Involvement of the Thalamus, Hippocampus, and Brainstem in Hypsarrhythmia of West Syndrome: Simultaneous Recordings of Electroencephalography and fMRI Study.

BACKGROUND AND PURPOSE: West syndrome is a developmental and epileptic encephalopathy characterized by epileptic spasms, neurodevelopmental regression, and a specific EEG pattern called hypsarrhythmia. Our aim was to investigate the brain activities related to hypsarrhythmia at onset and focal epileptiform discharges in the remote period in children with West syndrome using simultaneous electroencephalography and fMRI recordings. MATERIALS AND METHODS: Fourteen children with West syndrome underwent simultaneous electroencephalography and fMRI at the onset of West syndrome. Statistically significant blood oxygen level-dependent responses related to hypsarrhythmia were analyzed using an event-related design of 4 hemodynamic response functions with peaks at 3, 5, 7, and 9 seconds after the onset of each event. Six of 14 children had focal epileptiform discharges after treatment and underwent simultaneous electroencephalography and fMRI from 12 to 25 months of age. RESULTS: At onset, positive blood oxygen level-dependent responses were seen in the brainstem (14/14 patients), thalami (13/14), basal ganglia (13/14), and hippocampi (13/14), in addition to multiple cerebral cortices. Group analysis using hemodynamic response functions with peaks at 3, 5, and 7 seconds showed positive blood oxygen level-dependent responses in the brainstem, thalamus, and hippocampus, while positive blood oxygen level-dependent responses in multiple cerebral cortices were seen using hemodynamic response functions with peaks at 5 and 7 seconds. In the remote period, 3 of 6 children had focal epileptiform discharge-related positive blood oxygen level-dependent responses in the thalamus, hippocampus, and brainstem. CONCLUSIONS: Positive blood oxygen level-dependent responses with hypsarrhythmia appeared in the brainstem, thalamus, and hippocampus on earlier hemodynamic response functions than the cerebral cortices, suggesting the propagation of epileptogenic activities from the deep brain structures to the neocortices. Activation of the hippocampus, thalamus, and brainstem was still seen in half of the patients with focal epileptiform discharges after adrenocorticotropic hormone therapy.

Increased susceptibility to apoptosis in CD45(+) myeloma cells accompanied by the increased expression of VDAC1.

Expression of CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45(+) U266 proliferates in response to a growth factor, interleukin-6. Here, we show that CD45(+) myeloma cell lines were more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress, than CD45(-) cells. Reactive oxygen species and calcium ion seemed to be involved in the susceptibility to apoptosis of CD45(+) U266. The activation of the src family kinases associated with CD45 phosphatase played an important role in the augmented apoptosis in CD45(+) U266 by oxidative stress. These results indicate that the CD45-expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45(+) myeloma cells dependently upon the circumstantial stimuli. Furthermore, voltage-dependent anion channel (VDAC) 1 was identified as a gene highly expressed in CD45(+) U266 by cDNA subtraction. The increased expression of VDAC1 seemed to augment the sensitivity to the ER-stress because the VDAC1-transfected U266 was more susceptible to the thapsigargin-induced apoptosis. Thus, CD45 expression accompanied by the increased VDAC1 expression sensitizes myeloma cells to the various extracellular stimuli that trigger apoptosis via the mitochondrial pathways.

Multi-layered network structure of amino acid (AA) metabolism characterized by each essential AA-deficient condition.

The concentrations of free amino acids in plasma change coordinately and their profiles show distinctive features in various physiological conditions; however, their behavior can not always be explained by the conventional flow-based metabolic pathway network. In this study, we have revealed the interrelatedness of the plasma amino acids and inferred their network structure with threshold-test analysis and multilevel-digraph analysis methods using the plasma samples of rats which are fed diet deficient in single essential amino acid. In the inferred network, we could draw some interesting interrelations between plasma amino acids as follows: 1) Lysine is located at the top control level and has effects on almost all of the other plasma amino acids. 2) Threonine plays a role in a hub in the network, which has direct links to the most number of other amino acids. 3) Threonine and methionine are interrelated to each other and form a loop structure.

