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Ribonuclease (RNase) H2 is involved in the removal of ribonucleotides embedded in genomic DNA. Eukaryotic RNase H2 is a heterotrimer consisting of the catalytic A subunit (RH2A) and the accessory B and C subunits. This study aimed to compare the cellular activities of wild-type ribonuclease (RNase) H2 and its variants with a mutation causing neuroinflammatory autoimmune disease, Aicardi–Goutières syndrome (AGS). We first analyzed cellular RNase H2 activity and ribonucleotide content in the genomic DNA of RH2A-knockout (KO) mouse fibroblast NIH3T3 cells after transfection with a transient expression plasmid encoding mouse wild-type RH2A. From 4 h after transfection, the RNase H2 activity increased and the amount of ribonucleotides decreased, as compared with the corresponding non-transfected RH2A-KO cells. This demonstrated the rapidness of ribonucleotide turnover in mammalian genomic DNA and the importance of continuous expression of RNase H2 to maintain the ribonucleotide amount low. Next, we expressed mouse RH2A variants with a mutation corresponding to a human AGS-causing mutation in RH2A-KO NIH3T3 cells. Neither increase in RNase H2 activity nor decrease in ribonucleotide amount was observed for G37S; however, both conditions were observed for N213I and R293H. This corresponded with our previous results on the activity of recombinant human RNase H2 variants.

Streptomyces incarnatus NRRL8089 produces the antiviral, antifungal, antiprotozoal nucleoside antibiotic sinefungin. To enhance sinefungin production, multiple mutations were introduced to the rpoB gene encoding RNA polymerase (RNAP) β-subunit at the target residues, D447, S453, H457, and R460. Sparse regression analysis using elastic-net lasso-ridge penalties on previously reported H457X mutations identified a numeric parameter set, which suggested that H457R/Y/F may cause production enhancement. H457R/R460C mutation successfully enhanced the sinefungin production by 3-fold, while other groups of mutations, such as D447G/R460C or D447G/H457Y, made moderate or even negative effects. To identify why the rif cluster residues have diverse effects on sinefungin production, an RNAP/DNA/mRNA complex model was constructed by homology modeling and molecular dynamics simulation. The 4 residues were located near the mRNA strand. Density functional theory–based calculation suggested that D447, H457, and R460 are in direct contact with ribonucleotide, and partially positive charges are induced by negatively charged chain of mRNA.

Mammalian RNase H2 is a heterotrimeric enzyme consisting of one catalytic subunit (A) and two accessory subunits (B and C). RNase H2 is involved in the removal of a single ribonucleotide embedded in genomic DNA and removal of RNA of RNA/DNA hybrids. In humans, mutation of the RNase H2 gene causes a severe neuroinflammatory disorder Aicardi-Goutières syndrome (AGS). Here, we examined the activity and stability of six recombinant human RNase H2 variants bearing one AGS-causing mutation, A-G37S (Gly37 in the A subunit is replaced with Ser), A-N212I, A-R291H, B-A177T, B-V185G, or C-R69W. The activity of A-G37S was 0.3–1% of that of the wild-type RNase H2 (WT), while those of other five variants were 51–120%. In circular dichroism measurement, the melting temperatures of variants were 50–53°C, lower than that of WT (56°C). These results suggested that A-G37S had decreased activity and stability than WT, while other five variants had decreased stability but retained activity. In gel filtration chromatography of the purified enzyme preparation, WT migrated as a heterotrimer, while A-R291H eluted in two separate peaks containing either the heterotrimer or only the A subunit, suggesting that some AGS-causing mutations affect the heterotrimer-forming stability of RNase H2.

