Search PubMed⌕ Search

Biomedical subjects

Y Mizuno

Publications and source records attributed to Y Mizuno.

At least 73 records · Page 4Linked to original sources
PubMed2001

Amelioration of experimental autoimmune encephalomyelitis with anti-OX40 ligand monoclonal antibody: a critical role for OX40 ligand in migration, but not development, of pathogenic T cells.

OX40 (CD134) and its ligand (OX40L) have been implicated in T cell activation and migration. In this study, we examined the contribution of these molecules to the pathogenesis of experimental autoimmune encephalomyelitis (EAE) by administering a neutralizing mAb against murine OX40L (RM134L) to proteolipid protein (139-151) peptide-induced EAE in SJL mice. Administration of RM134L effectively ameliorated the disease in both actively induced and adoptively transferred EAE models. Histological examination showed that the RM134L treatment greatly reduced mononuclear cell infiltration into the spinal cord. The RM134L treatment did not inhibit the development of pathogenic T cells, given that proliferative response and IFN-gamma production by draining lymph node cells were not reduced or rather enhanced upon restimulation with proteolipid protein (139-151) in vitro, and these cells effectively transferred EAE to naive SJL mice. Flow cytometric analyses showed that the RM134L treatment inhibited the accumulation of OX40-expressing CD4(+) T cells and the migration of adoptively transferred CD4(+) T cells in the spinal cord. Immunohistochemical staining showed that OX40L was most prominently expressed on endothelial cells in the inflamed spinal cord. These results suggest that the OX40/OX40L interaction plays a critical role for the migration of pathogenic T cells into the CNS in the pathogenesis of EAE.

Adoptive Transfer↗
PubMed2001

Aldosterone production is activated in failing ventricle in humans.

BACKGROUND: Recent reports have indicated that aldosterone is produced in extra-adrenal tissues in animals. The present study was designed to examine whether aldosterone is produced in human heart. METHODS AND RESULTS: Plasma levels of aldosterone, BNP, and angiotensin-converting enzyme were measured in anterior interventricular vein (AIV), coronary sinus (CS), and aortic root (Ao), respectively, in 20 patients with left ventricular systolic dysfunction (LVSD), 25 patients with LV diastolic dysfunction (LVDD), and 23 control subjects. Aldosterone levels were significantly higher in AIV and CS than Ao in LVSD (98+/-10 versus 72+/-9 pg/mL, P:<0.001, and 97+/-11 versus 72+/-9 pg/mL, P:<0.001, respectively) and LVDD (87+/-10 versus 71+/-9 pg/mL, P:<0.01, and 84+/-10 versus 71+/-9 pg/mL, P:<0.01, respectively) groups, but no differences were observed in levels for these sites in the control group. Levels of ACE activity and BNP also were higher in AIV than Ao in both LV dysfunction groups. The difference in aldosterone levels between AIV and Ao and those in BNP and angiotensin-converting enzyme had a significant positive correlation with LVEDP and a significant negative correlation with LV ejection fraction in the LVSD group. CONCLUSIONS: Production of aldosterone, angiotensin-converting enzyme, and BNP are activated in failing human ventricle in proportion to severity.

Adult↗
PubMed2001

An apparently sporadic case with parkin gene mutation in a Korean woman.

OBJECTIVE: To report the clinical features and results of iodine I 123-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane (CIT) single photon emission computed tomography and molecular genetic analysis in a Korean woman with juvenile Parkinson disease with deletion in exon 4 of the parkin gene. DESIGN: Case report with molecular genetic analysis. PATIENT AND RESULTS: The patient had bradykinesia, postural imbalance, and postural tremor since the age of 12 years. She developed wearing off early in the disease course. The [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single photon emission computed tomography showed severe reduction of specific striatal CIT binding, comparable to that of Parkinson disease. The polymerase chain reaction products from the parkin gene showed homozygous exon 4 deletion. CONCLUSION: In this sporadic juvenile Parkinson disease case, severe nigrostriatal dopaminergic damage and homozygous exon 4 deletion in the parkin gene were demonstrated.

