the heart rate between the groups treated with and without TJ‐3022. The results indicate that processed Aconiti tuber (TJ‐3022) has protective effects in improving microcirculatory disturbances induced by endotoxin in rat mesentery. Copyright

Cryptogenic NORSE Its distinctive clinical features and response to immunotherapy

Objective: To report the distinctive clinical features of cryptogenic new-onset refractory status epilepticus (C-NORSE) and the C-NORSE score based on initial clinical assessments. Methods: A retrospective study was conducted for 136 patients with clinically suspected autoimmune encephalitis who underwent testing for autoantibodies to neuronal surface antigens between January 1, 2007, and August 31, 2016. Eleven patients with C-NORSE were identified. Their clinical features were compared with those of 32 patients with anti-NMDA receptor encephalitis (NMDARE). Results: The clinical outcome of 11 patients (median age, 27 years; 7 [64%] women) with C-NORSE was evaluated after a median follow-up of 11 months (range, 6–111 months). Status epilepticus was frequently preceded by fever (10/11 [91%]). Brain MRIs showed symmetric T2/fluid-attenuated inversion recovery hyperintensities (8/11 [73%]) and brain atrophy (9/11 [82%]). Only 2 of the 10 treated patients responded to the first-line immunotherapy, and 4 of the 5 patients treated with IV cyclophosphamide responded to the therapy. The long-term outcome was poor in 8 patients (73%). Compared with 32 patients with NMDARE (median age, 27 years; 24 [75%] women), those with C-NORSE had more frequent prodromal fever, status epilepticus, ventilatory support, and symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, CSF oligoclonal bands, or tumor association, and had a worse outcome. The C-NORSE score was higher in patients with C-NORSE than those with NMDARE. Conclusions: Patients with C-NORSE have a spectrum of clinical-immunological features different from those with NMDARE. The C-NORSE score may be useful for discrimination between them. Some patients could respond to immunotherapy.

Sinitang (Shigyaku-to), a traditional Chinese medicine improves microcirculatory disturbances induced by endotoxin in rats

The present study investigated the effects of Sinitang (Japanese name: Shigyaku-to--a traditional Chinese medicine), on microcirculatory disturbances induced by endotoxin in rat mesentery. The changes of arteriolar diameter, the velocity of red blood cells in arterioles and venular microcirculation after endotoxin injection (6 mg x kg(-1), i.v.) were observed by videomicroscopy. Mean arterial pressure and heart rate were monitored continuously during the experiments. Sinitang significantly prevented the decrease of mean arterial pressure, controlled the reduced velocity and also, apparently inhibited the leukocyte extravasation across venules. However, there were no significant changes in the arteriolar diameter and the heart rate in all groups treated with or without Sinitang. The results indicate that Sinitang has protective effects to improve the microcirculatory disturbances induced by endotoxin in rat mesentery.

Some evidence supporting the safety of quadripulse stimulation (QPS)

To the Editor: Quadripulse transcranial magnetic stimulation (QPS) is a newly designed patterned repetitive transcranial magnetic stimulation (rTMS), which induces bidirectional, long-lasting after effects on the human motor cortex. Although QPS is a powerful tool for neurophysiologic research, there are concerns about its possible adverse effects, including induction of seizure and EEG abnormalities. In the original reports, the occurrence rates of after discharges were not significantly different between QPS and sham stimulation, and no spread of excitation was observed. Although these studies tentatively showed the safety of QPS, further investigation is needed. In this communication, we provide further evidence of the safety of QPS comparing the vital signs, neurologic status, serum prolactin (PRL) levels, and EEGs before and after QPS. We used eight healthy subjects aged 31 to 54 years (mean, 40.5 years) without any neurologic disorders. Before QPS, we determined the active motor threshold (AMT) of the right first dorsal interosseus (FDI) muscle by recording motor evoked potentials (MEPs; sampling rate of 10 kHz, high pass 100 Hz, low pass 3 kHz; Neuropack m, Nihon-Kohden, Japan). TMS was given over the hot spot of FDI by a figure-of-eight coil connected to MagStim 200 (The MagStim Co Ltd, UK). We used QPS protocols of successive four monophasic pulses delivered with interstimulus intervals of 5 milliseconds (QPS-5) or 50 milliseconds (QPS-50). One experimental session consisted of 360 trains of four pulses (1440 pulses in total) at the intensity of 90% AMT. Intertrain intervals were fixed at 5 seconds. QPS-5 and QPS-50 were used because previous studies reported that these protocols induced powerful potentiation and depression on the motor cortex, respectively. We measured vital signs in supine position for three times: before (Tpre), immediately after (T0), and 180 seconds after (T180) QPS. We also checked emotional state, headache, visual abnormality, dizziness, subjective hearing loss, tinnitus, aural fullness, weakness, paresthesia, and gait instability. We collected venous blood samples three times: before (Tpre), immediately after (T0), and 10 minutes after

Three cases of interstitial pneumonia with anti-signal recognition particle antibody

Anti-signal recognition particle antibody (SRP-Ab) is a myositisspecific antibody (MSA) that is found in serum of patients with myositis characterized by a necrotizing myopathy. Because patients with SRP-Abs have few extra-muscular manifestations,1 the clinical characteristics of interstitial pneumonia (IP) with SRP-Ab have not been clarified. Here, we present three cases of IP with SRP-Ab. Case 1: A 51-year-old man with a one-year history of cough and sputum was referred to our hospital for gradual progression of his symptoms. On admission, he did not have muscle pain or proximal muscle weakness. CK was markedly elevated (1160 U/L), and aldolase (16.2 U/L), KL-6 (1529 U/mL) and SP-D (312.4 ng/mL) were also elevated. Auto-immune antibodies analyzed were negative. Pulmonary function tests revealed restrictive respiratory dysfunction. His