Effective connectivity in temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: We hypothesized that temporal lobe epilepsy (TLE) patients with and without hippocampal sclerosis (HS) showed differences in their limbic networks. This study aimed to evaluate the role of the thalamus in TLE patients with HS. MATERIALS AND METHODS: Twenty-nine TLE patients with HS and 30 controls were enrolled in this study. In addition, we included eight TLE patients without HS as a disease control group. Using whole-brain T1-weighted MRIs, we analyzed the volumes of the limbic structures, including the hippocampus, thalamus, and total cortex, with FreeSurfer 5.1. We also investigated the effective connectivity among these structures using SPSS Amos 21 based on these volumetric measures. Moreover, we quantified correlations between epilepsy duration and the volumes of these structures. RESULTS: There was a statistically significant effective connectivity from the hippocampus to the thalamus in TLE patients with HS. Moreover, the volumes of the left and right thalamus were negatively correlated with epilepsy duration (r=-.42, P=.0315 and r=-.52, P=.0062, respectively). However, neither TLE patients without HS nor normal controls had a significant effective connectivity from the hippocampus to the thalamus. CONCLUSIONS: The limbic networks of TLE patients with and without HS could be different, and the thalamus might play a critical role in TLE patients with HS.

The effect of horse simulator riding on visual analogue scale, body composition and trunk strength in the patients with chronic low back pain.

BACKGROUND: Chronic low back pain (CLBP) is one of the most common musculoskeletal disorders, and thus effective treatments are required. Recently, real horseback riding has been reported to be beneficial for the patients. However, it has some limitations, such as limited approaches and safety issues. OBJECTIVE: The purpose of this study was to investigate the effect of horse simulator riding on back pain, body composition and trunk strength in the patients with CLBP. PARTICIPANTS: Forty-seven men with CLBP (mean age 20.55 ± 1.38 years) were randomly divided into a control group (n = 23) and a horse simulator riding group (n = 24), and visual analogue scale (VAS), body composition and isokinetic trunk strength were measured after 8 weeks for which subjects in a horse simulator riding group had performed the horse simulator exercise (HSE). RESULTS: Horse simulator exercise significantly reduced pain scores of VAS and enhanced isokinetic torques of trunk at 30 and 90°/s. There were also significantly increased muscle mass and decreased fat mass in horse simulator riding group. CONCLUSION: It can be inferred that HSE may be helpful in relief of back pain and recovery of back function through developing trunk strength and balancing the ratio of trunk flexor/extensor muscles.

Effect of omega-3 fatty acids on the modification of erythrocyte membrane fatty acid content including oleic acid in peritoneal dialysis patients.

Erythrocyte membrane fatty acids (FA), such as oleic acid, are related to acute coronary syndrome. There is no report about the effect of omega-3 FA on oleic acid in peritoneal dialysis (PD) patients. We hypothesized that omega-3 FA can modify erythrocyte membrane FA, including oleic acid, in PD patients. In a double-blind, randomized, placebo-controlled study, 18 patients who were treated with PD for at least 6 months were randomized to treatment for 12 weeks with omega-3 FA or placebo. Erythrocyte membrane FA content was measured by gas chromatography at baseline and after 12 weeks. The erythrocyte membrane content of eicosapentaenoic acid and docosahexaenoic acid was significantly increased and saturated FA and oleic acid were significantly decreased in the omega-3 FA supplementation group after 12 weeks compared to baseline. In conclusion, erythrocyte membrane FA content, including oleic acid, was significantly modified by omega-3 FA supplementation for 12 weeks in PD patients.

Association of adiponectin and leptin with serum lipids and erythrocyte omega-3 and omega-6 fatty acids in dialysis patients.

