Automated brain tissue assessment in the elderly and demented population: construction and validation of a sub-volume probabilistic brain atlas

OBJECTIVES: To develop an automated imaging assessment tool that accommodates the anatomic variability of the elderly and demented population as well as the registration errors occurring during spatial normalization. METHODS: 20 subjects with Alzheimer's disease (AD), mild cognitive impairment, or normal cognition underwent MRI brain imaging and had their 3D volumetric datasets manually partitioned into 68 regions of interest (ROI) termed sub-volumes. Gray matter (GM), white matter (WM), and cerebral spinal fluid (CSF) voxel counts were then made in the subject's native space for comparison against automated volumetric measures within three sub-volume probabilistic atlas (SVPA) models. The three SVPAs were constructed using 12 parameter affine (12 p), 2nd order (2nd), and 6th order (6th) transforms derived from registering the manually partitioned scans into a Talairach compatible AD population-based target. The three SVPA automated measures were compared to the manually derived measures in the 20 subjects' native space with a "jack-knife" procedure in which each subject was assessed by an SVPA they did not contribute toward constructing. RESULTS: The mean left and right GM ratio (GM ratio = [GM + CSF] / CSF) "r values" for the 3 SVPAs compared to the manually derived ratios across the 68 ROIs were 0.85 for the 12p SVPA, 0.88 for the 2nd SVPA, and 0.89 for the 6th SVPA. The mean left and right WM ratio (WM ratio = [WM + CSF] / CSF) "r values" for the 3 SVPAs being 0.84 for the 12p SVPA, 0.86 for the 2nd SVPA, and 0.88 for the 6th SVPA. CONCLUSION: We have constructed, from an elderly and demented cohort, an automated brain volumetric tool that has excellent accuracy compared to a manual gold standard and is capable of regional hypothesis testing and individual patient assessment compared to a population.     

Differences in postoperative outcomes, function, and cosmesis: open versus robotic thyroidectomy

Background  

Robotic thyroidectomy using a gasless transaxillary approach, first described in 2008, has become popular. This study compared outcomes, including postoperative distress and patient satisfaction, for patients undergoing robotic thyroidectomy with those for patients treated by conventional open thyroidectomy.     

Relationship between olfactory function and olfactory neuronal population in C57BL6 mice injected intraperitoneally with 3-methylindole

Objective

It is not known how many olfactory receptor neurons should be intact to maintain olfaction in mouse models treated with 3-methylindole. The aim of this study is to investigate the relationship between a simple olfactory test outcome and the olfactory neuronal population.

Study Design

Mouse model.

Setting

Animal laboratory of the Seoul National University Bundang Hospital.

Subjects and Methods

Olfactory dysfunction was induced by intraperitoneal injection of 3-methylindole in 38 six-week-old female C57BL6 mice. Olfactory function was evaluated by a food-finding test following 72-hour starvation. The olfactory neuronal population was quantified by olfactory marker protein (OMP) expression.

Results

The average time for finding food was 8.1 seconds in control mice. It was 13.4, 84.4, 90.1, and 111.4 seconds for mice injected with 100, 200, 300, and 400 μg/g of 3-methylindole, respectively. Harvesting the whole olfactory neuroepithelium, densitometric analysis showed significant decrease of OMP in the 300- and 400-μg/g groups as compared with controls (18.8% and 17.5% of relative density, respectively). In the olfactory bulb, there was a significant decrease of OMP in the 200-, 300-, and 400-μg/g groups (44.5%, 37.0%, and 9.0% of relative density, respectively). The food-finding time had a significant reverse correlation with the relative density of OMP both in the olfactory bulb and in the olfactory neuroepithelium.

Conclusion

Our study showed that olfactory impairment was correlated with olfactory neuronal population in mice treated with 3-methylindole. The food-finding test would be a useful tool that could be easily performed without special training in the 3-methylindole-treated C57BL6 anosmic mouse model.     