Amino acids are not only constituents of proteins, but also have multiple physiologic functions. Recent findings have revealed that ingested amino acids either activate luminal receptors or are metabolized, causing physiologic reactions in the gastrointestinal (GI) tract. We examined the effect of oral L-arginine L-glutamate (ArgGlu), a pharmaceutical amino acid salt used i.v. for the treatment of hyperammonemia, on gastric motor function in rats and dogs. Gastric emptying was determined using phenol red and 13C-breath test methods, whereas gastric relaxation was determined using the barostat method. ArgGlu (10-30 mg/kg, p.o.) dose-dependently promoted gastric emptying in rats. This effect was dependent on vagus nerve activation and comparable to that of the prokinetic mosapride. Intragastric ArgGlu (3-30 mg/kg intragastrically) also dose-dependently enhanced adaptive relaxation of rat stomachs, which was negated not by vagotomy of gastric branches, but by pretreatment with N omega-nitro-L-arginine methyl ester (20 mg/kg i.v.), a nitric oxide synthase inhibitor. Its relaxing effect on the stomach was also confirmed in dogs and was equally as efficacious as treatment with sumatriptan (1-3 mg/kg s.c.). ArgGlu (30 mg/kg p.o.) significantly reduced the half gastric emptying time in clonidine-induced delayed gastric emptying of solids in dogs, and its effect was comparable to that of cisapride (3 mg/kg p.o.). This study demonstrated that the pharmaceutical ingredient ArgGlu, currently used i.v., enhanced gastric motor function when administered orally, suggesting that it could be a new oral medicine indicated for treatment of upper GI hypofunction or dysfunction like functional dyspepsia.

The aim of the present study was to investigate two methods of determining liver stiffness in rats with various degrees of non-alcoholic steatohepatitis induced by a methionine- and choline-deficient (MCD) diet by comparing each finding with reference to histopathological liver findings. Twenty male Wister rats were fed an MCD diet for up to 32 weeks, and four were fed a normal diet. Ultrasound-based shear wave elastography (SWE) and mechanical compression testing using an Instron Universal Testing machine were performed on each rat at designated time points. After each examination, liver histopathology was analyzed to evaluate the degrees of steatosis, inflammation, and fibrosis based on non-alcoholic fatty liver disease (NAFLD) activity score, and each finding was compared with reference to liver histopathologic findings. Median liver stiffness values measured using SWE showed a stepwise increase with increasing histological inflammation score (P = 0.002), hepatic fibrosis stage (P = 0.029), ballooning score (P = 0.012), and steatosis grade (P = 0.030). Median liver stiffness measured using an Instron machine showed a stepwise increase only with increasing histological fibrosis stage (P = 0.033). Degree of liver stiffness measured by SWE and the Instron machine differed. SWE reflected mainly inflammation, whereas Instron machine-derived values primarily reflected fibrosis. This is the main source of discrepancies between measurements made with these two modalities.

This clinical study was conducted to evaluate the safety and short-term outcomes of irreversible electroporation (IRE) for the treatment of patients with hepatocellular carcinoma (HCC) in Japan. The study was designed in a prospective setting. Five patients (3 men and 2 women; mean age, 66.6 ± 5.8 years) with 6 HCCs were enrolled and treated using percutaneous ultrasound (US)-guided IRE. Safety was assessed based on adverse events and laboratory values. Local control was assessed using contrast-enhanced US with a perflubutane microbubble contrast agent, contrast-enhanced multiphase CT, and gadoxetic acid-enhanced MRI (EOB-MRI) at designated points. The tumors ranged in diameter from 11 to 28 mm (mean diameter, 17.5 ± 6.3 mm). Five of the 6 tumors (83 %) were successfully treated, with no local recurrence to date (mean follow-up 244 ± 55 days). In 1 lesion located in liver segment 1, residual tumor was diagnosed at 7 days after intervention by follow-up EOB-MRI. No serious complications related to the IRE procedure were observed. The results of this study suggest that image-guided percutaneous IRE can achieve satisfactory local disease control, particularly for small HCCs, and is well tolerated by patients.

It is known that a variety of sized procoagulant vesicles that express tissue factor are released from several types of cells including monocytes by mechanisms related to the induction of apoptosis, while it has not yet been evaluated whether superoxide is involved in the production of such vesicles. Here, we report that a local anesthetic bupivacaine induces apoptosis in human monocytic cells THP-1 within a short observation period, where the shedding of procoagulant vesicles is associated. The property as procoagulant vesicles was evaluated using flow cytometry by the binding of FITC-conjugated fibrinogen to vesicles in the presence of fresh frozen plasma and the suppression of this binding by heparin. Bupivacaine (1 mg/ml) increased the apoptotic cells and procoagulant vesicles. LY294002 (100 µM), that inhibits the recruiting of intracellular component of NADPH oxidase to construct the activated form of this enzyme complex, or superoxide dismutase (1500 unit/ml) suppressed bupivacaine-provoked induction of apoptosis and the increase of procoagulant vesicles. We suggest that this simple experimental system is useful to explore the molecular mechanisms of action of superoxide in the shedding of procoagulant vesicles from human monocytic cells.

