Biomedical subjects

S Naganuma

Publications and source records attributed to S Naganuma.

At least 19 recordsLinked to original sources

PubMed2006

Enhanced expression of hepatocyte growth factor activator inhibitor type 2-related small peptide at the invasive front of colon cancers.

BACKGROUND: Hepatocyte growth factor activator inhibitor type 2-related small peptide (H2RSP) is a small nuclear protein abundantly expressed in the gastrointestinal epithelium. However, its functions remain unknown. AIMS: To investigate the expression and localisation of H2RSP in normal, injured and neoplastic human intestinal tissue. METHODS: Immunohistochemical examination and in situ hybridisation for H2RSP were performed using normal and diseased intestinal specimens. Its subcellular localisation and effects on the cellular proliferation and invasiveness were examined using cultured cells. RESULTS: In the normal intestine, H2RSP was observed in the nuclei of surface epithelial cells and this nuclear localisation was impaired in regenerating epithelium. In vitro, the nuclear translocation of H2RSP was observed along with increasing cellular density, and an overexpression of H2RSP resulted in a reduced growth rate and enhanced invasiveness. H2RSP expression was down regulated in well-differentiated colorectal adenocarcinomas. However, a marked up regulation of the cytoplasmic H2RSP immunoreactivity was observed in cancer cells at the invasive front. These cells showed low MIB-1 labelling, an enhanced p16 expression and nuclear beta-catenin. The number of H2RSP-positive cells in the invasive front of well-differentiated adenocarcinomas was considerably higher in the cases with lymph node metastases than in node-negative ones. CONCLUSION: In the normal intestine, the nuclear accumulation of H2RSP is a marker of differentiated epithelial cells. Although H2RSP was down regulated in colorectal adenocarcinomas, a paradoxical up regulation was observed in actively invading carcinoma cells. H2RSP immunoreactivity at the invasive front may serve as a marker of invasive phenotype of well-differentiated colon cancers.

Adenocarcinoma↗

PubMed2001

Identification of hepatocyte growth factor activator inhibitor type 2 (HAI-2)-related small peptide (H2RSP): its nuclear localization and generation of chimeric mRNA transcribed from both HAI-2 and H2RSP genes.

A novel small gene, designated hepatocyte growth factor activator inhibitor type 2 (HAI-2)-related small peptide (H2RSP) was cloned and characterized in the process of the search for splicing variant forms of HAI-2 by 3'-rapid amplification of cDNA ends (RACE). The gene consisted of 4 exons spanning approximately 1 kb and was located in 11 kb downstream of HAI-2 gene (19q.13.11). The novel transcript identified by 3'-RACE was thought to be chimerically transcribed from both HAI-2 (exons 1-7) and H2RSP (exons 2-4) genes. Wild-type H2RSP mRNA (0.5 kb) was detected abundantly in various tissues including the gastrointestinal tract, whereas chimeric mRNA (1.5 kb) was found mainly in the kidney, prostate, and placenta by Northern blot analysis. The predicted amino acid sequence of H2RSP contained two unique domains, namely the serine-rich region (exon 3) and the lysine-rich region (exon 4). Transfection of deleted series of H2RSP cDNAs fused to enhanced green fluorescent protein (EGFP) into HeLa cells revealed that H2RSP has nuclear localization signal in the lysine-rich region. Immunohistochemical study using anti-H2RSP polyclonal antibody indeed revealed the nuclear localization of this peptide in vivo. These results suggest that H2RSP and H2RSP/HAI-2 chimeric peptides might function as a transcriptional regulatory peptide at the nucleus.

Amino Acid Sequence↗

PubMed2000

YM-53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species.