Outcomes of flexor tendon repairs in zone 2 subzones with early active mobilization.

We report on the outcomes of flexor tendon repair in zone 2 subzones with early active mobilization in 102 fingers in 88 consecutive patients. There were 28, 53, 15, and six fingers with repairs in zones 2A to 2D, respectively. Rupture of the repair occurred in four fingers, all in zone 2B. Excluding those with repair ruptures, the mean total active motion was 230° (range 143°-286°). Evaluated with Tang's criteria, the outcomes were ranked excellent in 39 fingers, good in 46, fair in ten, poor in three, and failure in four. The outcomes in zone 2C were significantly inferior to those in zones 2B and 2D ( p = 0.02). Our results suggest that the tendon laceration in the area covered by the A2 pulley (zone 2C) is the most difficult area to obtain satisfactory active digital motion and tendon repair in zone 2B is the area where the risk of rupture is highest. LEVEL OF EVIDENCE: IV.

Clinical results of releasing the entire A2 pulley after flexor tendon repair in zone 2C.

UNLABELLED: We report the results of complete release of the entire A2 pulley after zone 2C flexor tendon repair followed by early postoperative active mobilization in seven fingers and their comparisons with 33 fingers with partial A2 pulley release. In seven fingers, release of the entire A2 pulley was necessary to allow free gliding of the repairs in five fingers and complete release of both the A2 and C1 pulleys was necessary in two. No bowstringing was clinically evident in any finger. Two fingers required tenolysis. Using Tang's criteria, the function of two digits was ranked as excellent, four good and one fair; there was no failure. The functional return in these seven fingers was similar with that in 33 fingers with partial A2 pulley release; in these patients only one finger required tenolysis. Our results support the suggestion that release of the entire A2 pulley together with the adjacent C1 pulley does not clinically affect finger motion or cause tendon bowstringing, provided that the other pulleys are left intact. LEVEL OF EVIDENCE: IV.

Outcomes of release of the entire A4 pulley after flexor tendon repairs in zone 2A followed by early active mobilization.

We report the outcomes of repair of the flexor digitorum profundus tendon in zone 2a in 22 fingers. The tendon was repaired with a six-strand repair method and the A4 pulley was completely released. Release of the C2 pulley combined with the A4 pulley was necessary in 12 fingers, nine fingers underwent a complete release of the A3, C2, and A4 pulleys, and one finger underwent a release of the C1, A3, C2, and A4 pulleys. The mean total active motion of the three finger joints was 234° at 5 to 12 months of follow-up. No bowstringing was noted in these fingers. The good and excellent recovery of active digital motion was in 20 (91%) out of 22 fingers according to Strickland's criteria or Tang's criteria. Our results suggest that release of the A3, C2, and A4 pulleys makes the repair surgery easier and does not cause tendon bowstringing.

2,3,5-Trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861), a selective inhibitor of the 5-lipoxygenase reaction and the biosynthesis of slow-reacting substance of anaphylaxis.

2,3,5-Trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861) inhibited 5-lipoxygenase of guinea pig peritoneal polymorphonuclear leukocytes (ID50, 0.8 microM). The inhibition was of competitive type. 12-Lipoxygenases and fatty acid cyclooxygenase were not affected below 10 microM. The formation of slow-reacting substance of anaphylaxis by the sensitized guinea pig lung was almost fully suppressed by the compound at 10 microM.

Clinical outcomes of early active mobilization following flexor tendon repair using the six-strand technique: short- and long-term evaluations.

We evaluated the factors influencing outcomes of flexor tendon repair in 112 fingers using a six-strand suture with the Yoshizu #1 technique and early postoperative active mobilization in 101 consecutive patients. A total of 32 fingers had injuries in Zone I, 78 in Zone II, and two in Zone III. The mean follow-up period was 6 months; 16 patients (19 fingers) participated in long-term follow-up of 2 to 16 years. The total active motion was 230° SD 29°; it correlated negatively with age. The total active motion was 231° SD 28° after repair of the lacerated flexor digitorum superficialis tendon, and was 205° SD 37° after excision of the flexor digitorum superficialis tendon ends (p = 0.0093). A total of 19 fingers showed no significant increases in total active motion more than 2 years after surgery. The rupture rate was 5.4% in our patients and related to surgeons' level of expertise. Five out of six ruptured tendons were repaired by inexperienced surgeons. Level of Evidence IV.