AIMS: Besides regulating energy metabolism, leptin promotes and adiponectin suppresses inflammation which is a common feature of end-stage renal disease (ESRD). Omega-3 fatty acids (n-3FA) exert anti-inflammatory actions by inhibiting pro-inflammatory signal transduction pathways whereas arachidonic acid (an n-6FA) facilitates inflammation by mediating inflammatory signals and serving as precursor of pro-inflammatory eicosanoids. Given the functional overlap between adipokines and n-3FA and n-6FA, we sought to explore their interrelationship in patients with ESRD. METHODS: 44 ESRD patients maintained on hemodialysis (HD), 29 patients receiving peritoneal dialysis (PD), and 10 healthy subjects were enrolled. Body mass index (BMI), plasma leptin, adiponectin, lipids and CRP and erythrocyte fatty acids were measured. RESULTS: Compared to controls adiponectin was elevated and leptin level was reduced in the ESRD group. Adiponectin levels were comparable among PD and HD patients, but leptin and BMI were higher in PD than in HD patients. Despite comparable BMIs, female patients had higher leptin than male patients. Leptin levels were positively associations with BMI, total and LDL cholesterol whereas adiponectin was inversely related with BMI, triglycerides and CRP and directly associated with HDL cholesterol in ESRD patients. Plasma adiponectin was directly associated with erythrocyte n-3 FA (r = 0.581, p = 0.023) and inversely associated with n-6FA (r = -0.640, p = 0.010) in the HD patients. CONCLUSION: A direct association was found between plasma levels of adiponectin and HDL and erythrocyte n-3FA in ESRD patients. Prospective trials are needed to explore the effect of n-3FA supplementation on plasma adipokines and markers of oxidative stress and inflammation in this population.

The implication of nigrostriatal dopaminergic degeneration in the pathogenesis of REM sleep behavior disorder.

BACKGROUND AND PURPOSE: The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is not clear despite its frequent association with Parkinson's disease (PD). We investigated whether the nigrostriatal dopaminergic system is involved in the development of idiopathic RBD. METHODS: Fourteen patients with RBD, 14 patients with PD and 12 normal controls were included in the study. The diagnosis of RBD was confirmed on polysomnography. All the participants performed single-photon emission computed tomography imaging 3 h after injection of [(123)I]FP-CIT. During REM sleep of the RBD patients, each 30-s epoch was rated as 'tonic' when there was at least 50% of tonically maintained chin electromyography (EMG) activity in the epoch. Phasic EMG activities were calculated as the percentage of 3-s mini-epoch containing phasic EMG events (leg and chin, separately). RESULTS: The RBD patients showed a trend of lower binding in the striatum than the normal controls (P = 0.07), and the significance was revealed in the putamen (P = 0.02). However, in 11 individual cases of the 14 RBD patients, the dopamine transporter (DAT) densities in the putamen still remained within the normal range. In the RBD patients, there was no correlation between EMG activities and DAT densities. CONCLUSIONS: Nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. The lack of correlation between RBD severity and DAT densities suggests that another pathogenic process not related to nigrostriatal dopaminergic transmission may be implicated in RBD.

Comparison of fatty acid contents of erythrocyte membrane in hemodialysis and peritoneal dialysis patients.

OBJECTIVE: Membrane fatty acid composition plays an important role in the cellular function. Erythrocyte fatty acid composition mirrors that of myocardium and is influenced by diet. Earlier studies have shown significant alterations of membrane fatty acid composition in ethnically mixed patients with end-stage renal disease. Given the impact of ethnic and dietary factors, we sought to examine membrane fatty acid composition in an ethnically homogeneous end-stage renal disease population residing in a coastal region of Korea with high fish consumption. DESIGN: Cross-sectional study. SETTING: Outpatient facility at Dong-A University Hospital, Busan, Republic of Korea. PATIENTS: We recruited 15 stable hemodialysis patients, 14 peritoneal dialysis patients, and 10 age- and gender-matched normal controls. Patients with significant malnutrition, short duration of dialysis, recent infection, malignancy, or liver disease were excluded. Dietary intake and use of omega-3 fatty acid supplements were determined. MAIN OUTCOME MEASURE: Erythrocyte membrane fatty acid contents measured by gas chromatography. RESULTS: Palmitoleic acid and alpha-linolenic acid levels were lower, whereas oleic acid, linoleic acid, and arachidonic acid levels were higher in patients with end-stage renal disease compared with the control group. Total monounsaturated fatty acids (palmitoleic acid and oleic acid) were significantly higher in peritoneal dialysis than in hemodialysis patients. Eicosapentaenoic acid and omega-3 docosapentaenoic acid were significantly higher, but total omega-6 fatty acids, omega-6/omega-3, and arachidonic acid/eicosapentaenoic acid ratios were significantly lower in hemodialysis patients consuming omega-3 supplements compared with those who did not. CONCLUSION: Patients with end-stage renal disease exhibited significant alterations in erythrocyte membrane fatty acids, which were partially modified by the dialysis modality and omega-3 fatty acid supplementation.

