Biomedical subjects

Ken-ichi Abe

Publications and source records attributed to Ken-ichi Abe.

14 recordsLinked to original sources

PubMed2006

Epigenetic silencing of interferon-inducible genes is implicated in interferon resistance of hepatitis C virus replicon-harboring cells.

BACKGROUND/AIMS: We previously established hepatitis C virus (HCV) replicon-harboring cell lines possessing two interferon (IFN)-resistant phenotypes: a partially resistant phenotype (alphaR series) and a severely resistant phenotype (betaR series). We recently found that the severe IFN resistance of the betaR-series cells is caused by the functional disruption of type I IFN receptors. Here, we aimed to clarify the mechanism(s) underlying the partial IFN resistance of the alphaR-series cells. METHODS: alphaR-series cells were pre-treated with 5-azacytidine to evaluate the effects of DNA demethylation on IFN resistance. cDNA microarray analysis was carried out in order to compare 1alphaR cells, which belong to the alphaR series, treated with both 5-azacytidine and IFN-alpha with cells treated with 5-azacytidine or IFN-alpha alone. RESULTS: We found that the IFN-resistant phenotype of alphaR-series cells was impaired by treatment with 5-azacytidine. cDNA microarray analysis identified seven IFN-stimulated genes, which were up-regulated by 5-azacytidine treatment. We demonstrated here that the ectopic expression of each of these seven genes in 1alphaR cells frequently weakened the IFN resistance of these cells. CONCLUSIONS: The present results suggest that the epigenetic silencing of IFN-stimulated genes is implicated in the acquisition of a partially IFN-resistant phenotype of HCV replicon-harboring cells.

Antiviral Agents↗

PubMed2006

Different anti-HCV profiles of statins and their potential for combination therapy with interferon.

We recently developed a genome-length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti-HCV activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, called statins, and their effects in combination with IFN-alpha. Five types of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) were examined for their anti-HCV activities. Fluvastatin exhibited the strongest anti-HCV activity (IC50: 0.9 micromol/L), whereas atorvastatin and simvastatin showed moderate inhibitory effects. However, lovastatin, reported recently as an inhibitor of HCV replication, was shown to exhibit the weakest anti-HCV activity. The anti-HCV activities of statins were reversed by the addition of mevalonate or geranylgeraniol. Surprisingly, however, pravastatin exhibited no anti-HCV activity, although it worked as an inhibitor for HMG-CoA reductase. The combination of IFN and the statins (except for pravastatin) exhibited strong inhibitory effects on HCV RNA replication. In combination with IFN, fluvastatin also exhibited a synergistic inhibitory effect. In conclusion, statins, especially fluvastatin, could be potentially useful as new anti-HCV reagents in combination with IFN.

Antiviral Agents↗

PubMed2005

Mizoribine inhibits hepatitis C virus RNA replication: effect of combination with interferon-alpha.

Interferon (IFN)-alpha monotherapy, as well as the more effective combination therapy of IFN-alpha and ribavirin, are currently used for patients with chronic hepatitis C caused by hepatitis C virus (HCV) infection, although the mechanisms of the antiviral effects of these reagents on HCV remain ambiguous, and side effects such as anemia due to the administration of ribavirin present a problem for patients who are advanced in years. Using a recently developed reporter assay system in which genome-length dicistronic HCV RNA encoding Renilla luciferase gene was found to replicate efficiently, we found that mizoribine, an imidazole nucleoside, inhibited HCV RNA replication. The anti-HCV activity of mizoribine (IC50: approximately 100 microM) was similar to that of ribavirin. Using this genome-length HCV RNA replication monitor system, we were the first to demonstrate that the combination of IFN-alpha and ribavirin exhibited more effective anti-HCV activity than the use of IFN-alpha alone. Moreover, we found that the anti-HCV activity of mizoribine in co-treatment with IFN-alpha was at least equivalent to that of ribavirin. This effect was apparent in the presence of at least 5 microM mizoribine. Since mizoribine is currently used in several clinical applications and has not been associated with severe side effects, mizoribine is considered to be of potential use as a new anti-HCV reagent in combination with IFN-alpha.

Antiviral Agents↗

PubMed2005

cDNA microarray analysis to compare HCV subgenomic replicon cells with their cured cells.

