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Biomedical subjects

M Aoki

Publications and source records attributed to M Aoki.

At least 235 records · Page 13Linked to original sources
PubMed2000

Oligonucleotide-based gene therapy for cardiovascular disease: are oligonucleotide therapeutics novel cardiovascular drugs?

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease such as restenosis after angioplasty, vascular bypass graft occlusion, transplant coronary vasculopathy, for which no known effective therapy exists. One strategy for combating disease processes has been to target to the transcriptional process. Two approaches have been used to accomplish this. One is the use of antisense that is complimentary to the mRNA of interest. The second approach is the use of ribozymes, a unique class of RNA molecules that not only store information but also process catalytic activity. Ribozymes are known to catalytically cleave specific target RNA leading to degradation, whereas antisense inhibit translation by binding to mRNA sequences on a stoicheometric basis. Theoretically, ribozymes are more effective to inhibit target gene expression. Especially, the application of DNA technology such as antisense strategy to regulate the transcription of disease-related genes in vivo has important therapeutic potential. More recently, transfection of cis-element double stranded (ds) oligodeoxynucleotides (ODN) (= decoy) as a powerful tool in a new class of anti-gene strategies for gene therapy has been reported. Transfection of ds ODN corresponding to cis sequence will result in the attenuation of authentic cis-trans interaction, leading to the removal of trans-factors from the endogenous cis-elements with subsequent modulation of gene expression. This "decoy" strategy is not only a novel strategy for gene therapy as an anti-gene strategy, but also a powerful tool for the study of endogenous gene regulation in vivo as well as in vitro. In this review, we have focused on the future potential of oligonucleotide (antisense, decoy & ribozyme)-based gene therapy for the treatment of cardiovascular disease.

Cardiovascular Diseases↗
PubMed2000

Therapeutic angiogenesis induced by hepatocyte growth factor: potential gene therapy for ischemic diseases.

Recent progress in molecular biology has led to the development of gene therapy as a new strategy to treat a variety of cardiovascular diseases. Targeted diseases range from single gene deficiency diseases to more complex diseases in adults such as restenosis after angioplasty. One obvious major target in the field of gene therapy is ischemic diseases such as myocardial infarction, angina and peripheral arterial diseases (i.e. ASO (arteriosclerosis obliterans)). In a large proportion of such patients, the anatomical extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. Of importance, there is no optimal medical therapy for severe ischemic hearts and critical ischemic limbs. Therefore, novel therapies are required to treat these patients. Recently, the efficacy of therapeutic angiogenesis using VEGF (vascular endothelial growth factor) gene transfer has been reported in human patients with critical limb ischemia and myocardial ischemia. Thus, the strategy for therapeutic angiogenesis using angiogenic growth factors should be considered for the treatment of patients with critical limb ischemia or myocardial infarction. The endothelial cell specificity of VEGF has been considered to be an important advantage for therapeutic angiogenesis, as endothelial cells represent the critical cellular element responsible for new vessel formation. Indeed, human gene therapy for ASO and angina has already begun in the USA, with surprising and beneficial effects. We have focused on hepatocyte growth factor (HGF), which is a mesenchyme-derived pleiotropic factor that regulates cell growth, cell motility, and morphogenesis in various types of cells. Recently, HGF is also considered to be a powertul growth tactor for endothelial cells. In this review, we described the potential gene therapy for ischemic diseases using HGF.

Animals↗
PubMed2000

Graviceptive control of blood pressure in man.

The purpose of the study was to demonstrate a rapid 'graviceptive' influence on blood pressure in man. Subjects, sitting in an electrically powered car, made discrete head tilts, some of which were unpredictably accompanied by transient linear accelerations of the car i) with head tilting to align with the direction of the resulting inertial force vector (gravity + car acceleration) so that the graviceptors were not stimulated; ii) with head tilting in the opposite direction 'misaligning' which stimulated the graviceptors but otherwise maintained similarity of other sensory inputs. Stimuli were dispensed in a balanced, cross over, repeated measures design on 8 normal males. Recordings were made of arterial blood pressure in the left radial artery, the electrocardiogram and plethysmographic responses in the right hand first digit. Comparisons of 10s pre-stimulus baseline with 10s post stimulus responses. Misaligned head tilts provoked highly significant peak increases in systolic (7.6-9.4 mm Hg) and diastolic (5-6 mm Hg) BP and average BP over 10s was significantly raised. Head tilts maintaining alignment with the inertial force vector provoked raised systolic BP by 4-6 mm Hg for only one or two heartbeats. Head movements alone caused a slight lowering of BP. Effects were evident within 1-2 heartbeats of the acceleration onset. The results demonstrate that the graviceptors have a direct influence on BP in normal man. They also help to explain the profound vaso-vagal symptoms of patients with vertigo and why patients with autoregulatory impairment may be further compromised by uncontrolled accelerating and braking when they are transported in an ambulance.

