Biomedical subjects

H Uchino

Publications and source records attributed to H Uchino.

At least 37 records · Page 2Linked to original sources

PubMed2000

Faropenem transport across the renal epithelial luminal membrane via inorganic phosphate transporter Npt1.

We previously showed that the mouse inorganic phosphate transporter Npt1 operates in the hepatic sinusoidal membrane transport of anionic drugs such as benzylpenicillin and mevalonic acid. In the present study, the mechanism of renal secretion of penem antibiotics was examined by using a Xenopus oocyte expression system. Faropenem (an oral penem antibiotic) was transported via Npt1 with a Michaelis-Menten constant of 0.77 +/- 0.34 mM in a sodium-independent but chloride ion-sensitive manner. When the concentration of chloride ions was increased, the transport activity of faropenem by Npt1 was decreased. Since the concentration gradient of chloride ions is in the lumen-to-intracellular direction, faropenem is expected to be transported from inside proximal tubular cells to the lumen. So, we tested the release of faropenem from Xenopus oocytes. The rate of efflux of faropenem from Npt1-expressing oocytes was about 9.5 times faster than that from control water-injected Xenopus oocytes. Faropenem transport by Npt1 was significantly inhibited by beta-lactam antibiotics such as benzylpenicillin, ampicillin, cephalexin, and cefazolin to 24.9, 40. 5, 54.4, and 26.2% of that for the control, respectively. Zwitterionic beta-lactam antibiotics showed lesser inhibitory effects on faropenem uptake than anionic derivatives, indicating that Npt1 preferentially transports anionic compounds. Other anionic compounds, such as indomethacin and furosemide, and the anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid significantly inhibited faropenem uptake mediated by Npt1. In conclusion, our results suggest that Npt1 participates in the renal secretion of penem antibiotics.

Animals↗

PubMed2000

Impairment of early insulin response after glucose load, rather than insulin resistance, is responsible for postprandial hyperglycemia seen in obese type 2 diabetes: assessment using nateglinide, a new insulin secretagogue.

The insulin secretory pattern as a phenotype of type 2 diabetes is an impairment in the rapid, pulsatile secretion of insulin in response to a rise in blood glucose after meal-intake. The restoration of endogenous rapid insulin secretion after oral glucose load was established for the first time by using nateglinide, which is a newly developed insulin secretagogue, in obese patients with type 2 diabetes mellitus. It was clearly demonstrated that with nateglinide, serum insulin levels were quickly raised, and glycemic response curves were almost normalized with the same amount of insulin secretion during 180 min. Therefore, the lack of rapid, pulsatile secretion of insulin in response to glycemic rise after oral glucose load, rather than insulin resistance, is responsible for postprandial glycemic response in obese type 2 diabetes patients.

Adult↗

PubMed2000

[A successfully repaired case of methicillin-resistant Staphylococcus aureus infective endocarditis in a girl with VSD].

We report a successful case of active infective endocarditis due to Methicilin-Resistant Staphylococcus aureus (MRSA). A 2-year-old girl who had a ventricular septal defect (VSD) complained of persistent fever. Echocardiography showeda large vegetation on the tricuspid valve and a small VSD. She underwent vegetectomy, tricuspid valvoplasty and direct closure of VSD. Vancomycin treatment was also effective to abolish infection. She was discharged without any complication.

Child, Preschool↗

PubMed2000

Staphylococcal scalded skin syndrome with prosthetic valve endocarditis.

We report staphylococcal scalded skin syndrome (SSSS) in a 67-year-old man. He showed diffuse erythema with erosion on his face and erythema with giant desquamation on his neck, axilla, genitalia, chest and abdomen 39 days after a coronary artery bypass graft and aortic valve replacement. He died of cardiac rupture caused by myocardial necrosis, and autopsy findings demonstrated prosthetic valve endocarditis due to a strain of exfoliative toxin-B producing methicillin-resistant Staphylococcus aureus. To the best of our knowledge, this is the first case of SSSS caused by prosthetic valve endocarditis.

