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Biomedical subjects

T Uchida

Publications and source records attributed to T Uchida.

At least 19 recordsLinked to original sources
PubMed2007

A failure of mucocutaneous lymphangiogenesis may underlie the clinical features of lipoid proteinosis.

Lipoid proteinosis (LiP) (OMIM 247100) is a rare autosomal recessive disease caused by loss of function mutations in the extracellular matrix protein 1 gene, ECM1, on chromosome 1q21. LiP is characterized clinically by hoarseness in early infancy, followed by waxy papules and plaques on the face and body along with pox-like and acneiform scars. We studied a 20-year-old Japanese woman with LiP. She was born of consanguineous parents. Biopsy specimens obtained from a nodule on the elbow were used for histopathology, immunohistology and electron microscopy. Exons 6 and 7 of ECM1 were amplified by polymerase chain reaction (PCR) from genomic DNA from the proband, her parents, her brother and an unrelated person. PCR products were sequenced to detect the mutation. Histopathological examination revealed an irregular mass of calcium beneath deposits of a hyaline material in the dermis. Immunofluorescence double staining showed that the CD31-positive microvascular density was increased but that staining for the lymphatic-specific hyaluronan receptor LYVE-1 was drastically diminished in lesional compared with nonlesional skin of the patient and with normal skin. Electron microscopy revealed marked concentric reduplication of basal laminae not only around blood vessels but also around solitary dermal cells positive for Weibel-Palade bodies scattered in the hyaline material. Sequencing of the PCR products revealed a homozygous frameshift mutation, 507delT, in exon 6. This led to a premature stop codon 23 bp downstream. The results of immunopathological and ultrastructural characterization suggest that a failure of mucocutaneous lymphangiogenesis may underlie the clinical features of LiP. Identification of mutation 507delT in a Japanese patient with LiP further supports the thesis that this mutation represents a recurrent mutation in ECM1 in patients with LiP. To our knowledge, this case represents the first report of calcinosis cutis occurring in LiP.

Adult↗
PubMed2006

Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice.

AIMS/HYPOTHESIS: Endothelial cells are considered to be essential for normal pancreatic beta cell function. However, there have been no reports showing their importance for beta cell function. MATERIALS AND METHODS: Using mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells, we investigated the relation between islet vascular structure and beta cell function. RESULTS: Mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells had reduced islet vascular density with impaired formation of endothelial fenestration. While their fasting glucose and body weight were comparable with control mice, their glucose- and tolbutamide-induced rapid insulin release were impaired, thus resulting in glucose intolerance. On the other hand, glucose and KCl enhanced the levels of insulin secreted from islets isolated from these mice. In addition, the production of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in the islets was increased. Insulin content and expression of insulin I and pancreas duodenum homeobox 1 mRNA in the islets were also increased. CONCLUSIONS/INTERPRETATION: Our results indicate that an abnormal quality and quantity of blood vessels due to reduced expression of vascular endothelial growth factor-A in beta cells could be a cause of impaired insulin secretion without impairment of beta cell function.

Animals↗
PubMed2006

Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1.

Tumor suppressor p53 is essential for checkpoint control in response to a variety of genotoxic stresses. DNA damage leads to phosphorylation on the Ser/Thr-Pro motifs of p53, which facilitates interaction with Pin1, a pSer/pThr-Pro-specific peptidyl prolyl isomerase. Pin1 is required for the timely activation of p53, resulting in apoptosis or cell cycle arrest. To investigate the physiological relationship between Pin1 and p53, we created Pin1-/-p53-/- mice. These p53-deficient mice spontaneously developed lymphomas, mainly of thymic origin, as well as generalized lymphoma infiltration into other organs, including the liver, kidneys and lungs. Ablation of Pin1, in addition to p53, accelerated the thymic hyperplasia, but the thymocytes in these Pin1-/-p53-/- mice did not infiltrate other organs. The thymocytes in 12-week-old Pin1-/-p53-/- mice were CD4(-)CD8(-) (double negative) and had significantly higher levels of the intracellular form of Notch1 (NIC) than the thymocytes of p53-/- or wild-type mice. Presenilin-1, a cleavage enzyme for NIC generation from full-length Notch1 was increased in the thymocytes of Pin1-/-p53-/- mice. Pin1 depletion also inhibited the degradation of NIC by proteasomes. These results suggest that both Pin1 and p53 control the normal proliferation and differentiation of thymocytes by regulating the NIC level.