The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-fluoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a new inhibitor of squalene synthase, in reducing both plasma cholesterol and triglyceride levels, compared with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and fibrates, respectively. YM-53601 equally inhibited squalene synthase activities in hepatic microsomes prepared from several animal species and also suppressed cholesterol biosynthesis in rats (ED(50), 32 mg kg(-1)). In guinea-pigs, YM-53601 and pravastatin reduced plasma nonHDL-C (=total cholesterol - high density lipoprotein cholesterol) by 47% (P<0.001) and 33% (P<0.001), respectively (100 mg kg(-1), daily for 14 days). In rhesus monkeys, YM-53601 decreased plasma nonHDL-C by 37% (50 mg kg(-1), twice daily for 21 days, P<0.01), whereas the HMG-CoA reductase inhibitor, pravastatin, failed to do (25 mg kg(-1), twice daily for 28 days). YM-53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg(-1), daily for 5 days, P<0.001). In hamsters fed a high-fat diet, the ability of YM-53601 to lower triglyceride (by 73%, P<0.001) was superior to that of fenofibrate (by 53%, P<0.001), the most potent fibrate (dosage of each drug: 100 mg kg(-1), daily for 7 days). This is the first report that a squalene synthase inhibitor is superior to an HMG-CoA reductase inhibitor in lowering plasma nonHDL-C level in rhesus monkeys and is superior to a fibrate in significantly lowering plasma triglyceride level. YM-53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.

Animals↗

PubMed1998

Left heart bypass using the oscillated blood flow with totally implantable vibrating flow pump.

Aiming at a totally implantable ventricular assist device (VAD), a vibrating flow pump (VFP) was developed in Tohoku University. A transcutaneous energy transmission system (TETS) using an amorphous fiber was developed for the totally implantable VAD system. The VFP works with a higher frequency than the natural heart of a biological system, a frequency of 10-50 Hz. In this research, animal experiments on left heart bypass were performed with healthy goats. Blood from the apex of the left ventricle was received and was sent to the aorta so that an adequate supporting effect of the left heart was provided. In particular, the depression effect of the left ventricle was obvious. As a result, sufficient artificial heart flow was provided. For a totally implantable type VAD, left heart bypass of almost 100% may become necessary in some situations. Therefore, apex approaches of left heart bypass may be desirable. From an anatomical consideration, an apex of the heart is suitable for the VFP of this totally implantable type. In the left heart bypass for which the apex of the heart was used, an almost 100% bypass was possible. This is a requirement that is important when waiting for recovery of sufficient cardiac function. It is also important that left heart circulation is maintained fully by an artificial heart of the complete implantation type. The VFP was considered to be useful as a totally implantable type artificial heart from the results.

Animals↗

PubMed1998

Control of the pulmonary arterial resistance by the use of the oscillated assist flow.

In the clinical application of supporting circulation, the treatment of a patient with pulmonary hypertension is very important. We developed the electromagnetically driven vibrating flow pump (VFP) as a totally implantable type ventricular assist system. The artificial heart driven by electromagnetic forces creates high speed oscillation flow around 10-50 Hz. Assistance by high-speed oscillation flow has an interesting influence on the cardiovascular system. In this study, we carried out research on the influence such oscillation flow had on the pulmonary arterial vessels, and the supporting flow wave-form that controlled pulmonary vascular resistance was considered. Six healthy adult goats of both sexes were used in the experiments. We carried out inhalation anesthesia and performed intubation. The thorax was opened through left fourth rib resection. Right heart bypass was performed from the right atrium to the pulmonary artery. The flow of right heart assistance was maintained within 20-25% of total flow. Our purpose was to add flow of a specific high frequency to the right heart circulation. The hemodynamic parameters were recorded on a magnetic tape data recorder and input into a computer through an A-D converter. A result identified was that the pulmonary vascular resistance changed according to the alteration of the driving frequency of the VFP even during the same flow assistance. The resistance of the pulmonary arterial vessels became smaller when the driving of the VFP of 30 Hz was added to the right heart circulation. This was significant even when compared with continuous flow right heart assist. The characteristics of impedance appeared to have interesting alterations as well. Control of pulmonary vascular resistance by right heart assistance becomes possible if these results are applied. Accordingly, it may become one of the choices for treatment of a patient with pulmonary hypertension.

Animals↗

PubMed1997

Nonlinear mathematical analysis of the hemodynamic parameters during left ventricular assistance with oscillated blood flow.