Aged↗

PubMed1999

Effect of metformin on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats.

The effects of metformin treatment on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats were examined. Streptozotocin-induced diabetic rats were treated with low dose metformin (50-65 mg kg(-1) daily) or high dose metformin (500-650 mg kg(-1) daily) for 10 weeks. While the metformin-untreated diabetic group showed a significant increase of advanced glycation endproducts (6.1-fold in the lens, 1.6-fold in the sciatic nerve, 2.3-fold in the renal cortex, and 1.9-fold in plasma; all P < 0.01) compared with the healthy control group, both metformin-treated groups had significantly less advanced glycation endproduct deposition. The % decrease in the diabetes-induced increase in advanced glycation endproduct formation by low and high dose metformin treatment was 25% and 72% in the lens (both P < 0.01), 31% and 42% in the sciatic nerve (both P < 0.05), and 16% and 33% in the renal cortex (P < 0.05 and P < 0.01), respectively. However, the plasma advanced glycation endproduct level showed no significant difference from that in the untreated diabetic group, in spite of slight decrease in plasma glucose and glycated hemoglobin levels in the metformin-treated groups. The diabetes-induced sciatic nerve conduction velocity deficits were improved by 46% and 42% by low and high dose metformin treatment, respectively (both P < 0.01). These data suggest that metformin may have a direct antiglycative action, which in turn contributes to amelioration of peripheral nerve function. Thus, metformin treatment may be effective in the prevention of diabetic complications through not only lowering plasma glucose, but also directly inhibiting advanced glycation endproduct formation.

Animals↗

PubMed1999

Role and mechanisms of secondary mitochondrial failure.

Ischemia is accompanied by mitochondrial dysfunction, as assessed by measurements of mitochondrial respiratory activities in vitro. Following brief periods of ischemia, mitochondrial function is usually normalized during reperfusion. However, particularly after ischemia of longer duration, reperfusion may be accompanied by secondary mitochondrial failure. After short periods of ischemia this is observed in selectively vulnerable areas and, after intermediate to long periods of ischemia, in other areas as well. However, it has remained unsettled if the mitochondrial dysfunction is the result or the cause of cell death. Although it has been commonly assumed that such failure is secondary to cell injury by other mechanisms, recent results suggest that mitochondrial dysfunction may be the cause of cell death. Indirect evidence for this postulate is provided by experiments showing that cyclosporin A (CsA), when allowed to cross the blood-brain barrier, is a potent neuroprotectant. CsA is a virtually specific blocker of the mitochondrial permeability transition (MPT) pore, a voltage-gated channel allowing molecules and ions with a mass < 1500 Daltons to pass the inner mitochondrial membrane. Experiments on isolated cells in vitro demonstrate that cell calcium accumulation or oxidative stress triggers the assembly of an MPT pore, which leads to collapse of the mitochondrial membrane potential, to ATP hydrolysis, to enhanced production of reactive oxygen species (ROS), and to cell death. The beneficial effect of CsA could thus be related to its ability to block the MPT pore. Longer periods of ischemia, such as occurs after transient middle cerebral artery (MCA) occlusion, lead to pan-necrotic lesions (infarction). In the rat, recirculation following 2 h of MCA occlusion leads to partial normalization of the bioenergetic state but this is followed within 4-6 h by secondary bioenergetic failure. The latter seems unrelated to blockade of the microcirculation, but correlates to secondary mitochondrial failure. The brain damage incurred is ameliorated by the spin trap alpha-phenyl-N-butyl nitrone (PBN) and by the immunosuppressant FK506 even when given 1-3 h after the start of recirculation. The two drugs also prevent the secondary mitochondrial failure during early recirculation, suggesting that such failure is pathogenetically important. Probably, though, the mitochondrial dysfunction involves not only the assembly of an MPT pore but also other mechanisms. Since recirculation is associated with release of mitochondrial proteins it is not unlikely that such proteins, e.g. cytochrome c, trigger cascades of events leading to cell death.6.

