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Biomedical subjects

H Fujii

Publications and source records attributed to H Fujii.

At least 271 records · Page 15Linked to original sources
PubMed1999

Acute acalculous cholecystitis complicated by penetration into the liver after coronary artery bypass grafting.

BACKGROUND: Perforation or penetration due to acute acalculous cholecystitis is a rare complication after open-heart surgery. The mortality rate of this disease is high. METHODS: A 71-year-old woman complained of a sudden onset of right upper abdominal pain with development of peritoneal signs at 21 days after coronary artery bypass grafting. Abdominal ultrasonography and laboratory examination performed at 1 day earlier had revealed no abnormalities. Neither anticoagulants nor antiplatelet agents were administered following the bypass operation. An exploratory laparotomy was performed to locate a presumed embolization to the superior mesenteric artery. RESULTS: Laparotomy revealed acute acalculous cholecystitis complicated by penetration into the liver, causing a subserosal hematoma. The hematoma had ruptured into the abdominal cavity. A cholecystectomy was performed. The gallbladder wall which was in contact with the liver was necrotic. Most of the gallbladder mucosa was necrotic. Microscopical examination revealed atherosclerosis of the cystic artery which was partially obstructed by thrombus. CONCLUSIONS: Given the atherosclerotic condition of the cystic artery, hypotension during the bypass in combination with postoperative total parenteral nutrition and hypovolemia may have induced the cystic artery thrombosis. Surgeons who manage patients with cardiovascular disease should be aware of this potentially lethal development.

Acute Disease↗
PubMed1999

Scintigraphic evaluation of myocardial ischaemia using a new fatty acid analogue: iodine-123-labelled 15-(p-iodophenyl)-9-(R, S)-methylpentadecanoic acid (9MPA).

Iodine-123-labelled 15-(p-iodophenyl)-9-(R,S)-methylpentadecanoic acid (9MPA) is a branched fatty acid analogue for myocardial imaging, which has been recently designed for medium washout rates from the myocardium. The purpose of this study was to assess the clinical feasibility of use of 9MPA for the evaluation of myocardial ischaemia. Twenty-one patients were injected with 9MPA at rest, and sequential single-photon emission tomography (SPET) acquisitions were performed 5, 45 and 240 min after administration to calculate washout rates from the myocardium. The findings of 9MPA images were analysed in comparison with those of perfusion images with thallium-201 or sestamibi, coronary angiography and left venticulography. In general, reduction of 9MPA uptake was more remarkable than that of perfusion tracers. The findings of 9MPA early images correlated better with those of exercise perfusion images than with the rest images. Measured washout rates of 9MPA from ischaemic myocardium were significantly slower than those from normal myocardium. The majority of areas with abnormal 9MPA distribution manifested wall motion abnormality, while all areas with normal tracer distribution presented normal wall motion. The detectability of myocardial ischaemia was improved by adding mid and delayed images in six cases. However, both washout and fill-in patterns were encountered in ischaemic lesions, rendering the interpretation of images difficult. In conclusion, the results of this study indicated that 9MPA has acceptable myocardial uptake, that its use is feasible for the detection of ischaemia and that the abnormal distribution of the tracer correlates well with wall motion abnormality reflecting metabolic disorders.

Fatty Acids↗
PubMed1999

L-2-hydroxyglutaric aciduria: two Japanese adult cases in one family.

We report two adult Japanese sisters with L-2-hydroxy-glutaric aciduria (acidemia), both of whom were much older (aged 57, 47 years old) than previously reported patients (from neonate to 44 years old), and who presented with differing severity. Magnetic resonance imaging revealed typical subcortical white matter lesions in both cases and showed brainstem atrophy and thickness of the calvarium in the elder sister. L-2-Hydroxyglutaric acid levels were increased in urine, plasma, and cerebrospinal fluid. These cases suggest that organic acid analysis is necessary even in elderly patients who seem to have neurodegenerative disorders.