For the development of a totally implantable ventricular assist system (VAS), we have been developing the vibrating flow pump (VFP), which can generate oscillated blood flow with a relatively high frequency (10-50 Hz) for a totally implantable system. In this study, effects of left ventricular assistance with this unique oscillated blood flow were analyzed by nonlinear mathematics for evaluation as the entire circulatory regulatory system, not as a separate part of the system. Left heart bypasses using VFPs from the left atriums to the descending aortas were performed in chronic animal experiments using healthy adult goats. Electrocardiogram (ECG), arterial blood pressure, VFP pump flow, and flow of the descending aorta data taken while the goats were awake were recorded in the data recorder and analyzed in the personal computer system through the AD convertor. Using nonlinear mathematics, time series data were embedded into the phase space, and the Lyapunov numerical method, fractal dimension analysis, and power spectrum analysis were performed to evaluate the nonlinear dynamics. During left ventricular assistance with the VFP, Mayer wave fluctuations were decreased in the power spectrum, the fractal dimension of the hemodynamics was significantly decreased, and peripheral vascular resistance was significantly decreased. These results suggest that nonlinear dynamics, which mediate the cardiovascular dynamics, may be affected during LV bypass with oscillated flow. Decreased power of the Mayer wave in the spectrum caused the limit cycle attractor of the hemodynamics and decreased the peripheral resistance. Decreased sympathetic discharges may be the origin of the decreased Mayer wave and fractal dimension. These nonlinear dynamical analyses may be useful to design the optimal VAS control.

Animals↗

PubMed1997

Hemolysis test of disposable type vibrating flow pump.

The vibrating flow pump (VFP) can generate high frequency oscillated blood flow. Because of the high frequency driving with short stroke volume, the pump system can be small. The disposable type VFP (D-VFP) was developed for use for extracorporeal circulation. The electromagnetic actuator was detached from the vibrating tube, which was newly designed to be a disposable tube with a jellyfish valve. Hemolysis tests of the D-VFP, VFP, centrifugal pump, and roller pump were performed in a mock circulation study using goat blood. Plasma free hemoglobin was measured every 15 min under the same conditions. The plasma free hemoglobin of the D-VFP was 16 mg/dl although that of the VFP was 160 mg/dl at 30 min. The plasma free hemoglobin of the centrifugal pump and roller pump at 30 min were 3 mg/dl and 9 mg/dl, respectively. The hemolysis performance of the D-VFP may be studied further as a result of this study. Two important factors affecting hemolysis development may be the materials of which the vibrating tube is made and heat transmission from the actuator. The D-VFP has a smooth acrylic surface for blood contact compared with the metal surface of old type VFP. The electromagnetic actuator of the VFP surrounded the vibrating tube, so heat from the actuator could be easily transmitted to the blood. Because the D-VFP has a disposable vibrating tube that is detached from the actuator, heat is not readily transmitted to the blood. A mock circulation study of heat transmission was performed using the D-VFP and VFP. Results of the heat transmission study showed that the fluid temperature of the D-VFP was not increased and stayed at room temperature although that of the VFP increased approximately 1 degree C above room temperature. The D-VFP may be a good style for the development of the VFP for use for extracorporeal circulation.

Acrylates↗

PubMed1997

Development of a novel centrifugal pump: magnetic rotary pump.

The rotational axis of the centrifugal pump has some associated problems such as blood destruction and sealing between the axis and pump housing. To improve upon these deficits we have developed a new type of blood pump, the magnetic rotary pump (MRP). The MRP has an original design with no rotational axis and no impellers. We made a prototype MRP and examined its hemodynamics in mock circulation. The prototype MRP flow rate is only 1.0 L/min with an afterload of 30 mm Hg, and we have made some modifications in the size and drive mechanisms from these results. The modified MRP can achieve high flow rates and rotational speeds (6.0 L/min with an afterload of 100 mm Hg, 2,000 rpm) in a mock circuit, and the modified MRP was used for left heart assistance in an acute animal experiment. The MRP could maintain the hemodynamics of an anesthetized adult goat. These results suggest that the MRP needs to be improved in several areas, but the MRP may be useful as a blood pump.

Animals↗

PubMed1997

Pulmonary arterial impedance analysis by the use of the oscillated assist flow.

