Biomedical subjects
Publications and source records attributed to Takashi Takei.
Three-dimensionally ordered macroporous carbons were prepared from bimodal polymer-silica colloidal crystals; the resulting carbons had interconnected macropores, and the walls of the macropores were composed of hollow mesosized spheres.
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Previously, we discovered single-nucleotide polymorphisms (SNPs) associated with Immunoglobulin A (IgA) nephropathy in selectin genes, which were 712C>T(P238S) in L selectin, -642A>G in the promoter region of L selectin, and 1402C>T(H468Y) in E selectin. Interestingly, these SNPs were in nearly complete linkage disequilibrium, thus two haplotypes, disease-associated TGT and wild-type (Wt) CAC, were constructed. To investigate the functional significance of TGT haplotype, a stable CHO transfectant expressing a P238S-L-selectin variant (CHO-varL) and a recombinant adenovirus vector containing an H468Y-E-selectin variant (Ad-varE) were established and compared to their Wt counterparts. Under flow, CHO-varL exhibited significantly less adhesion over IL-1beta-activated HUVEC monolayers compared to CHO-wtL. Furthermore, a luciferase reporter construct, containing a promoter region of the L-selectin variant (luc-varL), exhibited significantly less transcription activity compared to Wt (luc-wtL). These results suggest that the adhesive interactions and expression level of L selectin in disease-associated haplotypes are significantly compromised, indicating a potential role of these SNPs in the pathogenesis of inflammatory diseases, including IgA nephropathy.
Silica gel was used as core particles to design a simple preparation for controlled delivery system with a high drug content. Drug loading was carried out by immersing the silica gel in a pre-heated drug solution or suspension. HPLC, SEM, DSC, PXRD analysis and N2 adsorption studies evaluated the drug-loading process. In the next step, the drug-loaded silica gel was coated with hydroxypropyl methylcellulose (HPMC) and an aqueous dispersion of ethylcellulose (Aquacoat) to control the drug release. The release profile was determined using a dissolution test. The results showed that silica gel could adsorb great quantities of the drug, up to about 450 mg/g, by repetition of the loading process. Evaluation of the drug-loading process indicates that drug deposition in the pores occurs during the loading process and the drug-loading efficacy is strongly related to the drug solubility. On the other hand, the dissolution test showed that the drug release could be controlled by polymer coating the drug-loaded silica gel. An HPMC undercoating effectively suppresses the drug release, as it smoothes the drug-loaded core surface and aids in the formation of a continuous Aquacoat coating film. The floating property was also observed during the dissolution test.
A 69-year-old woman, who had been diagnosed with interstitial pneumonia at 66 years of age, was admitted to our hospital because of high fever, purpura occurring on her arms and legs, and renal dysfunction. At the time of admission, her renal function had severely deteriorated (sCr 8.2 mg/dl, 24 h Ccr 6 ml/min), she had a severe high fever (BT 39.5 degrees C), back pain, a white blood cell count of 19,540/,microl, and a CRP level of 26.7 mg/dl. Blood and urine cultures yielded identical strains of E. coli. We diagnosed sepsis caused by pyelonephritis, and started intravenous meropenem trihydrate(MEPM) at 0.5 g/day. Her renal dysfunction was severe, so we started hemodialysis therapy. Immunological examination revealed the presence of ANCA-associated glomerulonephritis. Renal biopsy before steroid therapy confirmed the diagnosis of pauci-immune-type crescentic glomerulonephritis. Based on purpura and interstitial pneumonia, along with rapidly MPO-ANCA-positive progressive glomerulonephritis (RPGN) with acute renal failure, we diagnosed microscopic polyangitis (MPA). To treat sepsis and severe pyelonephritis, we started intravenous immunoglobulin 5 g (100 mg/kg)/day for 5 days before starting immunosuppressive steroid therapy (m-PSL 1 g/day, PSL 20 mg/day) for 3 days. These treatments improved her general condition and immediately improved her renal function. It is important to prevent infection during treatment using conventional immunosuppressive therapy. These findings suggest immunoglobulin therapy to be a safe immuno-suppressive treatment that is efficacious against ANCA-associated glomerulonephritis.
Immunoglobulin A (IgA) nephropathy is the most common form of primary glomerulonephritis worldwide. The pathogenesis of IgA nephropathy is unknown, but it is certain that some genetic factors are involved in susceptibility to the disease. Employing a large-scale, case-control association study using gene-based single-nucleotide polymorphism (SNP) markers, we previously reported four candidate genes. We report here an additional significant association between IgA nephropathy and an SNP located in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2) at chromosome 11q13.2-q13.4. The association (chi2 =17.1, p = 0.00003; odds ratio of 1.85 with 95% confidence interval of 1.39-2.50 in a dominant association model) was found using DNA from 465 affected individuals and 634 controls. The SNP (G34448A) caused an amino acid substitution from glutamine to lysine (E928K). As the gene product is involved in immunoglobulin-class switching and patients with the A allele revealed higher serum levels of IgA (p = 0.048), the amino acid change might influence a class switch to increase serum IgA levels, resulting in a higher risk of IgA nephropathy.
