Although the importance of free oxygen radical has been reported in acute lung injury, the direct evidence in vivo model was lacking. We report a new method, which for the first time allows direct detection of hydrogen peroxide in the intact rat pulmonary microcirculation. We used the computer image-analyzing system and 2',7'-dichlorofluorescin diacetate for the marker of hydrogen peroxide production in vivo. A rat sepsis model was produced by continuous infusion of endotoxin for 30, 60, and 120 min. Hydrogen peroxide production in the pulmonary microcirculation of the sepsis rat was higher than in the control rat at each time point (p < 0.01) and increased time-dependently (p < 0.01). Catalase (5,000 U/kg) almost completely inhibited the hydrogen peroxide production in the sepsis rat (p < 0.01). In high-power view, hydrogen peroxide was detected in granulocytes that adhered to the capillaries and endothelial cells that were adjoining adherent granulocytes. These observations suggest that hydrogen peroxide in the endothelium was diffused from granulocytes. In this study, we demonstrated direct evidence of hydrogen peroxide production from adherent granulocytes in intact rat lung treated with endotoxin. We conclude that endotoxin causes the granulocyte adhesion and oxidative stress to the endothelium due to adherent granulocytes within 30 min in the pulmonary microcirculation.

OBJECTIVE Pediatric epilepsy surgery is known to be effective, but early surgery in infancy is not well characterized. Extensive cortical dysplasia, such as hemimegalencephaly, can cause refractory epilepsy shortly after birth, and early surgical intervention is indicated. However, the complication rate of early pediatric surgery is significant. In this study, the authors assessed the risk-benefit balance of early pediatric epilepsy surgery as relates to developmental outcomes. METHODS This is a retrospective descriptive study of 75 patients who underwent their first curative epilepsy surgery at an age under 3 years at the authors’ institution between 2006 and 2019 and had a minimum 1-year follow-up of seizure and developmental outcomes. Clinical information including surgical complications, seizure outcomes, and developmental quotient (DQ) was collected from medical records. The effects of clinical factors on DQ at 1 year after surgery were evaluated. RESULTS The median age at surgery was 6 months, peaking at between 3 and 4 months. Operative procedures included 27 cases of hemispherotomy, 19 cases of multilobar surgery, and 29 cases of unilobar surgery. Seizure freedom was achieved in 82.7% of patients at 1 year and in 71.0% of patients at a mean follow-up of 62.8 months. The number of antiseizure medications (ASMs) decreased significantly after surgery, and 19 patients (30.6%) had discontinued their ASMs by the last follow-up. Postoperative complications requiring cerebrospinal fluid (CSF) diversion surgery, such as hydrocephalus and cyst formation, were observed in 13 patients (17.3%). The mean DQ values were 74.2 ± 34.3 preoperatively, 60.3 ± 23.3 at 1 year after surgery, and 53.4 ± 25.1 at the last follow-up. Multiple regression analysis revealed that the 1-year postoperative DQ was significantly influenced by preoperative DQ and postoperative seizure freedom but not by the occurrence of any surgical complication requiring CSF diversion surgery. CONCLUSIONS Early pediatric epilepsy surgery has an acceptable risk-benefit balance. Seizure control after surgery is important for postoperative development.

OBJECTIVECognitive risk associated with insular cortex resection is not well understood. The authors reviewed cognitive and developmental outcomes in pediatric patients who underwent resection of the epileptogenic zone involving the insula.METHODSA review was conducted of 15 patients who underwent resective epilepsy surgery involving the insular cortex for focal cortical dysplasia, with a minimum follow-up of 12 months. The median age at surgery was 5.6 years (range 0.3–13.6 years). Developmental/intelligence quotient (DQ/IQ) scores were evaluated before surgery, within 4 months after surgery, and at 12 months or more after surgery. Repeated measures multivariate ANOVA was used to evaluate the effects on outcomes of the within-subject factor (time) and between-subject factors (resection side, anterior insular resection, seizure control, and antiepileptic drug [AED] reduction).RESULTSThe mean preoperative DQ/IQ score was 60.7 ± 22.8. Left-side resection and anterior insular resection were performed in 9 patients each. Favorable seizure control (International League Against Epilepsy class 1–3) was achieved in 8 patients. Postoperative motor deficits were observed in 9 patients (permanent in 6, transient in 3). Within-subject changes in DQ/IQ were not significantly affected by insular resection (p = 0.13). Postoperative changes in DQ/IQ were not significantly affected by surgical side, anterior insular resection, AED reduction, or seizure outcome. Only verbal function showed no significant changes before and after surgery and no significant effects of within-subject factors.CONCLUSIONSResection involving the insula in children with impaired development or intelligence can be performed without significant reduction in DQ/IQ, but carries the risk of postoperative motor deficits.