Acceleration↗
PubMed2000

[A case of rhabdomyolysis with water intoxication confirmed by muscle biopsy].

A 32-year-old woman with chronic schizophrenia who took 8-10 liters of water for three years due to thirsty, admitted to our hospital because of convulsion and muscle weakness. Neurological finding on admission showed a mild disturbance of consciousness, moderate proximal muscle weakness, and muscle pain. Laboratory examination revealed marked serum hyponatremia(102 mEq/l) and high value of creatin kinase (1,259 IU/l). The level of creatin kinase reached a peak(39,700 IU/l) at the 5th hospital day. An analysis of the muscle biopsy specimen showed necrotic muscle fibers and opaque fibers, that was compatible with rhabdomyolysis. T 2 weighted magnetic resonance imaging of the brain showed a transient high signals in bilateral putamen but not in pons. She was diagnosed to have rhabdomyolysis due to water intoxication. The present case is the first rhabdomyolysis in Japan that was confirmed by muscle biopsy at an acute stage of water intoxication related with schizophrenia.

Adult↗
PubMed2000

[Pulmonary outflow tract reconstruction with autologous tissue during the Ross procedure: right ventricular characteristics in mid-term follow-up].

BACKGROUND: The Ross procedure requires the interposition of prosthetic or homograft extracardiac conduits to establish ventricle-pulmonary artery connection (RV-PA). These materials usually require multiple reoperations because of conduit failure. To avoid the re-replacement of currently available conduits, usage of autologous tissue may be preferable to reconstruct RV-PA connection during the Ross procedure, especially in the pediatric age group. METHOD: Ten patients (mean age 8.7 years, range 2-23) with congenital aortic valve disease underwent the Ross procedure between June, 1996 and July, 1998. To establish RV-PA continuity, autologous aortic wall including aortic valve with a gusset of pericardial tissue was used in six patients, rolled pericardial conduit with fresh pericardial bicuspid valve in three and one direct anastomosis of pulmonary posterior wall onto the right ventricle with a fresh pericardial monocusp valved patch. All patient's postoperative courses were uneventful. All patients were followed up (mean follow-up period: 21.6 +/- 6.6 months) and postoperative right ventricular characteristics, cardio-thoracic ratio (CTR) on chest X-ray and pulmonary valve function were evaluated. RESULTS: Postoperative right ventricular end-diastolic volume, right ventricular ejection fraction and right ventricular end-diastolic pressure did not change significantly (RVEDV: 128 to 113% of normal, RVEF: 56.4 to 51.5%, RVEDP: 5.9 to 10.1 mmHg). Pulmonary regurgitation during follow-up was mild in six patients and moderate in four. However, CTR decreased significantly over time (preop.: 56.5% postop.: 58.5%, late period: 53.4%). CONCLUSION: Our results support the concept of the reconstruction of pulmonary outflow tract without foreign materials during the Ross procedure. Longer follow-up are necessary to define the possible limitation of this technique.

Adult↗
PubMed2000

[On the differences in attitude and awareness of clinical doctors, health administrators and other health workers to tuberculosis treatment in Japan and the US].

Peculiarity of TB treatment in Japan is a higher rate and duration of hospitalization than in other developed countries. Improvement of the TB control policy in Japan necessitates reexamination of the issue of treatment policy, which requires consideration of recognition and understanding of the concept of TB infection, human rights and the protection of patients as well as the society. Therefore, this study aims at clarifying and analyzing the differences in TB treatment policies in Japan and the US. For the US, a questionnaire was sent to TB Directors of states and large cities in order to analyze TB control policies. Moreover, the author attended the NTCA meeting held in Chicago to interview 16 TB Directors. In Japan, the author sent the same questionnaire translated into Japanese to medical doctors in 54 National TB sanatoria. The hospitalization rates of new smear-positive TB patients were 100% (median) in Japan and 59% in the US. The periods of hospitalization of these patients were 150 days (median) in Japan and 10 days in the US. The total expenses of TB diagnosis and treatment per capita were approximately US $25,000 and 20,000, respectively in Japan and the US. If the DOT strategy were applied to the new smear-positive TB cases in Japan, those total expenses would be reduced to half. On the measures against the TB patients who pose a threat to the public, the US has the series of TB control strategies which contain the reporting system, home isolation, incarceration and penalties for violation, while Japan has only the strategy of hospitalization. The TB policies of Japan in future would need to focus more selectively and carry out thoroughly as seen in the US. The recommended TB policies for Japan obtained from this study are to set TB policies adapted to regional characteristics and to review the strategy against patients posing a threat to the public.

