Biomedical subjects

Naoki Takahashi

Publications and source records attributed to Naoki Takahashi.

At least 37 records · Page 2Linked to original sources

PubMed2004

Transforming property of TEL-FGFR3 mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML.

We previously reported a novel fusion between TEL and FGFR3 in a patient with peripheral T-cell lymphoma with t(4; 12)(p16;p13). Disease in this patient subsequently progressed to acute myelogenous leukemia (AML) with the same translocation. Sequence analysis of TEL-FGFR3 fusion transcripts suggested that these diseases originated from the same multipotent stem cell. To determine the transforming property of TEL-FGFR3, we established transfectants of this chimeric fusion gene and investigated the major signal pathways of TEL-FGFR3-induced transformation using various signal transduction inhibitors including SU5402 (fibroblast growth factor tyrosine kinase [FGFR TK] inhibitor). Our results indicated that (1) the expression of TEL-FGFR3 but not DeltaHLH-TEL-FGFR3 resulted in efficient focus formation in NIH/3T3 cells and conferred interleukin 3 independence to Ba/F3 cells by a constitutive tyrosine kinase activity probably through oligomerization by the HLH domain of TEL; (2) although effector proteins including classical mitogen-activated protein kinase (MAPK), p38 MAPK, phosphatidylinositol 3-kinase (PI3-K), mammalian target or rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT-3) and STAT-5 were activated in TEL-FGFR3 transformants, the growth of the transformants was inhibited by SU5402 (concentration that inhibits 50% [IC5)]=5 microM) and the PI3-K inhibitor, LY294002 (IC5)=10 microM) and wortmannin (IC50=5 microM), but not by U0126, SB203580, or rapamycin; and (3) injection of TEL-FGFR3 transformants induced lethal leukemia into syngeneic mice. Taken together, the leukemogenic potential of TEL-FGFR3 may be mediated in part through PI3-K.

Acute Disease↗

PubMed2004

Requirement for Mab21l2 during development of murine retina and ventral body wall.

The mab-21 gene was first identified because of its requirement for ray identity specification in Caenorhabditis elegans. It is now known to constitute a family of genes that are highly conserved from vertebrates to invertebrates, and two homologues Mab21l1 and Mab21l2 have been identified in many species. Here we describe the generation of Mab21l2-deficient mice, which have defects in eye and body wall formation. The mutant mouse eye has a rudimentary retina, as a result of insufficient invagination of the optic vesicle due to deficient proliferation, causing the absence of lens. The defects in optic vesicle development correlate with reduced expression of Chx10, which is also required for retina development; Rx, Lhx2, and Pax6 expression is not significantly affected. We conclude that Mab21l2 expression is essential for optic vesicle growth and formation of the optic cup, its absence causing reduced expression of Chx10. Mutant mice also display abnormal extrusion of abdominal organs, defects in ventral body wall formation, resulting in death in utero at mid-gestational stage. Our results reveal that Mab21l2 plays crucial roles in retina and in ventral body wall formation.

Abdomen↗

PubMed2004

PlexinA4 is necessary as a downstream target of Islet2 to mediate Slit signaling for promotion of sensory axon branching.

Slit is a secreted protein known to repulse the growth cones of commissural neurons. By contrast, Slit also promotes elongation and branching of axons of sensory neurons. The reason why different neurons respond to Slit in different ways is largely unknown. Islet2 is a LIM/homeodomain-type transcription factor that specifically regulates elongation and branching of the peripheral axons of the primary sensory neurons in zebrafish embryos. We found that PlexinA4, a transmembrane protein known to be a co-receptor for class III semaphorins, acts downstream of Islet2 to promote branching of the peripheral axons of the primary sensory neurons. Intriguingly, repression of PlexinA4 function by injection of the antisense morpholino oligonucleotide specific to PlexinA4 or by overexpression of the dominant-negative variant of PlexinA4 counteracted the effects of overexpression of Slit2 to induce branching of the peripheral axons of the primary sensory neurons in zebrafish embryos, suggesting involvement of PlexinA4 in the Slit signaling cascades for promotion of axonal branching of the sensory neurons. Colocalized expression of Robo, a receptor for Slit2, and PlexinA4 is observed not only in the primary sensory neurons of zebrafish embryos but also in the dendrites of the pyramidal neurons of the cortex of the mammals, and may be important for promoting the branching of either axons or dendrites in response to Slit, as opposed to the growth cone collapse.

Animals↗

PubMed2004

Multi-detector row computed tomographic angiography in pediatric heart transplant recipients: Initial observations.

