Mechanism of Voriconazole-Induced Transient Visual Disturbance: Reversible Dysfunction of Retinal ON-Bipolar Cells in Monkeys

PURPOSE. To investigate the mechanism of voriconazole-induced transient visual disturbance in humans. METHODS. Standard full-field electroretinograms (ERGs) were recorded from monkeys treated intravenously with voriconazole. In addition, photopic ERGs elicited by long-duration stimuli (ON-OFF response) were also recorded from monkeys receiving intravenous voriconazole or intravitreal 2-amino-4-phosphonobutyric acid (APB). RESULTS. Characteristic changes were observed in the waveform of the standard full-field ERGs obtained immediately after dosing of voriconazole as follows: electronegative combined rod-cone response (markedly attenuated b-wave and oscillatory potentials), undetectable rod response (eliminated b-wave); slightly abnormal single-flash cone response (flattened appearance in the bottom of the a-wave, mildly attenuated b-wave); and slightly abnormal 30 Hz flicker (mildly attenuated b-wave). The above changes fully recovered to baseline 24 hours after each dosing, along with a decrease in plasma voriconazole concentration. In addition, the change in the waveform of the ON-OFF response recorded in voriconazole-treated monkeys was quite similar to that recorded in APB-treated monkeys as follows: the b-wave was eliminated or prominently attenuated; and the a-and d-waves were not apparently attenuated. V oriconazole is a triazole antifungal agent with potent activity against a broad spectrum of clinically significant pathogens. 1-3 Voriconazole has been generally well tolerated in clinical trials 4 and postmarketing surveillances 5-7 with frequently reported adverse events of transient visual disturbances, which are described as enhanced/altered light perception, photopsia, photophobia, blurred vision, or color vision changes without any abnormality in the fundus oculi. Very few studies have focused on the detailed effect of voriconazole on retinal function, although the retina is generally considered to be the site of the visual disturbances because reversible decreases in the amplitude of the electroretinogram (ERG) were noted in voriconazole-treated humans. METHODS Animals A total of ten cynomolgus monkeys (Macaca fascicularis) between three and eight years of age were used in this study. The animals were housed individually in stainless steel cages in an animal study room where the environmental condition was set as follows: room temperature, 24°C; relative humidity, 60%; illumination, 12-hour lighting (7:00 to 19:00) at 150 to 300 luces. The animals were fed 100 g per animal per day of pellet food for monkeys (PS; Oriental Yeast Co., Ltd., Tokyo, Japan). Tap water from a feed-water nozzle was supplied ad libitum to the animals. All experimental procedures adhered to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, and were approved by the Institutional Animal Care Committee of DaiichiSankyo Co. Ltd. Drug Administration Voriconazole (VFEND for Intravenous Use; Pfizer Inc., New York, NY) was dissolved in physiologic saline. The dose formulation was administered intravenously at a rate of 0.2 mL/kg per minute for ten minutes to six animals with increasing doses of 0, 3, 6 and 12 mg/kg at intervals of one week or more, and the standard full-field ERGs were recorded as described below. Several months after the 12 mg/kg dosing, voriconazole was administered to three animals at 0 mg/kg and to another three animals at 6 mg/kg in the same manner, and the photopic ERG elicited by a long-duration stimulus (the ON-OFF response) was recorded as described below. Intravitreal injection of 2-amino-4-phosphonobutyric acid (APB) (Sigma-Aldrich; St. Louis, MO) was also conducted in two animals several weeks after the last dosing of voriconazole mentioned above. The techniques for intravitreal injection have been described in detail elsewhere

Development and evaluation of a jaw-tracking system for mice: reconstruction of three-dimensional movement trajectories on an arbitrary point on the mandible

Background: Mastication is one of the most fundamental functions for the conservation of life. The demand for devices for evaluating stomatognathic function, for instance, recording mandibular movements or masticatory muscle activities using animal models, has been increasing in recent years to elucidate neuromuscular control mechanisms of mastication and to investigate the etiology of oral motor disorders. To identify the fundamental characteristics of the jaw movements of mice, we developed a new device that reconstructs the three-dimensional (3D) movement trajectories on an arbitrary point on the mandible during mastication. Methods: First, jaw movements with six degrees of freedom were measured using a motion capture system comprising two high-speed cameras and four reflective markers. Second, a 3D model of the mandible including the markers was created from micro-computed tomography images. Then, the jaw movement trajectory on the certain anatomical point was reproduced by integrating the kinematic data of the jaw movements with the geometric data of the mandible. Results: The 3D movements at any points on the mandible, such as the condyle, molar, and incisor during mastication, could be calculated and visualized with an accuracy > 0.041 mm in 3D space. The masticatory cycle was found to be clearly divided into three phases, namely, the opening, closing, and occlusal phases in mice. Conclusions: The proposed system can reproduce and visualize the movements of internal anatomical points such as condylar points precisely by combining kinematic data with geometric data. The findings obtained from this system could facilitate our understanding of the pathogenesis of eating disorders or other oral motor disorders when we could compare the parameters of stomatognathic function of normal mice and those of genetically modified mice with oral behavioral dysfunctions

Visualization of mandibular movement relative to the maxilla during mastication in mice: integration of kinematic analysis and reconstruction of a three-dimensional model of the maxillofacial structure