Attitude of Health Personnel↗
PubMed2000

A novel phosphodiesterase type 4 inhibitor, YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one), with little emetogenic activity.

We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, that is structurally different from the other PDE4 inhibitors like rolipram. In the present study, the pharmacological profile of YM976 was investigated. YM976 exhibited a strong and competitive inhibition against PDE4 purified from human peripheral leukocytes with an IC(50) of 2.2 nM. IC(50) values of rolipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had no effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiated prostaglandin E(2)-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited tumor necrosis factor-alpha production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-inflammatory activities of PDE4 inhibitors were compared in rat carrageenan-induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell infiltration into the pleural cavity with oral ED(30) values of 9.1, 10, and 7.4 mg/kg, respectively. YM976 produced no emesis up to 10 mg/kg, whereas rolipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammatory effect of YM976 was examined in ferrets. YM976 dose dependently reduced carrageenan-induced leukocyte infiltration at the doses of 1, 3, and 10 mg/kg, p.o. On the other hand, rolipram failed to show obvious inhibition at doses that do not induce emesis. In conclusion, YM976 is a novel and orally active PDE4 inhibitor and possesses a good separation of emetogenicity from anti-inflammatory activity.

Animals↗
PubMed2000

[Cerebral oxygenation during non-blood prime cardiopulmonary bypass in congenital heart surgery].

To analyze oxygen delivery to the brain and cerebral cellular oxygenation during non-blood prime and blood prime cardiopulmonary bypass (CPB), 22 patients undergoing cardiac surgery with CPB were studied by near infrared spectroscopy (NIRS) monitor (NIRO 500, Hamamatsu Photonics). NIRS can assess continuously cytochrome oxidase (Cyt.aa 3) which is the terminal enzyme of the intramitochondrial respiratory chain. Patients were grouped according to conditions of CPB management: one group underwent repair with non-blood prime (group A, n = 12); the second group underwent with blood prime (group B, n = 10). Body weights ranged from 5.5 kg to 58 kg in group A, and 2.9 kg to 16 kg respectively. CPB was maintained at flow rates between 100 to 150 ml/kg/min. and the acid-base management strategy was alpha stat in all patients. No neurological complication was observed. NIRS date were expressed as changes from baseline where cannulation was prepared. The lowest value of Cyt.aa 3 was -2.7 +/- 0.7 mumol/l in the group A, and -3.9 +/- 1.0 mumol/l in the group B. From the standpoint of changes in Cyt.aa 3, non-blood prime cases we studied were speculated to be within a safety limit. In order to define the definite safety limits, however, further studies including the reduction velocity of Cyt.aa 3 signal as well as the absolute value of the lowest Cyt.aa 3 concentration are required.

Brain↗
PubMed2000

[Heparin monitoring during cardiopulmonary bypass in congenital heart surgery].

The Hepcon/HMS system automatically provides the activated clotting time and a whole blood heparin concentration. It also provides the adequate protamine dose by titration of protamine to heparin. 45 patients undergoing congenital heart surgery with cardiopulmonary bypass (CPB) were studied by the Hepcon/HMS device. We measured the heparin dose response before heparin administration, and the ration between the dose of protamine (ml) which was necessary for heparin neutralization at the termination of CPB and the dose of total heparin (ml) in each patient. The value of heparin dose response ranged 120-390 (mean 228) IU/kg. The ratio between protamine dose and heparin dose varied 0.11-0.99 (mean 0.55). There was a statistically significant correlation between the duration of CPB and this ratio (r = -0.51, n = 45, p = 0.0005). From the standpoint of variances in the value of heparin dose response, conventional way of the heparin administration according to the patient's body weight alone may cause inadequacy of anticoagulation during CPB. A dose of protamine determined by Hepcon device that is smaller than a conventional dose of protamine prevents inadvertent overdose and, therefore, can reduce the adverse effects excessive protamine has.

Adolescent↗
PubMed2000

Effect of a novel anti-inflammatory compound, YM976, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets.