BACKGROUND: The purpose of this study was to assess the feasibility and limitation of multi-detector row computed tomographic (MDCT) imaging for evaluating coronary arteries in pediatric heart transplant patients. METHODS: Coronary MDCT angiography was performed in eight pediatric heart transplant recipients. The presence of coronary calcification was evaluated. Luminal changes of the visualized coronary segments on MDCT images were compared with catheter angiographic findings and intravascular ultrasound. RESULTS: Coronary calcification was present in one patient who had severe coronary arteriopathy documented by intravascular ultrasound. In 48 coronary segments visualized on MDCT images, 33, 7, and 4 segments each had normal, luminal irregularities, and moderate stenoses, respectively, which were confirmed by catheter angiography. Twelve coronary segments could not be assessed because of severe motion artifacts. Image quality degradation was more pronounced in patients with higher heart rates. CONCLUSIONS: Noninvasive MDCT angiography is promising but requires further technical improvement to evaluate coronary arteries in pediatric heart transplant patients.

Adolescent↗

PubMed2004

Suppression of 3-deoxyglucosone and heparin-binding epidermal growth factor-like growth factor mRNA expression by an aldose reductase inhibitor in rat vascular smooth muscle cells.

Reactive carbonyl compounds and oxidative stress have been recently shown to up-regulate the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF), a potent mitogen for vascular smooth muscle cells (SMCs) produced by SMC themselves. Because the polyol pathway has been reported to influence the formation of carbonyl compounds and the oxidative stress in various cells, we conducted this study to investigate whether the polyol pathway affects HB-EGF expression along with the generation of carbonyl compounds and the oxidative stress in SMCs. We found that, compared with those cultured with 5.5mM glucose, SMCs cultured with 40 mM glucose showed the accelerated thymidine incorporation, elevated levels of intracellular sorbitol, 3-deoxyglucosone (3-DG), advanced glycation end products (AGEs), and thiobarbituric acid-reactive substances (TBARS) along with the enhanced expression of HB-EGF mRNA. An aldose reductase inhibitor (ARI), SNK-860, significantly inhibited all of these abnormalities, while aminoguanidine suppressed 3-DG levels and HB-EGF mRNA expression independent of sorbitol levels. The results suggest that the polyol pathway may play a substantial role in SMC hyperplasia under hyperglycemic condition in part by affecting HB-EGF mRNA expression via the production of carbonyl compounds and oxidative stress.

Aldehyde Reductase↗

PubMed2004

A high-spin and durable polyradical: poly(4-diphenylaminium-1,2-phenylenevinylene).

A purely organic, high-spin, and durable polyradical molecule was synthesized: It is based on the non-Kekulé- and non-disjoint design of a pi-conjugated poly(1,2-phenylenevinylene) backbone pendantly 4-substituted with multiple robust arylaminium radicals. 4-N,N-Bis(4-methoxy- and -tert-butylphenyl)amino-2-bromostyrene 5 were synthesized and polymerized with a palladium-phosphine catalyst to afford the head-to-tail-linked polyradical precursors (1). Oxidation of 1 with the nitrosonium ion solubilized with a crown ether gave the aminium polyradicals (1(+)()) which were durable (half-life > 1 month) at room temperature in air. A high-spin ground state with an average S = (4.5)/2 for 1a(+) was proved even at room temperature by magnetic susceptibility, magnetization, ESR, and NMR measurements.

Journal Article↗

PubMed2004

How to plan and perform a cardiac MR imaging examination.

Because of the enormous economic and social impact of cardiovascular disease in the United States there is a need for improved noninvasive diagnosis. Cardiac MR imaging isa versatile, comprehensive technique for assessing cardiac morphology and function. With an understanding of cardiac anatomy and physiology and MR imaging physical principles,cardiac MR imaging can be performed and can play an important role in patient management. This article provides the reader with a basic understanding of cardiac MR imaging and the practical applications required to perform cardiac MR imaging.

Cardiovascular Diseases↗

PubMed2004

Gadolinium-enhanced computed tomography angiography in multi-detector row computed tomography: initial observations.