Dual red imaging (DRI) is a new technology that can increase the visibility of deeper veins compared with narrow band imaging (NBI). As esophageal varices (EVs) are a vascular disease occurring in the submucosal layer, their visibility might be increased by DRI. We prospectively clarified whether the visibility of EVs with red color sign (RCS) can be increased by DRI, and clarified the relation between the visibility scores and the obtained endoscopic ultrasound (EUS) images. Forty patients were enrolled. The visibility of the EVs on DRI and NBI endoscopic images was evaluated by five observers in a blinded manner and was compared with a white light image (bad, 0; equal, 1; good, 2). The diameter of the lumen and the depth of the EVs and RCS from the epithelium were measured by EUS. The relation between the visibility scores and the EUS findings was investigated. The DRI scores were 1.66 ± 0.34 for the EV substance and 1.79 ± 0.28 for the RCS, whereas the NBI scores were 0.68 ± 0.38 and 0.41 ± 0.28, respectively. A significant negative correlation was found between the depth and the visibility score (r = −0.505, p = 0.001 for EVs; r = −0.458, p = 0.003 for RCS). DRI increased the visibility of the EVs and RCS. The visibility of the EVs or RCS in the shallower position was more enhanced by DRI. Visual recognition of the changing degrees of visibility by DRI enables the prediction of the depth of EVs.

Summary Background & aims Gut ischemia-reperfusion (I/R) is considered an important mechanism underlying multiple organ failure after severe surgical insults. We previously demonstrated an enteral diet enriched with whey-hydrolyzed peptide, fermented milk, and isomaltulose to have anti-inflammatory effects in a concanavalin A-induced hepatitis model. Here, we investigated whether the immune-modulating diet (IMD), could prevent systemic inflammation, thereby improving survival in a gut I/R model. Methods Mice were randomized into control enteral diet ( n = 58) or IMD ( n = 56) for 2 weeks’ feeding. In experiment 1, 39 mice underwent 45 min of gut ischemia, and were sacrificed at 3 h after reperfusion to collect blood samples. Plasma IL-6 and glucose levels were measured. In experiment 2, 75 mice underwent 60 min of ischemia, and their survival was observed until 48 h. Results Plasma IL-6 and glucose levels of the IMD group were significantly lower than those of control mice. In association with these changes, the IMD improved survival rate at early time points (12 and 30 h) after gut I/R ( p 2 test). Conclusions Nutritional management with the IMD may be useful for preventing systemic inflammatory response after gut I/R.

This study was planned to investigate whether bispectral index (BIS) value, calculation intracerebral concentration and the elapsed time from propofol (PPF) stop serve as an index of the recovery from amnesia. The amnesia effect was evaluated by the rate of the memory of visibility memory load which was shown a set of five-sheet pictures. A set of pictures were loaded in the maintenance and recovery term. After the full recovery from sedation, the pictures memorized by the object were counted. In Control group, research was done on the same schedule as PPF group but by saline instead of PPF. A correlation between the BIS value and OAA/S scale was observed. BIS recovered to control value was 10 minutes after stopping PPF. The rate of the memory kept about the control value 10 minutes after stopping PPF, there was no significant difference between control values. Calculation intracerebral concentration fell to about 0.7μg/ml by the stop, and had a correlation with the rates of the memory. In conclusion, these results suggest that the recovery from amnesia by PPF is obtained on the following conditions. 1) Over 10 minutes after PPF administration stop 2) BIS value over 86 3) Calculation intracerebral concentration under 1.1μg/ml

Objective To determine the optimal bolus injection rate of ultrasound (US) contrast agent in vascular imaging for focal liver lesions. Methods Thirteen patients with 13 focal liver lesions (5 hepatocellular carcinomas (HCCs) with cirrhosis, 4 liver metastases, 2 hemangiomas, 1 intrahepatic cholangiocarcinoma, 1 focal nodular hyperplasia) received two bolus injections of Sonazoid (at 0.5 and 2.0 mL/s) using an automatic power injector. The lesion-to-liver contrast ratio at peak enhancement was quantitatively evaluated. Enhancement of the lesions compared to liver parenchyma was assessed by two independent readers using a five-point scale and qualitatively evaluated by receiver operating characteristic (ROC) analysis. Results For all lesions, the contrast ratio was not significantly different between the two injection rates. For HCCs, the contrast ratio was higher at 0.5 mL/s (7.41 ± 6.56) than at 2.0 mL/s (4.28 ± 4.66, p = 0.025). For all lesions, the mean area under the ROC curve (AUC) was not significantly different between the two injection rates. For HCCs, the AUC was greater at 0.5 mL/s than at 2.0 mL/s (AUC: 0.86, p = 0.013). Conclusion In contrast-enhanced US, an injection rate of 0.5 mL/s is superior to an injection rate of 2.0 mL/s for the quantitative and qualitative analysis of HCCs in the cirrhotic liver.

