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Biomedical subjects

Y Kajimoto

Publications and source records attributed to Y Kajimoto.

At least 19 recordsLinked to original sources
PubMed1996

Involvement of the homeodomain-containing transcription factor PDX-1 in islet amyloid polypeptide gene transcription.

The AT-rich cis-motif A elements of the insulin gene promoter contribute to directing the gene's expression to pancreatic beta-cells, bound by a homeodomain-containing transcription factor, PDX-1/IPF1/STF-1/IDX-1. The islet amyloid polypeptide (IAPP; amylin) gene, which is also expressed in limited tissues such as pancreatic beta- and delta-cells, contained similar AT-rich sequences in its regulatory sequences. To understand the molecular basis of IAPP gene regulation, we evaluated the possible physiological significance of the motif in human IAPP gene regulation. All of the three typical A element-like sequences that matched the CT-box consensus (AT-1, -207/-202; AT-2, -154/-142; and AT-3, -88/-83) were shown to bind specifically to a nuclear factor in the beta-cell-derived MIN6 cells, which was subsequently identified immunologically as the insulin gene transcription factor PDX-1. When the promoter activity was examined in MIN6 cells, the disruption of AT-1 or AT-3 but not of AT-2 caused a marked reduction in the IAPP gene promoter. Thus, despite the observation that all the three A element-like regions could bind to PDX-1, the AT-2 site may not be involved in mediating the PDX-1 action in vivo. These observations suggest the involvement of PDX-1 in human IAPP gene regulation, which seems to be mediated through at least two A element-like cis-motifs in the gene promoter.

Amyloid↗
PubMed1996

Synthesis and selective coronary vasodilatory activity of 3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivatives: novel potassium channel openers.

A variety of compounds having a benzopyran such as levcromakalim generally exhibit potent antihypertensive activity. During extensive investigations aimed toward identifying K+ channel openers having selective coronary vasodilation without potent hypotensive and tachycardiac effects, we synthesized a series of 3,4-dihydro-2H-1-benzopyran-3-ol derivatives modified at positions 2, 4, and 6 in the benzopyran ring. Initially, compounds having two methoxymethyl groups at position 2 were found to show a selective effect on coronary blood flow (CoBF) relative to mean arterial pressure (MAP) in anesthetized dogs. To find more potent vasodilators, various benzopyran derivatives modified at position 4 were synthesized and structure-activity relationships were examined by evaluation of the extent and duration of the increase in CoBF in anesthetized dogs. As a result, compounds having a (1,6-dihydro-6-oxopyridazin-3-yl)amino group at position 4, in addition to the two methoxymethyl groups at position 2, were found to be more potent and to have an improved duration of action. Among these compounds, JTV-506, (-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-1-methyl-6-oxopyridaz in-3-yl)amino]-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol, exhibited good selectivity for its effect. Administration of this compound (0.03 mg/kg, p.o.) elicited an increase of CoBF without a change of systemic blood pressure and heart rate (HR) in conscious dogs. Further evaluation was performed with respect to (i) the selectivity of its action on the coronary artery versus the aorta and (ii) its effects on MAP, HR, and electrocardiographic ST elevation. As a result, JTV-506 was selected as a potent and selective coronary vasodilator with various pharmacological features favoring clinical development.

Animals↗
PubMed1996

Pancreatic islet cells express BST-1, a CD38-like surface molecule having ADP-ribosyl cyclase activity.

Cyclic ADP-ribose (cADPR), a well-known stimulator of ca(2+) release from the intracellular Ca(2+) pool, has recently emerged as a potential regulator of insulin secretion in pancreatic beta cells. As recently described, BST-1 is a glycosyl-phosphatidylinositol (GPI)-anchored surface molecule that exhibits homology with CD38 and Aplysia ADP-ribosyl cyclase. Like CD38, BST-1 has both ADP-ribosyl cyclase and cADPR hydrolase activities. As a step toward elucidating the physiological role of cADPR in insulin secretion we examined whether BST-1 is expressed in pancreatic islet cells. Sensitive reverse transcription-polymerase chain reaction detected almost as abundant expression of BST-1 mRNA in pancreatic islets as CD38 mRNA. Immunohistochemical analyses utilizing mirror image sections revealed that BST-1 protein is expressed in a majority of the cells in pancreatic islets and that at least beta cells and, to an even greater extent, alpha cells express BST-1. These observations suggest the involvement of multiple enzymes in the regulation of cADPR concentrations in pancreatic islet cells.

