Waves Out of the Korean Peninsula and Inter- and Intra-Species Replacements in Freshwater Fishes in Japan.

The Japanese archipelago is located at the periphery of the continent of Asia. Rivers in the Japanese archipelago, separated from the continent of Asia by about 17 Ma, have experienced an intermittent exchange of freshwater fish taxa through a narrow land bridge generated by lowered sea level. As the Korean Peninsula and Japanese archipelago were not covered by an ice sheet during glacial periods, phylogeographical analyses in this region can trace the history of biota that were, for a long time, beyond the last glacial maximum. In this study, we analyzed the phylogeography of four freshwater fish taxa, Hemibarbus longirostris, dark chub Nipponocypris temminckii, Tanakia ssp. and Carassius ssp., whose distributions include both the Korean Peninsula and Western Japan. We found for each taxon that a small component of diverse Korean clades of freshwater fishes migrated in waves into the Japanese archipelago to form the current phylogeographic structure of biota. The replacements of indigenous populations by succeeding migrants may have also influenced the phylogeography.

Ultraviolet Reflectance Structures of Peacock Feathers.

Male peacock (Pavo cristatus) tail feathers have an eyespot pattern with an inconspicuous black or dark blue center surrounded by brilliant, structural colors, such as blue, light brown, and yellow-green. Under ultraviolet A (UVA), the central part of the eyespot reflects UVA better than the surrounding parts. Herein, I examined various areas of eyespots on paraffin sections of feathers using an optical microscope, and characterized positional relationships between barbs and barbules. These analyses confirmed that barbules in the central part of the eyespot are in a horizontal position with respect to the barb, and that light transmission from the central part is less than that from the other parts. In addition, I compared microstructures of barbules in the central part of eyespot with those in surrounding areas using transmission electron microscope analysis. The melanin rods in the barbules reflecting yellow-green color comprise several ordered lattice structures. In contrast, melanin rods in the central part of the eyespot were only distributed in 1-3 layers on a part of the front side of the barbules. I also demonstrated that keratin structures of barbules are homogeneous in the central part of the eyespot, but have fibrous structures with many voids in the yellow-green parts. Collectively, the present observations suggest that feathers in the central part of the eyespot reflect UVA depending on the direction of irradiation, and these properties are governed by configurations of barbules relative to barbs, melanin rod distributions, and the presence of keratin structures with gaps.

Reflectance Spectra of Peacock Feathers and the Turning Angles of Melanin Rods in Barbules.

I analyzed the association between the reflectance spectra and melanin rod arrangement in barbules of the eyespot of peacock feathers. The reflectance spectra from the yellow-green feather of the eyespot indicated double peaks of 430 and 540 nm. The maximum reflectance spectrum of the blue feather was 480 nm, and that of the dark blue feather was 420 nm. The reflectance spectra from brown feathers indicated double peaks of 490 and 610 nm. Transmission electron microscopic analysis confirmed that melanin rods were arranged fanwise in the outer layer toward the barbule tips. In addition, using polarized light microscope, I attempted to determine whether the turning angles of melanin rods in the barbules reflected different colors. The turning angle of the polarizing axis of the barbules was supported by that of the melanin rods, observed using transmission electron microscopic images. To compare the turning angle of melanin rods in the respective barbules, I calculated the opening width of the fanwise melanin rods by dividing the width of the barbules by the turning angle of the polarizing axis of barbules and obtained a positive correlation between the reflectance spectra and opening width of the fanwise melanin rods. Moreover, the widely spreading reflection from the barbules may occur because of the fanwise melanin rod arrangement.

Acute Multiple Cerebral Infarction in a Patient with an Accessory Mitral Valve.

A 96-year-old woman developed hemiparesis 2 weeks after orthopedic surgery. Magnetic resonance imaging revealed multiple cerebral infarctions in the bilateral hemisphere. Transthoracic echocardiography revealed a mobile structure attached to the anterior mitral leaflet that protruded toward the left ventricular outflow tract. The structure was identified as an accessory mitral valve. Doppler echocardiography showed that there was no significant left ventricular outflow obstruction. This is a rare case of a silent accessory mitral valve that was detected after multiple cerebral infarctions.

Pustular-type drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to carbamazepine with systemic muscle involvement.

Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe reaction usually associated with maculopapular eruptions and systemic involvement. Here we report the first case, to our knowledge, of DIHS/DRESS due to carbamazepine with acute generalized pustular bacterid-like (AGPB-like) eruptions and skeletal muscle involvement. Reviewing our case and the published work, we discuss pustular-type DIHS/DRESS which, in most cases, involves acute generalized exanthematous pustulosis (AGEP)-like skin eruptions in response to carbamazepine. Pustular eruptions may appear in relatively few cases of DIHS/DRESS, in particular, when the causative drug is carbamazepine and, even in cases of intractable pustular bacterid-like eruptions, a reaction to a drug should be suspected. Skeletal muscle involvement may be associated with DIHS/DRESS as one of its systemic manifestations.

Synthesis and pharmacological evaluation of 2-(1-alkylpiperidin-4-yl)-n-[(1r)-1-(4-fluorophenyl)-2-methylpropyl]acetamide Derivatives as Novel Antihypertensive Agents.

We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca(2+) channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca(2+) channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca(2+) channels over L-type Ca(2+) channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca(2+) channels over L-type Ca(2+) channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.

Evaluation of the regional cerebral blood flow changes during long-term donepezil therapy in patients with Alzheimer's disease using 3DSRT.

BACKGROUND: We attempt to evaluate objectively the regional cerebral blood flow (rCBF) changes during long-term donepezil therapy and the relationship between the clinical response and rCBF change in patients with Alzheimer's disease (AD). PATIENTS AND METHODS: Thirty-one patients with mild-to-moderate AD (11 men, 20 female; mean age, 76.2 ± 6.7 years) were treated with donepezil and underwent brain perfusion single-photon emission computed tomography (SPECT) twice with an interval of 24.5 ± 4.2 months. The rCBF was calculated using 3-dimensional stereotaxic region of interest template, a fully automated each region of interest technique. We compared the differences in rCBF between baseline and follow-up SPECT studies. Moreover, all patients were divided into stabilized (n = 14) and nonstabilized subgroups (n = 17) based on Mini-Mental State Examination (MMSE) score changes and the changes in rCBF were compared between two subgroups. RESULTS: The mean MMSE score significantly decreased from 20.7 ± 4.6 at baseline to 16.5 ± 6.5 after 2 years. The mean rCBF significantly decreased in the widespread brain regions between the baseline and follow-up SPECT studies. The nonstabilized subgroup showed a significant decrease in rCBF of the parietal and temporal segments compared to the stabilized subgroup. CONCLUSION: The progression of cognitive deterioration may be related to rCBF affected by the neuropathologic changes of AD.

Synthesis and pharmacological evaluation of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents.

We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca(2+) channel blocker. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca(2+) channel blockers.

Synthesis and pharmacological evaluation of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel antihypertensive agents.

A series of 1-isopropyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and their bradycardic activities were evaluated in isolated guinea pig right atria. Structure-activity relationship studies revealed that the introduction of an appropriate substituent and its position on the 1,2,3,4-tetrahydroisoquinoline ring are essential for potent in vitro activity. Furthermore, the tether between the piperidyl moiety and the terminal aromatic ring is important for potent antihypertensive activity. Oral administration of 6-fluoro-1-isopropyl-2-{[1-(2-phenylethyl)piperidin-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline (3b) to spontaneously hypertensive rats (SHR) elicited antihypertensive effects without inducing reflex tachycardia, which is often caused by traditional L-type Ca²âº channel blockers.

Synthesis and pharmacological evaluation of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents.

We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that dialkyl substituents at the benzylic position play an important role in increasing inhibitory activity. Oral administration of N-[2-ethyl-2-(4-fluorophenyl)butyl]-1-(2-phenylethyl)piperidine-4-carboxamide (20d) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.

Brain perfusion differences in parkinsonian disorders.

We aimed to objectively examine the brain perfusion differences between PD, Parkinson variant of multiple system atrophy, and progressive supranuclear palsy. (99m) Tc ethylcysteinate dimer single-photon emission CT (SPECT) was performed in 28 patients with PD, 12 with Parkinson variant of multiple system atrophy, 19 with progressive supranuclear palsy, and 17 age- and sex-matched control subjects. A voxel-by-voxel group analysis, using statistical parametric mapping 8, was performed to detect the differences of regional cerebral blood flow among three diseases and control groups. Regional cerebral blood flow was measured using the noninvasive Patlak plot method and calculated using a fully automated region of interest technique. Progressive supranuclear palsy showed decreased regional cerebral blood flow in the cingulate gyrus and thalamus, whereas Parkinson variant of multiple system atrophy showed decreased regional cerebral blood flow in the cerebellum, compared with other patients and controls. Regional cerebral blood flow in the thalamus could be used to discriminate progressive supranuclear palsy from other diseases and control subjects with high sensitivity. These findings suggest that parkinsonian disorders, such as PD, Parkinson variant of multiple system atrophy, and progressive supranuclear palsy show a distinct SPECT pattern in the frontal cortex, thalamus, and cerebellum. Moreover, the measurements of regional cerebral blood flow in the thalamus and cerebellum may be helpful in screening for the differential diagnosis of parkinsonian syndrome.