目的:乳腺穿刺吸引細胞診での, 検体処理方法による細胞診断の行いやすさの違いについて検討した.方法:乳腺腫瘤184例に対し各症例とも吹き出し, パッチン, すり合わせの3法で穿刺吸引材料を処理し標本を作製した. 結合性, 不規則重積, 筋上皮細胞との2相性, 細胞質, 核形不整およびクロマチンの6項目に関し, 細胞観察や良悪性の判定に適した部分の標本上に占める割合の多寡などを比較検討した.成績:細胞異型が目立ち細胞判定が容易な悪性症例群 (71例) と異型が目立たず判定が困難な悪性群 (59例) で, 大型・中型集塊における不規則重積の有無, 筋上皮細胞との2相性, 細胞質の性状, 核形不整, クロマチンの観察や判定に関し, すり合わせ法で作製された標本で適した部分が有意に多かった. 上皮増生を伴う良性例 (14例) では, 不規則重積と筋上皮細胞を評価しやすい部分がすり合わせ法で多かった. 逆に吹き出し法とパッチン法では適した部分が少ないことに加え, 細胞や核が濃縮し本来の異型性が忠実に表現されないなど質的に劣る場合もあった.結論:不規則重積の有無と個々の細胞所見が把握しやすい集塊をより多く含み, 組織型推定も行いやすい “すり合わせ法” が検体処理に適していた.

In order to investigate specific behavior of some greenhouse gases in a vacuum desiccator, the desorption process of CO 2 , N 2 O or H 2 O from a thin film of poly(methyl methacrylate) (PMMA) was mainly followed by FT-IR method. Water molecules desorb rapidly in 3 h and N 2 O gas in 12 h, while a longer time of 72 h was needed to desorb CO 2 gas from a thin film of PMMA. We obtained new infrared data for CO 2 , N 2 O and H 2 O sorbed in PMMA film. An additional shoulder at 3420 cm −1 besides two peaks at 3630 and 3550 cm −1 was observed in the IR spectra of the water species sorbed in PMMA. Species of N 2 O in PMMA has a peak at 2223 cm −1 , which is same as one in the gas phase. Since two types of desorption, rapid and slow, were observed in the case of CO 2 two kinds of physisorbed species were present in thin film of PMMA. The peak at 2338 cm −1 is the species strongly sorbed while the peak at 2336 cm −1 and the shoulder near 2365 and 2315 cm −1 are the species weakly sorbed.

The vasodilatory action of potassium channel openers through a membrane hyperpolarizing action is well known, but little is known about the effect of these drugs on ischemia-induced glutamate release in the brain. We evaluated the effects of a potassium channel opener (Y-26763), given intravenously at 0.03 mg/kg/h from 50 min prior to occlusion until 3 h postocclusion, on cerebral blood flow, extracellular glutamate concentration, and infarct volume in rats with focal ischemia. Y-26763 significantly inhibited the increase in extracellular glutamate concentration at 50 and 60 min of ischemia with a significant reduction of mean arterial blood pressure. However, there was no significant difference in blood flow in the core of infarcted cortex or in infarct volume between Y-26763- and vehicle-treated groups. These results suggest that Y-26763 inhibited presynaptic glutamate release through hyperpolarizing the membrane, but infarct volume was not reduced because of insufficient perfusion owing to its hypotensive effect.

