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Biomedical subjects

K Wada

Publications and source records attributed to K Wada.

At least 19 recordsLinked to original sources
PubMed2006

Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates.

Recombinant adeno-associated viral (rAAV) vector-mediated overexpression of alpha-synuclein (alphaSyn) protein has been shown to cause neurodegeneration of the nigrostriatal dopaminergic pathway in rodents and primates. Using serotype-2 rAAV vectors, we recently reported the protective effect of Parkin on alphaSyn-induced nigral dopaminergic neurodegeneration in a rat model. Here we investigated the neuronal specificity of alphaSyn toxicity and the effect of Parkin co-expression in a primate model. We used another serotype (type-1) of AAV vector that was confirmed to deliver genes of interest anterogradely and retrogradely to neurons in rats. The serotype-1 rAAV (rAAV1) carrying alphaSyn cDNA (rAAV1-alphaSyn), and a cocktail of rAAV1-alphaSyn and rAAV1 carrying parkin cDNA (rAAV1-parkin) were unilaterally injected into the striatum of macaque monkeys, resulting in protein expression in striatonigral GABAergic and nigrostriatal dopaminergic neurons. Injection of rAAV1-alphaSyn alone decreased tyrosine hydroxylase immunoreactivity in the striatum compared with the contralateral side injected with a cocktail of rAAV1-alphaSyn and rAAV1-parkin. Immunostaining of striatonigral GABAergic neurons was similar on both sides. Overexpression of Parkin in GABAergic neurons was associated with less accumulation of alphaSyn protein and/or phosphorylation at Ser129 residue. Our results suggest that the toxicity of accumulated alphaSyn is not induced in non-dopaminergic neurons and that the alphaSyn-ablating effect of Parkin is exerted in virtually all neurons in primates.

Animals↗
PubMed2006

Adolescent smoking behaviour and cigarette brand preference in Japan.

OBJECTIVES: As part of efforts to develop a smoking control strategy for Japanese adolescents, the results of two nationwide surveys on adolescent smoking behaviour were compared. DESIGN: Descriptive study on smoking behaviour among high school students was conducted. Self-reporting anonymous questionnaires were administered to 115,814 students in 1996 and 106,297 in 2000 through randomly sampled junior and senior high schools throughout Japan. MAIN OUTCOME MEASURES: Smoking prevalence, proportion of smokers by usual sources of cigarettes, national estimated cigarettes consumed by minors, share of cigarette brands smoked by high school students. RESULTS: The experiment rate among junior high school boys decreased in 2000 compared with that in 1996, whereas current and daily smoking rates did not. Although prevalence among Japanese girls was much lower than that among boys, prevalence among girls increased in 2000. The main source of cigarettes among high school smokers was vending machines. The proportion of smokers who usually purchased cigarettes from vending machines increased in 2000, in spite of the 1998 introduction of restrictions on night-time operations. Japanese adolescents were more likely than adults to smoke American cigarette brands, and the adolescent market share of American brands has increased rapidly, especially for menthol brands. CONCLUSIONS: This survey revealed the seriousness of the problem of smoking behaviour among Japanese high school students, and suggested that this behaviour may be influenced by social environmental factors, including the marketing strategies of the tobacco industry. Action should be taken to reduce the prevalence and impact of pro-tobacco marketing messages and to abolish cigarette vending machines.

Adolescent↗
PubMed2006

Disruption of neuromedin B receptor gene results in dysregulation of the pituitary-thyroid axis.