Pulmonary arterial impedance is an important and interesting characteristic that can be used to evaluate the physiological properties of the pulmonary vessel. However, power spectrum analysis of the pulmonary artery pressure and flow pattern have suggested that peak power in the relatively high frequency range (> 10 Hz) is significantly low; thus, we cannot analyze the vessel properties in the high frequency range. In this study, we used the newly developed vibrating flow pump (VFP), which can generate oscillated blood flow with a relatively high frequency (10-50 Hz) for right heart bypass, to evaluate the pulmonary arterial impedance pattern in the high frequency range. Acute animal experiments of the right heart bypass from the right atrium to the pulmonary artery using 6 healthy adult goats were performed. The flow pattern and pressure of the pulmonary artery, electrocardiograms (ECGs), and arterial and right atrial pressures were continuously monitored during the experiments. Spectral analysis of the hemodynamic parameters using the fast Fourier transform (FFT) method was performed to evaluate the spectral properties. The coherence function, transfer function, and phase patterns were calculated to analyze the impedance pattern in the relatively high frequency area. Previously, various investigators had tried to analyze the impedance patterns of the pulmonary artery; however, they could not analyze the impedance patterns over 10 Hz because the spectral patterns of the pulmonary flow do not have high power at high frequencies. These physiological analyses may be useful in designing the optimal pulmonary circulation.

Animals↗

PubMed1997

Pharmacological properties of YM17E, an acyl-CoA:cholesterol acyltransferase inhibitor, and diarrheal effect in beagle dogs.

YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureido]methyl]ben zene dihydrochloride) was found to be a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT) in rabbit liver and intestine microsomes. Dixon plot analysis revealed that YM17E inhibited microsomal ACAT in a non-competitive manner. YM17E induced a marked decrease in serum cholesterol, especially in non-high-density lipoprotein (HDL) fractions, in cholesterol-fed rats and rats fed normal chow. Measurement of bile secretion after oral administration of YM17E in cholesterol-fed rats showed that the drug markedly accelerated the secretion of bile acids and neutral sterols. Furthermore, absorption of [3H]cholesterol from the gut of cholesterol-fed rats was significantly inhibited by YM17E. From these results, the hypocholesterolemic activity of YM17E in these animals resulted from both a decrease in cholesterol absorption from the gut and the stimulation of excretion of cholesterol from the liver into bile. However, YM17E caused secretory diarrhea in beagle dogs at near lipid lowering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was significantly reduced while its cholesterol lowering effect became stronger. These results suggest that the inhibition of intestinal and/or liver ACAT increases the risk of diarrhea development which, however, can be avoided by controlled drug administration in beagle dogs.

Animals↗

PubMed1997

Development of intracoronary local adhesive delivery technique.

Acute coronary occlusion may occur in weak coronary atherosclerotic lesions, including dissection, ulceration or thrombus. In some cases of occlusion "bail-out" is performed by using recently developed New Devices. However, these have not yet completely solved the problem to this end, we designed a new method of coronary revascularization, the Intracoronary Local Adhesive Delivery Technique, utilizing antithrombotic and absorbable adhesive injected locally into the fragile and morbid arterial wall using a drug delivery PTCA catheter more flexible than the existing New Devices. This adhesive strengthened and hardened the lesions. In this study, we examined the efficacy of making an adhesive cylinder in arteries of similar size to the coronary, through acute animal experiments using the existing clinical adhesives and drug delivery PTCA catheters and 12 femoral arteries of adult goats. We were successful in forming firm tunnels along the inside of six arteries, infused with approximately 0.04 ml Cyanoacrylate. These tunnels were observed with intravascular ultrasound (IVUS) imaging and evaluated microscopically. These results suggest the feasibility of this method as a new approach for making synthetic resinous stents.

Absorption↗

PubMed1997

Development and evaluation of totally implantable ventricular assist system using a vibrating flow pump and transcutaneous energy transmission system with amorphous fibers.

