Novel Olig 1-coding variants and susceptibility to multiple sclerosis.
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Adult↗
Biomedical subjects
M Ban
Publications and source records attributed to M Ban.
The BDNF-Val66Met polymorphism: implications for susceptibility to multiple sclerosis and severity of disease.
Neurodegeneration following inflammatory injury is considered to be a pathological correlate of irreversible disability in patients with multiple sclerosis. The availability of neurotrophins could influence the probability or rate of disease progression and the time of onset. The BDNF-Val66Met-polymorphism leads to altered intracellular transport and secretion of BDNF, and is thus a logical candidate for a gene that influences susceptibility and, more specifically, the clinical course of multiple sclerosis. In order to test this hypothesis we genotyped the polymorphism in 951 UK multiple sclerosis trio families, but found no evidence for association before (p=0.63) or after stratification for clinical course (p=0.73).
Brain-Derived Neurotrophic Factor↗
A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients.
The association of multiple sclerosis with alleles/haplotypes from the HLA region on chromosome 6p21 is well established although the remainder of the genome remains relatively unexplored. We have completed a genome-wide screen for linkage disequilibrium in a cohort of Australian multiple sclerosis patients positive for HLA-DRB1*1501. A total of 4346 microsatellite markers provided through the "Genetic Analysis of Multiple sclerosis in EuropeanS" (GAMES) collaborative were analysed in DNA separately pooled from cases (n=217) and controls (n=187). Associations were found in four genomic regions (12q15, 16p13, 18p11 and 19q13) previously identified in linkage genome screens. Three additional regions of novel association were also identified (11q12, 11q23 and 14q21). Further analysis of these regions is required to establish whether the associations observed are due to epistatic interaction with the HLA locus.
Adult↗
A genome screen for linkage in Australian sibling-pairs with multiple sclerosis.
The role of genetic factors in determining susceptibility to multiple sclerosis is well established but, despite the global distribution of the disease, systematic efforts to locate susceptibility genes have concentrated exclusively on populations from the Northern Hemisphere. We performed a genome wide screen of linkage in the Australian population using a panel of 397 microsatellite markers in 54 affected sibling-pairs. Multipoint linkage analysis revealed four regions of suggestive linkage (on chromosomes 2p13, 4q26-28, 6q26 and Xp11) and 18 additional regions of potential linkage (at 1q43-44, 3q13-24, 4q24, 4q31-34, 5q11-13, 6q27, 7q33-35, 8p23-21, 9q21, 13q31-32, 16p13, 16p11, 16q23-24, 17p13, 18p11, 20p12-11, Xp21-11 and Xq23-28). Our results contribute to the available data adding new provisional regions of linkage as well as increasing support for areas previously implicated in genetic susceptibility to multiple sclerosis.
Australia↗
The 2.6 A resolution structure of Rhodobacter capsulatus bacterioferritin with metal-free dinuclear site and heme iron in a crystallographic 'special position'.
Bacterioferritin from Rhodobacter capsulatus was crystallized and its structure was solved at 2.6 A resolution. This first structure of a bacterioferritin from a photosynthetic organism is a spherical particle of 24 subunits displaying 432 point-group symmetry like ferritin and bacterioferritin from Escherichia coli. Crystallized in the I422 space group, its structural analysis reveals for the first time the non-symmetric heme molecule located on a twofold crystallographic symmetry axis. Other hemes of the protomer are situated on twofold noncrystallographic axes. Apparently, both types of sites bind heme in two orientations, leading to an average structure consisting of a symmetric 50:50 mixture, thus satisfying the crystallographic and noncrystallographic symmetry of the crystal. Five water molecules are situated close to the heme, which is bound in a hydrophobic pocket and axially coordinated by two crystallographic or noncrystallographically related methionine residues. Its ferroxidase center, in which Fe(II) is oxidized to Fe(III), is empty or fractionally occupied by a metal ion. Two positions are observed for the coordinating Glu18 side chain instead of one in the E. coli enzyme in which the site is occupied. This result suggests that the orientation of the Glu18 side chain could be constrained by this interaction.
Bacterial Proteins↗
Relationship between IgE positive cell numbers and serum total IgE levels in mice treated with trimellitic anhydride and dinitrochlorobenzene.