The hepatitis C virus (HCV) replicon system carrying autonomously replicating HCV subgenomic RNA in human hepatocyte cells is a potent tool for basic studies of HCV, such as viral replication and drug development. Recently, we developed two HCV subgenomic replicons (50-1 and 1B-2R1) derived from two HCV strains, 1B-1 and 1B-2, respectively. Since the expression of HCV proteins is thought to affect the host cells' gene expression profiles, we attempted to identify target genes of HCV proteins using microarray analysis (9970 genes) by comparing 50-1 and 1B-2R1 replicon cells with their "cured cells", from which the replicons had been eliminated by prolonged treatment with interferon-alpha. The results showed that HCV replicons could have a variety of expression profiles in human hepatocytes. The results also showed that 2 and 6 genes were commonly up-regulated (more than 2.0-fold) and down-regulated (less than 0.50-fold), respectively, in both 50-1 and 1B-2R1 replicon cells compared with their cured cells. The differential expression profiles of genes selected by the microarray analysis were confirmed with standard RT-PCR and real-time LightCycler PCR. It was noteworthy that the commonly down-regulated genes contained large multifunctional proteases 2 and 7, which are known as catalytic subunits of immunoproteasome, and serine proteinase inhibitor clade C. Our microarray analysis demonstrated that HCV subgenomic replicons can change the gene expression profiles of host cells, and it allowed us to compile the first list of genes that the replicons transcriptionally regulate.

Base Sequence↗

PubMed2004

cDNA microarray analysis of lactoferrin expression in non-neoplastic human hepatocyte PH5CH8 cells.

Lactoferrin (LF), a milk protein belonging to the iron transporter transferrin family, is known as a primary defense protein against pathogenic microorganisms. Previously, we found that bovine and human LFs prevented hepatitis C virus infection in cultured human hepatocytes by a direct interaction with the virus. Since LF is proposed to have transcriptional regulatory activity in addition to its antimicrobial function, we sought to identify the target genes that these two types of LF have in common. To this end, we were the first to perform microarray analysis (9970 genes) using human hepatocytes that expressed bovine or human LF by retrovirus-mediated gene transfer. In the results, LF could give a variety of expression profiles in the human hepatocytes, and showed that 9 and 19 genes were commonly up-regulated (more than 2.0-fold) and down-regulated (less than 0.50-fold), respectively, in both bovine and human LF-expressing cells compared with control cells. Among these genes, we found that gamma-aminobutyric acid (GABA)-B receptor 2 was transcriptionally down-regulated by bovine and human LFs, but not by human transferrin. Furthermore, we obtained the suggestive result that LF may modulate the level of intracellular cAMP. This modulation is one of the cellular responses that the GABA-B receptor modifies. This is the first report of microarray analysis applied to search inclusively for the target genes of LF.

Animals↗

PubMed2004

Open-loop analysis of transfer characteristics from blood pressure to heart rate using an effectively total artificial heart.

It is desirable for the dynamic behavior of the drive rate of the artificial heart to be as similar as possible to that of the recipient's heart rate (HR) before implantation. This requires a model which can simulate the behavior of HR on the basis of only the information measured with the limited number of approvable implanted sensors. This article provides a linear time series model for explaining the behavior of HR only with aortic pressure and right atrial pressure. This could be obtained from open-loop analysis using a total artificial heart, which was introduced for measuring HR in vivo and for eliminating its effect on blood pressure. The model was identified in a goat equipped with a special biventricular assist device called the effectively total artificial heart (ETAH). The ETAH was introduced to make an open loop and awake situation in the animal with almost intact autonomic nerves, which could enhance the accuracy and reliability of the identification of the model. The adequacy of the proposed model was ascertained in several data sets measured in two goats, which were different from the data set used for identification. Most of the mean estimation errors were less than 3 beats/min and auto-correlation analysis showed approvable statistical appropriateness. However, it was clarified through comparison with the 1/R control method that the proposed model has a few problems still to be solved before its future implementation as an automatic controller of the TAH.

Animals↗

PubMed2003

Can personality traits predict pathological responses to audiovisual stimulation?

The "Pockemon shock" is the most famous accident in the history of the broadcasting industry in Japan. Based on the experiences of this unfortunate accident from famous animation program "Pocket Monster", this study focused on the psychology and psychosomatics of the patients. A head-mounted display was used as the three-dimensional image presentation device and "Descent", a free software shooting game, was used as the software. Ten healthy adult male volunteers were used in this experiment after obtaining their informed consent. The oxygen metabolic change in the anterior lobe of the brain was measured by near infrared spectroscopy and recorded on an electrocardiogram. The mental scaling tendency of the object was analyzed using the type A behavior pattern and the hostility scaling. The Cook and Medley hostility (HO) scale from the Minnesota multiphasic personality inventory (MMPI) was also used in this experiment. From this scaling methodology, the paranoid scale, cynicism scale, lie scale, social support quality and social support quantity were calculated. All measured time series data were kept in the normal range, and no fatal arrhythmia or epilepsy were observed during experiments. In some cases, the brain oxygen metabolism may completely differ for the objects of Type A and Type B behavior patterns. On the whole, correlation did not become significant in type A scaling and hostility scaling. In a comparison of the percent changes of the HF in HRV with lie scaling, significant negative correlation was observed. The social support quantity was calculated from Cook and Medley, and significant negative correlations were observed with percent changes of LF/HF in HRV. The lie scale and social support quantity are opposite scaling. The sympathetic nervous system and parasympathetic nervous system have an opposite function also. Therefore, our results showed an interesting phenomenon, when considering the relationship between the autonomic function and the pathophysiological reaction to the audiovisual stimulations. As for the photo sensitive epilepsy, it was reported to be only 5-10% for all patients. Therefore, 90% or more of the cause could not be determined in patients who started a morbid response. The results in this study suggest that the autonomic function was connected to the mental tendency of the objects. By examining such directivity, it is expected that subjects, which show morbid reaction to an audiovisual stimulation, can be screened beforehand.