Brain↗
PubMed1999

Expression of platelet-derived growth factor proteins and their receptor alpha and beta mRNAs during fracture healing in the normal mouse.

Platelet-derived growth factor (PDGF), abundant in bone tissue, has been reported to stimulate mesenchymal cell proliferation and migration. To elucidate the functional roles of PDGF during fracture healing, we investigated the expression of PDGF-A and -B chain proteins and receptor alpha and beta mRNAs in fractured mouse tibiae. Twelve-week-old male BALB/c mice were operated on to make a closed fracture on the proximal tibia. On days 2, 4, 7, 10, 14, 21, and 28 after the operation, the fractured tibiae were excised, fixed with 4% paraformaldehyde, decalcified with 20% EDTA, and embedded in paraffin to prepare 7-microm sections. Immunohistochemistry using polyclonal antibodies against human PDGF-A and -B chains was carried out by the avidin-biotin-peroxidase method. For in situ hybridization, we used digoxigenin-labeled single-stranded DNA probes specific for mouse PDGF receptors alpha and beta generated by unidirectional polymerase chain reaction. In the inflammatory phase on days 2-4 after the fracture, mesenchymal cells gathering at the fracture site expressed the PDGF-B chain and beta receptor mRNA. At the stage of cartilaginous callus formation on day 7, the immunoreactivity for PDGF-A and -B chains on proliferating and hypertrophic chondrocytes and the signals of alpha and beta receptor mRNAs on proliferating chondrocytes became manifest. At the stage of bony callus and bone remodeling on days 14-21, the predominant expression of the PDGF-B chain and beta receptor was observed on both osteoclasts and osteoblasts. On day 28, signals for PDGF ligand proteins and receptor mRNAs diminished. The coincidental localization of PDGF ligands and their receptors implies a paracrine and autocrine mechanism. Our data suggested that PDGF contributed in part to the promotion of the chondrogenic and osteogenic changes of mesenchymal cells from the early to the midphase of fracture healing; the functions mediated by the beta receptor, including cell migration, might be prerequisites to the recruitment of mesenchymal cells in the initial step and to the interaction between osteoclasts and osteoblasts in the bone remodeling phase.

Animals↗
PubMed1999

Epithelial cell proliferation activity of the biliary ductal system with congenital biliary malformations.

Congenital biliary malformations such as anomalous arrangement of the pancreaticobiliary ductal system (AAPB), congenital cystic dilatation of the common bile duct (CCDB), and congenital biliary strictures at the hepatic hilum (CBSH) are newly designated disease entities and are frequently found in adult patients with biliary malignancy such as gallbladder carcinoma, common bile duct carcinoma, and intrahepatic bile duct carcinoma. In the present study, the relationship of these malformations and biliary malignancy was investigated. We studied 61 gallbladders of patients with AAPB and 56 gallbladders of patients without AAPB; 16 common bile ducts of patients with CCDB (12 with AAPB and 4 without AAPB) and 11 gallbladders of patients without CCDB; and 17 intrahepatic bile ducts of patients with CBSH and 6 intrahepatic bile ducts of patients without CBSH. Tissue sections from the mucosa of the gallbladder, common bile duct, and intrahepatic bile duct were stained for proliferating cell nuclear antigen (PCNA). The PCNA labeling indexes of patients with these malformations were significantly higher than those of patients without these malformations (P < 0.05). Cell proliferation of the epithelia in the biliary ductal system in patients with these congenital biliary malformations was accelerated. Consequently, these congenital malformations appear to be an important risk factor for the occurrence of biliary malignancy.

Adult↗
PubMed1999

Tumor angiogenesis predicts recurrence with normal serum carcinoembryonic antigen in advanced rectal carcinoma patients.

