Chul-ng Woo

Changes in glucose metabolism and metabolites during the epileptogenic process in the lithium-pilocarpine model of epilepsy

Purpose:  The metabolic and biochemical changes that occur during epileptogenesis remain to be determined. 18F‐Fluorodeoxyglucose positron emission tomography (FDG‐PET) and proton magnetic resonance spectroscopy (1H MRS) are noninvasive techniques that provide indirect information on ongoing pathologic changes. We, therefore, utilized these methods to assess changes in glucose metabolism and metabolites in the rat lithium‐pilocarpine model of epilepsy as markers of epileptogenesis from baseline to chronic spontaneous recurrent seizures (SRS).

Long-term neuroprotective effect of postischemic hypothermia in a neonatal rat model of severe hypoxic ischemic encephalopathy: a comparative study on the duration and depth of hypothermia.

It is not known whether deeper or longer hypothermia (HT) can achieve better neuroprotection against hypoxic ischemic encephalopathy (HIE) in neonates. To compare the neuroprotective effects of different durations and temperatures of postischemic HT in neonatal rats with severe HIE, 7-d-old rats were subjected to the Rice-Vannucci model for 150 min hypoxia. Only the rats with identified brain lesions in diffusion-weighted MRI were assigned to normothermia (NT, 36°C/48 h) or four HT (HT-30°C/48 h; HT-30°C/24 h; HT-33°C/48 h; and HT-33°C/24 h) groups. 1H-magnetic resonance spectroscopy (1H-MRS) and T2-weighted MRI were obtained serially, and functional studies were performed. HT groups showed significantly greater residual hemispheric volume and better rotarod and cylinder tests than did the NT group at 5 wk postischemia. HT groups also showed lower lactate-plus-lipid level in 1H-MRS than did the NT group at 7 d postischemia. All of these outcome variables, however, did not differ among the 4 HT subgroups, despite a trend toward greater residual brain volume in the 48-h HT versus 24-h HT subgroups. In conclusion, neither reducing the target temperature from 33 to 30°C nor prolonging the duration from 24 to 48 h produced further improvements in neurologic outcomes in neonatal rat with HIE.

Correlation between lactate and neuronal cell damage in the rat brain after focal ischemia: An in vivo 1H magnetic resonance spectroscopic (1H-MRS) study

Background: Increased levels of lactate are observed by 1H magnetic resonance spectroscopy (1H-MRS) in rat brains after stroke. However, it is not known whether the changes in lactate levels are predictive of the degree of neuronal damage. Purpose: To investigate the correlation between changes in lactate and lipid levels measured by 1H-MRS and neuronal cell damage in the rat brain. Material and Methods: A middle cerebral artery occlusion (MCAO) model was used to evaluate focal ischemia in rats (n=36). After MCAO for 90 min T2-weighted images (T2WIs), diffusion-weighted images (DWIs), and 1H-MRS data were obtained from brains immediately, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 3 days, and 7 days after reperfusion. Infarct volumes were measured in T2WIs obtained 4 weeks after reperfusion. The degree of neuronal damage was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining in three rats from each group at the same time as brain images were collected. Results: Creatine (Cr)-normalized lactate + lipid levels ([Lac+Lip]/Cr) were negatively correlated with Cr-normalized N-acetyl-L-aspartate levels (NAA/Cr) and positively correlated with TUNEL-positive cell numbers up to 24 hours after reperfusion. (Lac+Lip)/Cr at 6 hours and 9 hours was significantly correlated with NAA/Cr at 7 days, but there was no significant correlation between (Lac+Lip)/Cr during the first 24 hours and infarct volume at 4 weeks. Conclusion: Up to 24 hours after reperfusion, (Lac+Lip)/Cr was strongly negatively correlated with NAA/Cr, and was a good predictor of neuronal damage at 7 days; however, it was not predictive of final infarct volume at 4 weeks.

Removal of retrievable self-expandable urethral stents: experience in 58 stents

The purpose of this study was to retrospectively evaluate the safety and efficacy of removing retrievable self-expandable urethral stents using a retrieval hook wire. Under fluoroscopic guidance, the removal of 58 polyurethane or PTFE (polytetrafluoroethylene)-covered stents was attempted in 33 patients using a retrieval hook wire. Indications for removal were elective removal (n=21), stent migration (n=19), formation of tissue hyperplasia around or inside of the stent (n=14), stent deformity (n=3), and severe pain (n=1). The mean time the stents remained in place was 64.8±42.9 days (range, 1–177 days). Fifty-six (97%) of the 58 stents were successfully removed using the retrieval hook wire despite the following difficulties; hook wire disconnection (n=2), untied drawstrings (n=3), and polyurethane membrane disruption/separation (n=4). The removal procedure using a retrieval hook wire failed in two stents (3%) which had migrated into the urinary bladder. One of the two stents with migration into the urinary bladder was removed using a snare through the cystostomy route. The overall complication rate was 14% (seven hematuria cases and one urethral tear case), and all were minor and spontaneously resolved without further treatment. In conclusion, removal of retrievable urethral stents using a retrieval hook wire was safe and effective despite some technical difficulties. It is a useful method for allowing temporary stent placement and solving various complications of stent use.