Acoustic Stimulation↗

PubMed2003

Artificial myocardium with an artificial baroreflex system using nano technology.

Where is the place which should be helped in a patient with congestive heart failure? The answer may be contraction of the heart. At Tohoku University, development research of "the artificial myocardium" has been conducted, using a ball screw type electromagnetic motor. Furthermore, super-miniaturization is being attempted at present. Thus, a system with shape memory alloy is being developed. The cooling speed problem was solved by the application of the Peltier element. A drive at a speed equal to that of a heartbeat was realized by the application of this system. At present, a ventricular assist device is used for patients waiting for a heart transplant in Japan. An air driven type system disturbs a patient's QOL remarkably because it is connected to the drive device. With our concept, energy is provided by using the electromagnetic force from outside of the body by the use of transcutaneous energy transmission system. Magnetic shielding by amorphous fibers was used at Tohoku University to improve the total efficiency. A natural heart can alter the cardiac output corresponding to the demand. Artificial internal organs must participate in the system of the living body, too. Tohoku University has developed a resistance based artificial heart control algorithm, which simulated a baroreflex system to cope with every demand. Nano level sensing equipment is now under development at Tohoku University. At present, development is being conducted aiming at an "intelligent artificial myocardium".

Baroreflex↗

PubMed2003

In vivo test of pressure head and flow rate estimation in a continuous-flow artificial heart.

To avoid using sensors with low biocompatibility and low durability in implantable total artificial heart (TAH) systems, the authors previously proposed a new method for estimating instantaneous values of flow rate and pressure head on the basis of voltage, current, and rotational speed in a motor driven centrifugal pump. The previous in vitro experiments showed that the proposed estimator could automatically compensate for the effect of the change in blood viscosity on the estimation accuracy by employing two kinds of autoregressive exogenous models. In this study, validity and reliability of this estimation method were ascertained in an acute animal experiment. In the experiment, two centrifugal blood pumps were implanted into an adult goat as a total artificial heart. Results of estimation were compared with true values when blood viscosity was changed by injecting physiological saline. The results indicated that the system could successfully estimate pressure head by compensating the change of viscosity, although the estimation accuracy of the in vivo estimation was not so high as that of the previous in vitro tests.

Animals↗

PubMed2003

Recent progress in artificial organ research at Tohoku University.

Tohoku University has developed various artificial organs over the last 30 years. Pneumatic driven ventricular assist devices with a silicone ball valve have been designed by the flow visualization method, and clinical trials have been performed in Tohoku University Hospital. On the basis of these developments, a pneumatic driven total artificial heart has been developed and an animal experimental evaluation was conducted. The development of artificial organs in Tohoku University has now progressed to the totally implantable type using the transcutaneous energy transmission system with amorphous fibers for magnetic shielding. Examples of implantable systems include a vibrating flow pump for ventricular assist device, an artificial myocardium by the use of shape memory alloy with Peltier elements, and an artificial sphincter for patients with a stoma. An automatic control system for artificial organs had been developed for the ventricular assist devices including a rotary blood pump to avoid suction and to maintain left and right heart balance. Based upon the technology of automatic control algorithm, a new diagnostic tool for evaluating autonomic nerve function has been developed as a branch of artificial organ research and this new machine has been tested in Tohoku University Hospital. Tohoku University is following a variety of approaches aimed at innovation in artificial organs and medical engineering fields.

Academic Medical Centers↗

PubMed2003

Outflow control for avoiding atrial suction in a continuous flow total artificial heart.

Continuous flow blood pumps, such as axial flow and centrifugal pumps, have been gaining interest as circulatory devices for total artificial hearts (TAHs) because of their smaller size and simpler structure compared to pulsatile pumps. However, continuous flow pumps are more prone to atrial wall suction than pulsatile pumps are. Sudden increases in flow rate to meet changes in physiological demand, especially in the left pump, often cause atrial wall suction. In this study, a control algorithm to prevent atrial wall suction from occurring in the left atrium by controlling the rotational speed of the right pump, instead of reducing the cardiac output of the left pump, was developed and investigated. The method was tested in a mock circulatory system and in acute animal experiments with adult goats. Two centrifugal pumps were used to totally replace the circulatory function of the natural heart. The cardiac output of each pump was determined independently by a control algorithm running on a computer connected through a serial interface to the pump driving units. Results showed that left atrial wall suction could be prevented using this method, and that the method could be performed simultaneously with physiological control of the artificial heart.

