Takayuki Tokimoto

Effects of Kanamycin on the Auditory Evoked Responses During Postnatal Development of the Hearing of the Rat

The ototoxic effects of kanamycin were studied in rats during the early postnatal period and at an adult age. Brain stem potentials as well as auditory cortical potentials were used for the estimating of ototoxic damage. The auditory potentials decreased promptly and markedly in the animals which were treated daily with 400 mg/kg body weight of kanamycin starting from the 11th day after birth. In these animals, the auditory potentials were almost completely abolished within 10 days after the beginning of the kanamycin treatment. However, when the same amount of kanamycin was applied earlier or later than that, i.e., avoiding the period of the initial appearance and the greatest development of auditory functions (from the 11th to the 15th day after birth in the rat), the auditory potentials were not apparently damaged. In light and scanning electronmicroscopy, marked ototoxic changes were observed which underlay the functional damage. The meaning of these findings is discussed.

An experimental study on the progressiveness of cochlear damage by aminoglycoside drug.

The administration of the aminoglycoside antibiotics often gives rise to sensori-neural hearing loss. in a study undertaken to explore the progression of hearing loss caused by these drugs, guinea pigs were administered with kanamycin, a representative member of this family of antibiotics, and subsequently were investigated for the presence or absence of hearing loss and its progressive-ness during and after the period of medication in terms of audiogenic brain stem response (BSR). Further, in an attempt to investigate the relationship between the function and morphology of a KM-damaged inner ear, light microscopic as well as scanning and transmission electron microscopic examinations were made of the cochleas excised from the treated animals. the results are summarized as follows(1) Four distinct wave forms, i.e., P1, P2, P3 and P4, were seen in BSR tracings from normal guinea pigs.(2) a comparative study was made of BSR amplitude as an index of hearing. in the group receiving KM in consecutive daily dos...

Effects of X-ray Irradiation on Hearing in Guinea Pigs

Effects of X-ray irradiation on the hearing with CM and ABR to both air- and bone-conduction stimuli were studied continuously from immediately after the irradiation to a few weeks later. At 2, 4, and 6 krad, only slight conductive hearing impairment was found, but at 8 krad or more, CM and ABR disappeared abruptly, after having increased briefly. Advanced sensorineural hearing loss appeared at about 10 hours after irradiation ended at 8 krad, at about 6 hours at 10 krad, and at about 3 hours at 12 krad. More severe hearing impairment was observed at higher frequencies and the endocochlear d.c. potential (EP) decreased at about 7 hours after 10 krad irradiation. Histologically, no discernible changes in the hair cells or sensory hairs were found with a scanning electron microscope at about 6 hours after 10 krad irradiation, while with a transmission electron microscope, the outer hair cells in the basal coil of the cochlea were found to be mostly destroyed. However, no changes could be found in the inner hair cells or other supporting cells.

Synergetic effects of Ca2+ and Cu2+ on phase transition in phosphatidylserine membranes

Abstract In complexes of divalent metals with large exchange rate constant ( K H 2 O ) of the coordinated H 2 O, such as Ca 2+ and Cu 2+ , the cubic structure in the ligand field is usually unstable and conformation changes are easily induced. We observed the molecular motion of phosphatidylserine (PS) in an amphipathic solvent (water / methanol / chloroform) by 1 H-NMR and ESR using Ca 2+ and / or Cu 2+ , which has a similar K H 2 O to that of Ca 2+ . We found that Ca 2+ did not hinder the molecular movements of PS. However, Cu 2+ reduced the movements of both headgroups and the double bonds in the fatty acids of PS. By addition of both Ca 2+ and Cu 2+ , phase transition to a soft solid phase in the PS membrane was observed at room temperature. The results indicate that the headgroups are clustered in two-dimensional network with each ligand field displaced from the aqueous phase to the water / oil interface. The structure changes of the polar headgroups after the binding of divalent cations are considered to trigger the phase transition of this acidic phospholipid membrane.

Ferroelectric diffused electrical bilayer model for membrane excitation

The gating mechanism of localized ion-conducting pores or channels in excitable membranes is discussed based on the ferroelectric model hypothesized by Leuchtag, and excitation is analyzed by a diffused electrical bilayer model. By the application of a self-organized chemical model to such membranes, which have ferroelectric transmembrane units, the membrane potential in ionic circumstances of aqueous electrolytic media is described by a nonlinear equation derived from a phenomenological function for a parameter that characterizes a phase transition of the membranes. The excitation appears with a jump in the potential at one of the points on the bifurcation sets at which the discriminant of the equation equals zero; the point represents the reaction threshold. Because the membrane potential is controlled by two variables (control parameters) in the nonlinear state equation, the jump is cusp catastrophic. The potential of a few types of membranes has been calculated by assuming suitable functions for these...