Animals↗

PubMed1999

Enhanced tumor growth and invasiveness in vivo by a carboxyl-terminal fragment of alpha1-proteinase inhibitor generated by matrix metalloproteinases: a possible modulatory role in natural killer cytotoxicity.

Matrix metalloproteinases (MMPs) are believed to contribute to the complex process of cancer progression. They also exhibit an alpha1-proteinase inhibitor (alphaPI)-degrading activity generating a carboxyl-terminal fragment of approximately 5 kd (alphaPI-C). This study reports that overexpression of alphaPI-C in S2-020, a cloned subline derived from the human pancreas adenocarcinoma cell line SUIT-2, potentiates the growth capability of the cells in nude mice. After stable transfection of a vector containing a chimeric cDNA encoding a signal peptide sequence of tissue inhibitor of metalloproteinase-1 followed by cDNA for alphaPI-C into S2-020 cells, three clones that stably secrete alphaPI-C were obtained. The ectopic expression of alphaPI-C did not alter in vitro cellular growth. However, subcutaneous injection of the alphaPI-C-secreting clones resulted in tumors that were 1.5 to 3-fold larger than those of control clones with an increased tendency to invasiveness and lymph node metastasis. These effects could be a result of modulation of natural killer (NK) cell-mediated control of tumor growth in nude mice, as the growth advantage of alphaPI-C-secreting clones was not observed in NK-depleted mice, and alphaPI-C-secreting clones showed decreased NK sensitivity in vitro. In addition, production of alphaPI and generation of the cleaved form of alphaPI by MMP were observed in various human tumor cell lines and in a highly metastatic subline of SUIT-2 in vitro. These results provide experimental evidence that the alphaPI-degrading activity of MMPs may play a role in tumor progression not only via the inactivation of alphaPI but also via the generation of alphaPI-C.

Adenocarcinoma↗

PubMed1999

Neuroprotective properties of propofol and midazolam, but not pentobarbital, on neuronal damage induced by forebrain ischemia, based on the GABAA receptors.

BACKGROUND: The mechanism of the neuroprotective effects of propofol was compared to two other types of intravenous (i.v.) anesthetics (i.e., benzodiazepine; midazolam and barbiturate; pentobarbital) using Mongolian gerbils focusing on GABA receptor subtypes. METHODS: Neuronal injury was induced by a 4-min occlusion of the common carotid arteries followed by reperfusion. One week after occlusion, animals were transcardially perfused for histochemistry. Neuronal death in four brain regions was evaluated by direct visual counting of acidophilic neurons. RESULTS: Seven days after this ischemic episode, severe neuronal injury was measured in the hippocampal CA1 area (> 98% of total cells damaged) and parietal cortex (> 35%). Also lateral thalamus and caudate putamen were damaged but to a lesser extent (about 10%). The neuronal injury in these areas was significantly attenuated by propofol, midazolam and the GABAA agonist, muscimol, intraperitoneally administered 15 min prior to ischemia. This neuroprotective property, however, was lacking with pentobarbital and GABAB agonist baclofen. Concomitant pretreatment with subthreshold doses of propofol and muscimol significantly reduced the amount of cell death induced by brain ischemia. On the other hand, pretreatment with the GABAA antagonist bicuculline significantly inhibited the neuroprotective effects of propofol. However, a GABAB antagonist, phaclofen, was without effect on neuronal damage and on neuronal protection of propofol. CONCLUSION: These results indicate that activation of GABAA receptors, which include the specific binding subunits for propofol and midazolam, but not pentobarbital, plays a role in the inhibition of neuronal death induced by brain ischemia.

Anesthetics, Intravenous↗

PubMed1999

Secretion of protease nexin-II/amyloid beta protein precursor by human colorectal carcinoma cells and its modulation by cytokines/growth factors and proteinase inhibitors.