We have developed a vibrating flow pump (VFP) that can generate oscillated blood flow with a relatively high frequency (10-50 Hz) for a totally implantable ventricular assist system (VAS). To evaluate the newly developed VAS, left heart bypasses, using the VFP, were performed in chronic animal experiments. Hemodynamic parameters were recorded in a data recorder in healthy adult goats during an awake condition and analyzed in a personal computer system through an alternating-direct current converter. Basic performance of the total system with a transcutaneous energy transmission system were satisfactory. During left ventricular assistance with the VFP, Mayer wave fluctuations of hemodynamics were decreased in the power spectrum, the fractal dimensions of the hemodynamics were significantly decreased, and peripheral vascular resistance was significantly decreased. These results suggest that cardiovascular regulatory nonlinear dynamics, which mediate the hemodynamics, may be affected by left ventricular bypass with oscillated flow. The decreased power of the Mayer wave in the spectrum caused the limit cycle attractor of the hemodynamics and decreased peripheral resistance. These results suggest that this newly developed VAS is useful for the totally implantable system with unique characteristics that can control hemodynamic properties.

Animals↗

PubMed1996

Effects of exhaustive endurance exercise and its one-week daily repetition on neutrophil count and functional status in untrained men.

Whereas endurance exercise is known to induce marked neutrophilia, it remains to be fully understood as to whether the cell functions are altered as well as whether the adaptability of the responses to training occurs. To address both of these issues, we undertook the present longitudinal investigation in ten healthy untrained men (20-24 years, VO2max 39.1 +/- 4.2 ml/kg/min). The exercise protocol was 7 consecutive sessions of the same workload performed each day for 1.5 h at an intensity of 70% of VO2max. Peripheral blood samples were obtained before, immediately after, and 1 h after exercise on Days 1, 4, and 7, and served for determination of total and differential leukocyte counts, chemotaxis and chemiluminescence of neutrophils. Acute endurance exercise caused marked peripheral neutrophilia with significant increase in both absolute number and relative proportion of band neutrophils (p < 0.01, respectively), indicating partial recruitment of bone marrow neutrophils. While chemotaxis remained unaltered following exercise, reactive oxygen species generation of neutrophils, measured by luminol-dependent chemiluminescence upon stimulation with opsonized zymosan, was not only significantly enhanced following exercise (p < 0.01), but also associated with the proportional increase in band neutrophils (r = 0.727, p < 0.05), suggesting that neutrophils mobilized from the bone marrow following endurance exercise may possess higher responsiveness. On the other hand, the magnitude of the exercise-induced changes was reduced gradually by daily repeated exposure to endurance exercise, but none of the trends were significant except the decline in resting segmented neutrophil counts (p < 0.05) at least during a 1-wk period of repeated exercise sessions.

Adaptation, Physiological↗

PubMed1996

Extracting 1/f fluctuation from the arterial blood pressure of an artificial heart.

We have studied the fluctuations of an artificial circulation for the analysis of the physiological aspects; however, the conventionally used fast Fourier transform (FFT) method cannot separate harmonic oscillations, such as respiratory and Mayer waves, from the 1/f fluctuation, which has been though to represent underlying fractal dynamics. Fractal structure was shown in the strange attractor with chaotic dynamics, which is thought to be a flexible and intelligent system. In this study, the coarse-graining spectral analyzing (CGSA) method was utilized to quantitatively evaluate the proportion of the 1/f fluctuation in the total power in the frequency domain and to analyze artificial circulation in the whole system. We implanted two pneumatically actuated ventricular assist devices as biventricular bypasses (BVBs) in chronic animal experiments using 4 healthy adult goats. To compare the natural and prosthetic circulation of each experimental animal, the BVB-type complete prosthetic circulation model with electrically induced ventricular fibrillation was adopted. All hemodynamic parameters of natural and prosthetic circulation were recorded under awake conditions and calculated with the use of a personal computer. With the use of the CGSA method, time-series data of the hemodynamics were analyzed and fractal percentages, extracting the 1/f fluctuation from a given time series, were calculated. Fractal percentages of the arterial blood pressure were 85.8 +/- 10.7% and 82.0 +/- 7.3% with natural and artificial circulation, respectively (not significant [NS]). 1/f fluctuation showed the characteristics of being fractal in a time series. The fractal structure showed robustness and error resistance in nonlinear dynamics. Therefore, our results suggest that the circulatory regulatory system of the artificial heart may have desirable characteristics such as error resistance.