We evaluated the effects of YM976, a selective inhibitor of phosphodiesterase type 4, on antigen-induced eosinophil infiltration into the lungs in rats, mice, and ferrets. In rats, YM976 inhibited the accumulation of eosinophils at an oral ED(50) value of 1.7 mg/kg, and in C57Black/6 mice, exhibited a dose-dependent inhibition at an ED(50) value of 5.8 mg/kg. In the same dose range in the same mouse model, YM976 suppressed interleukin-5 production. We then compared the inhibitory effect of chronic administration with that of single administration in another rat model of eosinophilia induced by repeated antigen exposure. YM976 administered chronically offered more potent inhibition (ED(50) = 0.32 mg/kg p.o.) than a single dose (1.4 mg/kg p.o.). These results indicated that chronic administration is more effective in antigen-induced eosinophilia than a single administration. Emetogenicity is known to be a major adverse effect of phosphodiesterase type 4 inhibitors. We compared the anti-inflammatory activity of YM976 with its emetic activity in ferrets, in which it dose dependently suppressed eosinophil infiltration at an ED(50) value of 1.2 mg/kg, but induced no emesis at 10 mg/kg. This suggested that the compound exhibits a considerable dissociation between its anti-inflammatory and emetic effects. In summary, YM976 inhibited eosinophil infiltration in a dose-dependent manner in rats, mice, and ferrets. In ferrets, it suppressed antigen-induced eosinophil infiltration without emesis. Additionally, we demonstrated that the inhibitory effect on eosinophil infiltration was increased by chronic administration. In conclusion, YM976 is a promising drug for the treatment of diseases involving eosinophil activity, such as asthma.

Animals↗
PubMed2000

[Mild brain hypothermia for influenza encephalitis/encephalopathy and its significance].

During the Winter or Influenza season in Japan, there has been an increase in the number of patients presenting with Central Nervous System complaints or symptoms. One of the causes is reported be Influenza encephalitis/encephalopathy. Some of these patients undergo a course of Reye's Syndrome, Acute Necrotizing Encephalopathy (ANE), or Hemorrhagic Shock and Encephalopathy(HSE), of which the pathologic features are still unknown. It is likely that the major underlying feature is cerebral edema, caused by impairments in the blood-brain barrier, which is mediated by inflammatory cytokines. Mild brain hypothermia may be an effective treatment in preventing cerebral edema by preventing the cytokine activation and elevations in brain temperature. A combination of mild brain hypothermia and high-dose corticosteroid therapy is thought to be effective in the treatment of influenza encephalitis/encephalopathy.

Brain Diseases↗
PubMed2000

[A family with oculopharyngeal muscular dystrophy with (GCG)9 expansion in which a sister had neck as well as proximal and her brother proximal lower limb muscle weakness].

We report a 58-year-old woman (patient 1) and her 60-year-old brother (patient 2) with autosomal dominant oculopharyngeal muscular dystrophy. Patient 1 first noticed blepharoptosis and neck weakness at age 55. On neurological examination, she showed bilateral blepharoptosis and weakness in the neck and upper proximal limbs. Serum creatine kinase (CK) level was slightly elevated. Her older brother first noticed blepharoptosis and lower limb weakness at age 51. On neurological examination, he showed bilateral blepharoptosis, slight ophthalmoparesis and bilateral iliopsoas muscle weakness. Serum CK level was normal. Esophageal fluoroscopy disclosed dysfunction of the constrictor pharyngeal muscles. Muscle biopsy of them showed myopathic changes with rimmed vacuoles. The (GCG)9 mutation in the poly (A) binding protein 2 gene was identified, which was the same as seen in the large French-Canadian kindred in Quebec in Canada. The clinical phenotype in patient 2 is similar to that of French-Canadian patients but it in patient 1 is different in distribution of muscle weakness.

DNA-Binding Proteins↗
PubMed2000

Antigraviceptive neck muscle responses to "moving up and moving down" in human.

The responses of neck muscle to sudden transit from one 'g' to hyper 'g', work to support the head and remain the relative position of head on trunk as common observed: i.e. in sudden acceleration or deceleration by car or ejection of pilot from aircraft. Accordingly it is highly possible that the neck muscle responses to moving up may be important to prevent the neck injury due to sudden linear acceleration such as moving up against gravity. However little is known about the evaluation of mechanism of this reflex. Therefore the present study was conducted with two aims. The first aim was to investigate the neck muscle responses to vertical linear acceleration bv 0.4 g produced with an electro-hydraulic servo-system. We chose the vertical linear acceleration because it activates mainly sacculus, from which afferents have been demonstrated to be connected directly to sternocleidomastoid muscle in animals and human. The second aim was to determine whether there is a difference of neck muscle response to moving down and moving up.