Trypsin inhibitors secreted by human colorectal adenocarcinoma cell lines were analyzed by reverse zymography. Among eleven cell lines analyzed, the major inhibitor secreted was protease nexin-II (PN-II), a secreted form of amyloid beta protein precursor (APP) containing a Kunitz-type serine proteinase inhibitor domain. Expression of the APP gene was also confirmed in the cell lines and the main APP mRNA species were PN-II types. The APP gene expression was constant during cell growth in vitro. On the other hand, the rate of extracellular PN-II accumulation markedly increased after long-term serum-free maintenance of the confluent culture. The extracellular accumulation of PN-II was also strongly stimulated either by interleukin-1beta (IL-1beta) treatment or to a lesser extent by basic fibroblast growth factor, tumor necrosis factor-alpha, hepatocyte growth factor or epidermal growth factor. Neither serum depletion- nor IL-1beta-induced stimulation of extracellular PN-II accumulation were accompanied by obvious alteration of the levels of APP mRNA and cellular APP holoprotein, suggesting that the enhanced extracellular accumulation of PN-II might result from up-regulation of the secretory pathway of APP. The IL-1beta-induced PN-II secretion was significantly inhibited by relatively high concentrations (50-200 microg/ml) of aprotinin, a serine proteinase inhibitor, in a dose-dependent manner without obvious cell-toxic effects.

Adenocarcinoma↗

PubMed1999

[Catheter drainage of late cardiac tamponade guided by computed tomography].

Delayed cardiac tamponade is an unusual but serious complication of cardiac surgery. Echocardiography and computed tomography (CT) are well established methods for the detection of pericardial effusions. Catheter insertion guided by CT has been used to accomplish non operative drainage of symptomatic postoperative pericardial effusion in seven cases. These patients were grouped into four types according to distribution of the fluid. General pericardial effusion around the heart is classified as type 1, effusion adjacent to the right side of the heart as type 2 and left side as type 3, effusion localized only at the apex as type 4. CT imaging is useful not only to localize and assess the size of the effusions, but also to select the way of catheter insertion. As the fluid might be trapped in compartments, for instance right-sided or left sided type, investigation of the pericardial spaces is important in planning a catheter pericardiocentesis.

Aged↗

PubMed1999

Roles of intestinal trefoil factor (ITF) in human colorectal cancer: ITF suppresses the growth of colorectal carcinoma cells.

Intestinal trefoil factor (ITF) is a member of trefoil peptide family and is expressed almost exclusively in the goblet cells of small intestine and colon. Its expression is up-regulated by inflammatory and ulcerative conditions in the intestinal mucosa, and ITF has a role to maintain the mucosal integrity and repair the damaged mucosa. On the other hand, human colorectal carcinoma cells also express ITF peptide. In this review, we discussed the current views on the biological functions of ITF in the intestinal mucosa, and its suppressive effect on the growth of colorectal carcinoma cells.

Cell Differentiation↗

PubMed1998

Amelioration by cyclosporin A of brain damage in transient forebrain ischemia in the rat.