ADP-ribosyl Cyclase↗
PubMed1996

Symptomatic hypertrophic pacchionian granulation mimicking bone tumor: case report.

OBJECTIVE AND IMPORTANCE: Osteolytic lesions can be seen in various diseases, and they also resemble the markings normally found on the cranium. We present a rare case of symptomatic hypertrophic pacchionian granulation mimicking bone tumor in the calvaria. CLINICAL PRESENTATION: A 46-year-old woman suffered from a small hump accompanied by pain in the right frontoparietal region. A plain radiograph revealed two punched-out lesions. Precontrast-enhanced computed tomographic scans demonstrated hypodense masses, with partial defect of the outer table of the cranium. Magnetic resonance imaging demonstrated hypointense masses in the T1-weighted image and hyperintense masses in the T2-weighted image, with capsule-like contrast enhancement by gadolinium diethylenetriamine penta-acetic acid. INTERVENTION: The masses were totally resected with attached bone and dura. One of them had destroyed the outer table of the cranium. The affected portions of the masses lacked the dura and partially adhered to the brain surface. Histologically, hypertrophic pacchionian granulation was diagnosed. CONCLUSION: The patient has had no recurrence for 2 years. This case suggests the need to include hypertrophic pacchionian granulation in the differential diagnosis of punched-out lesions.

Cranial Sinuses↗
PubMed1996

The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells.

The glycolytic enzyme glucokinase plays a primary role in the glucose-responsive secretion of insulin, and defects of this enzyme can cause NIDDM. As a step toward understanding the molecular basis of glucokinase (GK) gene regulation, we assessed the structure and regulation of the human GK gene beta-cell-type promoter. The results of reporter gene analyses using HIT-T15 cells revealed that the gene promoter was comprised of multiple cis-acting elements, including two primarily important cis-motifs: a palindrome structure, hPal-1, and the insulin gene cis-motif A element-like hUPE3. While both elements were bound specifically by nuclear proteins, it was the homeodomain-containing transcription factor insulin promoter factor 1 (IPF1)/STF-1/PDX-1 that bound to the hUPE3 site: IPF1, when expressed in CHO-K1 cells, became bound to the hUPE3 site and activated transcription. An anti-IPF1 antiserum used in gel-mobility shift analysis supershifted the DNA protein complex formed with the hUPE3 probe and nuclear extracts from HIT-T15 cells, thus supporting the involvement of IPF1 in GK gene activation in HIT-T15 cells. In contrast to the insulin gene, however, neither the synergistic effect of the Pan1 expression on the IPF1-induced promoter activation nor the glucose responsiveness of the activity was observed for the GK gene promoter. These results revealed some conservative but unique features for the transcriptional regulation of the beta-cell-specific genes in humans. Being implicated in insulin and GK gene regulations as a common transcription factor, IPF1/STF-1/PDX-1 is likely to play an essential role in maintaining normal beta-cell functions.

Amino Acid Sequence↗
PubMed1996

PDX-1 induces insulin and glucokinase gene expressions in alphaTC1 clone 6 cells in the presence of betacellulin.

The pancreatic beta- and alpha-cells are developmentally related to each other but reveal diverse gene expression patterns. Among the two important transcription factors for insulin gene expression, IEF1 is present both in alpha- and beta-cells, but PDX-1/IPF1/STF-1/IDX-1, a homeodomain-containing transcription factor, is present in beta-cells but not in alpha-cells. To elucidate the function of PDX-1 in the expression of beta-cell-specific genes, we established stable alphaTC1 clone 6 (alphaTC1.6)-derived transfectants expressing PDX-1 and examined the changes in the gene expression patterns in them. The exogenous expression of PDX-1 in alphaTC1.6 cells alone could induce islet amyloid polypeptide (IAPP) mRNA expression in the cells but not the expression of insulin, glucokinase, or GLUT2 gene. However, when betacellulin was added to the medium, the PDX-1-expressing alphaTC1.6 cells, but not the control alphaTC1.6 cells, came to express insulin and glucokinase mRNAs. This did not occur with other growth factors such as epidermal growth factor, transforming growth factor alpha, and insulin-like growth factor I. GLUT2 mRNA remained undetectable in the PDX-1--expressing alphaTC1.6 cells. These observations demonstrate the potency of PDX-1 for the expression of the insulin, glucokinase, and IAPP genes and suggest that certain regulatory factors, which can partially be modified by betacellulin, also contribute to the beta-cell specificity of gene expression.