Resveratrol enhances 5-hydroxytryptamine type 3A receptor-mediated ion currents: the role of arginine 222 residue in pre-transmembrane domain I

Resveratrol, which is found in grapes, red wine, and berries, has many beneficial health effects, such as anti-cancer, neuro-protective, anti-inflammatory, and life-prolonging effects. However, the cellular mechanisms by which resveratrol acts are relatively unknown, especially in terms of possible regulation of receptors involved in synaptic transmission. 5-Hydroxytryptamine type 3A (5-HT(3A)) receptor is one of several ligand-gated ion channels involved in fast synaptic transmission. In the present study, we investigated the effect of resveratrol on mouse 5-HT(3A) receptor channel activity. 5-HT(3A) receptor was expressed in Xenopus oocytes, and the current was measured using a two-electrode voltage clamp technique. Treatment of resveratrol itself had no effect on the oocytes injected with H(2)O as well as on the oocytes injected with 5-HT(3A) receptor cRNA. In the oocytes injected with 5-HT(3A) receptor cRNA, co- or pre-treatment of resveratrol with 5-HT potentiated 5-HT-induced inward peak current (I(5-HT)) with concentration-, reversible, and voltage-independent manners. The EC(50) of resveratrol was 28.0±2.4 μM. The presence of resveratrol caused a leftward shift of 5-HT concentration-response curve. Protein kinase C (PKC) activator or inhibitor had no effect on resveratrol action on I(5-HT). Site-directed mutations of pre-transmembrane domain 1 (pre-TM1) such as R222A, R222D, R222E, R222K, and R222T abolished or attenuated resveratrol-induced enhancement of I(5-HT), indicating that resveratrol might interact with pre-TM1 of 5-HT(3A) receptor. These results indicate that resveratrol might regulate 5-HT(3A) receptor channel activity via interaction with the N-terminal domain and these results further show that resveratrol-mediated regulation of 5-HT(3A) receptor channel activity might be one of cellular mechanisms of resveratrol action.     

Ginsenosides attenuate kainic acid-induced synaptosomal oxidative stress via stimulation of adenosine A(2A) receptors in rat hippocampus

Treatment with ginsenosides attenuated KA-induced seizures and oxidative stress in the synaptosome, and reduced synaptic vesicles at the presynaptic terminals dose-dependently. The adenosine A(2A) receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl) xanthine reversed the ginsenoside-mediated pharmacological actions. Neither the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine nor the adenosine A(2B) receptor antagonist alloxazine affected the ginsenoside-mediated pharmacological actions. Our results suggest that ginsenosides block KA-induced synaptosomal oxidative stress, associated with hippocampal degeneration, through activation of adenosine A(2A) receptors.     

Protection against kainate neurotoxicity by ginsenosides: attenuation of convulsive behavior, mitochondrial dysfunction, and oxidative stress

We previously demonstrated that kainic acid (KA)-mediated mitochondrial oxidative stress contributed to hippocampal degeneration and that ginsenosides attenuated KA-induced neurotoxicity and neuronal degeneration. Here, we examined whether ginsenosides affected KA-induced mitochondrial dysfunction and oxidative stress in the rat hippocampus. Treatment with ginsenosides attenuated KA-induced convulsive behavior dose-dependently. KA treatment increased lipid peroxidation and protein oxidation and decreased the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio to a greater degree in the mitochondrial fraction than in the hippocampal homogenate. KA treatment resulted in decreased Mn-superoxide dismutase expression and diminished the mitochondrial membrane potential. Furthermore, KA treatment increased intramitochondrial Ca(2+) and promoted ultrastructural degeneration in hippocampal mitochondria. Treatment with ginsenosides dose-dependently attenuated convulsive behavior and the KA-induced mitochondrial effects. Protection appeared to be more evident in mitochondria than in tissue homogenates. Collectively, the results suggest that ginsenosides prevent KA-induced neurotoxicity by attenuating mitochondrial oxidative stress and mitochondrial dysfunction.     

