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Biomedical subjects

K Urakami

Publications and source records attributed to K Urakami.

At least 19 recordsLinked to original sources
PubMed2004

Brain-derived neurotrophic factor gene polymorphisms and Alzheimer's disease.

Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimer's disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP)--i.e., C270T and G196A--in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, p = 0.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, p = 0.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, p = 0.035) or positive for AD family history (2.8 vs. 7.1%, p = 0.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.

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PubMed2004

Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients.

OBJECTIVES: To investigate a possible implication of inflammatory processes in the development of dementia in cerebrovascular disease. PATIENTS AND METHODS: We examined the levels of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 26), ischemic cerebrovascular disease without dementia (CVD) (n = 11), vascular dementia (VD) (n = 11), and other neurological disorders (n = 21) using sensitive enzyme-linked immunosorbent assay. RESULTS: The CSF concentrations of IL-6 were significantly elevated in patients with VD compared with those of patients with AD or CVD. CONCLUSION: The CSF IL-6 levels are increased in patients with VD, suggesting that inflammatory mechanisms may be involved in the development of cognitive decline in some patients with cerebrovascular disease. CSF IL-6 may be a biological marker for dementia in cerebrovascular disease.

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PubMed2004

Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease.

OBJECTIVE: To describe a novel missense mutation, Asp678Asn (D678N), in the amyloid precursor protein (APP) gene in a Japanese pedigree of probable familial Alzheimer's disease (FAD). SUBJECT: The proband was a women of 72. Symptoms of dementia that fulfilled the criteria for probable Alzheimer's disease appeared at about 60 years of age, and slowly worsened over more than 10 years without evident cerebrovascular complications, either clinically or neuroradiologically. METHODS: Polymerase chain reaction single strand conformational polymorphism (PCR-SSCP) analysis followed by sequence analysis was used to examine genomic DNA of the proband for mutations in the APP gene exons 16 and 17. RESULTS: Analysis of the APP exon 16 in the proband showed a GAC to AAC nucleotide substitution in codon 678 of the APP gene, causing an amino acid substitution of Asp to Asn (D678N). Heterozygosity of the APP D678N mutation was found in the proband and in the demented elder sister. CONCLUSIONS: The production and accumulation of mutated Abeta (Asn7-Abeta) or the misfunction of D678N mutant APP may have pathogenic properties for the development of Alzheimer's disease in this pedigree.

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PubMed2001

Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy.

Distinguishing corticobasal degeneration (CBD) from progressive supranuclear palsy (PSP) is clinically and pathologically difficult, and a useful biological marker to discriminative these two diseases has been a subject of clinical interest. In the present study, we assessed tau protein levels in cerebrospinal fluids by sandwich ELISA to distinguish CBD from PSP. The subjects consisted of 27 cases of CBD, 30 cases of PSP, and 36 healthy controls (CTL). The tau values in CBD were significantly higher than those in PSP (P<0.001) and those in CTL (P<0.001). The assay of CSF tau provided diagnostic sensitivity of 81.5% and specificity of 80.0% between CBD and PSP according to receiver-operating characteristic (ROC) curve analysis. When values were compared separately with respect to stage of the disease, differences in the values for moderate CBD vs. moderate PSP had the greatest significance (P<0.001 sensitivity 92.3%, specificity 100.0%), followed by cases of mild CBD and PSP (P<0.005, sensitivity 100.0%, specificity 87.5%). The values in severe CBD and PSP were not significantly different (P=0.07, sensitivity 100%, specificity 75.0%). Using data obtained from a larger number of disease cases, we confirmed our previous findings that tau protein levels in cerebrospinal fluids in patients with CBD are significantly higher than those in patients with PSP. Because tau protein levels in cerebrospinal fluids are significantly higher in early CBD cases than in early PSP cases, measurement of tau protein levels in cerberospinal fluids may be useful for the differential diagnosis of early CBD from early PSP.

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PubMed2001

Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease.