Regulatory mechanism of silkworm hemocyte adhesion to organs.

Circulating hemocytes in the body fluid of the silkworm are increased during the larval-larval molting period. We investigated hemocyte adhesion to organs mediating the selectin-selectin ligands during the feeding period and the larval-larval molting period using the lectin staining method, sugar chain digestion test with glycoside hydrolases, and the hemocyte adhesion inhibition test using monosaccharides. The results of these tests suggested that the selectin ligand involved in hemocyte adhesion was the Sialyl Lewis x-type, and the structure was changed from the feeding period to the larval-larval molting period. Beta-galactosidase appears to be an enzyme that eliminates N-acetylgalactosamine and sialylated N-acetylgalactosamine from the terminal of Sialyl Lewis x. Beta-galactosidase activation in skin basement membranes, muscle, fat bodies, midguts, and hemocytes increased markedly during the larval-larval molting period, and at that time, hemocytes were detached from organs. Adding 20-hydroxyecdysone or its analog, tebufenozide to cultured fat bodies increased ß-galactosidase activity in these tissues. Therefore, 20-hydroxyecdysone may induce a structural change in Sialyl Lewis x type sugar chains on the cell surface of silkworm's organs by increasing the ß-galactosidase activity to detach hemocytes from organs and increase the number of circulating hemocytes during the larval-larval molting period.

Induction of ß-catenin by the suppression of signal regulatory protein α1 in K562 cells.

The signal regulatory protein (SIRP) α1 is a cell surface receptor expressed predominantly in monocytes, granulocytes, dendritic cells, as well as hematopoietic stem cells. In contrast, SIRPα1 expression is significantly reduced in the majority of myeloid malignancies. SIRPα1 is a negative regulator of signaling and its reduced expression is considered to play a role in the pathogenesis of these diseases through aberrant signaling. To identify SIRPα1 downstream target genes, we established SIRP α1-knockdown chronic myeloid leukemia K562 (K562SIRPα1KD) cells expressing reduced levels of SIRPα1 by stably transfecting SIRPα1 siRNAs. Microarray analysis demonstrated that several genes, including ß-catenin, were significantly induced in K562SIRPα1KD cells. Real-time PCR and Western blot analyses, confirmed the induction of this gene. Phosphorylation of Ser9 of glycogen synthesis kinase (GSK) -3ß, results in the inactivation of GSK-3ß, leading to the induction of ß-catenin. We found significant phosphorylation of extracellular signal-regulated kinase (ERK), Akt, as well as of GSK-3ß-Ser9, which may play a role in the up-regulation of ß-catenin in K562SIRPα1KD cells. To our knowledge, this is a first report demonstrating the relationships between SIRPα1 and ß-catenin in leukemia cells.

[A case of limbic encephalitis repeated aphasic status epilepticus with periodic lateralized epileptiform discharges].

We report a case of limbic encephalitis repeated aphasic status epilepticus with periodic lateralized epileptiform discharges (PLEDs). A 51-year-old man developed convulsions, psychiatric symptoms such as anxiety, phobia and ease of anger, and Wernicke's aphasia. Analysis of the cerebrospinal fluid (CSF) showed increase of leukocyte count (148/microl, mononuclear cells). Brain magnetic resonance imaging (MRI) showed hyperintensity lesions in the left medial temporal area and basal frontal area on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. The electroencephalography (EEG) showed PLEDs over the left hemisphere, occurring at intervals of 0.5-1 Hz. Although his limbic symptoms improved, Wernicke's aphasia occurred periodically with PLEDs appearance. After the administration of antiepileptic drugs, his language performance improved, and PLEDs were completely disappeared. We diagnosed him limbic encephalitis with non-convulsive repeated aphasic status epilepticus with periodic lateralized epileptiform discharges. Aphasic status epilepticus should be considered in the patients with limbic encephalitis, and careful evaluation of aphasia and EEG should be necessary to diagnose of aphasic status epilepticus.

Relationship between thyroid hormone levels and regional cerebral blood flow in Alzheimer disease.