BACKGROUND AND PURPOSE: The transmantle sign is a characteristic MR imaging finding often seen in focal cortical dysplasia type IIb. The transmantle sign is typically hyperintense on T2WI and FLAIR and hypointense on T1WI. However, in some cases, it shows T1 high signal. We evaluated the imaging and pathologic findings to identify the causes of the T1 high signal in the transmantle sign. MATERIALS AND METHODS: We retrospectively reviewed the preoperative imaging data of 141 consecutive patients with histologically proved focal cortical dysplasia. We selected 25 patients with focal cortical dysplasia with the transmantle sign and divided them into groups based on the pathologic focal cortical dysplasia subtype and T1 signal of the transmantle sign. We evaluated the clinical, radiologic, and pathologic findings, including the number of balloon cells and dysmorphic neurons and the severity of gliosis or calcifications and compared them among the groups. RESULTS: Nine of the 25 patients had a T1-high-signal transmantle sign; the other 16 patients did not. All 9 patients with a T1-high-signal transmantle sign were diagnosed as type IIb (group A). Of the 16 patients with no T1-high-signal transmantle sign, 13 were diagnosed as having type IIb (group B), and the other 3 patients, as type IIa (group C). The number of balloon cells was significantly higher in group A than in the other groups, but there were no differences regarding dysmorphic neurons, the severity of gliosis, or calcifications. CONCLUSIONS: Approximately 6% (9/141) of this patient series had a T1-high-signal transmantle sign, and all were type IIb. The signal may reflect a rich density of balloon cells. This finding could support the differentiation of subtypes, especially type IIb.

The package insert of the antithrombotic agent warfarin warns users of its interaction with azole antifungals. However, information on the frequency or degree of these interactions is limited. In particular, the time to onset of azole-mediated prothrombin time prolongation, expressed as the international normalized ratio ( The antithrombotic agent, warfarin, shows large inter-and intra-individual differences in its pharmacokinetic and pharmacodynamic properties.1) Prothrombin time, expressed as the international normalized ratio (INR), is commonly used to adjust the individual maintenance dose of warfarin.1) Many drug-drug interactions also contribute to individual differences in warfarin dose. Sufficient understanding of these is therefore necessary for the safe and effective administration of warfarin.2) Details of interactions between warfarin and other drugs, such as the timing of onset or the degree of interaction, have yet to be elucidated. Therefore, it is difficult to decide whether or when INR should be measured.The warfarin package insert in Japan and some other reports suggest an increased risk of bleeding following coadministration of warfarin and azoles. [3][4][5][6] We recently encountered a patient at the Kyoto University Hospital, in whom the INR abruptly increased to >5 when a combination of warfarin and fluconazole (FLCZ) was administered. The inhibition of hepatic drug-metabolizing enzymes is described as the mechanism of this interaction between warfarin and azoles such as FLCZ, voriconazole (VRCZ), and itraconazole (ITCZ).3) However, we were unable to find specific information on the frequency of these interactions, their degree, or the time of onset of INR prolongation for each azole. To the best of our knowledge, there are no previous reports comparing the changes of INR following coadministration of azoles and warfarin in patients. Therefore, we retrospectively compared changes in the anticoagulant effects of warfarin in Japanese patients concomitantly administered with FLCZ, VRCZ, or ITCZ. PATIENTS AND METHODS Study PopulationPatients who were administered warfarin in combination with FLCZ, VRCZ, or ITCZ from April 2010 to March 2013 were analyzed. Patients were excluded under the following circumstances: (1) No INR data; (2) Altered dosage of other agents that were considered highly probable or probable to interact with warfarin 2) (e.g., miconazole oral gel, levofloxacin, and loxoprofen); (3) Increasing warfarin dosage after azole coadministration; (4) Observation of abnormal liver function. Liver function was considered abnormal if the aspartate aminotransferase or alanine aminotransferase level was≥the upper limit of normal×3, in accordance with the Common Terminology Criteria for Adverse Events v4.0.Study Protocol Patient age, sex, warfarin and azole dosing information, the reasons for administration of warfarin and azoles, and INR values were obtained from medical charts retrospectively. INR values were obtained within 2 weeks before commencing coadministration of warfarin and azol...