Cerebral glucose metabolism in oculopalatal tremor.

No study adopted the statistical parametric mapping (SPM) analyses of (18)F-fluorodeoxy glucose (FDG) PET in a large number of patients with oculopalatal tremor (OPT). To determine regional cerebral glucose metabolism in patients with OPT, nine patients with OPT underwent FDG-PET of the brain. Their glucose metabolism was compared with that of 50 normal controls (NC) by using SPM analyses. Three patients had bilateral and six showed unilateral pseudohypertrophic degeneration of the inferior olivary nucleus (ION) on MRI. Compared with NC, OPT patients did not show any metabolic derangement in the anterolateral medulla where the pseudohypertrophic ION locates. Instead, six patients with unilateral ION changes had hypometabolism in ipsilesional pontine tegmentum and hypermetabolism in contralesional thalamus. Their metabolic changes did not depend on the lateralization of ION changes. Our study failed to present any metabolic evidence for the role of ION in the generation of OPT. In part, the failure might originate from the different pathomechanism between OPT and pure palatal tremor or sensitivity/specificity issues of PET and SPM analyses. But, our results suggest that impaired cell groups of the paramedian tract and thalamic tremor cells may contribute to the generation of OPT.

Glucose metabolism in early onset versus late onset Alzheimer's disease: an SPM analysis of 120 patients.

The aims of this cross-sectional study were (i) to compare the overall glucose metabolism between early onset and late onset Alzheimer's disease in a large sample of patients; and (ii) to investigate the pattern of glucose metabolism as a function of dementia severity in early onset versus late onset Alzheimer's disease, using a statistical parametric mapping (SPM) analysis. Subjects consisted of four groups: 74 patients with early onset Alzheimer's disease, 46 patients with late onset of the disease, and two control groups age matched to each patient group. All the subjects underwent 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET under the same scanning conditions. Severity of dementia was rated with the Clincial Dementia Rating (CDR). Voxel-based SPM99 was used for statistical analyses. Overall glucose hypometabolism of early onset Alzheimer's disease patients was much greater in magnitude and extent than that of late onset patients, though both groups were similar in dementia severity: the early onset group showed more severe hypometabolism in parietal, frontal and subcortical (basal ganglia and thalamus) areas. When the decline of glucose metabolism was compared as a function of CDR stage, the slope was steeper in early onset than in late onset Alzheimer's disease. The rapid decline occurred at CDR 0.5-1 in the early onset group, whereas similar changes occurred at CDR 2-3 in the late onset group. The greater hypometabolism in early onset than in late onset patients is required to reach the same severity of dementia, probably reflecting greater functional reserve in younger than in older subjects. Alternatively, the metabolic decline curve suggests that the early onset patients may take a more rapid course in the reduction of glucose metabolism than the late onset patients.

Neuroprotective effect of Ginkgo biloba L. extract in a rat model of Parkinson's disease.