We surveyed a total of 570 cerebrospinal fluid (CSF) samples from a variety of diseases, including Alzheimer's disease (AD; n = 236), non-AD-demented and nondemented diseases (n = 239), and normal controls (n = 95) to quantitate levels of tau protein phosphorylated at serine 199 (CSF/phospho-tau199) by a recently established sandwich ELISA. The CSF/phospho-tau199 levels in the AD group were significantly elevated compared to those in all the other non-AD groups. Receiver operating characteristics curves showed that the diagnostic sensitivity and specificity for the AD group vs all the other non-AD groups using the CSF/phospho-tau199 were 85.2% and 85.0%, respectively. Furthermore, there was a significant positive correlation between CSF/phospho-tau199 and CSF/total-tau levels in the AD group. Elevated CSF/phospho-tau199 in the AD group was noted irrespective of age, gender, dementia severity, and number of apolipoprotein E4 alleles. Thus, we suggest that CSF/phospho-tau199 may be a novel and logical biomarker in supporting antemortem diagnosis of AD.

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PubMed2001

Compositional analysis of copoly (DL-lactic/glycolic acid) (PLGA) by pyrolysis-gas chromatography/mass spectrometry combined with one-step thermally assisted hydrolysis and methylation in the presence of tetramethylammonium hydroxide.

Rapid and precise compositional analysis of copoly (DL-lactic/glycolic acid) (PLGA) was performed by pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) combined with one-step hydrolysis and methylation in the presence of tetramethylammonium hydroxide (TMAH). Pyrolysis of PLGA with TMAH gave two characteristic products, derivatives of DL-lactic acid and glycolic acid, which directly reflect the average molar composition of PLGA. The analytical results for PLGA samples with various compositional ratios were in good agreement with those obtained by 1H-NMR spectrometry, and the precision was satisfactory.

Gas Chromatography-Mass Spectrometry↗
PubMed2001

Determination of residual solvents in pharmaceuticals by thermal desorption-GC/MS.

A novel method for the determination of residual solvents in pharmaceuticals by thermal desorption (TD)-GC/MS has been established. A programmed temperature pyrolyzer (double shot pyrolyzer) is applied for the TD. This method does not require any sample pretreatment and allows very small amounts of the sample. Directly desorbed solvents from intact pharmaceuticals (ca. 1 mg) in the desorption cup (5 mm x 3.8 mm i.d.) were cryofocused at the head of a capillary column prior to a GC/MS analysis. The desorption temperature was set at a point about 20 degrees C higher than the melting point of each sample individually, and held for 3 min. The analytical results using 7 different pharmaceuticals were in agreement with those obtained by direct injection (DI) of the solution, followed by USP XXIII. This proposed TD-GC/MS method was demonstrated to be very useful for the identification and quantification of residual solvents. Furthermore, this method was simple, allowed rapid analysis and gave good repeatability.

Adsorption↗
PubMed2001

[Causative genes in Alzheimer's disease].

Recently, some Alzheimer-associated genes have been found: amyloid precursor protein (APP), apolipoprotein E (apoE), presenilin 1 (PS-1) and presenilin 2 (PS-2). First, we examined mutations of APP, PS-1, and PS-2 genes in familiar Alzheimer's disease (FAD) (7 cases) found in San-in district by single-strand conformation polymorphism and sequence analysis. These seven cases with FAD did not show any mutations of APP, PS-1, and PS-2 genes. Other susceptibility genes of FAD still remain to be not identified. Many reports have established that apoE genotype distribution for the epsilon 4 allele is a susceptibility factor for the earlier onset and more rapid progression of Alzheier's disease (AD). However, the cause of sporadic AD (SAD) has not been elucidated fully. Other genetic factors may be associated with development of SAD. Second, we investigated the association between polymorphisms of the estrogen receptor (ER) alpha gene and SAD. The frequencies of P and X alleles in SAD were significantly higher than those in the control group (p < 0.05). Polymorphisms of the ER alpha gene may be a genetic risk factor for SAD. The apoE genotype is a genetic factor closely related SAD, but it is not full by appreciated how apoE has an effect on developing AD. There are few reports on the quantitative change of apoE, namely the expression of apoE mRNA. Third, ApoE mRNA level in the brains of patients with Alzheimer's disease (27 cases) and Down's syndrome (11 cases) was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ApoE mRNA level in the DS as well as AD was significantly higher than that in control group (p < 0.05, p < 0.05, respectively). High levels of apoE mRNA in AD and DS may play an important role in the development of Alzheimer pathology.

Alzheimer Disease↗
PubMed2001

[Analysis of causative genes and genetic risk factor in Alzheimer's disease].