The level of thyrotropin (TSH) secretion is determined by the balance of TSH-releasing hormone (TRH) and thyroid hormones. However, neuromedin B (NB), a bombesin-like peptide, highly concentrated in the pituitary, has been postulated to be a tonic inhibitor of TSH secretion. We studied the pituitary-thyroid axis in adult male mice lacking NB receptor (NBR-KO) and their wild-type (WT) littermates. At basal state, NBR-KO mice presented serum TSH slightly higher than WT (18%, P< 0.05), normal intra-pituitary TSH content, and no significant changes in alpha and beta TSH mRNA levels. Serum thyroxine was normal but serum triiodothyronine (T3) was reduced by 24% (P< 0.01) in NBR-KO mice. Pituitaries of NBR-KO mice exhibited no alteration in prolactin mRNA expression but type I and II deiodinase mRNA levels were reduced by 53 and 42% respectively (P< 0.05), while TRH receptor mRNA levels were importantly increased (78%, P< 0.05). The TSH-releasing effect of TRH was significantly higher in NBR-KO than in WT mice (7.1-and 4.0-fold respectively), but, while WT mice presented a 27% increase in serum T3 (P< 0.05) after TRH, NBR-KO mice showed no change in serum T3 after TRH. NBR-KO mice did not respond to exogenous NB, while WT showed a 30% reduction in serum TSH. No compensatory changes in mRNA expression of NB or other bombesin-related peptides and receptors (gastrin-releasing peptide (GRP), GRP-receptor and bombesin receptor subtype-3) were found in the pituitary of NBR-KO mice. Therefore, the data suggest that NB receptor pathways are importantly involved in thyrotroph gene regulation and function, leading to a state where TSH release is facilitated especially in response to TRH, but probably with a less-bioactive TSH. Therefore, the study highlights the important role of NB as a physiological regulator of pituitary-thyroid axis function and gene expression.

Animals↗
PubMed2006

The characteristics and measuring technique of refractory dissolved organic substances in urban runoff.

It is considered that refractory dissolved organic substances have caused an increase in the COD concentration in Lake Biwa in recent years. We investigated the organic matter in the first flush of stormwater runoff from a road in the watershed area of the lake, and studied the possibility of improvement in the water environment from that aspect. After percolating the stormwater through soil, we analyzed organic substances fractionated by using GPC-TC. And we examined the effect of removal of organic substances by comparing the peak height before and after percolation. In the result of the experiments, we found that soil infiltration reduced the refractory dissolved organic substance and we successfully designed a system for a simple and easy experimental facility to treat urban runoff.

Biodegradation, Environmental↗
PubMed2005

Mixed antagonistic effects of bilobalide at rho1 GABAC receptor.

Bilobalide was found to be a moderately potent antagonist with a weak use-dependent effect at recombinant human rho(1) GABA(C) receptors expressed in Xenopus oocytes using two-electrode voltage clamp methodology. Antagonism of bilobalide at homomeric rho(1) GABA(C) receptors appeared to be mixed. At low concentration, bilobalide (3 microM) caused a parallel right shift and surmountable GABA maximal response of the GABA dose-response curve characteristic of a competitive antagonist. At high concentrations, bilobalide (10-100 microM) caused nonparallel right shifts and reduced maximal GABA responses of GABA dose-response curves characteristic of a noncompetitive antagonist. The potency of bilobalide appears to be dependent on the concentrations of GABA and was more potent at lower GABA concentrations. The mechanism of action of bilobalide at rho(1) GABA(C) receptors appears to be similar to that of the chloride channel blocker picrotoxinin.

Animals↗
PubMed2005

Monocyte chemoattractant protein 1 and macrophage cyclooxygenase 2 expression in colonic adenoma.

