Biomedical subjects

Junko Abe

Publications and source records attributed to Junko Abe.

9 recordsLinked to original sources

PubMed2006

Methodological validation of an existing telemetry system for QT evaluation in conscious guinea pigs.

INTRODUCTION: Guinea pigs are suitable for in vivo QT assessment of newly discovered drugs at the pre-clinical stage because of the ease with which these animals can be handled, the lower amount of compound required for testing, and the similarity of the ion channels between the guinea pig heart and the human. Our purpose was to provide detailed methodological information on an existing telemetry recording system for use in evaluating QT interval prolongation in guinea pigs. METHODS: Hartley guinea pigs weighing 400-700 g were used to investigate the appropriate configuration of electrodes to record defined T-waves and the influence of the surgical implantation of a transmitter on the QT interval, as well as to determine the appropriate formula for QT correction. In addition, the validity of using telemetry-monitored guinea pigs was tested by using compounds with (positive references) or without (vehicles) a QT-prolonging effect. RESULTS: A lead with the negative pole placed between the scapulas and the positive pole positioned close to the sternum was found to be the most appropriate to obtain well-defined T-waves. The period for recovery from transmitter implantation was estimated to be at least 1 week. The best-fit formula for our telemetry guinea pig model was a modified Bazett's formula. QTc was prolonged significantly in guinea pigs given positive references, and the QTc was unaffected when the animals were given vehicles. DISCUSSION: We believe that the information provided herein will be a quite helpful guide for researchers to evaluate the QT interval reliably and reproducibly in this telemetry guinea pig model.

Animals↗

PubMed2006

Effect of additional auditory and visual stimuli on continuous performance test (noise-generated CPT) in AD/HD children -- usefulness of noise-generated CPT.

The continuous performance test (CPT) is designed to measure sustained attention quantitatively. Several CPTs are used clinically. We have made changes to the conventional type of visual CPT, by displaying auditory and visual noise along with target or non-target stimuli. By influencing the recognition of the subjects in this way, the changes were intended to increase the sensitivity of detection of inattention and impulsiveness, to make CPT more useful for diagnosis, and to examine the effect of noise on AD/HD children during CPT performance. Its usefulness for AD/HD diagnosis and the reaction of AD/HD children to noise were examined using newly developed computer software. Using this CPT analysis, a significant difference was observed in all measurements, except mean reaction time, between the control and AD/HD groups, showing that it was useful as a supplementary diagnostic method for AD/HD, and was more useful in the younger age group than in the older age group, as the same for conventional CPTs. As compared to no-noise sessions, commission and omission errors both increased significantly in auditory and visual noise sessions. Thus, analyzing the changes in measurements during noise sessions will improve the diagnosis of inattention and combined AD/HD subtypes. Furthermore, it was suggested that analysis of the effects of noise on AD/HD children will benefit their handling in an educational environment. Since omission errors were decreased in AD/HD children by noise during the CPT performance as compared to the control group, noise may induce attention in AD/HD children. The present study presents new findings on the responses to noise of AD/HD children during the CPT.

Acoustic Stimulation↗

PubMed2005

Effect of autonomic nervous function on QT interval in dogs.

The effects of drugs on the QT interval should be evaluated precisely in the early stages of drug development because QT prolongation can trigger the so-called torsades de pointes, a life-threatening polymorphic ventricular tachycardia. It has been reported that the QT interval is affected by autonomic nervous tone besides the heart rate. In this study, we investigated the direct effect of autonomic nervous tone on the QT interval using the parameters of heart rate variability in dogs, when the RR interval was constant (400 or 700 msec). Our results showed that the QT interval at the high HF (high vagal tone) or low LF/HF ratio (low sympathetic tone) was longer than that at the low HF (low vagal tone) or high LF/HF ratio (high sympathetic tone), when the RR intervals were constant, and that the effect of vagal tone on the QT interval might be somewhat stronger than that of the sympathetic tone. The present observations would support the idea that sympathetic as well as parasympathetic tone regulates QT interval and that QT interval may be controlled physiologically by myocardial autonomic nerves via and not via a sinus node. Therefore, a more precise correction formula of QT interval could be established using autonomic parameters other than RR interval (heart rate), while the QT interval is widely known to be dependent on the RR interval or heart rate.