Recently, some Alzheimer-associated genes have been found: amyloid beta protein precursor (APP), apolipoprotein E (apoE), presenilin 1 (PS-1), and presenilin 2 (PS-2). First, we failed to discover other susceptibility genes of familial Alzheimer's disease (FAD). However, we disClosed a novel mutation. Asp678Asn (D678N), in the APP gene in a pedigree of early-onset Japanese FAD. The alteration in the aggregation properties of mutant A beta may be involved in the pathogenesis of FAD with D678N APP mutation. Many reports have established that apoE genotype distribution for the epsilon 4 allele is a susceptibility factor for the earlier onset and more rapid progression of Alzheimer's disease (AD). However, the cause of sporadic AD (SAD) has not been elucidated fully. Other genetic factors may be associated with development of SAD. Second, we investigated the association between polymorphisms of the estrogen receptor (ER) alpha gene and SAD. The frequencies of P and X alleles in SAD were significantly higher than those in the control group (p < 0.05). Polymorphism of the ER alpha gene may be a genetic risk factor for SAD.

Alzheimer Disease↗
PubMed2000

The homozygous C677T mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for migraine.

Increased homocysteine levels are associated with various pathological conditions in humans, including stroke and cardiovascular disorders. Homocysteine acts as an excitatory amino acid in vivo and may influence the threshold of migraine headache. Frosst et al. [1995] reported an association between the homozygous C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and serum homocysteine levels. This study was designed to determine the prevalence of the MTHFR mutation in Japanese patients with migraine and tension-type headache (TH). Seventy-four patients with migraine headaches (22 with aura and 52 without aura), 47 with THs, and 261 normal controls were recruited. Genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. We detected that the incidence of the homozygous transition (T/T) in migraine sufferers (20.3%) was significantly higher than that in controls (9.6%). Moreover, the frequency of the T/T genotype in individuals with migraine headaches with aura was remarkably high (40.9%). The MTHFR T allele was more frequent in the migraine group than in the control group. Our results support the conclusion that the MTHFR gene, causing mild hyperhomocysteinemia may be a genetic risk factor for migraine. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:762-764, 2000.

Alleles↗
PubMed2000

Alpha2-macroglobulin gene polymorphisms show racial diversity and are not associated with Alzheimer's disease.

Two genetic markers of the plasma protein alpha2-macroglobulin, a 5 bp deletion/insertion at the 5' splice site of exon 18 (A2MI) and the GTC/ATC (VaIIO00IIe) in exon 24 (A2M2), may have roles in the development of Alzheimer's disease (AD). Genotyping and linkage analysis of these markers in 426 Japanese sporadic AD patients, 85 autopsy-confirmed Caucasian AD cases, and, as controls, 382 Japanese and 65 Caucasians who were cognitively normal and 140 Japanese Parkinson's disease patients showed racial diversity in the frequencies and relationship of the two markers. Comparison of genotype and allele frequencies, stratification of the samples by the presence of the apolipoprotein E epsilon4 allele, and logistic regression analysis revealed no association of these markers with AD in either racial group.

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PubMed2000

The N-terminal prepeptide is required for the production of spore cortex-lytic enzyme from its inactive precursor during germination of Clostridium perfringens S40 spores.

A spore cortex-lytic enzyme of Clostridium perfringens S40 is synthesized during sporulation as a precursor consisting of four domains. After cleavage of an N-terminal preregion and a C-terminal proregion, inactive proenzyme (termed C35) is converted to active enzyme by processing of an N-terminal prosequence with germination-specific protease (GSP) during germination. The present results demonstrated that the cleaved N-terminal prepeptide remained associated with C35. After the isolated complex was denatured and dissociated in 6 M urea solution, removal of urea regenerated a prepeptide-C35 complex which produces active enzyme when incubated with GSP. However, isolated C35 alone could not be activated by GSP. The prepeptide-C35 complex was more heat stable than active enzyme. Thus, non-covalent attachment of the prepeptide to C35 is required to assist correct folding of C35 and to stabilize its conformation, suggesting that the prepeptide functions as an intramolecular chaperone. Recombinant proteins, which have prepeptide covalently bonded to C35, were processed by GSP as well as the in vivo prepeptide-C35 complex, and the full length of the N-terminal presequence was needed to fulfil its role. Although the C-terminal prosequence is present as an independent domain which is not involved in the activation process of the enzyme, it appears that the N-terminal prosequence contributes to the regulation of enzyme activity as an inhibitor of the enzyme.

Amino Acid Sequence↗
PubMed2000

Neurotrophin-3 levels in cerebrospinal fluid from children with bacterial meningitis, viral meningitis, or encephalitis.

