Objective To investigate the distribution and elimination of a gadolinium containing high viscosity formulation of sodium hyaluronan (HYA gel) after injection to the middle ear. Materials and Methods The T1 contrast agent gadolinium-diethylenetriamine pentaacetic acid-bis methylamine (Gd-DTPA-BMA) was added to HYA gel and delivered to the middle ear of 13 albino guinea pigs by 3 different ways of injection. Magnetic resonance imaging was performed with a 4.7 T MRI system using a T1-weighted 3-dimentional rapid acquisition with relaxation enhancement sequence. Results An injection technique where the Gd-DTPA-BMA-containing HYA gel was delivered to the middle ear through a percutaneous injection through the auditory bulla after a small incision had been made in the tympanic membrane gave the best filling of the middle ear, covering the cochlea and the region of the round window niche for 24 hours in a majority of the ears studied. Ears injected without an incision in the tympanic membrane showed an immediate uptake of Gd-DTPA-BMA in the inner ear as a sign of rupture of the round window membrane. Conclusion A percutaneous injection of a HYA gel into the tympanic bulla is distributed in a predictable way and gives a good filling of the middle ear cavity. The HYA gel remains in close vicinity to the RWM for more than 24 hours. Injection should be performed after an incision of the tympanic membrane has been made to prevent rupture of the round window membrane.

OBJECTIVE:Previous in vivo experimental magnetic resonance imaging (MRI) investigations of the mammalian inner ear at 4.7 Tesla have indicated that intravenously injected gadolinium (Gd) penetrates the perilymphatic labyrinth, but not the endolymphatic membranous labyrinth. In the present study, high field MRI at 9.4T was used to visualize the in vivo mouse vestibulo-cochlea system, and to determine whether the endolymphatic system is permeable to a Gd complex.METHODS:A 9.4 T Varian magnet equipped with a 12 cm inner diameter gradient system with maximum gradient strength of 600 mT/m, a millipede coil (Varian design) and a Gd contrast agent were used for image acquisition in the normal C57 BL-6 mouse.RESULTS:High-resolution 2D and 3D images of the mouse cochlea were acquired within 80 minutes following intravenous injection of Gd. Gd initially permeated the perilymphatic scala tympani and scala vestibuli, and permitted visualization of both cochlear turns from base to apex. The superior, inferior and lateral semicircular canals were subsequently visualized in 3 planes. The membranous endolymphatic labyrinth was impermeable to intravenously injected Gd, and thus showed no apparent uptake of Gd at 9.4T.CONCLUSION:The 9.4T field strength MRI permitted acquisition of high resolution images of anatomical and physiological features of the normal, wild type mouse perilymphatic inner ear in vivo, and provided further evidence that the endolymphatic system is impermeable to intravenously injected Gd.

Neuropil deposition of beta-amyloid (A beta) peptides is believed to be a key event in the neurodegenerative process of Alzheimers disease (AD). An early and consistent clinical finding in AD is olfactory dysfunction with associated pathology. Interestingly, transgenic amyloid precursor protein (Tg2576) mice also show early amyloid pathology in olfactory regions. Moreover, a recent study indicates that axonal transport is compromised in the olfactory system of Tg2576 mice, as measured by manganese-enhanced magnetic resonance imaging (MEMRI). Here we tested whether the putative axonal transport deficit in the Tg2576 mouse model improves in response to a selective gamma-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560). Tg2576 mice or wild-type (WT) littermates were treated daily with MRK-560 (30 mu mol/kg) or vehicle for 4 (acute) or 29 days (chronic). The subsequent MEMRI analysis revealed a distinct axonal transport dysfunction in the Tg2576 mice compared with its littermate controls. Interestingly, the impairment of axonal transport could be fully reversed by chronic administration of MRK-560, in line with the significantly lowered levels of both soluble and insoluble forms of A beta found in the brain and olfactory bulbs (OBs) following treatment. However, no improvement of axonal transport was observed after acute treatment with MRK-560, where soluble but not insoluble forms of A beta were reduced in the brain and OBs. The present results show that axonal transport is impaired in Tg2576 mice compared with WT controls, as measured by MEMRI. Chronic treatment in vivo with a gamma-secretase inhibitor, MRK-560, significantly reduces soluble and insoluble forms of A beta, and fully reverses the axonal transport dysfunction.