BACKGROUND AND AIMS: Cyclooxygenase 2 (COX-2) expression in subepithelial macrophages of colorectal adenoma has been suggested as the first in a series of steps leading to colorectal tumorigenesis. We tested the hypothesis that chemokines released from human colorectal adenoma epithelium might be involved in COX-2 expression in macrophages of the lamina propria. METHODS: Endoscopic samples of sporadic colorectal adenomas were tested by enzyme linked immunosorbent assay for chemokines involved in macrophage chemotaxis. Localisation of adenoma macrophage chemoattractant protein 1 (MCP-1) and COX-2 were determined by immunohistochemistry. The effects of MCP-1, in the presence or absence of celecoxib, on COX-2 expression, and prostaglandin (PG) E(2) and vascular endothelial growth factor (VEGF) release, were examined in human macrophages isolated from peripheral blood. RESULTS: MCP-1 levels were markedly higher in adenoma with mild-moderate dysplasia (129.7 (19.9) pg/mg protein) and severe dysplasia (227.9 (35.4) pg/mg protein) than in normal colonic mucosa (55.8 (4.2) pg/mg protein). Other chemokine levels, macrophage inflammatory proteins (MIP)-1alpha and MIP-1beta, and the chemokine regulated on activation of normal T cell expressed and secreted (RANTES) did not vary significantly between adenoma and normal mucosa. MCP-1 levels in both adenoma and normal colonic mucosa increased significantly three hours after tissue cultivation in vitro. MCP-1 immunoreactivity was restricted to the adenoma epithelium, with no reactivity seen in adjacent normal epithelial cells. MCP-1 stimulated COX-2 expression and PGE(2) and VEGF release in human macrophages. Celecoxib, a selective COX-2 inhibitor, inhibited MCP-1-induced PGE(2) and VEGF release in macrophages. Addition of exogenous PGE(2) reversed this inhibitory effect on VEGF release, suggesting that MCP-1 in adenoma epithelial cells might be involved in COX-2 expression and subsequent macrophage activation. CONCLUSIONS: MCP-1 in colorectal adenoma epithelial cells might be involved in macrophage migration and COX-2 expression, leading to the subsequent development of colonic adenoma.

Adenoma↗
PubMed2005

Implications of corpus gastritis, atrophy and cyclooxygenase in the development of gastric erosions after curing Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori eradication decreases recurrence of peptic ulcers with marked improvement in histological inflammation, but gastric mucosal injuries may be developed even after eradication. PURPOSE: To investigate the mechanisms responsible for the development of gastric erosions after eradication, we analysed the relationship between clinicopathological risk factors and the occurrence of gastric erosion after curing H. pylori infection. PATIENTS: Sixty patients underwent endoscopy before, and 3, 6 and 12 months after the completion of H. pylori eradication. METHODS: Risk factors associated with the development of gastric erosions after eradication were assessed by multivariate analysis, and cyclooxygenase-1 and -2 immunoreactivity was histologically examined in the gastric mucosa before and after eradication. RESULTS: The cumulative prevalence of gastric erosions after H. pylori eradication was 38.3% within 1 year. Using multivariate analysis, corpus gastritis scores (inflammation score+activity score), corpus atrophy scores and an age of more than 50 years were found to be independent factors associated with the development of gastric erosion after eradication with odds ratios of 7.39, 0.13 and 5.00, respectively. Cyclooxygenase-2 immunoreactivity of the corpus was decreased for the non-erosion group after eradication, but not for the erosion group. CONCLUSIONS: Severe gastritis or less severe atrophy in oxyntic glands but not in pyloric glands before eradication may be involved in the development of gastric erosions after curing H. pylori infection.

Age Factors↗
PubMed2005

220-fs erbium-ytterbium:glass laser mode locked by a broadband low-loss silicon/germanium saturable absorber.

We demonstrate femtosecond performance of an ultrabroadband high-index-contrast saturable Bragg reflector consisting of a silicon/silicon dioxide/germanium structure that is fully compatible with CMOS processing. This device offers a reflectivity bandwidth of over 700 nm and subpicosecond recovery time of the saturable loss. It is used to achieve mode locking of an Er-Yb:glass laser centered at 1540 nm, generating 220-fs pulses, with what is to our knowledge the broadest output spectrum to date.

Journal Article↗
PubMed2005

Validity of self-reported height and weight in a Japanese workplace population.