Amyloid↗
PubMed1996

[Hemodynamic simulation study of cerebral arteriovenous malformations: changes of wall stress and early detection of NPPB].

Obliteration procedures for large high-flow arteriovenous malformations (AVM) were simulated using a compartmental flow model to investigate the role of altered autoregulatory conditions in the development of hyperperfusion and normal perfusion pressure breakthrough (NPPB). Since the arterioles are primarily responsible for autoregulatory function, the role of these structural changes on the development of hyperperfusion was also studied by evaluating the wall thickness (T), internal radius (Ri) and tangential wall stress (sigma). As the AVM flow was decreased during the obliteration procedures, the perfusion pressure (delta P) of the brain tissue surrounding the AVM increased. When the autoregulatory condition was impaired [AR (-)] and the lower limit of the autoregulatory pressure range (LAR) was shifted from 60 mmHg (LAR60) to 40 mm Hg (LAR40), the flow volume in the surrounding brain (Fb) increased markedly, from 67 ml/100g/min to 92 ml/100g/min, with the progress of the obliteration procedures. In these conditions, T/Ri was supposed to be constant and sigma value increased uniformly. In the presence of the autoregulatory mechanism [AR (+)], T/Ri increased against increasing delta P, which resulted in smaller sigma value than that under AR (-) conditions. When the contracted vascular wall yielded on the process of increasing wall stress, delta P and feeder pressure (Pf) decreased to some degree. Concomitantly increase of the sigma value and marked hyperperfusion developed in the brain. The yield of the contracted vascular wall would result in the decrease of a pressure gradient across the arteriole and the reciprocal increase of pressure load on the walls of the capillary and venula, which might lead to NPPB. Since the decrease of delta P or Pf during the progress of the obliterating procedures is considered specific to the appearance of hyperperfusion or NPPB, monitoring these parameters would be useful for its early detection. If the upper limit of the autoregulatory pressure range was assumed to decrease and become the yield point in the brain surrounding high flow AVMs, hyperfusion or NPPB could be considered to develop in the conditions with the autoregulatory pressure range being narrowed and/or shifted to the lower pressure level. Induced systemic hypotension was found to be effective in reducing the magnitude of Fb, delta P, and Pf when induction was appropriately performed in stepwise fashion. T/Ri and sigma were kept in narrow ranges compared to those before induction of hypotension.

Arterioles↗
PubMed1995

Expression of CD38 gene, but not of mitochondrial glycerol-3-phosphate dehydrogenase gene, is impaired in pancreatic islets of GK rats.

Goto-Kakizaki (GK) rat, a rodent model of spontaneously occurring non-insulin dependent diabetes mellitus (NIDDM), exhibits impaired glucose-stimulated insulin secretion. To explore the background of the beta-cell dysfunction in NIDDM, we investigated whether and how the expression pattern of factors that would potentially be involved in the glucose-stimulated insulin secretion machinery is changed in GK rats. Using quantitative reverse transcription-PCR (RT-PCR) method, we found that the gene expression of CD38, a type 2 membrane protein which has ADP-ribosyl cyclase activity, is reduced by approximately 50% in islets of GK rats. Despite previous studies showing reduction in the FAD-linked mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) activity in GK rats, the mGPDH mRNA amounts were equal to those in the control Wistar rats, suggesting a difference that arose post-transcriptionally. These observations support the idea that multiple defects of the glucose-responsive insulin secreting machinery are involved in the development of diabetes in GK rats.

ADP-ribosyl Cyclase↗
PubMed1995

Ubiquitous, but variable, expression of two alternatively spliced mRNAs encoding mouse homologues of transcription factors E47 and E12.

Two basic helix-loop-helix (bHLH) transcription factors, E47 and E12, are involved in cell-specific gene expression as part of dimeric complexes which interact with the cis-acting motif E-box. Although both generated from a single gene (E2A) by means of alternative splicing, the structural difference in these bHLH regions between the two suggests that the two bHLH proteins may differ in some of their functions. As a step toward elucidating the individual implications of E47 and E12, we investigated the mRNA expression ratios of their homologues (A1 and kA1, respectively) in mouse tissues and cell lines. Both the A1 and kA1 mRNAs were ubiquitously expressed in all tissues examined. However, their ratios varied: e.g., skeletal muscle, 2.2 +/- 0.3 (mean +/- SE); spleen, 2.0 +/- 0.2; pancreatic islet cells, 1.2 +/- 0.2. The A1/kA1 ratios in the cell lines investigated were similar to those of their original tissues. In conclusion, the ubiquity in mRNA expression observed for both the E47 and E12 homologues in mouse provides support for their involvement in a broad range of transcriptional regulation. The variation in the A1/kA1 expression ratios, on the other hand, supports the idea that A1 (E47) and kA1 (E12) each have some unique roles in the functions of these E2A gene-encoded bHLH proteins.