Dynamic approach to self-organization or a phase transition

Abstract Self-organization or a non-equilibrium phase transition emerges through a quasi-equilibrium state which arises by the coupling of a primary and a partial system acting as an internal force. Such phenomena are studied by an equation of motion of molecules using an overdamped approximation which relates a cause (an internal force produced by an external force) and its effect on the molecular system. In a quasi-equilibrium state a force constant K 1 , which is called a transition parameter, is near zero and the potential bifurcates at the critical point ( K 1 = 0) where K 1 changes from positive to negative. The temperature dependence of K 1 may be represented by an average of the elastic constants between molecules. As a simple example, an ion flux change on membrane excitation is discussed by this dynamic theory.

A self-organized chemical model and reaction cascade

Some reaction cascades in biological systems are analyzed by a self-organized chemical model, an autocatalytic reaction. This model is described by the coupling of a primary system which stabilizes the initial stage of the reaction rapidly and a partial system which controls the primary system slowly. By the internal force caused by a trigger above the threshold, the coupled system in near-equilibrium is broken and changed into a new state. From the rate equation for the coupled system, a dimensionless nonlinear state equation, n = -n3 - un - v, is derived, where n is the concentration of intermediate, and u, v are dynamic variables of the system. This equation is similar to a nonequilibrium tri-molecular reaction. By using this chemical network theory, fibrin polymerization. F + F----fm----fp + X, where F is a fibrinogen molecule, fm is a fibrin monomer, fp is fibrin polymer, and X is small peptides released from fibrinogen, is discussed as an excellent example of the enzyme reaction cascade.

Nitric oxide generation in aqueous solutions of cigarette smoke and approaches to its origin.

Abstract By using the ESR spin trapping technique with the NmethylDglucamine dithiocarbamate (MGD)2-Fe(II) complex, the generation of nitric oxide (NO), a gaseous free radical, was observed in NO spin trapping solution bubbled with the filtered mainstream of cigarette smoke. The ESR signal with a threeline spectrum characteristic of an NO radical, which was not observed immediately after bubbling of smoke, started rapidly increasing with time up to around 25 min after the last addition of ferrous ions Fe(II), and then slowly approached a peak value dependent on the burned cigarette mass and on the smoking speed. The production of NO was, however, much affected by air oxidation and enhanced by the addition of ascorbic acid. A certain concentration of sodium nitrite (NaNO2) solution, in which nitrite NO2 is assumed as the main origin of the NO, mimicked closely the time course of NO generation resulting from the smoke of one cigarette. The cigarette smoke that was passed through alkaline pyrogallol solution as a deoxidizer; however, it exhibited an unchanged intensity of NO signal throughout the measurement. These results strongly suggest that NO would be gradually reproduced from NO2 in the reductive aqueous solution containing excess Fe(II) through NO2, which is initially formed and is concomitantly oxidized from NO in cigarette smoke.

Ferroelectric diffused electrical bilayer model for membrane excitation. II: Voltage clamped responses

Abstract The opening and closing mechanism of Na+ channels in excitable membranes has been discussed by applying our chemical self-organized theory to the ferroelectric diffused electrical bilayer model modified from Leuchtags ferroelectric hypothesis for the channel gating. A state equation for membrane potential η is described by η3 + Aη + B = 0, where A and B are the control variables related to dipole-dipole and dipole-ion interactions, respectively. By a stimulus above the threshold, A and B move along the equilibrium space of the above equation and membrane excitation occurs with a cusp catastrophe at a point on the bifurcation sets when A < 0; T < T c. The Na± current or -conductance in the voltage clamp method is analyzed by use of the functions for Ȧ and [Bdot] modified from Zeemans formulas and the experimental results have been explained successfully by this model.

Network formation in negative charged membranes by two divalent cations and the catastrophe

The ligands of Ca2+-Cu2+-phosphatidylserine (PS) complexes in membrane networks at the water-oil interface through the symmetry breaking instability and the head groups of PS molecules were changed into a solid-like state. A first step in this transition is described by the following scheme in one unit in which the molar ratio is Ca2+: Cu2+: PS = 1:2:4; [Oh]+2[Oh]*----3[Oh]*, where [Oh]* denotes a little distorted ligand structure [LnM2+...2H2O] from [LnM2+2H2O], where Ln is PS molecules (n = 2 to Cu2+ and 4 to Ca2+). All the ligands are changed to [D4h] by the unit-unit interaction due to the network formation; [Oh]*----[D4h]. The whole system is equivalent to Schlögls scheme and is given by a cubic state equation for suitable variables transformations: x = -x3 - ux - v, where x corresponds to the concentration of [Oh]*, and u and v are related to rate constants in the first and the second steps, and they also depend on the initial [Oh] and the final [D4h] concentrations. This system is transferred into a new state with a cusp catastrophe.