Background: Mastication is one of the most fundamental functions for the conservation of human life. To clarify the pathogenetic mechanism of various oral dysfunctions, the demand for devices for evaluating stomatognathic function has been increasing. The aim of the present study was to develop a system to reconstruct and visualize 3-dimensional (3D) mandibular movements relative to the maxilla, including dynamic transition of occlusal contacts between the upper and lower dentitions during mastication in mice.Methods: First, mandibular movements with six degrees of freedom were measured using a motion capture system comprising two high-speed cameras and four reflective markers. Second, 3D models of maxillofacial structure were reconstructed from micro-computed tomography images. Movement trajectories of anatomical landmark points on the mandible were then reproduced by integrating the kinematic data of mandibular movements with the anatomical data of maxillofacial structures. Lastly, 3D surface images of the upper dentition with the surrounding maxillofacial structures were transferred to each of the motion capture images to reproduce mandibular movements relative to the maxilla. We also performed electromyography (EMG) of masticatory muscles associated with mandibular movements.Results: The developed system could reproduce the 3D movement trajectories of arbitrary points on the mandible, such as incisor, molars and condylar points with high accuracy and could visualize dynamic transitions of occlusal contacts between upper and lower teeth associated with mandibular movements.Conclusions: The proposed system has potential to elucidate the mechanisms underlying motor coordination of masticatory muscles and to clarify their roles during mastication by taking advantage of the capability to record EMG data synchronously with mandibular movements. Such insights will enhance our understanding of the pathogenesis and diagnosis of oral motor disorders by allowing comparisons between normal mice and genetically modified mice with oral behavioral dysfunctions

The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis

C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta 2-glycoprotein I (beta 2GPI), implicating oxLDL/P2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta 2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/R2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta 2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of adierosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta 2GPI complexes correlated with total cholesterol and hemoglobin Al c. Thus, the generation of CRP/oxLDL/beta 2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/R2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis

トライアスロン競技の生理的特性について

本研究は, トライアスロンレースの運動強度を推定することと, その運動強度を示したペース配分を測定することを目的に行われた。そこで, 実際にレースに参加した選手のレース中の心拍数を測定し, 3種目のペースを測定した。さらに実験室で運動強度と心拍数の関係を測定した。測定は, 推定する誤差を小さくするために, 3種目それぞれについて行った。結果は次のとおりであった。1) 今回の80.4kmのトライアスロンにおいて, 測定できた2名は約3時間半を要した。運動強度と心拍数の平均値は, 65%Vo_2max, 153拍/分, および89%Vo_2max, 170拍/分を示した。2) 水泳, 自転車のペースは, ほぼ一定であったが, ランニングに入ってからペースが上がるものと下がるものがいた。以上の結果から, トライアスロンの運動強度は, 時間や距離によってオーバーペースにならない最適な強度があり, これは従来走運動で報告されてきた値に近いことが示唆された。The purpose of this study was to estimate oxygen consumption and to measure race pace during actual triathlon race. The subjects were 3 triathletes who participated in Anjou triathlon race (swimming 1.3km, bicycling 65.1km, running 14km). Heart rates were recorded with a portable heart rate recorder during the race, and race pace was also recorded at each section. After one month from the race, oxygen uptake and heart rate at three type of exercises were measured in laboratory for estimating the physiological intensity of race. These data were utilized to estimate the average %Vo_2 max at each section during the race. The results were as follows. In this 80.4km triathlon race, average %Vo_2 max and average heart rate were obtaind in two subjects, one indicated 65%Vo_2max and 153 beats/min, and the other indicated 89% Vo_2 max and 170 beats/min, respectively. From these data it is suggested that the shorter the distance is, the higher the %Vo_2 max is

Angular distribution control of extreme ultraviolet radiation from laser-produced plasma by manipulating the nanostructure of low-density SnO 2 targets

金沢大学先端科学・社会共創推進機構We have found that the divergence of a relatively monochromatic extreme ultraviolet (EUV) emission from a laser-produced plasma can be manipulated by changing the target morphology which is a porous low-density tin oxide (Sn O2) structure. The fundamental light of a Nd-YAG laser was irradiated on the target with laser intensity of ∼ 1011 W cm2 and pulse duration of 10 ns. The nanostructure and density of the targets were tuned by a combination of colloidal polymer template and sol-gel processes [Gu, Nagai, Norimatsu, Fujioka, Nishimura, Nishihara, Miyanaga, and Izawa, Chem. Mater. 17, 1115 (2005)], which has a merit in large-scale preparation. When the target has an open cell nanostructure, the EUV emission directed predominantly along target normal, while a closed cell target exhibited divergent emission. The angular distribution may be affected by the orientation of the microstructured initial target, and this phenomenon can be applied to wavefront control of EUV emission. © 2006 American Institute of Physics.Embargo Period 12 month

100m疾走の後半における走スピード, ピッチおよびストライドの変化

本研究では, 成人男子7名を被験者にして, 100m疾走中の後半における走スピード, ピッチ数およびストライド長の変化を明らかにした。本研究で得られた結果は, 次のように要約できる。1) 100m疾走後半の50mから100mまで, 走スピードは減少し続けた。2) 100m疾走後半の50mから100mまで, ピッチ数は減少し続けた。3) 100m疾走後半の50mから90mまでストライド長はほぼ一定を保ったが, 90mから100mまでの区間ではストライド長は急激に増加した。The purpose of this study was to measure running speed, stride length and step frequecny in the latter half of 100m sprint running. The subjects used in this study were four collegiate jumpers, 2 graduate students and an assistant of Chukyo University. All were healthy males. Each run was filmed at 50 frames/sec with Photosonics and Bolex 16mm cameras. Stride length and step frequency was measured from film analysis. Resultes obtanied from this study were summarized as follows. 1. Running speed and step frquency were gradually decreased in the latter half 50m of 100m sprint running. 2. Stride length was almost constant from 50m to 90m. After that, however, it was significantly decreased