Translational bionnarkers in Alzheimer's disease based on non-invasive in vivo methods are highly warranted. H-1 magnetic resonance spectroscopy (MRS) is non-invasive and applicable in vivo in both humans and experimental animals. In vivo H-1 MRS and 3D MRI were performed on brains of double transgenic (tg) mice expressing a double mutant human P-amyloid precursor protein APP(K670N,M671L) and human mutated presenilin gene PS1M146L, and wild-type (wt) littermates at 2.5, 6.5 and 9 months of age using a 9.4T magnet. For quantification, LCModel (TM) was used, and the data were analyzed using multivariate data analysis (MVDA). MVDA evidenced a significant separation, which became more pronounced with age, between tg and wt mice at all time points. While myo-inositol and guanidoacetate were important for group separation in young mice, N-acetylaspartate, glutamate and macrolipids were important for separation of aged tg and wt mice. Volume segmentation revealed that brain and hippocampus were readily smaller in tg as compared to wt mice at the age of 2.5 months. Amyloid plaques were seen in 6.5 and 9 months, but not in 2.5 months old animals. In conclusion, differences in brain metabolites could be accurately depicted in tg and wt mice in vivo by combining MRS with MVDA. First differences in metabolite content were readily seen at 2.5 months, when volume defects in tg mice were present, but no amyloid plaques. (c) 2007 Elsevier Inc. All rights reserved.

<正>目的:探讨用4．7特斯拉试验用磁共振成像系统能否在豚鼠中检测内淋巴积水。方法:20只白色或者杂色豚鼠用于该研究。5只正常豚鼠作为对照组,15只豚鼠用于制作内淋巴积水模型。9只内淋巴囊破坏组中的5只和6只内淋巴囊完整组(与乙状窦游离)动物采用 gadolinium(Gd)-DTPA-BMA增强MRI检测内淋巴积水。结果:由于 Gd-DTPA-BMA主要进入鼓阶和前庭阶,耳蜗的三个阶可在所有动物中由MRI清晰显示。在内淋巴囊完整组,内淋巴囊手术后6天MRI即可检测到内淋巴积水,并且由组织学证实。在内淋巴囊破坏组中的1 只动物,因内耳屏障的严重破坏而使Gd-DTPA-BMA快速漏入中阶, MRI可检测到该变化,其听力损失为60dB。结论:用Gd-DTPA-BMA 增强的高分辨MRI可检测出内淋巴积水,有可能对积水程度进行定量测试。在Gd-DTPA-BMA的帮助下,内耳屏障损伤或可能的膜破裂可以被检出。图4表4参12

Early diagnosis of Alzheimer's disease (AD) would be supported by the detection of new in vivo biomarkers. Magnetic resonance spectroscopy (MRS) provides means to study metabolites of the brain over time. A non–hypothesis driven analysis of the spectroscopy data may be appropriate to characterize the fingerprint of complex MRS data with large numbers of variables. In vivo MRS was performed using a 9.4/30 T horizontal Bruker magnet. 8–17 transgenic (tg) APP/PS1 mice and 11–13 wild type (wt) littermates per time point were investigated at the age of 2.5, 4.5, 6.5 and 9 months, respectively. A water suppressed PRESS pulse sequence was used to acquire the spectrum in a volume of 8 mm3 of hippocampus. Data acquisition was followed by processing using LCModel and multivariate data analysis using PLS–DA. Relative values of 10 variables (Glutamate (Glu), Glutamate/Glutamine (Glx), myo–Inositol (Ins), N–Acetylaspartate (NAA), N–Acetylaspartate/N–Acetylaspartylglutamate, (tNAA), Taurine (Tau), Glycerophosphocholine/Phosphocreatine (tCho), macromolecules/lipids (MM09), (MM09Lip09), (MM14) were derived with LCModel. Scatter plots of PLS–DA models showed a significant separation between tg and wt at the age of 4.5 (Q2=0.134), 6.5 (Q2=0.134) and 9 (Q2=0.146) months. 2.5 month old mice showed a tendency for separation without reaching statistical significance. Leave one out prediction with cut off value of 0.5 classified samples with the following sensitivity and specificity: 82% and 75% at 2.5, 71% and 77% at 4.5, 72% and 85% at 6.5, 55% and 83% at 9 months. The most important variables for separation were tCho and Glu or NAA and tNAA at 6.5 or 9 months, respectively. Regression analysis revealed a significant decrease of Glu, Glx, MM09, MM09LIP09 with age for tg and wt. No significant change with age was observed for NAA, Ins, Tau or tCho. tNAA significantly decreased with age in tg but not wt. Differences in composition and changes with age of brain metabolites could be accurately depicted in tg and wt mice in vivo by combining MRS with LC–Model and PLS–DA. Separation between tg and wt was possible earliest at 4.5 months of age. The sensitivity and specificity of the method averaged 80% and 70% respectively.