Adult↗
PubMed2001

Parkin is linked to the ubiquitin pathway.

Autosomal recessive juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease. AR-JP is characterized by selective and massive loss of dopaminergic neurons in the substantia nigra of the midbrain and absence of Lewy bodies, the pathological hallmark of idiopathic Parkinson's disease. Parkin, the causative gene of AR-JP, encodes a 52-kDa protein that is a RING-type ubiquitin (Ub) protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) belonging to a cognate class of UbcH7 or UbcH8. Analysis of parkin mutations in AP-JP patients reveals that the functional loss of parkin as an E3 enzyme is the molecular basis of AR-JP. Thus it is now clear that AR-JP is due to failure of proteolysis mediated by the Ub-proteasome system and accumulation of as yet unidentified protein(s) causes nigral neuronal death without formation of Lewy bodies. These findings should shed new light on the mechanisms underlying neurodegeneration in sporadic Parkinson's disease as well as AR-JP.

Animals↗
PubMed2001

Q-angle influences tibiofemoral and patellofemoral kinematics.

Numerous surgical procedures have been developed to correct patellar tracking and improve patellofemoral symptoms by altering the Q-angle (the angle between the quadriceps load vector and the patellar tendon load vector). The influence of the Q-angle on knee kinematics has yet to be specifically quantified, however. In vitro knee simulation was performed to relate the Q-angle to tibiofemoral and patellofemoral kinematics. Six cadaver knees were tested by applying simulated hamstrings, quadriceps and hip loads to induce knee flexion. The knees were tested with a normal alignment, after increasing the Q-angle and after decreasing the Q-angle. Increasing the Q-angle significantly shifted the patella laterally from 20 degrees to 60 degrees of knee flexion, tilted the patella medially from 20 degrees to 80 degrees of flexion, and rotated the patella medially from 20 degrees to 50 degrees of flexion. Decreasing the Q-angle significantly tilted the patella laterally at 20 degrees and from 50 degrees to 80 degrees of flexion, rotated the tibia externally from 30 degrees to 60 degrees of flexion, and increased the tibiofemoral varus orientation from 40 degrees to 90 degrees of flexion. The results show that an increase in the Q-angle could lead to lateral patellar dislocation or increased lateral patellofemoral contact pressures. A Q-angle decrease may not shift the patella medially, but could increase the medial tibiofemoral contact pressure by increasing the varus orientation.

Aged↗
PubMed2001

Substance use and sexual transmission risk behavior of HIV-positive men who have sex with men.

We examined substance use in relationship to transmission risk behavior (unprotected insertive, UIAI, or receptive anal intercourse, URAI) between HIV-positive men who have sex with men (MSM) and their HIV-negative or unknown serostatus partners. Men who engaged in transmission risk behavior with casual partners were more likely than men who did not engage in such behavior to have used various substances. Users of certain drugs were specifically less likely to use condoms with HIV-negative or unknown status partners than users. Of men who drank alcohol, those who drank more frequently before or during sex engaged in significantly more UIAI with casual partners. Of men who used drugs, those who used more frequently before or during sex were more likely to engage in URAI with casual partners. In multivariate analyses, use of inhalants as well as drinking before or during sex predicted UIAI, while use of inhalants as well as noninjection drug use before or during sex predicted URAI. HIV prevention programs for HIV-positive MSM should focus on decreasing substance use and use specifically before or during sex. Developing prevention programs for substance-using MSM is critical to improve community health and decrease HIV transmissions.

Adult↗
PubMed2001

Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk.