Although increased total serum IgE levels have been suggested as being predictive parameters of airway hypersensitivity caused by low molecular weight chemicals, it is not yet clear what level of serum total IgE in chemically-treated animals would translate to potential risk of inducing an immediate type hypersensitivity in human beings. Quantitative determination of IgE-bearing positive cells induced by chemicals in the tissue, particularly in respiratory airway, could help to resolve this problem. In BALB/c mice, serum total IgE concentrations and tissue IgE-bearing positive cell numbers were investigated following topical exposure to the chemicals, trimellitic anhydride (TMA) and dinitrochlorobenzene (DNCB), known in human as a respiratory and dermal sensitizer, respectively. In groups of mice 8 and 10 weeks of age, there were less individual variations in 25% TMA-induced serum total IgE increase than in other groups of mice 6, 12 and 16 weeks of age. When chemical concentrations of 1, 2 and 3% DNCB and of 6.25, 12.5 and 25% TMA were studied, we observed that the increase in IgE was dose-dependent for both chemicals, r=0.96; P=0.03 for DNCB and r=0.99; P=0.002 for TMA. However, the increase in serum total IgE induced by TMA was at least twice that induced by DNCB and was associated with the numbers of IgE bearing cells in the tracheal lamina propria (r=0.67, P=0.0003). A respiratory hypersensitivity caused by TMA, but not by DNCB, may be partly due to the presence of immuno effector cells bearing IgE at their surface in airway microenvironments, and their presence might be related to the higher level of serum total IgE. The IgE bearing positive cells could, therefore, help to identify chemicals which have the potential risk of inducing an immediate type hypersensitivity in humans.
Aging↗
The ototoxic effects induced in rats by treatment for 12 weeks with 2-butenenitrile, 3-butenenitrile and cis-2-pentenenitrile.
Brainstem auditory and visual evoked-potentials were studied in male Sprague-Dawley rats during subchronic oral treatment with three unsaturated aliphatic nitriles. The rats were given, by gastric intubation, doses of 10, 20 and 40 mg x kg(-1) 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg x kg(-1) of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Rats in the high dosage groups exhibited a complete disappearance of the five waves of the auditory evoked-potentials. There was a decrease in the amplitudes of the 2nd component of the auditory evoked-potentials. Those changes were not reversible at the 8th week of the recovery period. A dose-dependent effect on inner and outer hair cells was observed in the organ of Corti. The basal part of the cochlea was the most affected. Though no measurements were made of systemic exposure, a tentative ranking of decreasing ototoxicity of these three unsaturated nitriles might be proposed based on the electrophysiological deficiencies and histological losses observed: 3-butenenitrile >cis-2-pentenenitrile >cis/trans-2-butenenitrile. Moreover, rats treated with those nitriles showed a corneal opacity as well as a decrease in the amplitude and lengthening of the peak latencies of the visual evoked-potentials. These latter changes were reversible by the end of the 8th week of the recovery period and appeared to be related to the opacity of the cornea.
Administration, Oral↗
The number and distribution of Merkel cells in rudimentary polydactyly.
BACKGROUND: Rudimentary polydactyly histologically reveals a marked neural proliferation in the dermis and a large number of Meissner corpuscles in the dermal papillae. OBJECTIVE: Our study was performed to determine whether this neural proliferation is related to Merkel cells. METHOD: Using an antibody to cytokeratin 20, we examined the number and distribution of Merkel cells in 5 cases of rudimentary polydactyly, including an immature case without Meissner corpuscles. RESULTS: Only the case without Meissner corpuscles had a markedly large number of Merkel cells and some dermal Merkel cells. CONCLUSION: The normal number of Merkel cells in the mature cases suggests that abundant Merkel cells may appear at first and disappear after the development of neural proliferation. Merkel cells may be associated with the generation of cutaneous nerve plexus and nerve endings in the upper dermis, and possibly with the development of Meissner corpuscles, at the early stage of rudimentary polydactyly.
Adult↗
Enthalpic destabilization of glycosylated lysozymes constructed by genetic modification.
To understand the role of polyglycosylation in protein stability, the thermodynamic changes in the denaturation of various polymannosyl lysozyme mutants (R21T, G49N, R21T/G49N) constructed by genetic modification were analyzed using differential scanning calorimetry (DSC). The denaturation temperature and the enthalpy change for unfolding of the lysozymes were reduced with an increase in the length of the polymannose chain and the number of binding sites to a protein, although the polymannosyl lysozymes revealed apparent heat stability in that no aggregation was observed and the enzymatic activity was conserved under conditions in which the wild-type lysozyme coagulated [S. Nakamura et al., J. Biol. Chem. 268 (1993) 12706-12712]. The reversibility of the denaturation of polymannosyl lysozymes was observed in the DSC curves obtained by reheating after heat denaturation, while it was not observed for the wild-type lysozyme. Based on these results, the polymannosyl lysozyme seems to easily refold due to the excellent reversibility of denaturation, despite the decreases in the enthalpic stabilization due to the strain in the protein molecule by the introduction of a polysaccharide chain.