Alternative Splicing↗
PubMed1995

Asymptomatic hyperglycaemia is associated with increased intimal plus medial thickness of the carotid artery.

Atherosclerotic changes have not been demonstrated directly in asymptomatic hyperglycaemic non-diabetic subjects, although high mortality due to coronary heart disease has been reported. We measured arterial wall thickness non-invasively, in order to directly demonstrate atherosclerosis of the carotid arteries of hyperglycaemic non-diabetic subjects and to evaluate its risk factors. The thicknesses of the intimal plus medial complex (IMT) of the carotid arteries of 112 asymptomatic hyperglycaemic non-diabetic subjects (aged 22-81, 95 males and 17 females) were compared with those of 55 healthy male subjects and 211 non-insulin-dependent NIDDM male diabetic patients. The subjects were subgrouped into impaired glucose-tolerant (IGT) subjects who had a 2-h glycaemic level of more than 7.8 mmol/l, and non-IGT subjects whose 2-h glycaemic levels were within 6.7-7.7 mmol/l. Non-IGT and IGT subjects showed significantly greater IMTs than age-matched healthy males and showed no significant differences compared to age-matched NIDDM patients. Multivariate analysis demonstrated that the risk factors for IMT of non-IGT and IGT subjects were age and systolic blood pressure. According to data on the accumulation of atherogenic risks (hypertension, dyslipidaemia, and smoking), IMT increased linearly in non-IGT and IGT subjects. However, non-IGT and IGT subjects without hyperlipidaemia, hypertension, or smoking risk still had significantly greater IMT than age-matched normal males (1.019 +/- 0.063 vs 0.770 +/- 0.111 mm, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Delayed changes in neural visinin-like calcium-binding protein gene expression caused by acute phencyclidine administration.

Phencyclidine (PCP) induces a psychotomimetic state that closely resembles schizophrenia, and PCP-treated animals can serve as a model for schizophrenia. The effects of PCP on the gene expression of NVP-1, a novel Ca(2+)-binding protein, were studied in rats. After 24 hours, the NVP-1 mRNA level in the nucleus accumbens showed a significant decrease of 42%. This result suggests that alterations in Ca(2+)-binding protein may be involved in the pathology of PCP-induced psychosis and, presumably, schizophrenia.

Actins↗
PubMed1995

Stereo-videomicrography projection system for use at scientific meetings. A technical note.

A new stereoscopic projection system has been developed for simultaneous viewing of microsurgical procedures by hundreds of participants at neurosurgical meetings. The video images recorded from each eyepiece of an operating microscope were projected onto two wide screens, which were viewed by two converging eyes or by cross-sight. The system was simple and proved to be of great practical use although it yielded minor eyestrain and required some practice.

Equipment Design↗
PubMed1995

Controlled release of lidocaine from injectable gels and efficacy in rat sciatic nerve block.

PURPOSE: Methods of delaying the action of local anesthetics are important, since short duration of action limits their use in the treatment of postoperative and chronic pain. The present study evaluated the use of low-viscosity gels in prolonging the release of lidocaine. METHODS: Release of lidocaine from 2% lidocaine.HCl containing methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodiumcarboxymethyl cellulose (CMC), and poloxamer 407 (PO) gels was studied in phosphate buffer, pH 7.4, at 37 degrees C. Commercial metylcellulose gel (MCcom) served as control. The in vivo efficacy of the respective gel formulations were evaluated in rats. The gel was injected into the vicinity of the sciatic nerve and nociception and motor function were tested. RESULTS: The cumulative amount of lidocaine released during 8 hr was slowest from the PO gel, followed by the CMC, HPMC and MC gels. The antinociceptive effect was not prevented by the motor block and lasted longest with the PO gel. Good linear and rank order correlation was obtained between in vitro and in vivo results. The microscopic examination of the tissue samples revealed only mild or no irritation of the skeletal muscle tissue by the PO, HPMC, and CMC gels. CONCLUSIONS: Based on these results poloxamer gel proved to be the most promising carrier for lidocaine.

Animals↗
PubMed1995

Monitoring lung compliance and end-tidal oxygen content for the detection of venous air embolism.