Carbamazepine (CBZ) is a commonly used antiepileptic drug known to block voltage-gated sodium channels. Infants exposed to CBZ in utero show reduced head circumference, for reasons unknown. We investigated CBZ's effect on neural growth in megencephaly (mceph/mceph) mice lacking functional Kv1.1. Mice fed with CBZ were assessed for brain structure size, seizure behavior and expression of markers for neuronal plasticity and rescue in brain. CBZ counteracted brain overgrowth and the increased size of neurons in the mceph/mceph mouse. These effects of CBZ occurred at doses that did not fully suppress epileptic behavior. Furthermore, CBZ normalized Bdnf mRNA levels and mRNA species encoding Nogo signaling pathway proteins. In conclusion, CBZ protects efficiently against abnormal growth and abnormal expression patterns of nerve growth signaling systems in the mceph/mceph brain. These observations and the effect of CBZ in utero suggest that CBZ treatment might be advantageous in some types of human idiopathic megalencephaly.

Objective To find out whether it is possible to visualize experimental endolymphatichydrops in the cochlea using magnetic resonance imaging (MRI) at 4.7 T. Methods Twenty albino orpigmented guinea pigs were used. Five normal guinea pigs were used as controls. Fifteen guinea pigswere subjected to procedures promoting endolymphatic hydrops. Five of 9 animals in the endolymphaticsac damaged group and 6 animals in the endolymphatic sac intact group (dissection from sigmoid sinus)were evaluated for endolymphatic hydrops using MRI with gadolinium (Gd)- DTPA- BMA contrast agent.Hearing was tested with electrocochleography. The surface area of three partitions of the cochlea wasused to quantify endolymphatic hydrops. Results The fine structure of the three partitions of the cochleawas visualized with MRI in all animals as Gd- DTPA- BMA appeared mainly in scala tympani andvestibuli. As early as 6 days after endolymphatic sac surgery, endolymphatic hydrops started to appear asvisualized by MRI and also verified with histology. Severe damage to the inner ear barrier with Gd-DTPA- BMA leakage into scala media was detected with MRI in one endolymphatic sac- damaged animalwhich had a 60 dB hearing loss. Conclusions Endolymphatic hydrops can be visualized with highresolution MRI by using Gd- DTPA- BMA and it is possible to quantify the extent of endolymphatichydrops. Damage to the inner ear barrier or possible rupture of membranes can be shown with theassistance of Gd- DTPA- BMA.

Precise, non-invasive determination of the aetiology and site of pathology of inner ear disorders is difficult. The aim of this study was to describe an alternative method for inner ear visualization, based on local application of the paramagnetic contrast agent gadolinium. Using a 4.7 T MRI scanner, high contrast images of all four cochlear turns were obtained 3.5 h after placing gadolinium on the round window membrane. Gadolinium cleared from the cochlea within 96 h. Auditory brainstem response measurements performed on a separate group of animals showed no significant threshold shifts after the application, indicating that gadolinium is non-toxic to the guinea pig cochlea.

Objective-To assess the advantages of binaural hearing for cochlear implant (CI) users using a hearing aid (HA) for the contralateral ear.Material and Methods-The subjects comprised 3 males and 3 females (age range 48-84 years). All of them had been using a CI and HA for > 6 months. Their speech perception was examined in quiet using monosyllables and Japanese Hearing in Noise Test (J-HINT) sentences. Speech perception in noise was examined using J-HINT sentences. Late cortical waves were measured while subjects listened to 1 kHz frequent and 2 kHz target tone stimuli. The latency of the event-related potential (P300) wave was compared for monaural and binaural hearing conditions.Results-Three subjects showed significantly better results for binaural than monaural (CI alone) hearing for monosyllables and HINT sentences (p < 0.05; paired t-test). Subjects with better speech perception had been using an HA for longer than those with poor performance (18.3 vs 4.0 years). The overall average score was better for binaural than monaural hearing in the speech perception test under quiet and noisy conditions. Comparison of the latency of the P300 wave under monaural and binaural hearing conditions showed a significantly shorter latency for the latter (p = 0.02; paired t-test).Conclusions-Although the use of an HA alone showed marginal benefit for CI users, binaural hearing (CI+HA) resulted in a significant improvement in speech perception under various circumstances.