Binding Sites↗
Effects of nickel sulfate on pulmonary natural immunity in Wistar rats.
This study was designed to investigate the in vivo effect of nickel sulfate on the pulmonary non-specific immune defences. Groups of four male Wistar rats were treated with a single intratracheal instillation of NiSO(4) at different doses: 1, 2, 4 and 8 micromol of NiSO(4) per rat. Control rats received a corresponding instillation of the saline vehicle. The effect of NiSO(4) on the cytotoxic activity of the pulmonary natural killer (NK) cells and alveolar macrophages (AM), as well as the pulmonary production of cytokines such as alpha-tumor necrosis factor (TNF-alpha) and gamma-interferon (IFN-gamma), were examined 1, 2 and 7 days later. Spontaneous NK-cytotoxicity towards mouse-derived tumor cell line, Yac-1 was suppressed 1 day after treatment at doses of 2 micromol/rat and above with only one result significant (P<0.05); 2 days after treatment the suppression was increased with all results significant at the same doses; 1 week after treatment NK activity restoration was observed except for the highest dose, 8 micromol/rat. AM-mediated cytotoxicity towards mouse-derived tumor cell line, 3T12, did not show any significant difference in treated and untreated animals. In contrast, whereas moderate levels of TNF-alpha were detected in the broncho-alveolar lavage (BAL) fluid supernatants of controls, the NiSO(4) treatment highly suppressed TNF-alpha production with a maximum observed after 2 days. TNF-alpha suppression was found to be transient, at least with the lowest NiSO(4) dose, with levels returning to normal after 7 days. A non-significant increase in IFN-gamma was observed in the BAL fluids of treated animals at each time of examination. Taken together, these results indicate that NK cell activity and TNF-alpha secretion are sensitive targets for instilled NiSO(4) in Wistar rats.
Animals↗
A refractory case of secondary erythermalgia successfully treated with lumbar sympathetic ganglion block.
A 59-year-old Japanese man with myasthenia gravis, who had a 10-year history of temperature-sensitive pain in the lower extremities, i.e. improved by cooling and worsened by warming, consulted us because the pain had become intolerable during the previous 4 months. Bilateral erythema, swelling and large ulcers were noted on the calves, dorsal aspects of the feet, and soles. Laboratory data showed thrombocythaemia and a positive antibody to the acetylcholine receptor, but were negative for antinuclear and antiphospholipid antibodies. A diagnosis of secondary erythermalgia was made because of the clinical features, the laboratory data, and the lack of family history of this disease. Although steroid pulse therapy, oral aspirin and antiserotonin drugs were ineffective, bilateral lumbar sympathetic ganglion block succeeded in relieving the severe pain and curing the ulcers. The clinical course in our patient suggests that sympathetic ganglion block may be one of the most effective treatments for secondary erythermalgia. Although the mechanism of this effect is uncertain, microcirculation disturbance in secondary erythermalgia, if any, may be improved by this block.
Erythromelalgia↗
Role of the cyclic AMP response element binding complex and activation of mitogen-activated protein kinases in synergistic activation of the glycoprotein hormone alpha subunit gene by epidermal growth factor and forskolin.