Animals↗
PubMed2006

Short-term methotrexate could reduce early immune reactions and improve outcomes in umbilical cord blood transplantation for adults.

Post transplant immune disorders are problematic in cord blood transplantation (CBT) for adult patients, and optimal prophylaxis has not been established. We investigated whether intensive graft-versus-host disease (GVHD) prophylaxis using short-term methotrexate (MTX) has a prognostic impact on CBT. Post-CBT immune reactions were classified according to time course as pre-engraftment immune reaction (PIR), engraftment syndrome (ES) or acute GVHD. Between March 2001 and November 2005, a total of 77 patients underwent CBT at eight transplantation centers. Median age was 48 years (range, 18-69 years). Preparative regimens comprised myeloablative (n=31) or reduced-intensity (n=46). Acute GVHD prophylaxis included cyclosporine alone (n=23), tacrolimus alone (n=12), cyclosporine plus MTX (n=17), tacrolimus plus short-term MTX (n=23) or cyclosporine plus methylprednisolone (n=2). Cumulative incidences of PIR, ES and grade II-IV GVHD were 36, 12 and 23%, respectively. Short-term MTX exerted significant favorable effects on post-CBT immune reactions (hazard ratio, 0.55; 95% confidence interval (95% CI), 0.31-0.98; P=0.04) in multivariate analysis. Overall survival rates for patients with and without short-term MTX at day 180 were 59% (95% CI, 42-73%) and 16% (95% CI, 6.6-30%) (P=0.0001), respectively. Short-term MTX could offer one optimal regimen to reduce immune reactions and improve outcomes in CBT.

Adolescent↗
PubMed2006

Amelioration of glucose tolerance by hepatic inhibition of nuclear factor kappaB in db/db mice.

AIMS/HYPOTHESIS: Recent studies have identified the involvement of inhibitor IkappaB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor kappaB (NF-kappaB), the distal target of IKK, in hepatic glucose metabolism. METHODS: To inhibit NF-kappaB activity, db/db mice were infected with adenovirus expressing the IkappaBalpha super-repressor. RESULTS: The IkappaBalpha super-repressor adenovirus infection caused a moderate reduction of NF-kappaB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A, also known as PGC-1alpha). Furthermore, the production of super-repressor IkappaBalpha suppressed the increase in blood glucose level after pyruvate injection. CONCLUSIONS/INTERPRETATION: Our results indicate that moderate inhibition of NF-kappaB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1alpha gene expression in db/db mice, and suggest that inhibition of NF-kappaB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.

AMP-Activated Protein Kinases↗
PubMed2006

Constitutively active CCK2 receptor splice variant increases Src-dependent HIF-1 alpha expression and tumor growth.

Gastrointestinal (GI) cancers ectopically express multiple splice variants of the cholecystokinin-2 (CCK(2))/gastrin receptor; however, their relative contributions to the cancer phenotype are unknown. The aim of this study was to compare the effects of CCK(2) receptor (CCK(2)R) and CCK(2i4sv)R expression on cell growth both in vitro and in vivo using a human epithelial cell model, HEK239. In vitro, receptor variant expression did not affect cell proliferation either in the absence or presence of agonist. However, in vivo, the expression of CCK(2i4sv)R, but not CCK(2)R, increases HEK293 tumor growth in a constitutive, Src-dependent manner. Enhanced tumorigenicity of CCK(2i4sv)R is associated with an Src-dependent increase in the transcription factor, hypoxia-inducible factor-1alpha, its downstream target, vascular endothelial growth factor and tumor micro-vessel density, suggesting that CCK(2i4sv)R may contribute to the growth and spread of GI cancers through agonist-independent mechanisms that enhance tumor angiogenesis.

