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In this report, we present the case of a female infant with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) associated with a novel frameshift mutation (c.842dupT) in exon 5, the last exon of SOX10. She had severe hypoganglionosis in the small intestine and entire colon, and suffered from frequent enterocolitis. The persistence of ganglion cells made both the diagnosis and treatment difficult in the neonatal period. She also showed hypopigmentation of the irises, hair and skin, bilateral sensorineural deafness with hypoplastic inner year, severe demyelinating neuropathy with hypotonia, and diffuse brain hypomyelination. The p.Ser282GlnfsTer12 mutation presumably escapes from nonsense-mediated decay and may generate a dominant-negative effect. We suggest that hypoganglionosis can be a variant intestinal manifestation associated with PCWH and that hypoganglionosis and aganglionosis may share the same pathoetiological mechanism mediated by SOX10 mutations.

A novel methodology for the efficient synthesis of 3-aryloxindoles from isatin derivatives was developed. The methodology involves the formation of an oxindole having a phosphate moiety at the C-3 position via the [1,2]-phospha-Brook rearrangement under Bronsted base catalysis followed by palladium-catalyzed cross-coupling with aryl boron reagents. The one-pot synthesis of 3-aryloxindoles from isatin derivatives is also described.

A novel methodology for the efficient synthesis of 3-aryloxindoles from isatin derivatives was developed. The methodology involves the formation of an oxindole having a phosphate moiety at the C-3 position via the [1,2]-phospha-Brook rearrangement under Bronsted base catalysis followed by palladium-catalyzed cross-coupling with aryl boron reagents. The one-pot synthesis of 3-aryloxindoles from isatin derivatives is also described.

Atypical hemolytic uremic syndrome (aHUS), which is defined as non-Shiga toxin-associated hemolytic uremic syndrome, is a type of thrombotic microangiopathy. This syndrome presents with hemolytic anemia, thrombocytopenia, and acute kidney injury. Excessive complement activation due to genetic disorders of the complement system or production of autoantibodies to factor H (FH) causes the disease. We report a successful treatment course using eculizumab and recombinant human soluble thrombomodulin (rTMD) for a 7-year-old girl with aHUS due to anti-FH autoantibodies. Although her chief complaints were abdominal pain and loose stools, we were finally able to diagnose her with aHUS because Shiga toxin-producing Escherichia coli was not detected in her feces and a hemolytic assay analyzing FH function was positive. We administrated rTMD to our patient because of signs of disseminated intravascular coagulation. Soon after the therapeutic intervention, the platelet count began to increase and abdominal pain was moderately improved. Plasma exchange limited the efficacy of her disease. Therefore, we administered eculizumab, monoclonal humanized antibody against C5, 3 weeks after admission. Platelet counts immediately increased and kidney function gradually recovered. Genetic disorders were not detected. However, anti-FH autoantibody was observed. There were no symptoms for recurrence of aHUS or kidney dysfunction for 15 months, as a result of the administration of eculizumab every other week. In conclusion, combination therapy of eculizumab and rTMD was effective for an aHUS patient. This therapy may be helpful for improving the prognosis and long-term kidney function of aHUS patients.

Personality and emotional factors are supposed to influence the course of skin diseases, such as psoriasis and atopic dermatitis. Few reports exist, however, showing distinct personality traits among patients with psoriasis, atopic dermatitis patients and healthy controls. The aim of the present study was to examine personality differences among psoriasis patients, atopic dermatitis patients and healthy controls in Japan. A total number of 51 psoriasis patients, 97 atopic dermatitis patients and 48 healthy individuals were enrolled in the study. Questionnaires of Yatabe-Guilford Personality Inventory were administered individually. These groups were evaluated by 12 dimensions of temperaments. According to the dimension scores, personality was defined as five groups. Atopic dermatitis patients showed significantly higher scores regarding temperaments of depression, feelings of inferiority, nervousness and lack of objectivity than psoriasis patients. Regarding a temperament of cyclic tendency and lack of cooperativeness, female atopic dermatitis patients showed significantly higher scores than female psoriasis patients. Regarding general activity, female atopic dermatitis patients showed significantly lower scores than those of female psoriasis patients. No significant difference in scores of temperaments of lack of agreeableness, rhathymia, thinking extraversion, ascendance and social extraversion were detected among psoriasis patients, atopic dermatitis patients and healthy controls. The personalities of male psoriasis patients were significantly different from those of atopic dermatitis patients and healthy controls. Female psoriasis patients showed a significantly different personality profile from that of atopic dermatitis patients, but not from healthy controls. Japanese psoriasis and atopic dermatitis patients show distinct personality profiles suggesting that specific a psychosomatic approach may be required during the treatment.