The aim of these studies was to elucidate a role for epidermal growth factor (EGF) signaling in the transcriptional regulation of the glycoprotein hormone alpha subunit gene, a subunit of chorionic gonadotropin. Studies examined the effects of EGF and the adenylate cyclase activator forskolin on the expression of a transfected alpha subunit reporter gene in a human choriocarcinoma cell line (JEG3). At maximal doses, administration of EGF resulted in a 50% increase in a subunit reporter activity; forskolin administration induced a fivefold activation; the combined actions of EGF and forskolin resulted in synergistic activation (greater than eightfold) of the alpha subunit reporter. Mutagenesis studies revealed that the cyclic AMP response elements (CRE) were required and sufficient to mediate EGF-forskolin-induced synergistic activation. The combined actions of EGF and forskolin resulted in potentiated activation of extracellular signal-regulated kinase (ERK) enzyme activity compared with EGF alone. Specific blockade of ERK activation was sufficient to block EGF-forskolin-induced synergistic activation of the alpha subunit reporter. Pretreatment of JEG3 cells with a p38 mitogen-activated protein kinase inhibitor did not influence activation of the alpha reporter. However, overexpression of c-Jun N-terminal kinase (JNK)-interacting protein 1 as a dominant interfering molecule abolished the synergistic effects of EGF and forskolin on the alpha subunit reporter. CRE binding studies suggested that the CRE complex consisted of CRE binding protein and EGF-ERK-dependent recruitment of c-Jun-c-Fos (AP-1) to the CRE. A dominant negative form of c-Fos (A-Fos) that specifically disrupts c-Jun-c-Fos DNA binding inhibited synergistic activation of the alpha subunit. Thus, synergistic activation of the alpha subunit gene induced by EGF-forskolin requires the ERK and JNK cascades and the recruitment of AP-1 to the CRE binding complex.
Choriocarcinoma↗
Tufted angioma of adult onset, revealing abundant eccrine glands and central regression.
Tufted angioma (angioblastoma) usually occurs in infancy. Some lesions reveal proliferation of eccrine glands and some undergo spontaneous regression. We report a lesion from the left lateral chest of a 58-year-old male, which had appeared 5 years ago and gradually increased in size. Its color had faded out centrally. Histological examination showed many angiomatous lobules on the border of the lesion but few in the central portion. Abundant eccrine sweat glands, small venules and dense connective tissue were seen in both areas. The histology and the clinical course suggested that central regression occurred in the lesion. Out of 211 reported cases, we found 4 cases that had annular lesions spreading centrifugally. Though these lesions were not examined histologically, they were suspected to regress in the central portions. We suggest that central regression can rarely occur in tufted angioma.
Age of Onset↗
Changes in the levels of mRNAs for GH/prolactin/somatolactin family and Pit-1/GHF-1 in the pituitaries of pre-spawning chum salmon.
Changes in the levels of pituitary mRNAs encoding GH, prolactin (PRL) and somatolactin (SL) were determined in pre-spawning chum salmon (Oncorhynchus keta) caught at a few key points along their homing pathway in 1994 and 1995. Furthermore, we analyzed relationships between expression of pituitary-specific POU homeodomain transcription factor (Pit-1/GHF-1) and GH/PRL/SL family genes. In 1994, seawater (SW) fish and matured fresh-water (FW) fish were sequentially captured at two points along their homing pathway, the coast and the hatchery. In addition to these two points, maturing FW fish were captured at the intermediate of the two points in 1995. The levels of hormonal mRNAs were determined by a quantitative dot blot analysis using single-stranded sense DNA as the standard. Relative levels of Pit-1/GHF-1 mRNAs were estimated by Northern blot analysis. In 1994, the levels of GH/PRL/SL family mRNAs except for PRL mRNA in the male FW fish were 1.8-4 times higher than those in the SW fish. In 1995, the level of PRL mRNA was somewhat sharply elevated in the maturing FW fish soon after entry into the FW environment, while that of SL mRNA was gradually increased during upstream migration from the coast to the hatchery. The levels of 3 kb Pit-1/GHF-1 mRNA in the FW fish were higher than those in the SW fish in both 1994 and 1995. The present results indicate that expression of genes for the GH/PRL/SL family and Pit-1/GHF-1 is coincidentally enhanced in homing chum salmon. Moreover, the present study suggests that expression of the SL gene is elevated with sexual maturation, whereas that of PRL gene is elevated with osmotic change during the final stages of spawning migration.
Animals↗
Serum-borne factor(s) of 1,1-dichloroethylene and 1,2-dichlorobenzene-treated mice inhibited in vitro antibody forming cell response and natural killer cell activity.