Many studies have established the usefulness of serum carcinoembryonic antigen (CEA) oriented serial monitoring for predicting recurrence and prognosis; however, few studies have so far investigated serum CEA-negative recurrence. The aim of this study was to elucidate the nature of CEA-negative recurrence regarding tumor angiogenesis. Fifty-seven patients with T3/T4 rectal cancer were divided into the two groups according to the serum CEA status. Angiogenesis was defined as the intratumoral vessel count by immunohistochemical staining using CD31. The CD31 count was significantly higher in the recurrent patients in both groups and the ratio of nodal involvement was significantly higher in the recurrent patients of the CEA-negative group. Local recurrence mainly developed in the CEA-negative group; however, the CD31 count did not predict the sites of recurrence nor the relapse period in the both groups. A multivariate analysis showed a high CD31 count >26) to be a prognostic factor not only for recurrence but also for survival (P = 0.001, 0.043, respectively). These results suggest that a high degree of tumor angiogenesis in sections of T3/T4 rectal cancer may therefore be an important predictor for CEA-negative recurrence.

Adenocarcinoma↗
PubMed1999

Beta-catenin mutations are frequent in human hepatocellular carcinomas associated with hepatitis C virus infection.

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide. Hepatitis B virus and hepatitis C virus infections, exposure to aflatoxin, and excessive intake of alcohol have been identified as major risk factors. However, the molecular mechanisms underlying their development are still poorly understood. Recently, beta-catenin, one of the key components of the Wnt signaling pathway, has been found to be mutated in about 20% of HCCs, suggesting a role of the Wnt pathway in their development. In this study, we examined beta-catenin and APC mutations in 22 HCCs associated with HCV infection, using single-strand conformation polymorphism (SSCP) followed by direct DNA sequencing. beta-Catenin mutations were found in nine (41%) cases, but no APC mutations were found. beta-Catenin immunohistochemistry revealed nuclear accumulation of beta-catenin protein in all nine tumors with a beta-catenin mutation and two additional tumors without a mutation. These results suggest that activation of the Wnt signaling pathway by beta-catenin mutation contributes significantly to the hepatocellular carcinogenesis associated with HCV infection.

Adenomatous Polyposis Coli Protein↗
PubMed1999

Genotype of glutathione S-transferase and other genetic configurations in myelodysplasia.

We examined polymorphisms of glutathione S-transferase (GST) genes in 159 Japanese patients with myelodysplasia and compared the incidence with that in 43 normal individuals to clarify their pathogenetic significance in myelodysplasia. In individuals with the GSTT1 null genotype, the odds ratios for disease risk were elevated to 2.65 (95%CI; 1.27-5.52) in de novo MDS, 4.62 (1.48-14.4) in therapy-related AML, and 2.94 (1.07-8.07) in AML with triliniage dysplasia. Other representative polymorphisms of GSTs had a similar incidence among patients with myelodysplasia, and those of the controls and other hematological disorders. To further investigate the genetic pathway of myelodysplasia, the association between GST genotype and karyotype or configurations of TP53 and NRAS was evaluated, but no relationship was noted. These results suggest that the GSTT1 null genotype may play a role in an increased risk of myelodysplasia unrelated to other mechanisms of myelodysplasia, such as chromosomal alterations or mutation of TP53 or NRAS.

Acute Disease↗
PubMed1999

Recurrent clear cell carcinoma of the ovary changing into producing parathyroid hormone-related protein (PTH-rP) with hypercalcemia.

We experienced the case of a clear cell carcinoma of the ovary arising from an endometrial cyst, which started to produce parathyroid hormone-related protein (PTH-rP) in a recurrent tumor, thus inducing hypercalcemia. Using immunohistochemical analysis, we demonstrated that the primary carcinoma was immunonegative for PTH-rP, but that the recurrent carcinoma was strongly immunopositive for PTH-rP.

Adenocarcinoma, Clear Cell↗
PubMed1999

GFR alpha3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion.