Increasing evidence indicates a significant role for vitamin K in bone metabolism and osteoporosis. In this study, we found a large geographic difference in serum vitamin K2 (menaquinone-7; MK-7) levels in postmenopausal women. Serum MK-7 concentrations were 5.26 +/- 6.13 ng/mL (mean +/- SD) in Japanese women in Tokyo, 1.22 +/- 1.85 in Japanese women in Hiroshima, and 0.37 +/- 0.20 in British women. We investigated the effect of Japanese fermented soybean food, natto, on serum vitamin K levels. Natto contains a large amount of MK-7 and is eaten frequently in eastern (Tokyo) but seldom in western (Hiroshima) Japan. Serum concentrations of MK-7 were significantly higher in frequent natto eaters, and natto intake resulted in a marked, sustained increase in serum MK-7 concentration. We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings indicate that the large geographic difference in MK-7 levels may be ascribed, at least in part, to natto intake and suggest the possibility that higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women.

Aged↗
PubMed2001

Sensitive determination of midazolam and identification of its two metabolites in human body fluids by column-switching capillary high-performance liquid chromatography/fast atom bombardment-mass spectrometry.

Midazolam is a benzodiazepine and is widely prescribed for preanesthesia or general anesthesia. Overdose or intoxication cases of midazolam have been reported. In Japan, smuggled midazolam tablets could be involved in some criminal cases. Midazolam and its two metabolites were extracted by the solid-phase extraction method using Bond Elut SCX cartridges. The compounds were analyzed by on-line capillary high-performance liquid chromatography/fast atom bombardment-mass spectrometry. Midazolam and its two metabolites were well separated on the chromatogram, and each mass spectra gave [M+H](+) ion as a base peak. Deuterium-labeled midazolam was synthesized as an internal standard; it has enabled precise and reproducible quantitation of midazolam in blood samples. The calibration curve showed excellent linearity in the range of 2-200 ng/ml in spiked serum. The detection limit was 300 pg/ml (signal-to-noise ratio=3). The whole blood and urine samples from the victim of a homicide case were analyzed, and the midazolam concentration in the whole blood was estimated to be 163 ng/ml. The present method should be useful in clinical and forensic toxicology, because of its high sensitivity and specificity.

Journal Article↗
PubMed2001

The parkin gene S/N167 polymorphism in Australian Parkinson's disease patients and controls.

This study determined the frequencies of a G-to-A transition (S/N167) polymorphism in exon 4 of the parkin gene in Australian Parkinson's disease patients and control subjects. The genotype of each subject was determined using the polymerase chain reaction and restriction-fragment-length-polymorphism analysis. Overall, the A allele was significantly less common in the Parkinson's disease group (1.7%) compared with the control group (3.8%, OR=0.43, 95% CI=0.19-1.00, P<0.05), although the frequency in the young onset Parkinson's disease group (6.6%) was not significantly different to controls. The A allele is less common in Australian Caucasian subjects compared to Japanese Parkinson's disease patients and appears to be under-represented in older-onset Parkinson's disease.

Journal Article↗
PubMed2001

Obsessive-compulsive-like behavioral changes in pure akinesia.

Pure akinesia is a disorder characterized by profound freezing in the absence of rigidity or tremor that is not improved by levodopa therapy. We report two cases of pure akinesia who developed obsessive-compulsive-disorder- (OCD-) like behavior during their illness. Although the pathophysiological mechanism underlying freezing is unclear, the coexistence of pure akinesia and OCD-like behavior suggests that both symptoms have a common pathological basis in these two cases, presumably damage to the pallidum.

Journal Article↗
PubMed2001

Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP).

Autosomal recessive juvenile parkinsonism (ARJP) is a distinct clinical and genetic entity characterized by highly selective neuronal death in the substantia nigra (SN) and locus coeruleus neurons without Lewy body formation. The mechanism of neuronal death of ARJP is still unknown. Our study demonstrated that iron staining was more intense in ARJP than in both controls and sporadic Parkinson's disease (PD), and there were differences in the pattern of distribution of iron staining between ARJP and PD. In addition neurites of SN in ARJP showed intense iron staining. Thus, we postulate that oxidative stress may play an important role in the neurodegeneration that occurs in ARJP.