OBJECTIVE: To assess the validity of self-reported height and weight in a Japanese workplace population, and to examine factors associated with the validity of self-reported weight. DESIGN: Comparison of self-reported height and weight with independent measurement. SUBJECTS: In total, 4253 men and 1148 women aged 35-64 y (mean measured body mass index (BMI): 23.3 kg/m(2) in men, 21.9 kg/m(2) in women) were included in the study. MEASUREMENTS: Self-reported height and weight were obtained by a self-administered questionnaire. Measured height and weight were based on annual health checkups. Sex, age, measured BMI, and the presence of hypertension, diabetes, and hyperlipidemia were examined as potential factors associated with the accuracy of self-reported weight. RESULTS: Self-reported height and weight were highly correlated with measured height and weight for men and women (Pearson's r for men and women: 0.979 and 0.988 in height, 0.961 and 0.959 in weight, 0.943 and 0.950 in BMI, respectively). For men, mean differences+/-2 s.d. of height and weight were 0.078+/-2.324 cm and -0.034+/-5.012 kg, respectively, and for women 0.029+/-1.652 cm and 0.024+/-4.192 kg, respectively. The prevalence of obesity with BMI > or =25 kg/m(2) based on self-reported data (23.6 and 11.5% for men and women, respectively) was slightly smaller than that based on measured data (24.9 and 12.4%, respectively). Specificity and sensitivity, however, were quite high for both men and women (sensitivity was 85.8 and 85.2%, and specificity was 97.0 and 98.9%, respectively). The subjects with higher measured BMI significantly underestimated their weight compared with those with smaller BMI after adjustments for age in men and women. Furthermore, the presence of diabetes in men and age in women affected self-reported weight. Neither the presence of hypertension nor hyperlipidemia was associated with reporting bias. CONCLUSION: The self-reported height and weight were generally reliable in the middle-aged employed Japanese men and women. However, it should be remembered that self-reported weight was biased by actual BMI and affected by age and the presence of diabetes.

Adult↗
PubMed2005

Preventive therapy for non-steroidal anti-inflammatory drug-induced ulcers in Japanese patients with rheumatoid arthritis: the current situation and a prospective controlled-study of the preventive effects of lansoprazole or famotidine.

BACKGROUND: There is a lack of evidence for the efficacy of preventive medications for peptic ulcers (PUs) among long-term users of non-steroidal anti-inflammatory drugs (NSAIDs) in Japan. AIM: To estimate the preventive effect by normal dose, not high-dose histamine-H2 receptor antagonists (H2RA) for NSAID-induced ulcers. METHODS: We designed two different studies to assess the efficacy of anti-ulcer agents in rheumatoid arthritis (RA) in patients treated over a long term with NSAIDs. An investigative survey divided patients into those not taking anti-ulcer agents (non-medication group); those taking mucosal protective agents (mucosal protectant group), H2RA (H2RA group), proton pump inhibitors (PPI group), or a prostaglandin E1 analog (PG) (PG group). The second study compared prospectively the preventive effects of either famotidine 20 mg bd (famotidine group) or lansoprazole 15 mg daily (lansoprazole group) in patients with PU scars. RESULTS: The prevalence of PU in the H2RA group was significantly lower compared to the mucosal protectant group (P < 0.05), and the mucosal protectant group was not significantly different to the non-medication group. The prospective study revealed that the PU onset rate of the famotidine group was 8% (1/13), and lansoprazole group was 15% (2/13), indicating no significant differences between the two. CONCLUSIONS: In Japan, normal-dose H2RA is expected to be a new PU preventive treatment strategy in patients requiring long-term NSAID therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2004

Effect of localization of missense mutations in SCN1A on epilepsy phenotype severity.

BACKGROUND AND METHODS: Many missense mutations in the voltage-gated sodium channel subunit gene SCN1A were identified in patients with generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI), although GEFS+ is distinct from SMEI in terms of clinical symptoms, severity, prognosis, and responses to antiepileptic drugs. The authors analyzed the localization of missense mutations in SCN1A identified in patients with GEFS+ and SMEI to clarify the phenotype-genotype relationships. RESULTS: Mutations in SMEI occurred more frequently in the "pore" regions of SCN1A than did those in GEFS+. These SMEI mutations in the "pore" regions were more strongly associated than mutations in other regions with the presence of ataxia and tendency to early onset of disease. The possibility of participation of ion selectivity dysfunction of the channel in the pathogenesis of SMEI was suggested by a mutation in the pore region (R946C) identified in a SMEI patient. CONCLUSIONS: There was a significant phenotype-genotype relationship in generalized epilepsy with febrile seizures plus and severe myoclonic epilepsy of infancy with SCN1A missense mutations. More severe sodium channel dysfunctions including abnormal ion selectivity that are caused by mutations in the pore regions may be involved in the pathogenesis of SMEI.