The neuroprotective effects of a standardized extract of Ginkgo biloba L. (EGb 761) were investigated on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in the nigrostriatal dopaminergic system of the rat brain. Rats were given a week of pretreatment with daily administrations of EGb 761. Unilateral striatal injection of 6-OHDA was followed by treatment with EGb 761 for a week. Serial measurement of contralateral forepaw adjusting steps revealed a progressive deficit in motor activity. At 8 weeks after 6-OHDA lesion the number of contralateral forepaw adjusting steps was significantly higher in rats that were treated with high doses of EGb 761 (100 mg/kg daily) than in those treated with low doses (50 mg/kg) or with the vehicle. Dopamine neuron loss in the substantia nigra and a depletion in striatal dopamine corresponded with behavioural deficit. These data suggest that the neuroprotective effects of EGb 761 reduce the behavioural deficit in 6-OHDA lesions in rat and also indicates a possible role for the extract in the treatment of Parkinson's disease.

Ex vivo purging of leukemia cells using tumor-necrosis-factor-related apoptosis-inducing ligand in hematopoietic stem cell transplantation.

The aim of this study was to evaluate the potential of tumor-necrosis-factor-related apoptosis-inducing ligand TRAIL to eradicate leukemia cell lines, while sparing normal hematopoietic stem cells. Human Jurkat and Molt-4 cell lines were used to optimize the purging process in umbilical cord blood (UCB) mononuclear cells. The Jurkat cell line was TRAIL sensitive and TRAIL-resistant Molt-4 cell line became sensitive after being treated with TRAIL and a low dose of doxorubicin (0.1 micro M), but UCB mononuclear cells remained resistant. DR4 expression was increased when Jurkat cells were treated with TRAIL, and DR5 expression increased after exposing Molt-4 cells to TRAIL plus a low dose of doxorubicin for 24 h. The expression of DR4 and DR5 in UCB mononuclear cells was unchanged after treatment with TRAIL, a low-dose doxorubicin, or TRAIL plus a low dose of doxorubicin. In TRAIL-sensitive Jurkat cells, caspases 8, 9, 3, and 7 were activated by TRAIL treatment and activation of caspases was augmented by TRAIL plus a low dose of doxorubicin than TRAIL or a low dose of doxorubicin alone in Molt-4 cells. Experiments involving mixture of UCB mononuclear cells and Jurkat or Molt-4 cells showed a marked eradication of leukemia cells and the limiting dilution assay demonstrated an eradication rate of more than 4 logs after 24 h incubation with 100 ng/ml of TRAIL in Jurkat cells. In the case of Molt-4 cells, the eradication rate was about 3 logs when TRAIL was used in combination with a low dose of doxorubicin. No significant decrease in the number of granulocyte-macrophage colony-forming unit) (CFU-GM) colonies was detected when UCB mononuclear cells were treated with TRAIL in combination with a low dose of doxorubicin. These results suggest that TRAIL offers the possibility of being used as an ex vivo purging agent for autologous transplantation in hematologic malignancies.

Anti-angiogenic activity of torilin, a sesquiterpene compound isolated from Torilis japonica.

Torilin is a sesquiterpene compound purified from fruits of Torilis japonica (Umbelliferae). In this study, we demonstrated the anti-angiogenic activity of torilin using in vivo and in vitro assay systems. Torilin decreased both neovascularization of chick embryos in the chorioallantoic membrane assay and basic fibroblast growth factor-induced vessel formation in the mouse Matrigel plug assay. Torilin also reduced the proliferation and tube formation of human umbilical vein endothelial cells. In addition, the concentrated conditioned media obtained from torilin-treated HepG2 human hepatoblastoma cells blocked the angiogenic activation of torilin-untreated concentrated conditioned media, indicating that torilin may have an inhibitory effect on tumor-induced angiogenesis. To determine what molecules were involved in the anti-angiogenic activity, we examined the expression of hypoxia-inducible angiogenic factors in torilin-treated HepG2 cells. Torilin significantly down-regulated the expression of hypoxia-inducible vascular endothelial growth factor and insulin-like growth factor-II. Taken together, our data suggest that torilin may be a strong angiogenic inhibitor with the ability to decrease tube formation of vascular endothelial cells and to reduce expression of angiogenic factors of tumor cells.

Modulatory effect of ginseng total saponin on dopamine release and tyrosine hydroxylase gene expression induced by nicotine in the rat.