Subclinical thyroid disease and even variations in thyroid function within the normal range is associated with cognitive function and a risk of Alzheimer disease (AD). Several studies reported the effect of thyroid hormones on cerebral blood flow. The aim of this study was to objectively evaluate regional cerebral blood flow (rCBF) in association with thyroid hormone levels within the normal range in patients with AD. Serum thyroid-stimulating hormone (TSH), free T3, and free T4 levels were measured in 62 patients with AD (23 men and 39 women; age 56 to 91 y; mean age 77.3 y) and 27 control subjects (9 men and 18 women; age 61 to 93 y; mean age 75.8 y). The 99mTc ethylcysteinate dimer single photon emission computed tomography was performed in all subjects. The rCBF in the region of interest was measured by the noninvasive Patlak plot method and calculated using FineSRT, which is a fully automated region of interest technique. No significant correlation was found between thyroid hormone levels and Mini-Mental State Examination scores or global CBF values. Serum levels of TSH, but not free T3 or free T4, were significantly inversely correlated with rCBF in the middle and inferior temporal regions of right cerebral hemisphere in patients with AD. Control subjects showed no significant correlation between thyroid hormone levels and rCBF. Although these findings of a regional relationship must be considers preliminary, this study proposed the hypothesis that altered TSH levels within the normal range may be related to brain perfusion in right temporal region.

Evaluation of the effects of thyrotropin releasing hormone (TRH) therapy on regional cerebral blood flow in the cerebellar variant of multiple system atrophy using 3DSRT.

BACKGROUND: Thyrotropin releasing hormone (TRH) improves cerebellar ataxia and cerebellar perfusion in patients with spinocerebellar degeneration. It is not known whether TRH therapy can improve the cerebellar regional cerebral blood flow (rCBF) or not in patients with cerebellar variant of multiple-system atrophy (MSA-C). PATIENTS AND METHODS: Seven patients with MSA-C received TRH intravenously (2 mg/day) for 14 days. Clinical efficacy was assessed using the International Cooperative Ataxia Rating Scale (ICARS) and brain perfusion single photon emission-computed tomography was performed before and after therapy. The rCBF in each region of interest (ROI) was calculated using 3DSRT, a fully automated the ROI technique. RESULTS: The ICARS scores slightly improved in 6 of the 7 patients after TRH therapy, but this was not statistically significant. After TRH therapy, the cerebellar rCBF reduced in the 6 of 7 patients and the mean rCBF in cerebellum also significantly decreased (P=0.029, paired t-test), whereas the rCBF in the precentral segment tend to increase (P=0.048, paired t-test). CONCLUSION: TRH therapy may be less effective on cerebellar ataxia and cerebellar rCBF in MSA-C. The 3DSRT program may be useful for the evaluation of the efficacy of TRH therapy on cerebral blood flow.

Metallothionein-1 isoforms and vimentin are direct PU.1 downstream target genes in leukemia cells.

PU.1 is a key transcription factor for hematopoiesis and plays important roles in various hematological malignancies. To clarify the molecular function of PU.1, we initially tried to identify bona fide target genes regulated by PU.1. Dual microarrays were employed for this study to compare PU.1-knockdown K562 cells (K562PU.1KD) stably expressing PU.1 short inhibitory RNAs versus control cells and PU.1-overexpressing K562 cells (K562PU.1OE) versus control cells. In these analyses, we found that several genes, including metallothionein (MT)-1 isoforms (MT-1G and MT-1A) and vimentin (VIM), were markedly induced while Jun dimerization protein (JDP) 2 was suppressed in K562PU.1KD cells. Furthermore, the mRNA expressions of the MT-1 and VIM genes were inversely correlated and the mRNA expression of JDP2 was positively correlated with PU.1 mRNA expression in 43 primary acute myeloid leukemia specimens (MT-1G: R = -0.50, p < 0.001; MT-1A: R = -0.58, p < 0.0005; VIM: R = -0.39, p < 0.01; and JDP2: R = 0.30, p < 0.05). Next, we analyzed the regulation of the MT-1 and VIM genes. We observed increased associations of acetylated histones H3 and H4 with the promoters of these genes in K562PU.1KD cells. Sequence analyses of the regions approximately 1 kb upstream from the transcription start sites of these genes revealed numerous CpG sites, which are potential targets for DNA methylation. Chromatin immunoprecipitation assays revealed that methyl CpG-binding protein 2 (MeCP2) and PU.1 bound to the CpG-rich regions in the MT-1 and VIM promoters. Bisulfite sequencing analyses of the PU.1-bound regions of these promoters revealed that the proportions of methylated CpG sites were tightly related to the PU.1 expression levels.