Neurotrophin-3 levels were measured in the cerebrospinal fluid of 35 patients with bacterial meningitis, viral meningitis, or encephalitis by two-site enzyme immunoassay. Elevated cerebrospinal fluid levels of neurotrophin-3 were demonstrated in 8 of 18 patients with bacterial meningitis. Follow-up examination of the eight patients at the convalescent stage showed diminished cerebrospinal fluid levels of neurotrophin-3. In contrast, none of the 17 patients with viral meningitis or encephalitis showed an elevation of neurotrophin-3 levels in cerebrospinal fluid. No relationships were observed between neurotrophin-3 levels and cerebrospinal fluid cell numbers, cerebrospinal fluid protein levels, serum C-reactive protein concentrations, or outcome in bacterial meningitis. Since neurotrophin-3 is involved in the survival of neurons and the modulation of the immune system, neurotrophin-3 could play a neuroprotective or immunomodulatory role in bacterial meningitis.

Adolescent↗
PubMed2000

Degradation products generated by sonication of benzyl alcohol, a sample preparation solvent for the determination of residual solvents in pharmaceutical bulks, on capillary gas chromatography.

Benzyl alcohol used as the sample preparation solvent in the determination of residual solvents in pharmaceutical bulks yielded benzene, toluene, and benzaldehyde on capillary gas chromatography (GC) by sonication. The factors responsible for compounds generated are discussed. The quality of benzyl alcohol and the type of sonicator were not involved in the generation of benzene, toluene, and benzaldehyde, whereas matrix contributions were observed. The degradation profiles of benzyl alcohol and its analogous compounds obtained by pyrolysis-GC/mass spectrometric analysis were similar to those obtained by sonication, suggesting that benzyl alcohol is degraded by the high local heat generated by sonication. Consequently, no matter how long it may take to dissolve bulk substances in benzyl alcohol completely, we do not recommend the use of a sonicator in sample preparation for the determination of residual solvents in pharmaceutical bulks.

Benzyl Alcohols↗
PubMed2000

Determination of residual solvents in bulk pharmaceuticals by thermal desorption/gas chromatography/mass spectrometry.

Thermal desorption (TD) techniques followed by capillary GC/MS were applied for the analysis of residual solvents in bulk pharmaceuticals. Solvents desorbed from samples by heating were cryofocused at the head of a capillary column prior to GC/MS analysis. This method requires a very small amount of sample and no sample pretreatment. Desorption temperature was set at the point about 20 degrees C higher than the melting point of each sample individually. The relative standard deviations of this method tested by performing six consecutive analyses of 8 different samples were 1.1 to 3.1%, and analytical results of residual solvents were in agreement with those obtained by direct injection of N,N-dimethylformamide solution of the samples into the GC. This novel TD/GC/MS method was demonstrated to be very useful for the identification and quantification of residual solvents in bulk pharmaceuticals.

Chemistry, Pharmaceutical↗
PubMed1999

Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis.

Peritoneal membrane permeability deteriorates in peritoneal dialysis (PD) patients. We test whether glucose degradation products (GDPs) in PD fluids, glyoxal, methylglyoxal and 3-deoxyglucosone, stimulate the production of vascular endothelial growth factor (VEGF), a factor known to enhance vascular permeability and angiogenesis. VEGF increased in cultured rat mesothelial and human endothelial cells exposed to methylglyoxal, but not to glyoxal or 3-deoxyglucosone. VEGF also increased in peritoneal tissue of rats given intraperitoneally methylglyoxal. VEGF and carboxymethyllysine (CML) (formed from GDPs) co-localized immunohistochemically in mesothelial layer and vascular walls of the peritoneal membrane of patients given chronic PD. By contrast, in the peritoneum of non-uremic subjects, VEGF was identified only in vascular walls, in the absence of CML. VEGF production induced by GDPs may play a role in the progressive deterioration of the peritoneal membrane.

Animals↗
PubMed1999

Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population.

We compared the distribution of an insertion (I)/deletion (D) polymorphism of the gene coding for the angiotensin-converting enzyme (ACE) in 133 Japanese sporadic Alzheimer disease (AD) patients with 257 controls. The association between AD and ACE genotypes or alleles was found to be significant. The frequency of II genotypes was 1.4 times higher in AD than controls, while that of DD genotypes was only 0.4 times as high. The altered distribution of ACE alleles in patients with AD appeared to be independent of apolipoprotein E.

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