57歳女性。初診の約2年前に左踵内側の褐色局面に気付いた。以後大きさ, 色調に変化はなかった。当科初診時, 同部に8.9×11.9×1.0mm大の, 淡褐色～褐色の扁平隆起性局面を認めた。全摘して組織学的に検討した。表皮には基底層部にメラノサイトの軽度の増数が見出され, 真皮浅層には顕著な線維化層が広範に認められた。この線維化層の下の真皮中深層部に異型細胞の増殖巣が見出され, 免疫染色にてS-100, MART-1陽性, HMB45陰性であった。組織学的に診断困難であったが, 悪性黒色腫を否定できないと考え, 原発巣の拡大再切除とセンチネルリンパ節生検を施行した。センチネルリンパ節の実質辺縁部にMART-1とHMB45陽性の細胞が数個散在性に見出された。本症例を悪性黒色腫と考え, 原発切除創周囲にインターフェロンβ蛋白の局注を施行している。

This study was conducted to investigate the effects of dietary diacylglycerol rich in α-linolenic acid (ALA-DAG) on body fat in human. The ALA-DAG contained 49% α-linolenic acid and was prepared from linseed oil using immobilized lipase. This study consisted of two types of dietary restriction and two types of diet. In test 1, 2.5-3.7g ALA-DAG was ingested as an edible oil under restriction of the amount of oil intake (50±5 g/d) for 12w (66 subjects). In tests 2 and 3, 2.5g ALA-DAG was ingested as a drink for 16w under calorie intake restriction determined based on subject’s calorie requirements (48 and 30 subjects, respectively). In all tests, after a 4 week control-diet period, the subjects started the diet and every 4 weeks during the test period, blood tests for fat metabolism were carried out and body indices (weight, waist, skinfold thickness, body fat computed with tomography) were measured. In subjects ingesting diets containing 2.5 g of ALA-DAG (test 1, 2 and 3), a significant decrease (-6.3∼-13.4%) of body fat area was observed. It was suggested that ALA-DAG had two characters of diacylglycerol and n-3 polyunsaturated fatty acid because of the high effectiveness of a small dose. These results showed that ALA-DAG improved fat metabolism and reduced body fat, and we speculate that ALA-DAG may be useful to reduce the risk of diseases associated with obesity.

The main objective of this study was to determine the influence of the degree of low density lipoprotein (LDL) oxidation and the location of oxidized LDL (oxLDL) on expression of adhesion molecules on endothelial cells (EC). OxLDL preparations 1-4 with different degrees of oxidative modification were studied. All preparations of oxLDL, after addition to the medium, stimulated the expression of intercellular adhesion molecule-1 (ICAM-1) by human umbilical vein endothelial cells (HUVEC) as determined by cell-ELISA. Concentration-dependent studies examining ICAM-1 expression by HUVEC showed that the minimal concentration of oxLDL which significantly stimulated ICAM-1 expression was 5 microg/ml, suggesting that the predicted physiological concentration of oxLDL in plasma may be not high enough to elicit a substantial increase of ICAM-1 expression in EC. In contrast, very small amounts (0.15 microg/well) of oxLDL-3 and 4, the more heavily oxidized LDL preparations, stimulated effectively ICAM-1 expression by HUVEC when located below the endothelial cell monolayer by immobilizing to type I collagen. The results suggest that the increased expression of ICAM-1 induced by accumulated oxLDL may be one of the mechanisms by which oxLDL contributes to atherogenesis.