1,1-Dichloroethylene and 1,2-dichlorobenzene administered to mice produced liver and/or kidney damage which was quantified in this study by a histochemical method. The in vitro effect of sera obtained from these mice on antibody forming cell (AFC) response and natural killer (NK) cell activity was investigated in parallel with the assessment of sera tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. 1,1-Dichloroethylene (100, 150 and 200 mg/kg) provoked liver and kidney damage. Peak kidney damage occurred 16 h after the dose was administered and at 24 h in the case of the liver. During the peak level of liver damage, a serum-borne immunosuppressive effect was also at its highest level. With respect to sera cytokine levels, an increase of TNF-alpha and IL-6 was detected earlier, i.e. 6 h after toxic administration, followed by a decrease that tended toward a baseline level. There was a relationship between the tissue damage induced by 1,1-dichloroethylene and the immunosuppressive effect of mice sera on AFC response and NK cell activity. 1,2-Dichlorobenzene (300, 500 and 600 mg/kg) provoked only liver damage. Peak liver damage severity was observed 48 h after toxic administration, whereas the highest serum-borne immunosuppressive effect was observed almost immediately, i.e. 6 h after administration. As regards sera cytokine levels, only TNF-alpha could be detected 6 h after administering 500 and 600 mg/kg doses of 1,2 dichlorobenzene. There was a relationship between the liver damage induced by 1,2-dichlorobenzene and the immunosuppressive effect of mice sera on the AFC response. In view of the above results, this study suggests that the immunosuppressive effect in sera of mice treated with 1,1-dichloroethylene and 1,2-dichlorobenzene may result from tissue damage, and that the increased levels of TNF-alpha and IL-6 in sera may contribute to this effect. Further studies are needed to clarify the factor(s) responsible, including transforming growth factor-beta1 (TGF-beta1) causing immunosuppression.
Animals↗
Novel antiallergic agents. Part I: Synthesis and pharmacology of pyrimidine amide derivatives.
We have synthesized many pyrimidine amide derivatives. Novel pyrimidine bis-glycolic amide derivatives showed moderate inhibition in the rat passive cutaneous anaphylaxis (PCA) assay by oral administration. Among these compounds, 2,4-bis(methoxyacetylamino)-6-piperidinopyrimidine (2i) exhibited significant inhibition. However the compound (2i) did not inhibit antigen-induced histamine or SRS-A release from lung fragments of the guinea-pig at less than 10(-4) M. Derivatives of 2i have also notable or moderate activity in the rat PCA assay. Compound 2h which has no oxygen atom at the alpha-position of the amide carbonyl group and, compound 17 which has no amide carbonyl group, showed no inhibition in the rat PCA assay. We supposed that both the amide carbonyl group and the oxygen atom at alpha-position of the amide carbonyl group play an important role in inhibiting the rat PCA reaction. These pyrimidine bis-glycolic amide derivatives have a novel structure and unique activity which suggests they may be potentially useful in the treatment of allergic diseases.
Administration, Oral↗
Novel antiallergic and antiinflammatory agents. Part I: Synthesis and pharmacology of glycolic amide derivatives.
A series of mono-glycoloylamino derivatives was synthesized by treatment of the corresponding aromatic monoamine derivatives with glycoloyl chloride derivatives in pyridine or dichloromethane, in the presence of a base such as triethylamine or pyridine. Hydrolysis of acetoxy compounds in aqueous ammonia and methanol solution produced hydroxy derivatives with ease. These compounds were tested in the rat PCA (passive cutaneous anaphylaxis) assay by oral administration. Thiazole and thiadiazole derivatives showed moderate inhibition in this assay. In contrast, benzothiazole and benzonitrile derivatives exhibited marked inhibition. In particular, compound 5t also showed marked inhibition of eosinophil adhesion to TNF (tumor necrosis factor) -alpha-treated HUVEC (human umbilical vein endothelial cells) in the range of 10(-8)-10(-5) M.
Administration, Oral↗
Novel antiallergic and antiinflammatory agents. Part II: Synthesis and pharmacology of TYB-2285 and its related compounds.
A series of m-bis(glycoloylamino)benzene derivatives was synthesized by treatment of the corresponding m-diaminobenzene derivatives with glycoloyl chloride derivatives in pyridine. Hydrolysis of acetyl compounds gave hydroxy derivatives, from which other acyl derivatives could be synthesized. These compounds were tested in the rat PCA (passive cutaneous anaphylaxis) assay by oral administration. Benzonitrile derivatives (4c, 5c, 6c, 4h, 5h) exhibited notable inhibition in this assay. Compounds 5c and 6c also showed remarkable inhibition of eosinophil adhesion to TNF- (tumor necrosis factor) alpha-treated HUVEC (human umbilical vein endothelial cells) in the range of 10(-8)-10(-5) M. Compound 5c is now under investigation in Japan as TYB-2285 (Figure 1) for asthma and atopic dermatitis in phase II clinical studies.
Administration, Oral↗