Animals↗

PubMed1996

Spectral analysis of hemodynamics during left ventricular assistance.

In order to analyze the autonomic nervous system during left ventricular (LV) assistance, fluctuations in hemodynamic derivatives were evaluated by a spectral analyzing method using a fast fourier transform (FFT) methodology. After the left pleural cavity was opened through the fourth intercostal space under general anesthesia, a pneumatically driven ventricular assist system was implanted as in left heart bypasses in chronic animal experiments, using three healthy adult goats. Hemodynamic parameters with and without LV assistance were recorded on a magnetic tape in the awake condition then analyzed in a computer system through an A-D convertor. Power spectral analysis was performed on a beat-to-beat basis for the evaluation of the fluctuations. During copulsation mode LV assistance, Mayer wave fluctuations (0.1 Hz) were significantly increased compared with counterpulsation mode LV assist, suggesting an increase in sympathetic tone. Co-pulsation mode LV assist is reported to increase the afterload of the natural left ventricle, thus, the sympathetic tone may be increased to maintain a natural heart output.

Analysis of Variance↗

PubMed1996

Fluctuations of the hemodynamic derivatives during left ventricular assistance using oscillated blood flow.

To analyze the autonomic nervous system during left heart bypass with a vibrating flow pump (VFP), fluctuations in hemodynamic derivatives were evaluated by the spectral analysis method using fast fourier transform methodology. After the left pleural cavity was opened through the fourth intercostal space under general anesthesia, a VFP was implanted as the left heart bypass device in chronic animal experiments using 3 healthy adult goats. Hemodynamic parameters with and without VFP assistance were recorded on magnetic tape in awake animals and were analyzed by computer through an analog to digital convertor. Power spectral analysis was performed on a beat-to-beat basis for the evaluation of the fluctuations. During left heart bypass with the VFP, Mayer wave fluctuations were decreased significantly although respiratory waves were not changed significantly. These results suggest that sympathetic nervous system modulation was changed under the influences of the left heart bypass with VFP. By using this analysis methodology, truly physiologic ventricular assistance may be achieved.

Animals↗

PubMed1995

Totally implantable ventricular assist system using a vibrating flow pump.

A totally implantable ventricular assist system (VAS), including a drive system and a percutaneous electric energy transmission system, was developed and evaluated in acute animal experiments using adult goats. This newly designed VAS mainly consists of a vibrating tube, coils, magnets, and a jelly-fish valve as the outlet valve. For energy transmission, a new implantable transmitter with a plain weave structure was proposed as a noncontacting transform by using the spinal amorphous magnetic fibers. The fluid mechanical and hemodynamic properties and the efficiency of the energy transmission system were evaluated in acute animal experiments using healthy adult goats. This vibrating electromagnetic artificial heart (AH) could generate more than 10 L/min as output volume, with 10 Hz vibration using 20 volts as supplied voltage. The total efficiency of the percutaneous energy transmission system was 76%, and temperature increases were within the acceptable range, suggesting the usefulness of our newly developed implantable VAS.

Animals↗

PubMed1995

Experimental study of physiological advantages of assist circulation using oscillated blood flow.

To estimate the effect of oscillated blood flow on hemodynamics in an awake condition, left ventricular assist circulation using oscillated blood flow was performed on 3 adult goats as chronic animal examination. A vibrating flow pump (VFP) was used for generating high-frequency oscillated flow. The blood flow rate of assisted circulation was approximately 1.0 L/min, and the driving frequency of VFP was 25 Hz. Systemic vascular resistance and arterial impedance were calculated in this study. Systemic vascular resistance during assist circulation was decreased compared with that without assistance. Oscillated blood flow may be effective in decreasing vascular resistance. Moreover, it was suggested from the study of arterial impedance that motive characteristics of the vascular wall against changing blood pressure may keep their normal reaction. Therefore, oscillated blood flow may be used for left ventricular assist circulation as concluded from the study of the characteristics of blood vessels.

Animals↗