Klippel-Trenaunay syndrome (KTS) is a rare disorder associated with the triad of 1) capillary vascular malformation, 2) varicose veins and/or venous malformation, 3) and soft tissue and/or bony hypertrophy. A six-month old, 6.0-kg-weight male pediatric patient was scheduled for ventriculo-peritoneal shunt operation for hydrocephalus caused by obstructive aqueductus cerebri. At the age of three months, he was diagnosed as KTS by extensive capillary vascular malformation and soft tissue hypertrophy of the right leg. Physical examination showed prominent vascular malformation over his anterior thoracic and abdominal wall, and soft tissue hypertrophy was only on his right leg. Simultaneously, he was complicated with congenital hydrocephalus because of obstructive aqueductus cerebri. His head and skull were enlarged and his head measurement reached 55 cm (chest measurement 32 cm). Anesthetic management of KTS patients should be prepared with blood transfusion against massive hemorrhage and hypovolemic shock. Furthermore, KTS patients should be always considered to have airway difficulty due to the soft tissue hypertrophy, upper and airway hemangiomas. Therefore, we planned safer tracheal intubation following practice guidelines for management of the difficult airway.

This is the first report which demonstrates the presence of glutathione peroxidase in the autopsied brain of 5 patients without cerebral infarction and 21 patients with cerebral infarction by the indirect enzyme-labeled antibody technique with monoclonal antibody to human glutathione peroxidase. In 2 out of 5 patients without cerebral infarction, a weak reaction for glutathione peroxidase was demonstrated both in neurons and glia. In 6 patients who had died within 5 days after stroke, no staining was observed in infarcted brain tissue except in macrophages. In all 15 patients who had died more than 6 days after stroke, however, a reaction for glutathione peroxidase was demonstrated in the cytoplasm of glial cells in the marginal area around the infarction, and there was a patchy reaction in the cytoplasm of macrophages in the core lesion. These results suggest that glutathione peroxidase in glial cells of the marginal area around the infarction may play a protective role against lipid peroxidation after cerebral infarction, or alternatively, may be involved in the healing process after ischemia.

脳虚血時に増加する線条体のグルタミン酸放出に及ぼすnitric oxide (NO) 合成酵素阻害薬の作用について検討した.Wistar ratの両側線条体にmicrodialysis probeを挿入し, 一側の線条体にはNO合成酵素阻害薬であるN-ω-nitro-L-arginine100μMを局所灌流投与し, 対側には対照のためにリンゲル液のみを灌流した.このratに14分間の一過性前脳虚血を負荷し, グルタミン酸放出量の左右差を比較した.NO合成酵素阻害薬投与側の細胞外グルタミン酸濃度は対照側に比し, 虚血時35.6%, 再灌流時59.0%の有意な高値を示した.更に, このNO合成酵素阻害薬によるグルタミン酸濃度の高値は, L-arginine500μMを同時に局所灌流投与することにより完全に抑制された.以上より, 脳局所でのNOは虚血時および再灌流時のグルタミン酸過剰放出を抑制し, グルタミン酸放出量の調節の観点からは虚血神経細胞に対して保護的に働く可能性が示唆された.

Methionine (Met) is biosynthesized by the activated methyl cycle and S-methylmethionine (SMM) cycle in one-carbon (C1) metabolism in plants. It is converted to S-adenosylmethionine (SAM) which serves as a precursor for many metabolites including glycinebetaine, methylated polyols, polyamines and ethylene which accumulate in plants in response to salinity. We have investigated how the Met biosynthetic pathway is regulated under saline conditions at the transcriptional level in Arabidopsis thaliana plants. Within Met biosynthesis-related genes, the expression of homocysteine methyltransferase (HMT) and methionine methyltransferase (MMT) genes in SMM cycle had altered toward increasing Met production by the presence of NaCl. We have determined the salinity tolerance of an Arabidopsis mmt mutant with an insertional mutation in the single copy of the AtMMT gene. Although the mmt mutant showed comparable germination and shoot growth with wild type under normal conditions, NaCl treatment caused severe repression of germination rate and shoot growth in the mmt mutant compared with in the wild type. These results indicate that the utilization of SMM is important for the salinity tolerance of Arabidopsis plants at the germination and early growth stages.