Animals↗

PubMed2005

Practical application of guinea pig telemetry system for QT evaluation.

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Animals↗

PubMed2004

Aromatic residues located close to the active center are essential for the catalytic reaction of flap endonuclease-1 from hyperthermophilic archaeon Pyrococcus horikoshii.

Flap endonuclease-1 (FEN-1) possessing 5'-flap endonuclease and 5'-->3' exonuclease activity plays important roles in DNA replication and repair. In this study, the kinetic parameters of mutants at highly conserved aromatic residues, Tyr33, Phe35, Phe79, and Phe278-Phe279, in the vicinity of the catalytic centers of FEN-1 were examined. The substitution of these aromatic residues with alanine led to a large reduction in kcat values, although these mutants retained Km values similar to that of the wild-type enzyme. Notably, the kcat of Y33A and F79A decreased 333-fold and 71-fold, respectively, compared with that of the wild-type enzyme. The aromatic residues Tyr33 and Phe79, and the aromatic cluster Phe278-Phe279 mainly contributed to the recognition of the substrates without the 3' projection of the upstream strand (the nick, 5'-recess-end, single-flap, and pseudo-Y substrates) for the both exo- and endo-activities, but played minor roles in recognizing the substrates with the 3' projection (the double flap substrate and the nick substrate with the 3' projection). The replacement of Tyr33, Phe79, and Phe278-Phe279, with non-charged aromatic residues, but not with aliphatic hydrophobic residues, recovered the kcat values almost fully for the substrates without the 3' projection of the upstream strand, suggesting that the aromatic groups of Tyr33, Phe79, and Phe278-Phe279 might be involved in the catalytic reaction, probably via multiple stacking interactions with nucleotide bases. The stacking interactions of Tyr33 and Phe79 might play important roles in fixing the template strand and the downstream strand, respectively, in close proximity to the active center to achieve the productive transient state leading to the hydrolysis.

Amino Acid Sequence↗

PubMed2004

Parasympathetic blockade promotes recovery from atrial electrical remodeling induced by short-term rapid atrial pacing.

The purpose of the present study was to assess the influence of autonomic blockade on shortening of effective refractory period (ERP) induced by short-term rapid atrial pacing (RAP) and its recovery process. Fifteen patients (8 men, 7 women, age 52 +/- 16 years) without structural heart disease and without a history of atrial fibrillation were included in this study. All patients underwent RAP at a cycle length of 300 ms for 5 minutes, after which the ERP was measured in all patients at 1, 3, 5, 7.5, and 10 minutes following cessation of RAP. In ten patients, these RAP and measurements of ERPs were repeated after administration of propranolol (P) and subsequent administration of atropine (P + A), respectively. In the remaining five patients atropine (A) was given first and then the administration of propranolol followed (P + A). Relative to the baseline value, the ERP immediately after RAP did not differ significantly from the Control(C), P, A, or P + A (C, 79%+/- 8%; P, 82%+/- 9%; A, 80%+/- 6%; P + A, 82%+/- 13%). However, the ERP 3 minutes after cessation of RAP was significantly (P < 0.05) longer in A (93%+/- 4%) and P + A (97%+/- 5%) than that in C (86%+/- 5%) and P (86%+/- 5%). The recovery time for ERP to return to pre-RAP value was significantly shorter during A and P + A than during either C or P (C, 536 +/- 161 s; P, 503 +/- 172 s; A, 282 +/- 111 s; P + A, 291 +/- 147 s; P < 0.05). Parasympathetic blockade may promote recovery from ERP shortening induced by short-term RAP.