The immunosuppressant drug cyclosporin A (CsA) is considered to be inherently protective in conditions of ischemia, e.g. in hepatic and cardiac tissue. However, investigations of effects of CsA on neuronal tissue have been contradictory, probably because the blood-brain barrier (BBB) is virtually impermeable to CsA. In the present study, we exploited the finding that the insertion of a syringe needle into brain parenchyma obviously disrupts the BBB and allows influx of CsA, and explored whether CsA, given as intraperitoneal injections daily for 1 week before and 1 week after forebrain ischemia of 7 or 10 min duration, ameliorates the damage incurred to the hippocampal CA 1 sector. In other experiments, the needle insertion and the first i.p. injection of CsA were made 30 min after the start of recirculation, with continued daily administration of CsA during the postinsult week. In animals which were injected with CsA in daily doses of 10 mg kg-1, but in which no needle was inserted, the drug failed to ameliorate CA1 damage, whether the ischemia had a duration of 7 or 10 min. Likewise, needle insertion had no effect on CA1 damage if CsA was not administered. In contrast, when CsA was given to animals with a needle insertion, CA1 damage was dramatically ameliorated, whether treatment was initiated 1 week before ischemia, or 30 min after the start of recirculation. The effect of CsA seemed larger than that of any other drug proposed to have an anti-ischemic effect in forebrain/global ischemia. Injection of tritiated CsA in one animal with BBB disruption lead to detectable radioactivity throughout the ventricular system, suggesting a generalised increase of the entry of CsA across the BBB. The results demonstrate that immunosuppressants of the type represented by CsA markedly ameliorate delayed neuronal damage after transient forebrain ischemia, provided that they can pass the BBB. It is discussed whether the effect of the drug is one involving calcineurin, a protein phosphatase, or if CsA counteracts a permeability transition of the inner mitochondrial membrane, assumed to occur in response to adverse conditions, e.g. gradual accumulation of Ca2+ in the mitochondria in the postischemic period.

Analysis of Variance↗

PubMed1998

Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98).

A cDNA was isolated from rat C6 glioma cells by expression cloning which encodes a novel Na+-independent neutral amino acid transporter designated LAT1. For functional expression in Xenopus oocytes, LAT1 required the heavy chain of 4F2 cell surface antigen (CD98), a type II membrane glycoprotein. When co-expressed with 4F2 heavy chain, LAT1 transported neutral amino acids with branched or aromatic side chains and did not accept basic amino acids or acidic amino acids. The transport via LAT1 was Na+-independent and sensitive to a system L-specific inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid. These functional properties correspond to those of the classically characterized amino acid transport system L, a major nutrient transporter. In in vitro translation, LAT1 was shown to be a nonglycosylated membrane protein consistent with the property of 4F2 light chain, suggesting LAT1 is at least one of the proteins formerly referred to as 4F2 light chain. LAT1 exhibits relatively low but significant amino acid sequence similarity to mammalian cationic amino acid transporters and amino acid permeases of bacteria and yeasts, indicating LAT1 is a new member of the APC superfamily. Because of highly regulated nature and high level of expression in tumor cell lines, LAT1 is thought to be up-regulated to support the high protein synthesis for cell growth and cell activation. The cloning of LAT1 is expected to facilitate the research on the protein-protein interaction in the transporter field and to provide a clue to the search for still unidentified transporters.

Amino Acid Sequence↗

PubMed1998

Evaluation of hepatocyte growth factor activator inhibitor expression in normal and malignant colonic mucosa.

Gene expression of hepatocyte growth factor activator inhibitor (HAI), a recently identified Kunitz-type serine proteinase inhibitor, was analyzed in a series of human colorectal carcinoma cell lines and in human colorectal tissues. All of the 14 cell lines derived from adenocarcinoma of the colorectum expressed HAI in vitro, whereas a colon carcinoma cell line of neuroendocrine origin did not. In vivo, HAI was consistently expressed in the normal colorectal mucosa. Although the expression of HAI mRNA was conserved in adenocarcinoma tissues of the colorectum, the levels of expression were decreased in the adenocarcinoma tissues compared to the normal counterparts. There was a tendency towards an inverse correlation, albeit not well defined, between the amounts of HAI mRNA and the tumor progression. Immunohistochemical study indicated that HAI protein is present predominantly on the surface of epithelial cells of the colon and the immunoreactivity was decreased in the adenocarcinoma cells.

Adult↗

PubMed1998

Comparative analysis of expression of hepatocyte growth factor and its receptor, c-met, in gliomas, meningiomas and schwannomas in humans.