Is a Flared Stent Effective for Decreasing Stent Migration in Canine Prostatic Urethra

Background: Prostatic urethral stents are effective in relieving obstructions caused by benign prostatic hyperplasia (BPH). However, migration of these stents occurs frequently. Purpose: To evaluate the efficacy of a flared stent for decreasing the migration rate in comparison with a straight stent in a canine prostatic urethral model. Material and Methods: The flared stent (15 mm in diameter and 20 mm in length) was flared up to 19 mm at both ends to prevent migration. A straight stent with the same size was straight without flaring. Both stents were made of a nitinol wire filament and covered with an expanded polytetrafluoroethylene (ePTFE) membrane. The flared stent was inserted in the prostatic urethra of 10 dogs (group 1) and the straight stent in the prostatic urethra of 12 dogs (group 2). Follow-up retrograde urethrography (RUG) was performed 1, 4, and 8 weeks after stent placement. Fishers exact test was used to compare the migration rate between the two groups. When stent migration occurred during the follow-up period, the same type of stent was inserted again. Results: Three of 10 (30.0%) flared stents migrated into the urinary bladder between 1 week and 4 weeks after placement. Seven of 12 (58.3%) straight stents migrated into the urinary bladder 1 (n = 3), 4 (n = 1), and 8 (n = 3) weeks following placement. The flared stent group showed lower migration rate than the straight stent group, but the migration rate did not reach statistical significance (P = 0.231). After the second stent placement, one of three (33.3%) flared stents migrated again after 4 weeks and two of seven straight stents (28.6%) after 1 week. Conclusion: Although the migration rate was not statistically significant, the flaring of the stent seemed to reduce the migration rate in comparison with straight stents in a canine prostatic urethral model. However, the migration rate of the flared stent was still high, and further developments are required to decrease migration rate.

Effects of Irradiation Using a Radioisotope-filled Balloon on Tissue Hyperplasia Caused by Stent Placement in a Canine Urethral Model

Purpose: To evaluate 20 Gy and 40 Gy of intraluminal beta-irradiation using a 188Re-7mercaptoacetyltriglycine (MAG3)-filled balloon catheter to reduce tissue hyperplasia caused by covered stent placement for 12 weeks of follow-up in a canine urethral model. Material and Methods: Ten dogs underwent 188Re-MAG3-filled balloon dilatation immediately after stent placement; 20 Gy at 1-mm tissue depth in group I (n = 5) and 40 Gy in group II (n = 5), whereas 5 dogs (group III) underwent conventional balloon dilatation only. Results: There were no significant differences among the three groups for percentage diameter of stenosis, although this was highest in group III. There was a tendency toward lower mean thickness of the epithelial layer and the papillary projection for out-stent area, and thickness of the papillary projection and degree of inflammatory cells for in-stent area in groups I and II compared with group III. Thickness of the papillary projection in out-stent area was significantly different among the three groups (P = 0.031). It was significantly less thick in group I than in group III (P<0.05), whereas group II was not significantly different from group III. Conclusion: 188Re-MAG3-filled balloon dilatation has the potential to reduce tissue hyperplasia after 12 weeks of follow-up in a canine urethral model. The use of 20 Gy compared to 40 Gy did not show significant differences.

Reduction in Renal Ischemia-Reperfusion Injury in Mice by a Phosphoinositide 3-Kinase p110gamma-Specific Inhibitor.

Background Although renal ischemia-reperfusion injury (IRI) can cause delayed graft function, a targeted therapy is not yet available. Because phosphoinositide 3-kinases (PI3K) p110&ggr; and p110&dgr; play important roles in immune cell migration and function, we investigated the effects of PI3K p110&ggr;- and p110&dgr;-specific inhibitors in a murine renal IRI model. Methods Renal function was assessed by serum creatine and hematoxylin-eosin staining. Immune cell migration was assessed by flow cytometry and an in vitro cell migration assay using Transwell plates. Gene expression analysis and a multiplex cytokine/chemokine assay were performed to find cytokines/chemokines whose expression was upregulated in renal IRI and affected by p110&ggr;-specific inhibitor. Results The PI3K p110&ggr;-specific inhibitor, but not p110&dgr;-specific inhibitor, significantly reduced serum creatine levels and acute tubular necrosis. These were accompanied by reduced infiltration of B cells and reduced expression of CXCL9, a CXCR3 ligand, suggesting that p110&ggr; plays an important role in B-cell migration toward injured kidneys. An in vitro cell migration assay revealed for the first time that B-cell migration to injured kidney cells and to CXCL9 requires p110&ggr;. Conclusions p110&ggr;-specific inhibitor ameliorates renal IRI by reducing necrosis and immune cell migration. This inhibitor may have the potential to reduce renal graft failure caused by renal IRI.