Age of Onset↗
PubMed2004

Microarray expression analysis of gad mice implicates involvement of Parkinson's disease associated UCH-L1 in multiple metabolic pathways.

Parkinson's disease (PD) is thought to be caused by environmental and genetic factors. Mutations in four genes, alpha-synuclein, parkin, DJ-1, and UCH-L1, have been identified in autosomal inherited forms of PD. The pathogenetic cause for the loss of neuronal cells in PD patients, however, remains to be determined. Due to the rarity of mutations in humans with PD, the analysis of animal models might help to further gain insights into the pathogenesis of familial PD. For UCH-L1, deficiency has been described in gad mice leading to axonal degeneration and formation of spheroid bodies in nerve terminals. Here, we investigated the gene expression pattern of the brain of 3-month-old Uch-l1-deficient gracile axonal dystrophy (gad) mice by microarray analysis. A total of 146 genes were differentially regulated by at least a 1.4-fold change with 103 being up-regulated and 43 being down-regulated compared with age and sex matched wildtype littermate mice. The gene products with altered expression are involved in protein degradation, cell cycle, vesicle transport, cellular structure, signal transduction, and transcription regulation. Most of the genes were modestly regulated, which is in agreement that severe alteration of these pathways might be lethal. Among the genes most significantly down-regulated is the brain-derived neurotrophic factor which might be one aspect of the pathogenesis in gad mice. Interestingly, several subunits of the transcription factor CCAAT/enhancer binding protein are up-regulated, which plays a central role in most altered pathways.

Animals↗
PubMed2004

The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma.

Traumatic injury to the brain and spinal cord results in an early inflammatory response that is initiated by the release of proinflammatory cytokines followed by the infiltration and accumulation of polymorphonuclear leukocytes (PMNLs). The role of the inflammatory cascade on traumatic outcome remains controversial. Pleiotropic cytokines appear to function both protectively and destructively. The induction of cytokines can lead to the expression of the inducible form of nitric oxide synthase (iNOS), which in turn provokes the release of excessive amounts of nitric oxide (NO) that may participate in the pathogenesis of tissue injury. Hypothermia has been reported by various groups to be neuroprotective in brain and spinal cord trauma. We studied the effect of therapeutic hypothermia on cerebral IL-1beta concentrations, PMNL accumulation and iNOS activity after traumatic brain injury (TBI) and spinal cord injury (SCI). Based on current data therapeutic hypothermia may protect in models of traumatic injury by modulating deleterious inflammatory processes.

Brain↗
PubMed2004

Monitoring of the generation of non-mutagenic benzoic acid compounds during the manufacture of erythrosine.

The generation of 2-(2',4'-dihydroxybenzoyl) benzoic acid (DHBBA) and 2-(2',4'-dihydroxy-3',5'-diiodobenzoyl) benzoic acid (DHDIBBA) during the manufacture of erythrosine (Food Red No. 3) was examined. DHBBA is formed as an intermediate during the synthesis of fluorescein, and as fluorescein is produced, it is gradually consumed. However, under inappropriate reaction conditions, it remains in the resulting fluorescein at the termination of synthesis. DHDIBBA is easily obtained by the iodination of DHBBA. These compounds are also found when erythrosine is heated in excessive alkali. The results of the Ames test using DHBBA and DHDIBBA showed they did not possess mutagenic activity. The results clearly demonstrated that establishment of an upper limit for DHBBA and DHDIBBA is important in the quality control of fluorescein and erythrosine.

Benzoic Acid↗
PubMed2004

Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis.