Alternative Splicing↗
PubMed2006

Growth inhibition efficacy of an adenovirus expressing dual therapeutic genes, wild-type p53, and anti-erbB2 ribozyme, against human bladder cancer cells.

The altered expression of both p53 and erbB2 is strongly related to the disease status and the outcome of bladder cancers. We examined the antitumor efficacy by the modulation of these genetic alterations with a newly designed dual-gene-expressing adenovirus (Ad-p53/erbB2Rz), which expresses p53 and anti-erbB2 ribozyme simultaneously in human bladder cancer cells. Cell growth inhibition efficacy along with biological responses of this virus was compared with other viral vectors (Ad-p53, which expresses wild-type p53 cDNA, and Ad-erbB2Rz, which expresses anti-erbB2 ribozyme, solely or in combination). Sufficient transgene expression in targeted cells and the altered expression of the targeted genes and their encoded proteins were obtained by each therapeutic vector. Each of the three therapeutic viral vectors inhibited bladder cancer cell growth, and the putative additive antitumor effect was shown by the combination of two of the therapeutic vectors. Furthermore, Ad-p53/erbB2Rz had superior therapeutic efficacy when the same titers of viruses were infected. Nonspecific vector-related toxicity was minimized by reducing the total amount of viral titers by using the dual-gene-expressing adenovirus. Modulation of multiple genetic abnormalities might enhance the therapeutic efficacy, and vector-related toxicity could be minimized when the total amount of viral titers are reduced.

Adenoviridae↗
PubMed2006

The effect of intrathecal fentanyl added to hyperbaric bupivacaine on maternal respiratory function during Cesarean section.

BACKGROUND: Subarachnoid blockade with local anesthetics induces respiratory depression. Although the addition of fentanyl to bupivacaine has become popular in subarachnoid blockade for Cesarean section, there is no information on the effect of intrathecal fentanyl on maternal spirometric respiratory function in parturients undergoing Cesarean section. METHODS: We tested the effect of the addition of intrathecal fentanyl to hyperbaric bupivacaine on maternal spirometric performance in 40 consenting parturients undergoing Cesarean section. The parturients were randomized into two groups: those receiving 2.0 ml of hyperbaric bupivacaine 0.5% and 0.4 ml of saline intrathecally and those receiving 2.0 ml of hyperbaric bupivacaine and 0.4 ml of fentanyl (20 microg) intrathecally. We performed spirometry on arriving at the operation room and 15 min after subarachnoid blockade. RESULTS: Subarachnoid blockade with bupivacaine significantly decreased the peak expiratory flow rate, but did not induce significant changes in vital capacity and forced vital capacity. The addition of intrathecal fentanyl to bupivacaine improved the quality of subarachnoid blockade, but did not lead to a deterioration in respiratory function compared with intrathecal bupivacaine alone. CONCLUSIONS: The addition of intrathecal fentanyl to hyperbaric bupivacaine did not lead to a deterioration in maternal spirometric respiratory function in parturients undergoing Cesarean section.

Adult↗
PubMed2005

Analysis of long-term gene expression in neurons of the hippocampal subfields following traumatic brain injury in rats.