Background Oral administration of enzymatic hydrolysate of cow’s milk whey protein (WPH) has been reported to produce an anti-inflammatory effect. Since inflammation plays a role in dermatitis of allergic disease, we examined the influence of WPH on the development of atopic dermatitis (AD)-like skin lesions, induced in NC/Nga mice by the mite antigen Dermatophagoides pteronyssinus (Dp). Methods AD-like skin lesions were induced on the pinnae and backs of NC/Nga mice by daily application of Dp for 4 weeks. Mice were fed cow’s milk casein (control), WPH or casein protein hydrolysate (CPH) diets for 2 weeks prior to Dp application. Clinical skin conditions were evaluated periodically by a clinical severity score, total serum IgE and soluble E-selectin levels were measured by enzyme linked immunosorbent assay (ELISA). Results WPH-fed mice showed significantly less AD-like skin lesions than those fed casein diets at 2 and 4 weeks after Dp application. In contrast, CPH-fed mice had manifestations in a similar manner as casein-fed mice did, and did not show an inhibitory effect. Serum soluble E-selectin levels, known as a marker of disease activity in AD patients, were significantly lower in the WPH diet group. Conclusions Our results suggest that in addition to its hypoallergenicity an anti-inflammatory function, dietary WPH might be useful for reducing the severity of AD-like skin lesions.

AIM: To evaluate the usefulness of three-dimensional (3D) shear-wave elastography (SWE) in assessing the liver ablation volume after radiofrequency (RF) ablation. METHODS: RF ablation was performed in vivo in 10 rat livers using a 15-gauge expandable RF needle. 3D SWE as well as B-mode ultrasound (US) were performed 15 min after ablation. The acquired 3D volume data were rendered as multislice images (interslice distance: 1.10 mm), and the estimated ablation volumes were calculated. The 3D SWE findings were compared against digitized photographs of gross pathological and histopathological specimens of the livers obtained in the same sectional planes as the 3D SWE multislice images. The ablation volumes were also estimated by gross pathological examination of the livers, and the results were then compared with those obtained by 3D SWE. RESULTS: In B-mode US images, the ablation zone appeared as a hypoechoic area with a peripheral hyperechoic rim; however, the findings were too indistinct to be useful for estimating the ablation area. 3D SWE depicted the ablation area and volume more clearly. In the images showing the largest ablation area, the mean kPa values of the peripheral rim, central zone, and non-ablated zone were 13.1 ± 1.5 kPa, 59.1 ± 21.9 kPa, and 4.3 ± 0.8 kPa, respectively. The ablation volumes depicted by 3D SWE correlated well with those estimated from gross pathological examination (r2 = 0.9305, P = 0.00001). The congestion and diapedesis of red blood cells observed in histopathological examination were greater in the peripheral rim of the ablation zone than in the central zone. CONCLUSION: 3D SWE outperforms B-mode US in delineating ablated areas in the liver and is therefore more reliable for spatially delineating thermal lesions created by RF ablation.

We investigated the role of carbon monoxide as a neural modulator of extracellular glutamate concentration in rat hippocampus CA1in transient forebrain ischemia by using metalloporphyrins, which block the production of carbon monoxide through the inhibition of heme oxygenase (HO) activity. Infusion of 10 and 100 μ M zinc protoporphyrin IX, which inhibits nitric oxide synthase activity as well as HO activity, significantly increased glutamate concentration compared with that on the vehicle-treated side. However, infusion of 100 μ M tin mesoporphyrin IX, which inhibits only HO activity, did not affect glutamate concentration in ischemia. Our results therefore do not support the hypothesis that carbon monoxide acts as a neural messenger through the modulation of extracellular glutamate concentration in ischemia.

Although a number of studies have demonstrated the neuroprotective effects of antagonists of postsynaptic N-methyl-d-aspartate (NMDA) and non-NMDA receptors in cerebral ischemia, little is known about the treatment of cerebral infarction through presynaptic blocking of extracellular glutamate release. We evaluated the effects of a presynaptic selective N-type calcium channel antagonist (SNX-111, given intravenously by continuous infusion at 5 mg/kg/h from 20 min prior to occlusion until 2 h postocclusion) on blood flow, extracellular glutamate, and infarct volume in rats with permanent occlusions of the right middle cerebral and right common carotid arteries plus 1-h transient occlusion of the left common carotid artery. There was no significant difference in CBF in the occluded cortex during the experiment between the treated and vehicle groups. SNX-111 significantly reduced total amount of extracellular glutamate during the experiment and the peak value of the glutamate after occlusion from 44.2 ± 15.8 μ M (mean ± SD) to 21.4 ± 11.4 μ M (p < 0.01). Infusion of SNX-111 also significantly reduced the cortical volume of infarction from 47.2 ± 5.8 to 19.9 ± 7.3% (p < 0.0001). These results suggest that SNX-111 has a protective effect against focal ischemia through the inhibition of glutamate release from presynaptic sites, although SNX-111 may also affect the release of other neurotransmitters.