It is well established that the n-3 polyunsaturated fatty acids influence lipid metabolism and reduce the serum triacylglycerol level. We previously reported that a dietary diacylglycerol rich in α-linolenic acid (ALA-DAG) significantly reduced body fat. In this study, we investigated the effects of the ingestion of ALA-DAG (2 g/day) for 12 weeks on body fat (test 1), lipid metabolism after ingestion for 6 weeks (test 2), and resting metabolism after ingestion for 6 weeks (test 3). The visceral fat area determined by computed tomography decreased significantly (11.3%, p

Abstract —Our previous studies have shown that Fc gamma receptor (FcγR)-mediated uptake of LDL-containing immune complexes (oxLDL-ICs) by human monocyte-derived macrophages leads to not only transformation of macrophages into foam cells but also macrophage activation and release of cytokines. It has been shown that cross-linking of FcγR triggers activation of signal transduction pathways that alter gene expression in macrophages. In this study, we determined whether engagement of FcγR by oxLDL-ICs leads to activation of mitogen-activated protein (MAP) kinase pathway, a signaling cascade serving many important functions, including the regulation of gene expression, in THP-1 macrophage-like cells. Our results from immunoblotting, using specific anti-phosphorylated MAP kinase antibodies, showed that oxLDL-ICs induced extracellular signal regulated kinase 2 (ERK2) MAP kinase phosphorylation in THP-1 macrophage-like cells in time- and dose-dependent manners. Cholesterol loading before stimulation led to a longer phosphorylation of ERK2. Nuclear translocation of phosphorylated ERK was markedly increased after the stimulation. Moreover, our data showed that oxLDL-IC induction of MAP kinase was prevented by human monomeric IgG1, suggesting that the specific engagement of type I FcγR by oxLDL-IC is responsible for the MAP kinase activation. Finally, we showed that human anti-oxLDL autoantibody-containing immune complexes immobilized on type I collagen induced MAP kinase activation in THP-1 cells. These results strongly suggest that oxLDL-IC, which has been detected in atherosclerotic plaques, may play an important role in macrophage activation and atherogenesis.

It has been reported that tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor that regulates the extrinsic blood coagulation pathway, is not expressed in human, bovine, rabbit, or rat liver. Here, we found that TFPI is efficiently expressed in Macaque monkey liver. Monkey hepatocytes were identified as the expression cells by Northern blot analysis. The hepatocytes were stained with anti-human TFPI antibody, as were endothelial cells of the small vessels. We isolated and sequenced the 5'-flanking 1.4 kb regions of monkey and human TFPI genes, and found them to show 92.6% identity in their nucleotide sequences. We measured their transcriptional activities using a luciferase reporter gene and showed that the activity of the monkey TFPI gene is higher than that of the human gene in monkey primary hepatocytes. Although the binding motif of hepatocyte nuclear factor-1 is present only in the monkey gene, the site does not seem to be involved in the transcriptional activity. Mutagenetic analyses revealed that the region from -138 to +28 in the monkey gene is important for the expression of TFPI in hepatocytes. The present study indicates that the expression of the monkey TFPI gene is regulated by different mechanisms from the human TFPI gene.