Expression of hepatocyte growth factor (HGF) and c-met, a proto-oncogene that encodes a receptor for HGF, was examined in 45 cases of human primary intracranial tumors by means of RT-PCR. In gliomas, HGF and c-met mRNAs were preferentially expressed in high-grade tumors. Co-expression of both genes was observed in glioblastomas (6/15) and in one anaplastic astrocytoma (1/5) but not in low-grade astrocytomas (0/3). By contrast, the c-met gene was consistently expressed in meningiomas (12/14) and schwannomas (8/8). The presence of c-Met protein was confirmed in the tumor cells of glioblastoma, meningioma and schwannoma by immunohistochemical staining. Moreover, all of the schwannoma cases co-expressed the HGF gene. These observations suggest that HGF/c-met expression is somehow related to the disease progression in gliomas, whereas c-Met protein might have an important fundamental biological role in meningioma and schwannoma. Moreover, since all of the schwannoma cases concomitantly expressed the ligand (HGF) and the receptor (c-met) genes, HGF may act in an autocrine fashion in schwannoma.

Astrocytoma↗

PubMed1998

[Spontaneous splenic rupture after mitral valve replacement for infective endocarditis].

We report a successful treatment of massive bleeding due to spontaneous splenic rupture after mitral valve replacement. A 61-year-old man was admitted to our hospital for intermittent high fever. An echocardiogram demonstrated a large vegetation on the posterior cusp of the mitral valve and mitral regurgitation of moderate degree. Staphylococcus epidermidis was cultured from his arterial blood. He underwent a mitral valve replacement after 3 weeks of antimicrobiological therapy with penicillin G crystalline and minocycline hydrochloeide. The patient fell into hemorrhagic shock on postoperative day 11 after complaining dull pain on his left upper abdomen for 3 days. A computed tomography demonstrated a splenic rupture and massive hematoma in the retroperitoneum. A splenic arterial embolization was done before splenectomy. The blood and clot of 2800 g were sucked from peritoneal and retroperitoneal cavities. There were no mycotic aneurysms nor abscess but the torn capsule on the swelled and partially necrotic spleen. The patient discharged uneventfully on postoperative day 43. Infective endocarditis frequently causes splenic infarction but rarely splenic rupture. Anticoagulation therapy after mitral valve replacement might have emphasized the bleeding in the patient.

Endocarditis, Bacterial↗

PubMed1998

Diagnostic and biological significance of sideroblastic erythropoiesis in the myelodysplastic syndromes.

We retrospectively reviewed clinical and hematologic features of nine patients with acquired idiopathic sideroblastic anemia (AISA). Seven of them had ringed sideroblasts (RS) more than 15% of marrow nucleated cells. RS persisted in the marrow even in the remaining two patients who had a relatively low marrow erythroblasts despite RS ranging from 1/4 to half of the marrow erythroid series. However, RS declined in proportion in another two patients of the nine whose disease progressed to refractory anemia with excess of blasts (RAEB), although a high proportion of RS reappeared in one patient at the time of relapse following allogeneic marrow transplantation. A similar decline of RS concomitant with disease progression was also seen in seven additional patients with RAEB or RAEB in transformation (RAEB-t) with sideroblastic erythropoiesis. Cytogenetic abnormalities, although rare initially, became detectable either at the time of disease progression or at the worsening of anemia in AISA. These observations suggest that the majority of AISA fall in the category of myelodysplasia, and that a progressive decline in RS is part of the natural history of myelodysplasia. Closer follow-up of the proportion of RS in patients with AISA is warranted to better understand its biologic significance.

Adolescent↗

PubMed1998

Aortic valve replacement through the transected aorta in a patient with aortic stenosis and a calcified ascending aorta.

This report describes a surgical approach of aortic valve replacement in a patient with a calcified ascending aorta, calcified aortic valve stenosis and coronary artery disease. The aortic valve was replaced with a 19 mm St. Jude Medical prosthetic valve through the transected aorta while the distal ascending aorta was cross-clamped at a narrow but not calcified band approximately 4.5 cm distal to the aortic anulus. These procedures were successfully done and no neurological deficit was found after surgery. The aortic valve replacement through the transected aorta may be one of the alternatives in selected patients with porcelain aortas and calcified aortic valves.

Aged↗