Atropine↗

PubMed2004

Survey of mixing commercially available corticosteroid ointments with other ointments and the anti-inflammatory activity of the admixtures.

We surveyed the prescriptions from the Department of Dermatology in a city hospital to determine the status of the use of admixtures of corticosteroid ointments with other ointments. Thirty percent of the prescriptions of topical ointment therapy for outpatients of the Department were for admixture ointments. They were prescribed for patients aged 2 months to over 90 years. The mixing ratios of corticosteroid ointments with other ointments were 1:1 to 5:3. One-to-one dilution was most frequently used. Corticosteroid ointments classified into strongest, very strong, strong and medium groups were used for admixtures. We studied the effect of admixture ointments on carrageenan-induced edema in rat hind paws to assess the anti-inflammatory activity of these admixtures. Dermovate, its 1:3-diluted preparation with white petrolatum and 1:1-diluted preparation of Lidomex with white petrolatum exerted significant anti-inflammatory activity (p < 0.05, compared with white petrolatum). These results suggest that the admixtures of different corticosteroid ointments have different anti-inflammatory activities. When admixture preparations are used, the properties of the corticosteroid and other ointments should be taken into account individually.

Adolescent↗

PubMed2002

Molecular structure and novel DNA binding sites located in loops of flap endonuclease-1 from Pyrococcus horikoshii.

The crystal structure of flap endonuclease-1 from Pyrococcus horikoshii (phFEN-1) was determined to a resolution of 3.1 A. The active cleft of the phFEN-1 molecule is formed with one large loop and four small loops. We examined the function of the conserved residues and positively charged clusters on these loops by kinetic analysis with 45 different mutants. Arg(40) and Arg(42) on small loop 1, a cluster Lys(193)-Lys(195) on small loop 2, and two sites, Arg(94) and Arg(118)-Lys(119), on the large loop were identified as binding sites. Lys(87) on the large loop may play significant roles in catalytic reaction. Furthermore, we successfully elucidated the function of the four DNA binding sites that form productive ES complexes specific for each endo- or exo-type hydrolysis, probably by bending the substrates. For the endo-activity, Arg(94) and Lys(193)-Lys(195) located at the top and bottom of the molecule were key determinants. For the exo-activity, all four sites were needed, but Arg(118)-Lys(119) was dominant. The major binding sites for both the nick substrate and double-stranded DNA might be the same.

Amino Acid Sequence↗

PubMed2001

Apoptosis in cerebrum of macular mutant mouse.

Neuronal cell death in the brain of macular mutant mouse, a model of copper metabolism abnormality, has features of both apoptosis and necrosis. Apoptotic cells were morphologically identified by the terminal deoxynucleotidyl transferase nick end-labeling (TUNEL) method and electron microscopy. Numerous TUNEL-positive cells were identified in the cerebral cortex, hippocampus and thalamus of the hemizygotes after postnatal day 11. Ultramicroscopic studies confirmed that a number of cells had apoptotic features characterized by condensation and segregation of the nuclei. Furthermore, genomic DNA gel electrophoresis revealed a laddering pattern in the hemizygous brain. Starvation, which produced a low body weight in normal mice similar to that seen in the hemizygotes, did not result in an increase of TUNEL-positive cells. We also found that there was no increase of apoptotic cells in the brains of heterozygotes and copper-supplemented hemizygotes. Immunocytochemical analysis revealed that the distribution of copper/zinc superoxide dismutase-containing cells differed from that of TUNEL-positive cells. These findings suggest that copper deficiency is a key factor triggering apoptosis in the brain of macular mutant mouse through a mechanism different from suppression of antioxidant action of the dismutase. The improved survival period of the copper-supplemented hemizygotes may be attributed, in part, to inhibition of excessive neuronal apoptosis identified in the late stage of the disease.

Animals↗