After experimental traumatic brain injury (TBI), widespread neuronal loss is progressive and continues in selectively vulnerable brain regions, such as the hippocampus, for months to years after the initial insult. To clarify the molecular mechanisms underlying secondary or delayed cell death in hippocampal neurons after TBI, we compared long-term changes in gene expression in the CA1, CA3 and dentate gyrus (DG) subfields of the rat hippocampus at 24 h and 3, 6, and 12 months after TBI with changes in gene expression in sham-operated rats. We used laser capture microdissection to collect several hundred hippocampal neurons from the CA1, CA3, and DG subfields and linearly amplified the nanogram samples of neuronal RNA with T7 RNA polymerase. Subsequent quantitative analysis of gene expression using ribonuclease protection assay revealed that mRNA expression of the anti-apoptotic gene, Bcl-2, and the chaperone heat shock protein 70 was significantly downregulated at 3, 6 (Bcl-2 only), and 12 months after TBI. Interestingly, the expression of the pro-apoptotic genes caspase-3 and caspase-9 was also significantly decreased at 3, 6 (caspase-9 only), and 12 months after TBI, suggesting that long-term neuronal loss after TBI is not mediated by increased expression of pro-apoptotic genes. The expression of two aging-related genes, p21 and integrin beta3 (ITbeta3), transiently increased 24 h after TBI, returned to baseline levels at 3 months and significantly decreased below sham levels at 12 months (ITbeta3 only). Expression of the gene for the antioxidant glutathione peroxidase-1 also significantly increased 6 months after TBI. These results suggest that decreased levels of neuroprotective genes may contribute to long-term neurodegeneration in animals and human patients after TBI. Conversely, long-term increases in antioxidant gene expression after TBI may be an endogenous neuroprotective response that compensates for the decrease in expression of other neuroprotective genes.

Animals↗
PubMed2005

Covalent cofactor attachment to proteins: cytochrome c biogenesis.

Haem (Fe-protoporphyrin IX) is a cofactor found in a wide variety of proteins. It confers diverse functions, including electron transfer, the binding and sensing of gases, and many types of catalysis. The majority of cofactors are non-covalently attached to proteins. There are, however, some proteins in which the cofactor binds covalently and one of the major protein classes characterized by covalent cofactor attachment is the c-type cytochromes. The characteristic haem-binding mode of c-type cytochromes requires the formation of two covalent bonds between two cysteine residues in the protein and the two vinyl groups of haem. Haem attachment is a complex post-translational process that, in bacteria such as Escherichia coli, occurs in the periplasmic space and involves the participation of many proteins. Unexpectedly, it has been found that the haem chaperone CcmE (cytochrome c maturation), which is an essential intermediate in the process, also binds haem covalently before transferring the haem to apocytochromes. A single covalent bond is involved and occurs between a haem vinyl group and a histidine residue of CcmE. Several in vitro and in vivo studies have provided insight into the function of this protein and into the overall process of cytochrome c biogenesis.

Binding Sites↗
PubMed2005

Effects of ranitidine on quality of gastric ulcer healing compared with famotidine: a randomized, controlled, multicenter trial.

Ranitidine has been found to have anti-inflammatory action as well as antisecretory action in experimental models. However, there are no reports in human gastric ulcer. The aim of this study was to investigate the effects of ranitidine compared with those of famotidine on the quality of gastric ulcer healing. We randomly assigned 69 consecutive patients with gastric ulcers to ranitidine (n = 34) or famotidine (n = 35) for 12 weeks, with endoscopic assessment of the quality of gastric ulcer healing and histological assessment of gastric mucosa 12 weeks after treatment started. Ulcer healing rates of over 95% were very similar in the two groups. The rates of ulcer scars with a flat pattern (good-quality healing) were significantly higher in the ranitidine group than in the famotidine group (per protocol, 63.0% and 34.5%, p = 0.033). The neutrophil infiltration score in the body mucosa treated with famotidine, but not ranitidine, significantly increased after treatment. In contrast, the mononuclear cell infiltration score in the antral mucosa treated with ranitidine, but not in that treated with famotidine, had significantly decreased. In conclusion, initial therapy with ranitidine significantly improved the quality of gastric ulcer healing and the histological scores of gastric mucosa compared with famotidine.