Community-Based Intervention for Prevention of Dementia in Japan.

Population aging is accelerating, with prolonged life expectancy and a decrease in birth rate. As age is a significant risk factor for dementia, we are confronted with an ever-increasing prevalence of mild cognitive impairment (MCI)/dementia. Thus, the Japanese National Center for Geriatrics and Gerontology launched a project to promote community-based research, including the development of an effective screening system for high-risk groups and intervention for dementia prevention. This review introduces the project, the Obu Study of Health Promotion for the Elderly, with the following strategic triad: 1) Identification of the target population by population screening; we regarded patients with MCI as the target population, and developed a screening test battery to identify MCI in a population screening setting. 2) Scientific evaluation of community-based intervention; we developed an interventional method combining exercise and cognitive training ("cognicise"). In practical settings, "cognicise" is programmed into multicomponent exercise intervention, which was reported to have benefits of cognitive improvement and reduction of brain atrophy based on randomized controlled trials. 3) Standardization of the methods of population screening and community-based intervention for evidence-based policy making and widespread implementation. Dementia prevention, or at least delaying the onset of dementia and/or stopping/slowing the progression of dementia, should benefit the whole society as well as individuals. It is our continuing challenge to improve the screening system and community-based intervention for dementia prevention through accumulation of evidence.

A 5 kDa protein (SCS23) from the 30 S subunit of the spinach chloroplast ribosome.

The proteins of the 30 S ribosomal subunits from spinach chloroplasts were investigated using a radical-free and highly reducing (RFHR) method of two-dimensional polyacrylamide gel electrophoresis (PAGE). Twenty-three proteins were resolved on the gel down to the smallest protein of 5 kDa. The N-terminal amino acid sequence of the 5 kDa protein showed no homology with that of any other protein stored in databases, and the copy numbers were estimated to be 0.88 +/- 0.16 and 0.72 +/- 0.04 in the 30 S subunits and the 70 S ribosomes, respectively. The results suggest that the 5 kDa protein, which we have called SCS23, may be an essential ribosomal protein specific to spinach chloroplasts.

Molecular cloning and characterization of a rice dehydroascorbate reductase.

Plant dehydroascorbate reductase (DHAR), which re-reduces oxidized ascorbate to maintain an appropriate level of ascorbate, is very important, but no gene or cDNA for plant DHAR has been cloned yet. Here, we describe a cDNA for a rice glutathione-dependent DHAR (designated DHAR1). A recombinant Dhar1p produced in Escherichia coli was functional. The expression sequence tag database suggests that Dhar1p homologs exist in various plants. Furthermore, the rice Dhar1p has a low similarity to rat DHAR, although the rice enzyme has a considerably higher specific activity than the mammalian one. The mRNA level of DHAR1, the protein level of Dhar1p and the DHAR activity in rice seedlings were elevated by high temperature, suggesting the protection role of DHAR at high temperature.

A new nonsteroidal analgesic-antiinflammatory agent. Synthesis and activity of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone and related compounds.

In order to examine analgesic and antinflammatory activities, various 2-alkyl- or 2-alkenyl-4-alkoxy-5-(substituted amino)-3(2H)-pyridazinones were prepared. Among the compounds prepared, 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (8) was evaluated to be the most attractive compound as an analgesic-antiinflammatory agent. Compound 8 was shown to be more potent in analgesic and antiinflammatory activities and less potent in toxicity than aminopyrine and phenylbutazone. Some pyridazinone derivatives in which possible active sites of 8 are eliminated and altered were prepared, and their activities were evaluated by means of analogous assays. On the basis of available data, the structure-activity relationship in a series of 4-alkoxy-2-substituted-5-(substituted amino)-3(2H)-pyridazinones was also discussed.

Studies on antianaphylactic agents. 6. Synthesis of some metabolites of 6-ethyl-3-(1H-tetrazol-5-yl)chromone and their analogues.