BACKGROUND: Osteoprotegerin (OPG) is a glycoprotein that inhibits osteoclast differentiation and activity. OPG-deficient mice develop severe osteoporosis and medial arterial calcification. The expression of OPG is detected in early atherosclerotic lesions in non-uraemic patients. We examined whether serum OPG is associated with aortic calcification in haemodialysis patients. METHODS: Serum OPG was measured in 102 patients who were undergoing haemodialysis. The aortic calcification index (ACI) was assessed by computed tomography scans. RESULTS: Serum OPG level, measured by enzyme-linked immunosorbent assay, was significantly greater in patients with higher ACI than in those with lower ACI. There was a direct relationship between ACI and serum OPG levels and a positive association between OPG and ACI (r = 0.483, P<0.0001). Multiple regression analyses indicated that serum OPG levels were independently associated with the severity of aortic calcification (P<0.0001). CONCLUSIONS: These findings show that serum OPG levels are associated with the extent of vascular calcification, suggesting that OPG may be involved in the development of vascular calcification in haemodialysis patients.
Left ventricular hypertrophy (LVH) is the most frequent cardiac abnormality in patients with end-stage renal disease (ESRD). Recent studies have shown that arterial stiffness is associated with mediacalcinosis in these patients. However, whether arterial stiffness and vascular calcification are associated with the LVH in patients with ESRD has not been well established. Forty-nine patients on chronic hemodialysis participated in this study. 1) To better understand the mechanism underlying the increased incidence of LVH, we studied the relation between LVH and each of arterial wall stiffness, aortic calcification, and numerous clinical parameters in 49 patients on chronic hemodialysis. 2) To evaluate the contribution of arterial stiffness and arterial calcification to LVH in hemodialysis patients, we performed the present clinical analysis on 49 patients on chronic hemodialysis. We used an automatic device to measure arterial pulse wave velocity (PWV) as an index of arterial wall stiffness. The aortic calcification index (ACI) was quantified morphometrically by CT scan. The left ventricular mass index (LVMI) was estimated by M-mode echocardiography. To understand the mechanism underlying the increased incidence of LVH, we examined the factors contributing to LVMI in these patients. The correlation between each of the study parameters and LVMI as an indicator of LVH was then examined. The LVMI value was correlated positively with PWV (r=0.439, p=0.0014), systolic blood pressure (r=0.421, p=0.0023), and ACI (r=0.467, p=0.0006). A stepwise linear regression analysis showed that PWV, systolic blood pressure, and ACI were independently associated with LVH in our subjects. These results suggest that LVH is associated with hypertension, increased arterial stiffness, and the extent of vascular calcification in hemodialysis patients, with vascular calcification being the most important contributor to the development of LVH. Alteration of pulsatile dynamics contributes to an increase in left ventricular load and thus is also related to the LVH in these patients. These results suggest that LVH is associated with hypertension, increased arterial stiffness, and the extent of vascular calcification in hemodialysis patients. Vascular calcification, which alters the pulsatile dynamics and thereby contributes to an increase in left ventricular load, is the most important contributor to the development of LVH in patients undergoing hemodialysis.
A series of aluminum-containing kanemite (Al-kanemite) samples with several Si/Al molar ratios were synthesized. The Al-kanemite samples were pillared with silica. X-ray diffractograms showed that the layered structure of the Al-kanemite samples was maintained at Si/Al= infinity approximately 10 but was broken at Si/Al = 5, 2.5, and 1. 29Si MAS NMR spectra of the Al-kanemite samples, except for that of Si/Al = 1, mainly showed peaks of Q(3) sites, which were attributed to Si(OSi)(3)(OH) groups, although peaks assigned to Si(OAl)(OSi)(2)(OH) were also seen. The 27Al MAS NMR spectra indicated that the Al-kanemite samples had only four-coordinate aluminum atoms. The FTIR spectra of pyridine adsorbed on the pillared Al-kanemite derivatives revealed Lewis acid sites on the surface. The nitrogen adsorption isotherms of the derivatives were classified as type I (Langmuir) absorption isotherms. Using the alpha(s) method, the specific surface areas of the derivatives were 572-756 m(2)g(-1), and the pore sizes were calculated as 1.25-1.83 nm. The pillared Al-kanemite derivatives had slit-shaped micropore structures.