Journal Article↗
PubMed2001

Parkin is associated with cellular vesicles.

We recently identified a novel gene, parkin, as a pathogenic gene for autosomal recessive juvenile parkinsonism. Parkin encodes a 52-kDa protein with a ubiquitin-like domain and two RING-finger motifs. To provide a insight into the function of parkin, we have examined its intracellular distribution in cultured cells. We found that parkin was localized in the trans-Golgi network and the secretory vesicles in U-373MG or SH-SY5Y cells by immunocytochemical analyses. In the subsequent subcellular fractionation studies of rat brain, we showed that parkin was copurified with the synaptic vesicles (SVs) when we used low ionic conditions throughout the procedure. An immunoelectromicroscopic analysis indicated that parkin was present on the SV membrane. Parkin was readily released from SVs into the soluble phase by increasing ionic strength at neutral pH, but not by a non-ionic detergent. To elucidate its responsible region for membrane association, we transfected with green fluorescent protein-tagged deletion mutants of parkin into COS-1 cells followed by subcellular fractionation. We demonstrated the ability of parkin to bind to the membranes through a broad region except for the ubiquitin-like domain. The significance of SV localization of parkin is discussed.

Animals↗
PubMed2001

Developmental changes in the expression of parkin and UbcR7, a parkin-interacting and ubiquitin-conjugating enzyme, in rat brain.

Parkin is a product of the Park2 gene the mutation of which causes autosomal recessive juvenile parkinsonism (AR-JP) characterized by selective dopaminergic neuronal death and absence of Lewy bodies. Recently we found that parkin is directly linked to the ubiquitin (Ub)-proteasome pathway as a Ub-protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) UbcH7. Here we analysed by in situ hybridization the expression of mRNAs for parkin and UbcR7 (rat orthologue of human UbcH7) in the developing rat brain. Parkin mRNA increased in parallel with neuronal maturation, but was unevenly distributed in various brain regions after four postnatal days. The expression pattern of the UbcR7 mRNA was almost identical to that of the parkin mRNA in all cases examined. Both parkin and UbcR7 mRNAs were distributed in neurones but not glial cells. Our findings indicate that parkin is expressed not only in the substantia nigra, but also uniformly in various brain regions in a development-dependent manner. Co-expression of UbcR7 with parkin suggests that UbcR7 may interact with parkin in vivo for ubiquitination of yet unidentified target protein(s).

Animals↗
PubMed2001

Parkin and Parkinson's disease.

Parkin is the causative gene for an autosomal recessive form of Parkinson's disease. The gene was discovered in 1998. The parkin gene is a novel gene containing 12 exons spanning over 1.5 Mb and encodes a protein of 465 amino acids with a molecular mass of approximately 52,000 M(r). Various deletion mutations and point mutations have been discovered in patients with autosomal recessive Parkinson's disease. The substantia nigra and the locus coeruleus selectively undergo neurodegeneration without forming Lewy bodies. The parkin gene product, Parkin protein, has a unique structure with a ubiquitin-like domain in the amino-terminus and a RING finger motif in the carboxy terminus. The function of Parkin was not known until recently. During the year 2000, great progress was made in defining its function. First of all, Parkin was found to be a ubiquitin-protein ligase (E3), a component of the ubiquitin system, which is an important adenosine triphosphate-dependent protein degradation machinery. In addition, CDCrel-1, a synaptic vesicle associated protein, was found to be a substrate for Parkin as an E3. Although many studies still need to be performed to elucidate the molecular mechanism of the selective nigral neurodegeneration in this form of familial Parkinson's disease, it will not be too long before this is accomplished. In this review article, we evaluate the developments in this area published since 1 February 2000.

Animals↗