Several studies have demonstrated that behavioral activation induced by psychostimulants is prevented by ginseng total saponin (GTS), which has been known to act on the central dopaminergic system. In an attempt to investigate whether the effect of GTS is through its inhibitory action on the elevated dopaminergic transmission, we examined the effect of GTS on nicotine-induced dopamine (DA) release in the nucleus accumbens (NA) of freely moving rats using in vivo microdialysis. Systemic injection of nicotine (3 mg/kg; i.p.) produced a mild increase in extracellular DA of dialysates samples in the NA (132+/-13% over basal levels at the peak). GTS (100 mg/kg; i.p.) had no effect on resting levels of extracelluar DA. However, an increase in accumbens DA release produced by systemic nicotine was completely blocked by systemic pre-treatment with GTS (100 mg/kg; i.p.). In addition, the effect of GTS on nicotine-induced tyrosine hydroxylase (TH) and immediate early gene expression in ventral tegmental area (VTA) or NA regions was examined. A single injection of nicotine increased TH mRNA level at VTA region. GTS, which did not affect the basal TH mRNA expression, attenuated nicotine-induced TH mRNA expression. Nicotine slightly increased both c-fos and c-jun mRNA level and GTS, which did not affect the basal c-fos and c-jun mRNA expression, further enhanced nicotine-induced c-fos and c-jun mRNA level at both VTA and NA regions. Our results suggest that GTS may have an inhibitory action against nicotine-induced DA release in NA region and TH mRNA expression in VTA region. GTS may exert an potentiative effect on both c-fos and c-jun mRNA expression at NA region through inhibiting the release of DA in NA.

Preclinical impairment of the striatal dopamine transporter system in sporadic olivopontocerebellar atrophy: studied with [(123)I]beta-CIT and SPECT.

We investigated whether the dopamine (DA) transporter system is impaired in sporadic olivopontocerebellar atrophy (sOPCA) patients without clinical parkinsonism using the DA transporter radiotracer [(123)I]beta-CIT [2beta-carboxymethoxy-3beta-(4-iodophenyl)tropane] and single-photon emission computed tomography (SPECT). SPECT scans were acquired in 9 patients with sOPCA, 7 multiple system atrophy (MSA) patients with parkinsonism (MSA-P), and 7 age-matched healthy controls 20-24 h after the intravenous injection of [(123)I]beta-CIT. [(123)I]beta-CIT-specific binding in the striatum was determined as the radioactivity ratio of the striatum to the occipital cortex (specific binding ratio, SBR). In patients with sOPCA and MSA-P, SBRs in the right and left striatum and the mean SBR were significantly lower than those in controls (p < 0.05). The mean SBRs in patients with sOPCA and MSA-P were reduced to 69.0 and 60.7% of the control mean, respectively. However, there was no significant difference in SBRs between sOPCA and MSA-P patients. In sOPCA patients, the mean SBR was significantly correlated with the score of the clinical cerebellar function scale (r = -0.670, p = 0.024). These results indicate that even in the absence of clinical parkinsonism, the striatal dopaminergic system may be impaired in sOPCA. The DA transporter loss in sOPCA serves as another clue for sOPCA being a part of the spectrum of MSA.

Effect of ginseng total saponin on extracellular dopamine release elicited by local infusion of nicotine into the striatum of freely moving rats.

We investigated the effect of ginseng total saponin (GTS) on nicotine-induced dopamine (DA) release in the striatum of freely moving rats using an in vivo microdialysis technique. In order to further characterize the mechanism by which GTS affects DA release, the effect of GTS on K(+)-induced DA release was also examined. Local infusion of nicotine (1, 5, and 10 mM) into the striatum produced a dose-dependent increase in extracellular DA in dialysate samples (maximal response = 154.0 +/- 10.8%, 308.1 +/- 55.7%, and 499.9 +/- 77.9% over basal levels, respectively). GTS (100 mg/kg i.p.) had no effect on basal levels of extracellular DA. However, GTS inhibited maximal DA release induced by intrastriatal infusion of nicotine (1, 5, and 10 mM) by 35.3%, 36.6%, and 58.5%, respectively. Intra-striatal infusion of high K+ solution (100 mM) produced an increase in extracellular DA in the striatum (maximal response = 796.6 +/- 98.8% over basal levels). However, GTS had no effect on the K(+)-induced increase in extracellular DA. The present study demonstrated that GTS inhibited striatal DA release stimulated by local infusion of nicotine. This may reflect the blocking effect of GTS on the striatum-related behavior induced by nicotine as well as other psychostimulants. The results also suggest that GTS may act on presynaptic nicotinic acetylcholine receptors or receptor-operated Na+ channels in dopaminergic nerve terminals, but not on voltage-sensitive ion channels.