RATIONALE AND OBJECTIVES: The feasibility of using gadolinium contrast medium for computed tomography angiography (CTA) in multi-detector row computed tomography and the effect of contrast medium dilution was investigated. MATERIALS AND METHODS: Three pigs were each scanned in multiple sessions with injections of non-dilute and dilute contrast medium at a dose of 0.3 mmol/kg body weight. Non-spiral dynamic scanning at a fixed mid-abdominal aortic level and thoracoabdominal CTA were performed. RESULTS: The magnitude of peak aortic enhancement was not significantly different between dilute and non-dilute contrast medium injections (P = .88), but the former showed earlier enhancement (mean of 2.3 seconds sooner, P < .01) than the latter. CT angiography with gadolinium contrast medium showed much lower enhancement than iodine contrast medium, but small vessels were readily identifiable. CONCLUSION: Gadolinium contrast medium combined with multi-detector row computed tomography may provide clinically useful CTA. Dilution of contrast medium shortens the enhancement time but has little effect on the magnitude.

Angiography↗

PubMed2004

ydk1-D, an auxin-responsive GH3 mutant that is involved in hypocotyl and root elongation.

To study the GH3 gene family of Arabidopsis, we investigated a flanking sequence database of Arabidopsis activation-tagged lines. We found a dwarf mutant, named yadokari 1-D (ydk1-D), that had a T-DNA insertion proximal to a GH3 gene. ydk1-D is dominant and has a short hypocotyl not only in light but also in darkness. Moreover, ydk1-D has a short primary root, a reduced lateral root number, and reduced apical dominance. A GH3 gene, named YDK1, was upregulated in ydk1-D, and YDK1 transgenic plants showed the ydk1-D phenotype. YDK1 gene expression was induced by exogenously applied auxin and regulated by auxin-response factor (ARF)7. In addition, YDK1 gene expression was downregulated by blue and far-red (FR) lights. Strong promoter activity of YDK1 was observed in roots and flowers. These results suggest that YDK1 may function as a negative component in auxin signaling by regulating auxin activity.

Arabidopsis↗

PubMed2004

Intact PTH assay overestimates true 1-84 PTH levels after maxacalcitol therapy in dialysis patients with secondary hyperparathyroidism.

BACKGROUND: Although the so-called intact parathyroid hormone (iPTH) assay detects not only true 1-84 PTH (1-84PTH) but also large C-terminal PTH fragments, it remains inconclusive whether the 1-84PTH assay is more useful in clinical practice. Previous studies have shown that the results of these two PTH assays in dialysis patients are closely correlated. METHODS: Chronic dialysis patients whose plasma iPTH levels were >400 pg/ml were selected for inclusion in the present study. Following a 4 week wash-out time during which all vitamin D administration was halted, maxacalcitol was intravenously injected at the end of dialysis sessions three times per week for 24 weeks, at an initial dosage of 10 micro g. RESULTS: Ninety-seven patients with secondary hyperparathyroidism were included in our analysis. Their serum calcium levels were elevated from the start levels while phosphate levels remained unchanged. The plasma 1-84PTH levels constantly declined throughout the 24 weeks. Although the patients' plasma 1-84PTH and iPTH levels were closely correlated with each other both at the beginning of the study and after 24 weeks of maxacalcitol therapy, the ratio of 1-84PTH/iPTH consistently decreased throughout the study period (P<0.01). The changes in the ratio were significantly correlated with changes in serum calcium levels. CONCLUSIONS: Twenty-four weeks of intravenous maxacalcitol injection therapy significantly reduced the 1-84PTH/iPTH ratio. Estimated 1-84PTH levels from iPTH levels using a conversion formula obtained before the treatment were 21.0+/-20.4% higher than measured 1-84PTH levels after the therapy. Thus, iPTH measurement has a potential risk to overestimate 1-84PTH levels when evaluating the efficacy of maxacalcitol therapy in dialysis patients with secondary hyperparathyroidism.

Calcitriol↗

PubMed2004

Expression and interaction analysis of Arabidopsis Skp1-related genes.

Specific protein degradation has been observed in several aspects of development and differentiation in many organisms. One example of such proteolysis is regulated by protein polyubiquitination that is promoted by the SCF complex consisting of Skp1, cullin, and an F-box protein. We examined the activities of the Arabidopsis Skp1-related proteins (ASKs). Among 19 annotated ASK genes, we isolated 16 of the corresponding cDNAs (ASK1, 2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19), and examined their gene products for interactions with 24 representatives of F-box proteins carrying various classes of the C-terminal domains using the yeast two-hybrid system. As a result, we found diverse binding specificities: ASK1, ASK2, ASK11 and ASK12 interacted well with COI1, FKF1, UFO-like protein, LRR-containing F-box proteins, and other F-box proteins with unknown C-terminal motifs. We also observed specific interaction between F-box proteins and ASK3, ASK9, ASK13, ASK14, ASK16 and ASK18. In contrast, we detected no interaction between any of the 12 ASK proteins and F-box proteins containing CRFA, CRFB or CRFC domains. Both histochemical and RT-PCR analysis of eight ASK genes expression revealed unique expression patterns for the respective genes.