The aim of this study is to investigate the effect of geometric structure and surface wettability of glidant on tablet hardness. Geometric structure is defined, in this work, as three-dimensional structure such as porosity, particle size and specific surface area. A variety of silica was incorporated in direct compressive fillers as glidant and mixed powder was compressed in single punch tablet machine with and without 0.5 wt.% magnesium stearate. Flowability of mixed powder was evaluated with Carr's index measurement. In the case of unlubricated compression, tablet hardness decreased as a function of additional concentration of silica. Reduction rate directly depended on surface coverage of silica over filler surface and hydrophobicity. Since surface coverage is related to geometric structure, it can be concluded that structural influence plays an important role to determine tablet hardness. While, in the case of lubricated compression, either water adsorption amount or geometric structure effects on tablet hardness. Increase of tablet hardness was observed only when hydrophilic porous and small size nonporous silica were added. All the other silica had deleterious effect on tablet hardness and in particular hydrophobicity strongly reduced tablet hardness.
Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis of common incidence world-wide whose etiology and pathogenesis remain unresolved, although genetic factors are assumed to be involved in the development and progression of this disease. To identify genetic variations that might confer susceptibility to IgAN, we performed a case-control association study involving 389 Japanese IgAN patients and 465 controls. Genome-wide analysis of approximately 80,000 single-nucleotide polymorphisms (SNPs) identified a significant association between IgAN and six SNPs located in the PIGR (polymeric immuoglobulin receptor) gene at chromosome 1q31-q41. One of them, PIGR-17, caused an amino-acid substitution from alanine to valine at codon 580 (chi(2)=13.05, P=0.0003, odds ratio [OR] =1.59, 95% confidence interval [95% CI] =1.24-2.05); the OR of minor homozygotes to others was 2.71 (95% CI=1.31-5.61). Another SNP, PIGR-2, could affect promoter activity (chi(2)=11.95, P=0.00055, OR=1.60, 95% CI=1.22-2.08); the OR of minor homozygotes to others was 2.08 (95% CI=0.94-4.60). Pairwise analyses demonstrated that all six SNPs were in almost complete linkage disequilibrium. Biopsy specimens from IgAN patients were positively stained by antibody against the secretory component of PIGR, but corresponding tissues from non-IgAN patients were not. Our results suggest that a gene associated with susceptibility to IgAN lies within or close to the PIGR gene locus on chromosome 1q in the Japanese population.
The silica-pillared derivatives from kanemite (NaHSi(2)O(5).3H(2)O) were prepared by intercalation of dialkyldimethylammonium (DADMA) ion and pillaring with tetraethylorthosilicate. The formation of silica pillars between the silicate sheets was demonstrated by X-ray diffraction, (29)Si CP/MAS NMR, and TEM observation. The basal spacing depended on the chain length of DADMA. Nitrogen adsorption study showed that the specific surface area was enlarged over 1000 m(2) g(-1) by the pillaring and that the pore size was in the micropore region. Water and benzene adsorption isotherms revealed that the surface properties of the pillared derivatives show hydrophobic character.
Although intensive efforts have been undertaken to elucidate the genetic background of immunoglobulin A nephropathy (IgAN), genetic factors associated with the pathogenesis of this disease are still not well understood. We designed a case-control association study that was based on linkage disequilibrium among single-nucleotide polymorphisms (SNPs) in the selectin gene cluster on chromosome 1q24-25, and we found two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11) that were significantly associated with IgAN in Japanese patients. All eight SNPs were in almost complete linkage disequilibrium. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser (chi2=9.02, P=.0026, odds ratio = 2.73 [95% confidence interval [CI] 1.38--5.38] for His-to-Tyr substitutions; chi2=17.4, P=.000031, odds ratio = 3.61 [95% CI 1.91--6.83] for Pro-to-Ser substitutions), and SELL1 could affect promoter activity of the L-selectin gene (chi2=19.5, P=.000010, odds ratio = 3.77 [95% CI 2.02--7.05]). The TGT haplotype at these three loci was associated significantly with IgAN (chi2=18.67, P=.000016, odds ratio = 1.88 [95% CI 1.41--2.51]). Our results suggest that these eight SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype that involves interstitial infiltration.
Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Immunogenetic studies have not conclusively indicated that human leukocyte antigen (HLA) is involved. As a first step in investigating a possible relationship between HLA class II genes and IgAN, we analyzed the extent of linkage disequilibrium (LD) in this region of chromosome 6p21.3 in a Japanese test population and found extended LD blocks within the class II locus. We designed a case-control association study of single-nucleotide polymorphisms (SNPs) in each of those LD blocks, and determined that SNPs located in the HLA- DRA gene were significantly associated with an increased risk of IgAN ( P = 0.000001, odds ratio = 1.91 [95% confidence interval 1.46-2.49]); SNPs in other LD blocks were not. Our data imply that some haplotype of the HLA- DRA locus has an important role in the development of IgAN in Japanese patients.
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