In order to find out whether it is possible to visualize experimental endolymphatic hydrops in the cochlea with magnetic resonance imaging (MRI) at 4.7 T, we used 11 guinea pigs. Five normal guinea pigs were used as controls. Early manifestation of endolymphatic hydrops was evaluated in endolymphatic sac (ES)-intact animals (n = 6), and advanced manifestation in ES-damaged animals (n = 5) by means of MRI with gadolinium-diethylenetriaminepentaacetate-bismethylamide (Gd-DTPA-BMA) contrast agent. Hearing was tested with electrocochleography. The surface area of 3 partitions of the cochlea was used to quantify endolymphatic hydrops. The fine structure of the 3 partitions of the cochlea was visualized with MRI in all animals, as Gd-DTPA-BMA appeared mainly in the scala tympani and scala vestibuli. As early as 5 days after endolymphatic sac surgery, endolymphatic hydrops started to appear as visualized by MRI and also verified with histology. Severe damage to the inner ear barrier with Gd-DTPA-BMA leakage into the scala media was detected with MRI in 1 ES-damaged animal that had a 60-dB hearing loss. To conclude, endolymphatic hydrops can be visualized with high-resolution MRI by means of Gd-DTPA-BMA, and it is possible to quantify the extent of endolymphatic hydrops. Damage to the inner ear barrier or possible rupture of membranes can be shown with the assistance of Gd-DTPA-BMA.

OBJECTIVE:To investigate the pharmacokinetics of gadolinium in the perilymphatic fluid spaces of the cochlea in vivo using high-resolution MRI to obtain information concerning perilymph formation.MATERIAL AND METHODS:A Bruker Biospec Avance 47/40 experimental MRI system with a magnetic field strength of 4.7 T was used. Anesthetized pigmented guinea pigs were injected with the contrast agent Gd-diethylenetriaminepentaacetic acid-bismethylamide and placed in the magnet. The signal intensity of Gd in the tissues was used as a biomarker for dynamic changes in the perilymphatic fluid.RESULTS:The most rapid uptake of Gd in the perilymphatic fluid spaces occurred in the lower part of the modiolus, followed by the second turn of the scala tympani. Within the scala tympani, the distribution of Gd in the basal turn was significantly lower than that in the other turns. Destruction of the cochlear aqueduct was followed by an increase in Gd uptake in the perilymph instead of a reduction.CONCLUSIONS:These findings offer further evidence that the pervasive perilymphatic fluid derives from the cochlear blood supply via the cochlear glomeruli, which are in close proximity to the scala tympani within the modiolus, and the capillary in the spiral ligament. Cerebrospinal fluid communicates with perilymph via the cochlear aqueduct but is not the main source of perilymph. These findings are of relevance to the treatment of inner ear diseases, as well as to our understanding of the flow and source of perilymphatic fluid.

The morphology, time-course and volume of the in vivo uptake of the T1 contrast agent gadolinium (Gd) in the perilymphatic vestibulo-cochlea labyrinth, including the utricle, saccule, semicircular canals and scalae of the guinea pig inner ear were analyzed as Fourier transform signal intensity enhancement levels by 3D MRI at 4.7 T. The uptake of Gd as a function of time in the perilymphatic space of the vestibular labyrinth was shown by ANOVA and PLSD post hoc tests to be significantly less (p < 0.05) than that of the scala tympani of the cochlea 10, 30, 60 and 90 min after i.v. injection. Experimentally induced fistulae resulted in MRI detected morphological and quantitative alterations in Gd concentration in the perilymphatic labyrinthine space. The findings demonstrate that Gd-enhanced 3D MRI of the perilymphatic space may be used to examine the morphology, kinetics and intravenous substance delivery in the in vivo mammalian vestibulo-cochlea labyrinth.