Acceleration↗
PubMed1999

Dysferlin is a surface membrane-associated protein that is absent in Miyoshi myopathy.

Recently we reported that mutations in a muscle protein "dysferlin" are present in limb girdle muscular dystrophy-2B and a related, adult-onset, distal dystrophy known as Miyoshi myopathy (MM). We report that antibodies to dysferlin identify a protein of approximately 230 kDa and show that dysferlin is located in the muscle membrane. This protein is absent in MM and LGMD-2B muscle. By contrast, dystrophin and other dystrophin-associated proteins are normal in these patients. Thus, dysferlin is a membrane-associated protein that is not likely to be an integral component of the dystrophin complex. Although it is not essential for initial myogenesis, it appears to be critical for sustained normal function in mature muscle.

Dysferlin↗
PubMed1999

Serial changes in the rate of proteoglycan synthesis after chemonucleolysis of rabbit intervertebral discs.

STUDY DESIGN: Serial changes in the rate of proteoglycan synthesis in rabbit discs after chemonucleolytic treatment with chymopapain and chondroitinase ABC were measured using an in vitro method. OBJECTIVES: To determine the retained ability of the intervertebral disc to synthesize proteoglycans after chemonucleolytic treatment. SUMMARY OF BACKGROUND DATA: Most previous studies describe radiologic and histologic changes that occur after chemonucleolytic treatment. However, in humans it is not clear whether reconstitution of the disc space with normal nucleus proteoglycans can occur with time. METHODS: Twenty-five rabbits were treated with chymopapain (10 units/0.1 mL/disc) and chondroitinase ABC (5 units/0.1 mL/disc) by intradisc injection. Five rabbits were killed at each interval, 1, 2, 4, 8 and 12 weeks after injection. Radiologic changes in the disc height were noted, and the rate of proteoglycan synthesis was determined biochemically. RESULTS: After injection, no significant recovery of disc height was seen in either enzyme group after the initial disc narrowing. The average rate of proteoglycan synthesis in control rabbit intervertebral discs, those which had not been surgically treated, was 27.1 (x 10(-6) mmols sulphate/hour/dry weight). Twelve weeks after injection, the values were 21.6 in the saline group, 8.9 in the chondroitinase ABC group, and 8.2 in the chymopapain group. CONCLUSIONS: Doses within the therapeutic range can damage disc cells, at least in the rabbit, so that proteoglycan synthesis declined to 30% of control rates, and no significant recovery of disc height was observed.

Animals↗
PubMed1999

Structural Change in Dextran: Mechanism of Insolubilization by Adsorption on the Air-Liquid Interface.

To clarify the insolubilization mechanism of water-soluble dextran, the association of dextran in water was studied by dynamic light scattering measurements and a surface chemical approach. Dynamic light scattering measurements indicated that insolubilization of dextran is accompanied by a structural change in dextran. Surface tension data for dextran molecules revealed a structural change in dextran molecules at the air-liquid interface. These results suggest that insolubilization of dextran molecules occurred through an adsorption process at the air-liquid interface. Insolubilization of dextran molecules can be reduced by inhibition of this structural change in dextran molecules. The presence of boron as an impurity was found to trigger precipitation based on inductively coupled plasma mass spectrometry measurements and precipitation tests. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B.

The oncogene p3k, coding for a constitutively active form of phosphatidylinositol 3-kinase (PI 3-kinase), strongly activates myogenic differentiation. Inhibition of endogenous PI 3-kinase activity with the specific inhibitor LY294002, or with dominant-negative mutants of PI 3-kinase, interferes with myotube formation and with the expression of muscle-specific proteins. Here we demonstrate that a downstream target of PI 3-kinase, serine-threonine kinase Akt, plays an important role in myogenic differentiation. Expression of constitutively active forms of Akt dramatically enhances myotube formation and expression of the muscle-specific proteins MyoD, creatine kinase, myosin heavy chain, and desmin. Transdominant negative forms of Akt inhibit myotube formation and the expression of muscle-specific proteins. The inhibition of myotube formation and the reduced expression of muscle-specific proteins caused by the PI 3-kinase inhibitor LY294002 are completely reversed by constitutively active forms of Akt. Wild-type cellular Akt effects a partial reversal of LY294002-induced inhibition of myogenic differentiation. This result suggests that Akt can substitute for PI 3-kinase in the stimulation of myogenesis; Akt may be an essential downstream component of PI 3-kinase-induced muscle differentiation.

Animals↗