GFR alpha3 is a component of the receptor for the neurotrophic factor artemin. The role of GFR alpha3 in nervous system development was examined by generating mice in which the Gfr alpha3 gene was disrupted. The Gfr alpha3-/- mice exhibited severe defects in the superior cervical ganglion (SCG), whereas other ganglia appeared normal. SCG precursor cells in the mutant embryos failed to migrate to the correct position, and they subsequently failed to innervate the target organs. In wild-type embryos, Gfr alpha3 was expressed in migrating SCG precursors, and artemin was expressed in and near the SCG. After birth, SCG neurons in the mutant mice underwent progressive cell death. These observations suggest that GFR alpha3-mediated signaling is required both for the rostral migration of SCG precursors and for the survival of mature SCG neurons.

Animals↗
PubMed1999

Expression of multidrug resistance-associated protein in endometrial carcinomas: correlation with clinicopathology and prognosis.

The objective of the study reported here was to investigate the expression of multidrug resistance-associated protein (MRP) in endometrial carcinomas and to evaluate the relationship between its expression and clinical data. Using immunohistochemistry, we examined MRP expression in 15 normal endometria, 10 cases of endometrial hyperplasia, and 64 cases of endometrial carcinoma. The normal endometrial glands were weakly immunopositive throughout the menstrual cycle. In addition, we found a progressive increase in the MRP expression of the endometrial hyperplasias. Of the 64 cases of endometrial carcinoma, 62 (97%) expressed MRP. Of these 62 cases, 34 (55%) showed strong immunostaining (>/=50%) and 28 (45%) showed weak immunostaining (<50%). In particular, the intensity of the immunostaining was very strong in 25 (71%) of the 35 grade 1 carcinomas. There was a significant difference in MRP expression between the grade 1 carcinomas and the more poorly differentiated carcinomas (grade 2 or grade 3) (P <.01), especially at stages 1a and 1b (P <.001). However, beyond stage 1c, there was no significant difference in MRP immunoreactivity between the histologic differentiations. Furthermore, beyond stage 1c, those patients with strongly MRP-positive carcinomas had a relatively poorer survival rate than those with weakly MRP-positive carcinomas (P <.05). We concluded that MRP immunoreactivity was already present in normal endometrium and showed a progressive increase from endometrial hyperplasia to well-differentiated carcinoma. Beyond stage 1c, strongly MRP-positive carcinoma indicated a poorer survival rate.

ATP-Binding Cassette Transporters↗
PubMed1999

Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.

We conducted a phase I pharmacokinetic dose escalation study of a recombinant humanized anti-p185HER2 monoclonal antibody (MKC-454) in 18 patients with metastatic breast cancer refractory to chemotherapy. Three or six patients at each dose level received 1, 2, 4 and 8 mg kg(-1) of MKC-454 as 90-min intravenous infusions. The first dose was followed in 3 weeks by nine weekly doses. Target trough serum concentration has been set at 10 microg ml(-1) based on in vitro observations. The mean value of minimum trough serum concentrations at each dose level were 3.58 +/- 0.63, 6.53 +/- 5.26, 40.2 +/- 7.12 and 87.9 +/- 23.5 microg ml(-1) respectively. At 2 mg kg(-1), although minimum trough serum concentrations were lower than the target trough concentration with a wide range of variation, trough concentrations increased and exceeded the target concentration, as administrations were repeated weekly. Finally 2 mg kg(-1) was considered to be sufficient to achieve the target trough concentration by the weekly dosing regimen. One patient receiving 1 mg kg(-1) had grade 3 fever, one at the 1 mg kg(-1) level had severe fatigue defined as grade 3, and one at 8 mg kg(-1) had severe bone pain of grade 3. No antibodies against MKC-454 were detected in any patients. Objective tumour responses were observed in two patients; one receiving 4 mg kg(-1) had a partial response in lung metastases and the other receiving 8 mg kg(-1) had a complete response in soft tissue metastases. These results indicate that MKC-454 is well tolerated and effective in patients with refractory metastatic breast cancers overexpressing the HER2 proto-oncogene. Further evaluation of this agent with 2-4 mg kg(-1) weekly intravenous infusion is warranted.