Venous air embolism (VAE) is a recognized complication of surgery performed with the patient in the sitting position, but it occurs also during other operations. We report two cases of VAE, associated with a notable decrease in dynamic lung compliance, detected by side-stream spirometry. Based on these cases, an experiment with 10 pigs was designed to evaluate the usefulness of side-stream spirometry in the diagnosis of VAE. Three doses of air (0.5, 1.0 and 2.0 ml kg-1) were injected via the proximal part of a 5- French gauge pulmonary artery catheter. Only the largest dose was followed by haemodynamic deterioration. Significant increases in end-tidal oxygen content and decreases in dynamic lung compliance were detected with all doses of air together with conventional signs of VAE, that is increases in pulmonary artery pressures and arterial carbon dioxide tensions, and decreases in end-tidal concentration of carbon dioxide. We conclude that continuous monitoring of end-tidal oxygen concentration and side-stream spirometry offers valuable supplements to other monitoring techniques in the detection of VAE.

Adult↗
PubMed1995

Anaphylactoid skin reactions after intravenous regional anaesthesia using 0.5% prilocaine with or without preservative--a double-blind study.

Methylparaben, the preservative of various local anaesthetic solutions, is a potential allergen. In a double-blind study, 0.5% prilocaine with (Citanest, n = 100) or without (n = 100) methylparaben were compared for the occurrence of skin reactions after intravenous regional anaesthesia of the arm in surgical patients. Skin reactions were registered after the deflation of the tourniquet cuff, and intradermal tests were performed with 0.5% prilocaine, 0.1% methylparaben and saline in all patients. Seventeen patients in the Citanest group and four patients in the methylparaben-free prilocaine group developed erythematous skin reactions in the exposed arm after deflation of the tourniquet cuff (P < 0.05, between the groups). The skin symptoms disappeared within an hour and were always restricted to the region which had been anaesthetised. None of the affected patients had positive intradermal tests. The observed skin reactions are probably non-IgE-mediated anaphylactoid reactions in which the presence of methylparaben in the local anaesthetic solution plays a major role.

Adult↗
PubMed1995

A case of non-insulin dependent diabetes mellitus with antiinsulin antibody: effect of subcutaneous injection of human recombinant insulin-like growth factor-I.

We saw a 57-yr-old female non-insulin dependent diabetes mellitus (NIDDM) patient with antiinsulin antibody, in whom insulin-like growth factor-I (IGF-I) was shown to be effective as a blood glucose-lowering agent. Due to the presence of the antibody, the patient suffered from postprandial hyperglycemia and frequent hypoglycemia, which were uncontrollable even by multiple insulin injection therapy. In contrast to insulin injection (0.24 IU/kg body wt) which showed a delayed glucose-lowering effect, subcutaneous injection of recombinant human IGF-I (0.05-0.1 mg/kg body wt) caused a quick fall in plasma glucose levels. Prolongation of the glucose-lowering effect of "rapid-acting" insulin frequently caused subsequent hypoglycemia in this patient, but the effect of IGF-I seemed to have disappeared within the first three hours.

Diabetes Mellitus, Type 2↗
PubMed1994

Estrogen regulation of the insulin-like growth factor I gene transcription involves an AP-1 enhancer.

As a step toward elucidating the physiological role of insulin-like growth factor-I (IGF-I) in mediating estrogen action, we sought to determine the molecular basis of the phenomenon. In HepG2 cells expressing exogenous estrogen receptors (ER), a reporter gene plasmid containing 600 base pairs of the chicken IGF-I promoter enhanced expression of luciferase 8.6-fold in response to 10(-6) M 17 beta-estradiol, indicating that the IGF-I promoter is a target of estrogen regulation. Although no conventional estrogen-responsive element was identified within the promoter fragment, the AP-1 motif located therein was shown to be essential; the estrogen-responsive enhancement of the Fos-Jun binding to the AP-1 motif, which takes place by means of post-translational modification, mediates the estrogen action. A direct or indirect interaction between the estrogen-ER complex and the Fos-Jun complex seems to facilitate the Fos-Jun binding to the target DNA. Although ER binding to the target DNA was not considered to be involved in the signaling pathway, the DNA binding domain-deficient ER did not mediate the phenomenon, providing support for the existence of a unique function of the DNA binding domain of ER in facilitating some protein-protein interaction. In conclusion, our present observations demonstrate that the chicken IGF-I gene promoter is controlled by estrogen through a unique pathway involving Fos, Jun, and the DNA binding domain of ER.

Animals↗