The incubation of human macrophages with antigen antibody complexes prepared with rabbit anti-LDL and human LDL (LDL-IC) is followed by ingestion of those immune complexes (IC), massive cholesterol ester accumulation, cytokine release and overexpression of the LDL receptor. The massive accumulation of cholesterol esters and overexpression of the native LDL receptor are specifically induced by immune complexes containing native or modified LDL, but not by any other type of IC. We report the results of a series of experiments aimed at defining the receptor preferentially involved in LDL-IC uptake. Flow cytometry studies using CD16, CD32 and CD64 monoclonal antibodies showed a sharp reduction on the expression of CD64 (Fc gamma RI) both by human monocyte-derived macrophages and THP-1 cells after incubation with LDL-IC, suggesting preferential engagement of this type of Fc receptor. Blocking experiments with aggregate-free IgG1 and CD32 monoclonal antibody confirmed that blocking Fc gamma RI prevented both LDL-IC uptake and the upregulation of LDL receptors on THP-1 cells. In contrast, blocking Fc gamma RII did not affect either the uptake of LDL-IC or the expression of LDL receptors on the same cells. The preferential engagement of Fc gamma R-I by LDL-IC suggests a biological difference of LDL-IC relative to other types of IC and opsonized particles. The precise molecular mechanism(s) responsible for the paradoxical upregulation of LDL receptor after the uptake of LDL-IC remain to be elucidated.

The effect of fibrin on angiogenesis in vitro was investigated using an experimental model of tube formation by bovine capillary endothelial cells (BCEs) in type I collagen gel. One milligram per milliliter of fibrin added into type I collagen gel significantly increased the length of the tubular structures formed by BCEs in the gel by about 180% compared with type I collagen only. The facilitating effect of fibrin on tube formation by BCEs was inhibited by either anti-basic fibroblast growth factor (bFGF) IgG (25 micrograms/ml) or anti-urokinase type plasminogen activator (uPA) IgG (10 micrograms/ml) added to the gel and culture medium, but not by anti-tissue type plasminogen activator (uPA) IgG (10 micrograms/ml) added to the gel and culture medium, but not by anti-tissue type plasminogen activator (10 micrograms/ml) or non-immune IgG. The Arg-Gly-Asp (RGD) containing peptides (100 micrograms/ml) added to the culture medium also suppressed tube formation by BCEs in fibrin-containing type I collagen gel, but not in type I collagen gel. These results suggest that the increased release of bFGF and uPA by BCEs therefore plays a role in the angiogenic effect of fibrin in vitro, and the angiogenic effect of fibrin is mediated by the RGD sequence in fibrin, probably via the function of integrin receptor of the BCEs.

To improve the production of extracellular polysaccharides (EPS) in liquid cultures of Polianthes tuberosa (tuberose) cells, the viscosity of the culture medium was lowered by addition of mineral salts. In cultures in the medium supplemented with 30 mM CaCl2, higher production of EPS (6.5g/l) has been realized (vs. 4.6 g/l without CaCl2).

The effects of components of the medium on the production of extracellular polysaccharide (EPS) by cultured cells of Polianthes tuberosa (tuberose) were studied. Optimization of media components culturing in flask resulted in increasing EPS production from 1.4 to 4.1 g/l. In particular, relatively high concentration (10\s-5M) of 2,4-dichlorophenoxyacetic acid (2,4-D) markedly stimulated the production of EPS. Based on these results, EPS production by a 30-1 jar fermenter was attempted and the final rate of Production was 4.6 g/l at 30th day of culture. The EPS consisted mainly of acidic polysaccharides with glucuronic acid, mannose, arabinose, galactose, glucose and xylose.

Magnetic surface breaking due to finite pressure effect is analyzed for three‐dimensional magnetohydrodynamic equilibria of l=2 heliotron/torsatron configuration. Characteristics of magnetic island formation are numerically studied in detail. Main results are as follows: (i) There exists a clear‐cut boundary, which practically determines the position of the outermost closed surface. The boundary position shifts as beta increases, though not affected by the external axisymmetric fields. (ii) The clear‐cut boundary is maintained for a higher beta plasma as the aspect ratio of the configuration increases. For a low aspect ratio configuration, however, high beta equilibria with clear surfaces can be obtained by controlling the external poloidal field, especially the vertical field. (iii) The external l=1 field is particularly viable in controlling the breaking of magnetic surfaces.