Adult↗
PubMed2005

Induction of mononuclear cell infiltration into liver by Japanese herbal medicine.

Juzen-Taiho-To (JTT) is a Japanese herbal medicine that has been administered mainly to patients weakened by long illness. Currently, it has also been used for cancer patients and showed antitumor effects that have been reported as phagocytosis enhancement, cytokine induction and antibody production. In this study, we examined the effect of oral administration of JTT in mice on the immunological restoration of the liver, especially focused on natural killer (NK) T-cell induction. Mice were grouped to receive JTT or placebo orally for a period of 1, 3 and 7 days. After sacrifice, the liver tissue was fixed, embedded and stained with hematoxylineosin and some antibodies by common staining methods. Transmission electron microscope (TEM) observation was also carried out. Although the JTT-treated mice had the same appearance as the non-JTT-treated mice, their livers were infiltrated by massive mononuclear cells, some of which were aggregated in clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of interleukin (IL)-12 and massive infiltration of mononuclear cells with large granules in the liver of JTT-treated mice. Oral administration of JTT may induce the expression of IL-12 and be followed by immunological restoration such as NK T-cell induction in liver

Animals↗
PubMed2004

Chain elongation suppression of cyclic block copolymers in lamellar microphase-separated bulk.

Chain elongation suppression of cyclic block copolymers in microphase-separated bulk was determined quantitatively. Solvent-cast and annealed films are confirmed to show alternating lamellar structure and their microdomain spacing D increases with increasing total molecular weight M according to the relationship D proportional, variant M0.59, which agrees quite consistently with the theoretically predicted power law, i.e., D proportional, variant M3/5. This result is in contrast to the well-established issue for linear block copolymers, where the relationship D proportional, variant M2/3 has been confirmed to hold both experimentally and theoretically. This means that chain elongation of each component block is suppressed considerably, owing to their looped conformation in strongly segregated bulk.

Journal Article↗
PubMed2004

Remnant-like lipoprotein particles as risk factors for coronary artery disease in elderly patients.

Although remnant-like lipoprotein particles (RLPs) are known to be atherogenic, the relationship between serum RLP-cholesterol (RLP-C) level and coronary artery disease (CAD) has not as yet been evaluated. This clinical study was aimed at investigating the pathological significance of serum RLP-C among several coronary risk factors with a clear focus on elderly patients. We took fasting venous blood samples to determine lipid profiles including RLP-C from 188 patients with angiographically identified CAD and 68 control patients. Overall analysis showed that the RLP-C/HDL-C ratio was higher in both single-vessel CAD group (n = 67; p < 0.01) and multi-vessel CAD group (n = 121; p < 0.001) compared to controls. Further, multiple logistic regression analysis indicated that the diabetes, HDL-C and the RLP-C/HDL-C ratio could discriminate CAD patients from controls. In patients younger than 65 years, diabetes, HDL-C, LDL-C and the LDL-C/HDL-C ratio as well as the RLP-C/HDL-C ratio could discriminate CAD. In patients 65 aged years or older, however, diabetes, triglyceride and RLP-C as well as the RLP-C/HDL-C ratio could discriminate CAD, whereas LDL-C and the LDL-C/HDL-C ratio could not. These results led us to believe that the contribution of a given risk factor to the development of CAD in elderly patients may be different from that in younger patients. In elderly patients, RLP-C rather than LDL-C was strongly associated with the development of CAD. Accordingly, serum RLP-C levels may serve as a convenient and reliable index for assessing CAD.

Body Mass Index↗
PubMed2004

Preoperative stellate ganglion blockade prevents tourniquet-induced hypertension during general anesthesia.