SPECT measurement of iodine-123-beta-CIT binding to dopamine and serotonin transporters in Parkinson's disease: correlation with symptom severity.

Iodine-123-beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) binds with high affinity to dopamine (DA) and serotonin (5-HT) transporters. This study examined the correlation of single-photon emission computed tomographic (SPECT) measures of [123I]beta-CIT binding to DA and 5-HT transporters with symptom severity in Parkinson's disease (PD). Forty-six L-dopa-responsive PD patients (Hoehn-Yahr stage 1-3) had SPECT scans at 20-24 h after injection of [123I]beta-CIT. Specific to nondisplaceable uptake ratios (designated V"3) were calculated in the striatum and hypothalamic/midbrain region, where the binding of [123I]beta-CIT is associated primarily with DA and 5-HT transporters, respectively. Striatal V"3 was significantly correlated with Hoehn-Yahr stage and total, motor and activities of daily living scores of Unified Parkinson's Disease Rating Scale (UPDRS). There was a significant correlation between the sum of lateralizing motor UPDRS subscores (tremor, rigidity, bradykinesia) calculated for each side of limbs and V"3 values in the contralateral striatum. No significant correlation was found between striatal V"3 and UPDRS rating of mentation, behavior, and mood. Hypothalamic/midbrain V"3 was not significantly correlated with either Hoehn-Yahr stage or UPDRS scores including both motor and nonmotor measures. The significant correlation of SPECT measures of striatal [123I]beta-CIT binding with motor severity suggests that [123I]beta-CIT binding to striatal DA transporters can serve as an in vivo indicator of disease severity in PD, with potential utility in the serial monitoring of disease progression.

Pregnane glycoside multidrug-resistance modulators from Cynanchum wilfordii.

The methanol-soluble extracts of the roots of Cynanchum wilfordii showed a significant multidrug-resistance-reversing activity, and four known pregnane glycosides were isolated by bioassay-directed fractionation and separation. Their structures were identified as gagaminin 3-O-beta-D-cymaropyranosyl-(1-->4)-beta-D-oleandropyranosyl- (1-->4)-b eta-D-cymaropyranosyl-(1-->4)-beta-D-cymaropyranoside (1), wilfoside K1N (2), wilfoside C1N (3), and cynauricuoside A (4). In particular, compound 1, at a concentration level of 1 microM, was found to completely reverse the multidrug-resistance of KB-V1 and MCF7/ADR cells to adriamycin, vinblastine, and colchicine.

Torilin, a sesquiterpene from Torilis japonica, reverses multidrug-resistance in cancer cells.

A sesquiterpene compound reversing multidrug-resistance in cancer cells was isolated from the fruits of Torilis japonica and the structure was identified as torilin. Torilin potentiated the cytotoxicities of adriamycin, vinblastine, taxol and colchicine against multidrug-resistant KB-V1 and MCF7/ADR cells.

Mode of action of torilin in multidrug-resistant cancer cell lines.

The mechanism of action of multidrug-resistance reversing activity of torilin was studied. In vitro experiments for the accumulation and efflux of vinblastine clearly indicated that MDR reversing effects of torilin would directly be associated with the increase of the intracellular accumulation of anticancer drugs by blocking the drug efflux. Furthermore, torilin increased the membrane ATPase activity from KB-V1 cells, suggesting that torilin might function by inhibiting drug transport mediated by P-glycoprotein.