Age and body weight adjusted warfarin initiation program for ischaemic stroke patients

Background:  Despite its proven effect, anticoagulation is not recommended to the acute ischaemic stroke due to the risk of bleeding complications. The purpose of this study is development of individualized warfarin initiation program for acute or subacute stroke patients.
Methods:  Among stroke patients who regularly visited out-patient clinics, we included patients who have continuously taken the same dose of warfarin as the prothrombin time remained at target International Nomarlized Ratio (INR). We assessed potential variables that affect the maintenance dose of warfarin. Using these variables, we developed an individualized warfarin initiation program.
Results:  The median warfarin maintenance dose (interquartile range) in the 321 included patients was 4 (3–5) mg per day. Age (adjusted R ² = 0.221, P  <   0.001) and body weight (added to age, adjusted R ² = 0.238, P  =   0.008) were significant predicting factors of the dose. We classified the maintenance doses into high (HG), standard, and low group (LG) based on the distribution of maintenance doses. Decision tree analysis categorized younger (≤55 years old) and heavier (≥55 kg) patients into HG, and very old (≥80 years old) or low body weight (<55 kg among those >56 years old) patients into LG. We recommend 7 mg of warfarin as a standard initial dose, but 10 mg was recommended for HG patients and 5 mg for LG.
Conclusion:  We expect that this individualized program may reduce the time to target INR without excessive anticoagulation. Further prospective studies are needed to reveal the efficacy and safety of applying this program for acute stroke patients.     

Effect of Korean red ginseng extract in a steroid-induced polycystic ovary murine model

Experimental induction of polycystic ovary (PCO) in rodent resembling some aspects of human PCO syndrome was produced using the long-acting compound estradiol valerate (EV). Our previous study on the role of Korean red ginseng total saponins in a steroid-induced PCO rat model demonstrated that electro-acupuncture modulates nerve growth factor (NGF) concentration in the ovaries. In fact, the involvement of a neurogenic component in the pathology of PCO-related ovarian dysfunction is preceded by an increase in sympathetic outflow to the ovaries. In the present study, we tested the hypothesis that Korean red ginseng extract (KRGE) administration modulates sympathetic nerve activity in PCO-induced rats. This was done by analyzing NGF protein and NGF mRNA expression involved in the pathophysiological process underlying steroid-induced PCO. EV injection resulted in significantly higher ovarian NGF protein and NGF mRNA expression in PCO-induced rats compared to control rats, and PCO ovaries were counteracted by KRGE administration with significantly lower expression of NGF protein and NGF mRNA compared to EV treated ovaries. These results indicate that EV modulates the neurotrophic state of the ovaries, which may be a component of the pathological process by which EV induces cyst formation and anovulation in rodents. The first two authors contributed equally to this work.     

Quercetin Inhibits ��3��4 Nicotinic Acetylcholine Receptor-Mediated Ion Currents Expressed in Xenopus Oocytes

Quercetin mainly exists in the skin of colored fruits and vegetables as one of flavonoids. Recent studies show that quercetin, like other flavonoids, has diverse pharmacological actions. However, relatively little is known about quercetin effects in the regulations of ligand-gated ion channels. In the previous reports, we have shown that quercetin regulates subsets of homomeric ligand-gated ion channels such as glycine, 5-HT_3A and α7 nicotinic acetylcholine receptors. In the present study, we examined quercetin effects on heteromeric neuronal α3β4 nicotinic acetylcholine receptor channel activity expressed in Xenopus oocytes after injection of cRNA encoding bovine neuronal α3 and β4 subunits. Treatment with acetylcholine elicited an inward peak current (I_ACh) in oocytes expressing α3β4 nicotinic acetylcholine receptor. Co-treatment with quercetin and acetylcholine inhibited I_ACh in oocytes expressing α3β4 nicotinic acetylcholine receptors. The inhibition of I_ACh by quercetin was reversible and concentration-dependent. The half-inhibitory concentration (IC₅₀) of quercetin was 14.9±0.8 µM in oocytes expressing α3β4 nicotinic acetylcholine receptor. The inhibition of I_ACh by quercetin was voltage-independent and non-competitive. These results indicate that quercetin might regulate α3β4 nicotinic acetylcholine receptor and this regulation might be one of the pharmacological actions of quercetin in nervous systems.