BACKGROUND: Prolonged and excessive inflation of pneumatic tourniquets leads to a hyperdynamic circulatory response. Sympathomimetic activity is an important factor in tourniquet-induced hypertension. Stellate ganglion block specifically blunts sympathetic efferent nerves and prevents hypertension induced by sympathomimetic stimulation. The present study was performed to investigate the effects of stellate ganglion block (SGB) on arterial pressure and heart rate during prolonged tourniquet use under general anesthesia. METHODS: Twenty patients scheduled for knee arthroscopy were either treated with 10 ml of 1% lidocaine for SGB (SGB group; n = 10), or intramuscular injection (IM group; n = 10) before tourniquet inflation. Comparisons of systolic and diastolic arterial pressure and heart rate were made before and after the induction of anesthesia, 10 min after the lidocaine treatment, every 5 min during the first 60 min after tourniquet inflation, and immediately before and 5 min following deflation. The maximum values of the circulatory variables were compared. RESULTS: Tourniquet inflation caused increases in the circulatory variables in both groups. Systolic arterial pressure in the SGB group was significantly lower than that in the IM group after 55 min of tourniquet inflation. Diastolic arterial pressure also was significantly lower in the SGB group immediately before the deflation. The maximum values of the three hemodynamic variables were significantly lower in the SGB group. Arterial pressure significantly decreased after tourniquet deflation in the IM group. CONCLUSION: Ipsilateral SGB attenuated the hyperdynamic response mediated by prolonged tourniquet inflation during knee arthroscopy.

Adult↗
PubMed2004

Expression of enamel proteins and LEF1 in adamantinomatous craniopharyngioma: evidence for its odontogenic epithelial differentiation.

AIMS: Adamantinomatous craniopharyngioma (ACP) resembles histologically some odontogenic tumours, such as ameloblastoma and calcifying odontogenic cyst. However, there has been no evidence that ACP differentiates also functionally as odontogenic epithelium. The aim of this study was to gain evidence of odontogenic epithelial differentiation in ACP by means of immunohistochemistry. Among normal human tissues, enamel proteins are expressed exclusively in teeth, and lymphoid enhancer factor 1 (LEF1), in co-operation with beta-catenin, play an important role in tooth development. The expression of these proteins is therefore indicative of odontogenic epithelial differentiation. METHODS AND RESULTS: The expression of enamel proteins and LEF1 was examined in 10 adamantinomatous and six papillary craniopharyngiomas. All the ACPs showed a variable degree of enamel protein expression, including amelogenin, enamelin and enamelysin, mainly in ghost cells. LEF1 was also heterogeneously expressed in ACPs; remarkably, its expression pattern was identical to that of nuclear beta-catenin accumulation. In contrast, none of the papillary craniopharyngiomas expressed enamel proteins or LEF1. CONCLUSIONS: These results suggest that ACP consistently shows odontogenic epithelial differentiation. Since ACPs harbour beta-catenin mutation, the inappropriate activation of beta-catenin/LEF1 complex-dependent transcription may play a critical role in ACP tumorigenesis.

Adult↗
PubMed2004

Characterization of dental epithelial progenitor cells derived from cervical-loop epithelium in a rat lower incisor.

Dental epithelial progenitor cells differentiate into various cell types during development of tooth germs. To study this mechanism, we produced immortalized dental epithelial progenitor cells derived from the cervical-loop epithelium of a rat lower incisor. The expression patterns of cytokeratin 14, nerve growth factor receptor p75, amelogenin, Notch2, and alkaline phosphatase were examined by immunohistochemistry in both lower and higher cell densities. The patterns of each were compared in the dental epithelium of rat lower incisors. The results demonstrated that these cells could produce ameloblast lineage cells, stratum intermedium cells, stellate reticulum, and outer enamel epithelium. Furthermore, fibroblast growth factor 10 stimulated proliferation of dental progenitor cells and subsequently increased the number of cells expressing alkaline phosphatase. These results suggest that fibroblast growth factor 10 plays a role in coupling mitogenesis of the cervical-loop cells and the production of stratum intermedium cells in rat incisors.

Alkaline Phosphatase↗