Arabidopsis↗

PubMed2003

Decreased expression of glial cell line-derived neurotrophic factor signaling in rat models of neuropathic pain.

1. In an attempt to clarify whether glial cell line-derived neurotrophic factor (GDNF), a survival factor for subpopulations of primary afferent neurons, is involved in the states of neuropathic pain, we observed changes in the expressions of GDNF and its signal-transducing receptor Ret after nerve injury in two rat models of neuropathic pain. 2. In the rats treated with sciatic nerve ligation (chronic constrictive injury (CCI) model) or spinal nerve ligation at L5 (SNL model), the thresholds of paw withdrawal in response to mechanical or heat stimuli began to decrease on the injured side within the first week after the operation and the decreases in the thresholds persisted for more than 2 weeks. 3. In CCI-treated rats, the GDNF contents in L4 and L5 dorsal root ganglia (DRGs) on the injured side were markedly decreased at day 7 after the operation and stayed at low levels at day 14. In SNL-treated rats, comparable reductions of GDNF levels in L4 and L5 DRGs on the injured side were observed at 14 postoperative days. 4. Significant decreases of the percentages of DRG neurons expressing Ret were also observed at L4 DRGs in CCI-treated rats at 7 and 14 postoperative days and in SNL-treated rats at 14 days. 5. In CCI- or SNL-treated rats, continuous intrathecal administration of GDNF (12 microg day-1) using an osmotic pump suppressed the increased sensitivities to nociceptive stimuli to control levels. 6. The present results suggested that the dysfunction of GDNF signaling in the nociceptive afferent system may contribute to the development and/or maintenance of neuropathic pain states.

Animals↗

PubMed2003

Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup.

The neural recognition molecule NB-3, which belongs to the contactin subgroup of the immunoglobulin superfamily, is expressed exclusively in the nervous system and mainly upregulated at the early postnatal stage during mouse brain development. The expression of NB-3 in the cerebellum increases until adulthood. In contrast, the expression in the cerebrum declines to a low level after postnatal day 7. To characterize the functional roles of NB-3 in vivo, we generated NB-3-deficient mice by substituting a part of the NB-3 gene with the beta-galactosidase (Lac Z) gene. Complete overlap of the Lac Z expression in the heterozygous mouse brain with the NB-3 immunostaining pattern in the rat cerebellum and with the previously reported pattern of in situ hybridization of NB-3 transcripts indicated that Lac Z expression reflects the expression of NB-3 in the mouse brain. NB-3-deficient mice were viable and fertile. The formation and organization of all nuclei and layers throughout the brains of mutant mice appeared normal. Behavioral tests to examine motor function showed that the mice deficient for NB-3 were slow to learn to stay on the rotating rod in the rotorod test during repeated trials, and that they displayed dysfunction of equilibrium and vestibular senses in the wire hang and horizontal rod-walking tests. In contrast, the mutant mice showed no difference of grasp force from the wild-type mice. Thus, NB-3-deficient mice are impaired in motor coordination.

Animals↗

PubMed2003

Amyloidogenic synthetic peptides of beta2-microglobulin--a role of the disulfide bond.

To search for the essential regions responsible for the beta2-microglobulin (beta2-m) amyloid fibril formation, we synthesized six peptides corresponding to six of the seven beta-sheets in the native structure of beta2-m, and examined their amyloidogenicity. Among the peptides examined, peptide (21-31) (strand B) and the mixture of peptide (21-31) and (78-86) (strand F) showed fibril formation at both pH 2.5 and 7.5. Peptide (21-31) is the N-terminal half of the previously reported proteolytic fragment of beta2-m, Ser21-Lys41 (K3), suggesting that this region may be the essential core. Interestingly, the dimer formation of peptide (21-31) by the disulfide bond substantially facilitated the fibril formation, indicating that the disulfide bond is important for the structural stability of the fibrils.

Amino Acid Sequence↗

PubMed2003

Performing cardiac MR imaging: an overview.

Because of the enormous economic and social impact of cardiovascular disease in the United States, there is a need for improved noninvasive diagnosis. Cardiac MR imaging is a versatile, comprehensive technique for assessing cardiac morphology and function. With an understanding of cardiac anatomy and physiology as well as MR physical principles, cardiac MR imaging can be performed and play an important role in patient management.