The metabolites of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) (1), an orally effective antiallergic agent, and their analogues were synthesized to confirm the proposed structures and to determine their activity in the rat passive cutaneous anaphylaxis (PCA) test. A glucuronic acid metabolite (6) was assigned the structure 24b, 1-deoxy-1-[5-(6-ethylchromon-3-yl)tetrazol-1-yl]-beta-D-glucopyranuronate, by the comparison of 13C NMR, mass spectra, and TLC of isomeric compounds. In 13C NMR spectra, the shift difference of the tetrazole ring carbons between a pair of isomers was more remarkable than that of the glycosidic carbons. Therefore, the former is a useful criterion for distinguishing between such isomers. Some of the metabolities and analogues were active when administered intravenously, and two metabolites (2 and 3) were also effective upon oral administration.

Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines.

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.

Changes in quinone profiles of hot spring microbial mats with a thermal gradient

The respiratory and photosynthetic quinones of microbial mats which occurred in Japanese sulfide-containing neutral-pH hot springs at different temperatures were analyzed by spectrochromatography and mass spectrometry. All of the microbial mats that developed at high temperatures (temperatures above 68 degreesC) were so-called sulfur-turf bacterial mats and produced methionaquinones (MTKs) as the major quinones. A 78 degreesC hot spring sediment had a similar quinone profile. Chloroflexus-mixed mats occurred at temperatures of 61 to 65 degreesC and contained menaquinone 10 (MK-10) as the major component together with significant amounts of either MTKs or plastoquinone 9 (PQ-9). The sunlight-exposed biomats growing at temperatures of 45 to 56 degreesC were all cyanobacterial mats, in which the photosynthetic quinones (PQ-9 and phylloquinone) predominated and MK-10 was the next most abundant component in most cases. Ubiquinones (UQs) were not found or were detected in only small amounts in the biomats growing at temperatures of 50 degreesC and above, whereas the majority of the quinones of a purple photosynthetic mat growing at 34 degreesC were UQs. A numerical analysis of the quinone profiles was performed by using the following three parameters: dissimilarity index (D), microbial divergence index (MDq), and bioenergetic divergence index (BDq). A D matrix tree analysis showed that the hot spring mats consisting of the sulfur-turf bacteria, Chloroflexus spp., cyanobacteria, and purple phototrophic bacteria formed distinct clusters. Analyses of MDq and BDq values indicated that the microbial diversity of hot spring mats decreased as the temperature of the environment increased. The changes in quinone profiles and physiological types of microbial mats in hot springs with thermal gradients are discussed from evolutionary viewpoints.

Actions of antisecretory agents on proton transport in hog gastric microsomes.

The properties of K+-stimulated ATP hydrolysis (K+-ATPase) and vesicular accumulation of H+ (H+ accumulation) in hog gastric microsomes were investigated. The microsomes consisted of smooth surfaced vesicular particles, 70-300 nm in diameter. Both the activities of ATPase and the vesicular accumulation of H+ were stimulated by K+ in the presence of Mg2+, and enhanced by the K+-ionophore, valinomycin. However, there were differences in regulation of K+-ATPase and H+ accumulation by K+ ions, i.e. K+ at concentrations higher than 10 mM decreased K+-ATPase activity but further enhanced H+ transport. This observation suggests that the two reactions are partly independent. The H+ accumulation was inhibited by omeprazole, fenoctimine, spermine, and NaSCN, but not by cimetidine, prostaglandin E2, and atropine. The inhibitory effect of omeprazole on H+ accumulation paralleled the inhibition of K+-ATPase, while fenoctimine, spermine, and NaSCN suppressed H+ accumulation, without inhibiting K+-ATPase, under appropriate concentrations. In addition, the spontaneous diffusion of H+ across the microsomal membrane was markedly enhanced by fenoctimine, but not by the other agents used. These results indicate that omeprazole inhibits H+ accumulation by inhibiting K+-ATPase, fenoctimine suppresses H+ accumulation mainly by increasing the loss of accumulated H+ from the microsomal vesicles, spermine and NaSCN reduce H+ accumulation by inhibiting the transport of H+ into microsomal vesicles.