1981年から1990年の10年間に教室で経験したボーエン病30例およびボーエン癌2例について統計的に検討した。単発例26, 多発例6で, 男女差はなく, 70歳代に多い。好発部位は, 下肢8, 上肢7, 陰部, 体幹が各4の順である。内臓悪性腫瘍は32例中4例 (子宮頸癌, 耳下腺癌, 食道癌+胃癌, 前立腺癌) にみられ, 全例が単発例だった。多発例は6例中3例に砒素の関与が疑われた。また一般に, ボーエン病に合併する悪性腫瘍は皮膚癌が多く, 以下乳癌, 胃癌, 子宮癌の順だった。興味ある教室の4例をあわせて報告した。

The effects of annealing temperature on the room temperature tensile properties were investigated in a fine-grained Fe3Al based-alloy, and the correlation between microstructure, texture and tensile properties was discussed. Tensile elongation showed a peak as a function of annealing temperature. The highest elongation was obtained in the recrystallized samples annealed at 700°C. The decrease in the elongation with increasing annealing temperature above 700°C is attributed to the increase in the fraction of oriented grains with respect to the tensile direction. A high sensitivity to environmental embrittlement was observed in the partially recrystallized samples annealed at 650°C.

A thermomechanical process (TMP) for grain refinement was performed in bulk Fe3Al-based alloys containing ˜10% volume fraction of κ-Fe3AlC precipitates. In the TMP, κ particles play an important role in reducing the inhomogeneity of recrystallization due to the matrix orientation. The grain size was refined to ˜20 μm by optimizing the κ particle size. A fine-grained and pancake/recovered microstructure fabricated by the TMP showed more than 1200 MPa tensile strength and 8% tensile ductility at room temperature in air. The tensile strength of this material was higher than those of conventional wrought Fe3Al alloys at temperatures between room temperature and 500 °C, and the specific tensile strength was as high as that of the Ti-6Al-4V alloy at temperatures above 400 °C.

Three‐dimensional equilibrium and breaking of magnetic surfaces due to the finite beta effect in a l=2 heliotron/torsatron configuration are studied by using a newly developed three‐dimensional equilibrium code. The breaking is significantly suppressed as γc (pitch parameter) becomes smaller. An inward shift of the plasma by using the vertical field and elliptic (vertical) shaping using the quadrupole field can also suppress the breaking.

A high yield of extracellular polysaccharide (ECP) was obtained from callus cultures of tuberose (Polianthes tuberosa), which could be separated into an unadsorbed and two acidic fractions (TPS-1, -2) by ion-exchange column chromatography. The yields of each fraction were markedly increased by the addition of 10(-5) M 2,4-dichlorophenoxyacetic acid to the medium. Of the three fractions, the amount of TPS-1 accounted for over 60% of total yield of ECP, which was a predominant polysaccharide consisting of arabinose (Ara), mannose (Man) and galactose (Gal) as major neutral monosaccharides. Judging from the patterns of electrophoresis and ultra-centrifugation, TPS-1 was identified to be homogeneous. Methylation and GC-mass spectrometry analyses of this fraction revealed the presence of 1,2,3-linked Man, 1-linked Ara, 1,3-linked Ara, 1-linked Gal and 1,3,4-linked glucuronosyl (GlcUA) residues in a molar ratio of 1.0:1.08:0.85:0.75:1.08. Based on additional analyses of the mild acid hydrolysate and the absolute configuration of the constituent monosaccharides, a possible structure for TPS-1 was a glucuronomannan possessing the unit of -->4)-beta-D-GlcUAp-(1-->2)-alpha-D-Manp-(1--> with branching at the C-3 position, where -->1)-alpha-L-Araf, -->1)-beta-D-galp, -->1)-alpha-L-Araf-(3-->1)-alpha-L-Araf or -->1)-alpha-L-Araf-(3-->1)-beta-D-Galp were attached randomly. About 35% of the GlcUA moieties were present as methyl esters. Further confirmation was made by 1H and 13C NMR spectroscopy.