BACKGROUND AND AIM: Significant telomere shortening of hepatocytes is associated with replicative senescence and a non-dividing state in chronic liver disease, resulting in end stage liver failure and/or development of hepatocellular carcinoma. To prevent critical telomere shortening in hepatocytes, we have focused on oestrogen dependent transactivation of the human telomerase reverse transcriptase (hTERT) gene as a form of telomerase therapy in chronic liver disease. METHODS: We examined expression of hTERT mRNA and its protein, and telomerase activity (TA) in three human normal hepatic cell lines (Hc-cells, h-Nheps, and WRL-68) before and after treatment with 17beta-oestradiol. The effects of exogenous oestradiol administration were examined in a carbon tetrachloride (CCl(4)) induced model of liver fibrosis in rats. RESULTS: Expression of hTERT mRNA and its protein was upregulated by oestradiol treatment. Telomere length decreased in Hc-cells and h-Nheps with accumulated passages whereas with long term oestradiol exposure it was greater than without oestradiol. The incidence of beta-galactosidase positive cells, indicating a state of senescence, decreased significantly in oestradiol treated cells in comparison with non-treated cells (p<0.05). TA in both male and female rats with CCl(4) induced liver fibrosis was significantly higher with oestradiol administration than without (p<0.05). Long term oestradiol administration markedly rescued the hepatic telomere from extensive shortening in both male and female rats. CONCLUSION: These results suggest that oestradiol acts as a positive modulator of the hTERT gene in the liver. Oestrogen dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease.

Animals↗
PubMed2004

Profiling of methamphetamine-induced modifications of gene expression patterns in the mouse brain.

Recently described DNA microarray technology allows parallel screening of expression patterns and regulation of hundreds of thousands of genes. In the present study, we used a microarray to examine the gene expressions in the midbrains of mice sacrificed 24 h after completion of a 7-day treatment period consisting of a once-daily treatment with saline (SS), saline followed by a single 2 mg/kg of body weight dose of methamphetamine (METH) (S-METH), or repeated 2 mg/kg METH doses (M-METH) that produced sensitization and place preference (rewarding effect). We used the commercially available cDNA microarray. Approximately 80% of the assessed transcripts in the total brain reached the Affymetrix criteria for "present" and "changed," as well as displaying > or =1.5-fold differences in hybridization intensity difference values in a comparison of SS data to S-METH or M-METH data. S-METH gene expression changes were observed in both up- and down-regulation, with 13 transcripts upregulated and 13 downregulated, whereas the majority of M-METH gene expression changes were observed in down-regulation, with 5 transcripts upregulated and 21 downregulated. We identified several genes that altered expression in both the S-METH and M-METH groups: a transcription factor gene, cellular stress/molecular chaperones, and a cellular regulatory gene.

Animals↗
PubMed2003

NF-kappaB in epiretinal membranes after human diabetic retinopathy.

AIMS/HYPOTHESIS: Formation of epiretinal membranes (ERMs) in the posterior fundus results in progressive deterioration of vision. ERMs have been associated with numerous clinical conditions including proliferative diabetic retinopathy (PDR), but its pathogenic mechanisms are still unknown. This study was conducted to examine whether or not nuclear factor kappa B (NF-kappaB), a transcription factor that can be activated by various pathological conditions, is involved in the formation of ERMs after PDR. METHODS: ERM samples were obtained by vitrectomy from 22 cases with PDR aged 56+/-11 years with 18+/-10 years of diabetes and 15 cases with idiopathic ERM. They were processed for reverse transcription-polymerase chain reaction (RT-PCR) analysis. In addition, 5 ERM samples from PDR patients aged 51+/-16 years with 15+/-6 years of diabetes were processed for immunohistochemical analysis. RESULTS: NF-kappaB mRNA expression levels were higher (20 out of 22 cases vs. 9 out of 15 subjects in idiopathic ERM, p<0.05) in PDR subjects. Immunohistochemical analysis showed NF-kappaB protein expression in all the 5 ERMs derived from PDR patients, and that region was partially double-labelled with interleukin-8 (IL-8) and von Willebrand factor (vWF). CONCLUSIONS/INTERPRETATION: These results suggest a possibility that NF-kappaB is involved in the formation of ERMs after PDR, especially for the development of vascular endothelial cell component.

Adult↗