Algorithms↗

PubMed2002

Non-linear dynamic analysis of hemodynamic behavior during virtual reality immersion.

Several years ago, a famous accident occurred in Japan. Hundreds of children, who were watching a cartoon on television, suddenly complained of spasms and vertigo, and were taken to hospital. In this study, the autonomic nervous system was evaluated during audiovisual stimulation with three dimensional Virtual Reality (VR) imaging. In our previous studies, we designed the diagnosis machine for an autonomic function using multi-parameters, including electrocardiography, arterial blood pressure, respiration and stroke volume as detected by ultrasonic cardiography. Healthy adult volunteers were used in this experiment with their satisfactory informed consent. The three-dimensional content for VR included dinosaur images in a pre-historic scene. The content was projected on a wide screen and volunteers watched an audiovisual screen for about 20 minutes and the 3-D and 2-D images were compared. There was no significant arrhythmia during experiments in both images. No significant alteration was observed in the quantified hemodynamic data during the experiment. Spectral analysis was performed to evaluate the heart rate variability (HRV) during the experiment. LF, HF and LF/HF of HRV were calculated. However, there were no significant changes during the experiment. Significant change was observed in the fractal dimension of the stroke volume during 2-D and 3-D image VR immersion. Our results suggest that a significant response was observed in the autonomic function according to the 2-D or 3-D images. Our study, which aims at safe audiovisual stimulating equipment, must be developed.

Acoustic Stimulation↗

PubMedDate not supplied

Sensorless estimation of pressure head and flow of a continuous flow artificial heart based on input power and rotational speed.

The present study has proposed a new method for estimating the pressure head (P(t)[mm Hg]) and flow (Q(t)[L/min]) of a centrifugal pump on the basis of voltage (V(t)[V]), current (I(t)[A]), and rotational speed (N(t)[k(rpm)]) of the DC motor for a pump without any additional sensors. In the proposed estimation method, two auto-regressive exogenous (ARX) models are employed. One ARX model has an output, P(t) or Q(t), and three inputs, VI(t) = V(t)I(t) and N(t) and the steady state gain (K) of the system from VI(t) to N(t). It can be assumed that K may include the information on viscosity of blood. The coefficient parameters of this ARX model are identified in an off-line fashion before implantation of the pump. After implantation, P(t) or Q(t) is estimated by the same ARX model with the already identified parameters. The other ARX model is used to identify Kon the basis of VI(t) and N(t) in an on-line fashion every time the viscosity of blood may change. In the experiment, a mock circulatory system consisting of a centrifugal pump and a reservoir with 37% glycerin or water was employed. The root mean square error between measured Q(t) and its estimate obtained from the proposed method was 1.66L/min. On the other hand, a different method based on a single ARX model with inputs of VI(t) and N(t), but without the additional input of K, yielded the corresponding estimation error of 2.22L/min. This means that the proposed method can reduce its estimation error by about 25% in comparison with a method that cannot cope with the change in blood viscosity.

Blood Flow Velocity↗

PubMedDate not supplied

Recording vagal nerve activity for the control of an artificial heart system.

Monitoring cardiovascular control system information is important in considering the quality of life (QOL) of patients with artificial hearts. Natural heart circulation is controlled by an autonomic nervous system. Therefore, it is desirable to record autonomic nerve activity for the control of artificial heart systems. We directly recorded vagal nerve activity in long-term animal experiments. Six healthy adult goats were anesthetized with halothane inhalation, and thoracotomy was performed with the fourth rib resection during mechanical ventilation. Arterial blood pressure and right and left atrial pressures were continuously monitored with an inserted catheter. Cardiac output was measured by an electromagnetic flow meter attached to the ascending aorta. After the chest was closed, an incision was made in the left neck, and the left vagal nerve was separated. Stainless steel electrodes were inserted into the vagal nerve and fixed by a plasticizer. After the incision was closed, the goats were transferred to a cage and extubated after waking. Vagal nerve activity was measured using hemodynamic parameters when the animals were awake. Our results show that clear observation of autonomic nerve discharge was made through this experimental system for over 1 month. The tonus of the vagal nerve was significantly altered before body motion with hemodynamic changes, suggesting the possibility of prediction. These results suggest that information from autonomic nerves may help to control implantable artificial hearts or ventricular assist devices.

Animals↗