The administration of hydrogen sulphide prior to ischemic reperfusion has neuroprotective effects in an acute stroke model

Emerging evidence has suggested that hydrogen sulfide (H2S) may alleviate the cellular damage associated with cerebral ischemia/reperfusion (I/R) injury. In this study, we assessed using 1H-magnetic resonance imaging/magnetic resonance spectroscopy (1H-MRI/MRS) and histologic analysis whether H2S administration prior to reperfusion has neuroprotective effects. We also evaluated for differences in the effects of H2S treatment at 2 time points. 1H-MRI/MRS data were obtained at baseline, and at 3, 9, and 24 h after ischemia from 4 groups: sham, control (I/R injury), sodium hydrosulfide (NaHS)-30 and NaHS-1 (NaHS delivery at 30 and 1 min before reperfusion, respectively). The total infarct volume and the midline shift at 24 h post-ischemia were lowest in the NaHS-1, followed by the NaHS-30 and control groups. Peri-infarct volume was significantly lower in the NaHS-1 compared to NaHS-30 and control animals. The relative apparent diffusion coefficient (ADC) in the peri-infarct region showed that the NaHS-1 group had significantly lower values compared to the NaHS-30 and control animals and that NaHS-1 rats showed significantly higher relative T2 values in the peri-infarct region compared to the controls. The relative ADC value, relative T2 value, levels of N-acetyl-L-aspartate (NAA), and the NAA, glutamate, and taurine combination score (NGT) in the ischemic core region at 24 h post-ischemia did not differ significantly between the 2 NaHS groups and the control except that the NAA and NGT values were higher in the peri-infarct region of the NaHS-1 animals at 9 h post-ischemia. In the ischemic core and peri-infarct regions, the apoptosis rate was lowest in the NaHS-1 group, followed by the NaHS-30 and control groups. Our results suggest that H2S treatment has neuroprotective effects on the peri-infarct region during the evolution of I/R injury. Furthermore, our findings indicate that the administration of H2S immediately prior to reperfusion produces the highest neuroprotective effects.

Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy

β-Hydroxybutyrate (BHB) is a representative ketone body that may play a role in the mitigation of neonatal hypoxic-ischemic encephalopathy by altering energy metabolism. This study aimed to investigate the neuroprotective efficacy of exogenous BHB administration in a suckling rat model after hypoxia-ischemia (HI). Thirteen-day-old (P13) rat pups were subjected to 120 min of hypoxia according to the Rice-Vannucci model. BHB (5.0 mmol/kg, HI-BHB) or vehicle (0.9% saline, HI-Veh) was administered 0, 2, 4, and 6 h after HI induction. Pathologic injury scores and the number of TUNEL-positive cells were evaluated on P15. Residual hemispheric volume was measured with T2-weighted MRI (on P27) and functional tests, such as the negative geotaxis test, rope suspension test, rotarod test, novel object recognition test, and cylinder test, were performed. Systemic ketosis (approx. 2.0–3.0 mM/L) was well tolerated by the rat pups with no difference in the mortality rate between both groups. Compared with the HI-Veh group, the HI-BHB group demonstrated significantly lower pathological scores as well as fewer TUNEL-positive cells. The intact residual hemispheric and hippocampal volumes were greater in the HI-BHB group than the HI-Veh group. However, the results of functional tests did not differ between both groups. Postischemic BHB administration reduced brain injury in suckling rats after HI. The safe clinical application of our animal model to human infants with HI requires further investigation.

Neurochemical Changes Associated with Stress-Induced Sleep Disturbance in Rats: In Vivo and In Vitro Measurements

The goal of this study was to quantitatively assess the changes in the cerebral neurochemical profile and to identify those factors that contribute to the alteration of endogenous biomolecules when rats are subjected to stress-induced sleep disturbance. We exposed Sprague-Dawley rats (controls: n = 9; stress-induced sleep perturbation rats: n = 11) to a psychological stressor (cage exchange method) to achieve stress-induced sleep perturbation. In vivo magnetic resonance imaging assessments were carried out using a high-resolution 9.4 T system. For in vivo neurochemical analysis, a single voxel was localized in the right dorsal hippocampal region, and in vivo spectra were quantified for 17 cerebral neurochemical signals. Rats were sacrificed upon completion of the magnetic resonance spectroscopy protocol, and whole-brain tissue was harvested from twenty subjects. The dopamine and serotonin signals were obtained by performing in vitro liquid chromatography-tandem mass spectrometry on the harvested tissue. In the right dorsal hippocampal region, the gamma-aminobutyric-acid (GABA) and glutamine (Gln) concentrations were significantly higher in the sleep-perturbed rats than in the sham controls. The ratios of Gln/Glu (glutamate), Gln/tCr (total-creatine), and GABA/Glu were also significantly higher in the sleep-perturbed group, while serotonin concentrations were significantly lower in the sleep-perturbed rats. Pearson correlation results among individual rat data indicate that concentrations of dopamine (DA) and serotonin (5-HT) were significantly higher in SSP rats. A larger correlation coefficient was also observed for the SSP rats. Analysis of the correlation between the in vivo and in vitro signals indicated that the concentrations of Gln, 5-HT, and DA exhibited a significant negative correlation in the SSP rat data but not in that of control rats. The authors propose that the altered and correlated GABA, Gln, 5-HT, and DA concentrations/ratios could be considered key markers of neurological function in animal models of stress-induced sleep perturbation.