Antibodies, Monoclonal↗
PubMed1999

Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines.

We investigated the growth inhibitory activity of bestatin, an inhibitor of aminopeptidase N (CD13), on six human leukemic cell lines. Proliferation of all the cell lines except KG1 was inhibited by bestatin. P39/TSU, HL60 and U937 were highly sensitive, with 50% growth inhibitory concentrations (IC50) close to the maximum serum concentration when bestatin was orally administered at 30 mg in clinical application. All cell lines except for K562 highly expressed CD13, but a clear correlation between the sensitivity to bestatin and expression of CD13 was not observed. Other aminopeptidase inhibitors such as amastatin A, arphamenine B and WM15 antibody showed no growth inhibitory effects. To confirm the growth inhibitory effects of bestatin, we quantitatively examined DNA fragmentation in five bestatin-sensitive cell lines. Bestatin dose-dependently induced DNA fragmentation in those cell lines. In case of U937, bestatin induced DNA fragmentation quantitatively and DNA ladder and enhanced caspase-3 activity. Furthermore, the growth inhibition by bestatin was reduced by the caspase inhibitor Z-Asp-CH2-DCB. These results suggested that bestatin exhibits direct antileukemic effects against human leukemic cell lines through the induction of apoptosis.

Aminopeptidases↗
PubMed1999

Interleukin-11 (IL-11) enhances clonal proliferation of acute myelogenous leukemia cells with strong expression of the IL-11 receptor alpha chain and signal transducing gp130.

We examined the effect of recombinant human interleukin (IL)-11 alone or in combination with various colony-stimulating factors (CSFs), including IL-3, granulocyte/macrophage (GM)-CSF, granulocyte (G)-CSF, stem cell factor (SCF), flt3 ligand (FL), and thrombopoietin (TPO), on colony formation by leukemic progenitor cells (L-CFU) obtained from 33 patients with acute myelogenous leukemia (AML). Leukemic colony formation was found in approximately 70 to 80% of the patients in the presence of at least one of the above CSFs. Although IL-11 alone did not support L-CFU, the growth of these progenitors in the presence of other cytokines was enhanced by IL-11 in 16 out of 33 patients and it showed a synergistic action with G-CSF in 12 of them. This synergistic action occurred in seven out of nine M5 patients (French-American-British (FAB) classification). A single cell clone-sorting experiment clearly demonstrated that this synergistic effect was operative at the single progenitor cell level. The number of leukemic cells proliferating in the presence of G-CSF+IL-11 was significantly higher than in the presence of G-CSF alone, suggesting that IL-11 recruited dormant leukemic progenitors into the cell cycle. Flow cytometric analysis revealed that all types of AML blast cells (M0 approximately M6) ubiquitously expressed gp130, although the level of expression was significantly higher in M5 cells. In contrast, expression of the IL-11 receptor alpha chain (IL-11Ralpha) varied between FAB types. Blast cells obtained from M1, M3 and M5 patients showed higher levels of expression, with M5 cells showing the strongest expression. Interestingly, the leukemic progenitor cells for which proliferation was synergistically enhanced by IL-11 had significantly higher expression of both IL-11Ralpha and gp130. These results suggest that administration of IL-11 in vivo may stimulate the proliferation of leukemic progenitor cells, particularly M5 cells, in the presence of G-CSF, and that the responsiveness of L-CFU to IL-11 may be predicted by a simple receptor assay.

Acute Disease↗
PubMed1999

Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype.