A pre-clinical study has been carried out for the utilization of magnetite (Fe3O4) nanoparticles as a diagnostic tracer for MRI. Surfactant-coated Fe3O4 nanoparticles have been synthesized by a chemical coprecipitation method with a narrow particle size of around 6nm. Preliminary experiments demonstrated the feasibility of using superparamagnetic Fe3O4 nanoparticles as contrast agents in MR imaging.

MRI with a T1 contrast agent was used to investigate the normal and noise-damaged cochlea. The time course and distribution of the in vivo uptake of the gadodiamide chelate bound paramagnetic Gd ion (GdDTPA-BMA) throughout the membranous labyrinth of normal and impulse noise-damaged guinea pig cochleae were measured by MRI at 4.7 T. Simultaneous signal enhancement of the basal, medial and apical scala tympani (ST) and scala vestibuli (SV) was observed within 10 min following i.v. injection, reaching maximum levels at around 100 min. ANOVA and post hoc paired t-tests showed statistically significant differences in the levels and rates of Gd uptake-enhancement between the scalae. The ST revealed the most rapid and extensive enhancement throughout the period of active Gd uptake, while the SV showed comparatively slower and less enhancement, and the intact scala media (SM) indicated insignificant enhancement. The in vivo Gd penetration and enhancement of the membranous SM increased significantly in the noise-damaged cochlea, suggesting lesioning of the cochlear membranes.

The membranous labyrinth of the guinea pig cochlea and retrocochlear neural structures were investigated by magnetic resonance imaging (MRI) using an experimental system with a field strength of 4.7T and a single turn surface coil 25 mm in diameter, or standard resonators of 34 or 70 mm in diameter and gradient field strengths of 950 mTm and 200 mTm. High-resolution 2-D and 3-D images of 0.3-1.0 mm slice thickness were acquired by a rapid acquisition with relaxation enhancement (RARE) sequence and a standard multi-echo technique. Structural and dimensional aspects of the cochlea were resolved in vitro and in vivo down to <50 microm, showing the scala vestibule, scala media, scala tympani, spiral ganglia and the cochlear (eighth) nerve. In vivo perfusions with the gadodiamide (GdDTPA-BMA) chelate-bound paramagnetic gadolinium ion resulted in dynamic temporal enhancement of the scala vestibule and scala tympani, but did not penetrate the scala media.

The self-diffusion of water sorbed in wood pulp cellulose fibers was studied by using the pulsed gradient spin-echo (PGSE) method. The observed echo attenuation profiles deviate significantly from those of bulk liquids and can be decomposed into two components: one with a self-diffusion coefficient independent of the diffusion time, and one with an apparent diffusion coefficient that depends on the diffusion time. The relative amplitude of these two components for the different diffusion times used in the PGSE experiment is nearly constant. We attribute the two components to bulk water between cellulose fibers and to water in pores within the fibers, respectively. From the relative amplitude of the components and the known water content in the samples, the amount of water in pores inside the fibers was calculated to 1.4 g/g of cellulose fibers. The self-diffusion coefficient of the bulk water between the fibers is lower than that of neat water. This reduction is mainly caused by the obstruction effect of the cellulose fibers whereas the hydration effect is of minor importance. The apparent self-diffusion coefficient of water trapped in pores inside fibers is approximately one-third of that of the bulk water between fibers when the diffusion time is 12 ms and is reduced further by another factor of 3 when the diffusion time is increased to 80 ms. By using a sheet sample and applying the magnetic field gradient perpendicular or parallel to the sheet it was found that the diffusional motion of water in pores is anisotropic. These results indicate that the pores are elongated along the fiber axis having lengths ranging from a few micrometers up to 20 μm.

The nondispersive part of the interfacial tension between polymer solids and aqueous solutions has been determined by contact angle measurements on photooxidized polystyrene (PS). It is shown from contact angle measurements in air and in octane that the expressions for γs,aq includes a term that is proportional to γaqn and not to √γaqn as is often assumed. The proportionality factor is taken as an expression of the hydrophilicity of the surface. The development of oxidized surface groups was followed by ESCA. It is concluded that the degradation of PS upon UV curing includes an attack on the aromatic groups followed by a ring opening. The hydrophilicity shows a sharp at a certain oxidation level, which we interpret to be due to the ring opening.