Cardiovascular Diseases↗

PubMed2003

Glycosaminoglycan and proteoglycan inhibit the depolymerization of beta2-microglobulin amyloid fibrils in vitro.

BACKGROUND: Although several kinds of evidence suggest that glycosaminoglycans (GAGs) and proteoglycans (PGs) may contribute to the development of beta2-microglobulin-related (Abeta2m) amyloidosis, the precise roles of these molecules for the development of Abeta2m amyloidosis are poorly understood. METHODS: We investigated the effects of GAGs and PGs on the depolymerization of Abeta2m amyloid fibrils at a neutral pH, as well as on the formation of the fibrils at an acidic pH in vitro, using fluorescence spectroscopy with thioflavin T and electron microscopy. RESULTS: Depolymerization of Abeta2m amyloid fibrils at pH 7.5 at 37 degrees C was inhibited dose-dependently by the presence of some GAGs (heparin, dermatan sulfate, or heparan sulfate) or PGs (biglycan, decorin, or keratan sulfate proteoglycan). Electron microscopy revealed that a significant amount of Abeta2m amyloid fibrils remained in the reaction mixture with some lateral aggregation. Second, when monomeric beta2m was incubated with aggrecan, biglycan, decorin, or heparin at pH 2.5 at 37 degrees C for up to 21 days, the thioflavin T fluorescence increased depending on dose and time. Electron microscopy revealed the formation of rigid and straight fibrils similar to Abeta2m amyloid fibrils in beta2m incubated with biglycan for 21 days. CONCLUSION: These results suggest that some GAGs and PGs could enhance the deposition of Abeta2m amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of beta2m in the fibrils, as well as by acting as a scaffold for the polymerization of beta2m into the fibrils.

Amyloid↗

PubMed2003

Quantification of coronary artery calcium with multi-detector row CT: assessing interscan variability with different tube currents pilot study.

PURPOSE: To assess the interscan variability of coronary artery calcium as measured with different tube currents and quantification methods in prospective electrocardiography (ECG)-gated multi-detector row CT. MATERIALS AND METHODS: Thirty-three subjects who were asymptomatic for coronary heart disease underwent prospective ECG-gated, subsecond multi-detector row CT of the heart. Each subject underwent two consecutive CT examinations, the first with a dose of either 40 mAs (n = 18) or 80 mAs (n = 15) and the second with a dose of 150 mAs. Calcium volume and calcium score were calculated. Pearson correlation coefficient was computed between the calcium scores of high- and low-dose examinations. Interscan variability in these measurements (ie, the absolute percentage difference) was compared between the examinations with 40-150 mAs and those with 80-150 mAs by using an independent sample t test. In addition, the interscan variabilities of calcium scores between vessels were evaluated with repeated measures of analysis of variance. The interscan variabilities between calcium score and volume measurement were also compared with paired t tests. RESULTS: Twenty-seven of 33 subjects had coronary artery calcium deposits on both CT scans. Five subjects had no calcium deposit on either scan. One subject had calcium deposits on only one scan. The total calcium score between the high- and low-dose scans was highly correlated (r = 0.98) and was not significantly different (P =.58). The interscan variability of calcium score showed no significant difference with respect to subject (P =.25) or vessel (P =.84). The interscan variability of the calcium volume measurement was significantly lower than that of the calcium score with respect to both the subject (P <.01) and the vessel (P <.01). CONCLUSION: A dose of 40 mAs appears adequate for quantifying coronary artery calcium at multi-detector row CT. Interscan variability of multi-detector row CT is substantially reduced by using the calcium volume method.

Aged↗

PubMed2003

Computed tomography-guided percutaneous acetic acid injection therapy for functioning adrenocortical adenoma.

We reported the outcomes of computed tomography (CT)-guided percutaneous acetic acid injection therapy for functioning adrenocortical adenomas. With the patient in a prone position, the puncture needle was inserted vertically downward into the adenoma with frequent CT scanning. After confirmation by pilot injection with contrast medium, a small aliquot of 40-50% acetic acid was injected and repeated. Between 1997 and 2002, 18 sessions of CT-guided injection therapy, including one session of ethanol injection, were performed on 10 patients (five patients with primary aldosteronism and five patients with Cushing's or subclinical Cushing's syndrome) without any complications except transient upper abdominal pain during the acetic acid injection. The follow-up period ranged from 5-69 months. The treatment resulted in almost an extirpation of the adrenocortical hyperfunction in seven patients after one or two sessions. CT-guided percutaneous acetic acid injection might be a simple, cost-effective, and far less invasive treatment for small functioning adrenocortical adenomas.

Acetic Acid↗