We examined chromosomes and molecular aberrations in 21 patients with therapy-related leukemias (t-AML) or myelodysplastic syndromes (t-MDS). All patients showed abnormal karyotypes, and chromosomal losses of No. 5 and/or No. 7 (-5/5q- and/or -7/7q-) were identified in 12 patients. Among these 12, six patients (50%) harbored a TP53 mutation, and two of five examined showed microsatellite instability, suggesting replication error (RER+) phenotype. Meanwhile, among the other nine patients without -5/5q- and/or -7/7q-, none harbored a TP53 mutation, and none of five examined showed RER+ phenotype. Thus, TP53 mutations and RER+ phenotype were preferentially associated with specific chromosomal losses in t-AML/MDS. We then screened for mutational events in representative DNA mismatch repair genes; exons 5-7 and 12-15 of the hMSH2 gene and exon 9 of hMLH1. Notably, two unrelated patients showing RER+ phenotype had an identical missense alteration at codon 419 of hMSH2 in their marrow cells and fibroblasts, which were not found in 120 DNA samples from healthy volunteers or patients with other hematological disorders. Consequently, this study revealed a possible relationship of RER+ phenotype accompanying an hMSH2 alteration to the development of therapy-related AML/MDS in association with TP53 mutations and specific chromosomal losses, and suggests that some patients may be predisposed to myelodysplasia after chemotherapy for their primary tumor.

Adult↗
PubMed1999

Critical role of the membrane-proximal, proline-rich motif of the interleukin-2 receptor gammac chain in the Jak3-independent signal transduction.

BACKGROUND: The interleukin-2 receptor (IL-2R) consists of three subunits, the IL-2Ralpha, IL-2Rbetac, and IL-2Rgammac chains. The essential role of the IL-2Rgammac cytoplasmic domain, consisting of 86 amino acids, in signal transmission has been well documented. Particularly, the carboxyl ter-minal region containing 48 amino acids. is essential for the association with and activation of the Jak3 protein tyrosine kinase. On the other hand, little is known about the role of the rest of the IL-2Rgammac cytoplasmic region consisting of the membrane-proximal 38 amino acids. RESULTS: We show that a truncated mutant form of IL-2Rgammac which lacks the membrane-distal 48 amino acids is still capable of inducing the activation of Jak1 and Stat3/Stat5 in the absence of Jak3 activation. This membrane-proximal region can also mediate the IL-2-induced tyrosine phosphorylation of the p85 subunit of phosphatidylinositol-3-kinase (PI3K). Furthermore, these signalling events are completely abrogated when mutations are introduced into the proline-rich motif in this region. CONCLUSIONS: In this study, we identified a Jak3-independent signalling pathway(s) from the membrane-proximal region of IL-2Rgammac. Our results indicate that the proline-rich motif in this region plays a critical role in this signalling pathway(s). The present study may provide further insight into the mechanism of cellular responses mediated by IL-2 and other cytokines which utilize the IL-2Rgammac for their signal transmission.

Amino Acid Sequence↗
PubMed1999

Head, neck and trunk movements accompanying jaw tapping.

Several studies have examined the functional relationship between mandibular movement and head or body posture, but head and body motion during jaw movement have not been extensively investigated. Ten healthy participants performed repetitive jaw tapping movement. Piezoelectric accelerometers were attached on the surfaces of the participant's forehead, mentum, and over the spinous processes of the sixth cervical, twelfth thoracic and third lumbar vertebrae. The direction in which the antero-posterior acceleration signals appeared around the onsets of jaw opening and closing were observed for the period from the 6th to the 25th strokes of the jaw tapping. Around the onset of jaw opening, the forehead and the lumbar vertebra tended to move posteriorly, but the cervical and thoracic vertebrae moved anteriorly with significant frequencies. The directions of the motions of these locations reversed themselves at the beginning of jaw closing; so the motions of the forehead and the lumbar vertebra were opposed again to the ones of the cervical and thoracic vertebrae. The results suggest that the head extend-flex motion often accompanied the jaw open-close movement, and the motions of the neck and trunk existed, which would serve the purpose of promoting the mandible to move smoothly.

Acceleration↗