[Replication and transcription of genome complexed with basic proteins].
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DNA Replication↗
Biomedical subjects
K Nagata
Publications and source records attributed to K Nagata.
[Bax and Bcl-2 expression predict response to radiotherapy in human cervical cancer].
To establish a new predictor of the outcome of treatment for human cervical carcinoma, we investigated the relationship between the expression of the Bax and Bcl-2 proteins and the response to radiotherapy after administration of 10.8 Gy. A total of 44 patients with uterine cervical carcinoma were treated with definitive radiotherapy. On univariate analysis, Bax and Bcl-2 protein expression prior to radiotherapy did not correlate with survival. Increased Bax expression after 10.8 Gy correlated with good survival (p = 0.003). In contrast, increased Bcl-2 expression after 10.8 Gy correlated with poor survival (p < 0.0001). On multivariate analysis, Bcl-2 expression after 10.8 Gy of radiation was the most important predictor of treatment outcome. The levels of Bax and Bcl-2 expression after 10.8 Gy of radiotherapy are useful prognostic markers in patients with human cervical carcinoma.
Adenocarcinoma↗
Antisense oligonucleotides against collagen-binding stress protein HSP47 suppress collagen accumulation in experimental glomerulonephritis.
Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that has been shown to play a major role during the biosynthesis and secretion of procollagen molecules. The expression of HSP47 has been reported to increase in parallel with the expression of collagens during the progression of various fibrosis models. However, it remains unclear whether an inhibition of HSP47 overexpression would suppress collagen accumulation and thus reduce the progression of fibrotic diseases. In this study, we attempted to attenuate glomerular collagen accumulation by inhibiting the overexpression of HSP47 with antisense oligodeoxynucleotides in an experimental glomerulonephritis model induced by anti-Thy-1 antibodies. The administration of antisense oligodeoxynucleotides against HSP47 at the induction of the glomerular disease markedly suppressed the increased production of collagens and attenuated the histologic manifestations of the disease. These results provide direct evidence of a pivotal role for HSP47 in the pathogenesis of glomerulonephritis.
Animals↗
[Polyclonal B-cell lymphocytosis with clinical and hematological features resembling hairy cell leukemia].
A 49-year-old man was admitted to our hospital for investigation of splenomegaly and lymphocytosis. He had no significant past history and was not a smoker. Physical examination revealed massive splenomegaly and no palpable superficial lymph nodes. Hematological examination showed a hemoglobin concentration of 10.5g/dl, a platelet count of 9.8 x 10(4)/microliter, and a leukocyte count of 21.2 x 10(3)/microliter with 70% abnormal lymphocytes. In May-Giemsa stained blood films, the abnormal lymphocytes had round nuclei, abundant, pale cytoplasm, and slightly serrated edges. Phase-contrast microscopic and scanning electron microscopic examinations revealed many long surface villi. Tartrate-resistant acid phosphatase activity in these cells was negative. The abnormal lymphocytes had a CD5-, CD10-, CD11a+, CD11c+, CD19+, CD20+, CD22+ phenotype. These features were similar to those described for a variant form of hairy cell leukemia (HCL-Japanese variant). However, studies of Ig gene rearrangement and expression of sIg revealed a polyclonal proliferation of B cells. On the basis of these findings, this case was diagnosed as hairy B-cell lymphoproliferative disorder, a recently described condition characterized by polyclonal B-cell lymphocytosis and features resembling HCL-Japanese variant. Serological assays for antibodies against Epstein-Barr virus suggested a past infection. Splenectomy alleviated the anemia and thrombocytopenia, but not the lymphocytosis.
Antigens, CD↗
[Effect on hepatic function of hepatic artery infusion chemotherapy using epirubicin and mitoxantrone for advanced hepatocellular carcinoma].
This study was designed to assess the effect of hepatic dysfunction from hepatic artery infusion (HAI) in advanced hepatocellular carcinoma (HCC). The patients were randomly assigned to receive epirubicin (n = 12, Epi group) or mitoxantrone (n = 14, Mito group) once every 4 weeks between 1992 and 1996. HCC patients were given 6-8 mg of mitoxantrone or 30-40 mg epirubicin. There was hepatic dysfunction in 27 patients after HAI, showing similarly elevated GOT, GPT, and total bilirubin. In the Epi group, the GOT value was slightly higher than in the Mito group, but it was not significant. After HAI chemotherapy, the GOT value showed a more than two-fold elevation. Six patients in the Epi group and 2 in the Mito group showed a significant difference. Our results indicated that mitoxantrone had less impact on hepatic function following HAI therapy.
Antibiotics, Antineoplastic↗
[Long-term follow-up study with PET in a case of superficial siderosis].
Long-term follow-up study with positron emission tomography (PET) has been conducted in a patient with superficial siderosis for ten years. A 63-year-old right-handed woman began to exhibit a cerebellar ataxia when she was 52 years old. Thereafter she has been exhibiting a slowly progressive course of pyramidal signs, hearing loss, anosmia, bilateral sciatica and memory disturbance in addition to the cerebellar ataxia. Series of x-ray CT and MRI disclosed a progressive atrophy of the cerebellum, specifically in the superior vermis, and a mild diffuse atrophy in the cerebral hemispheres, whereas no significant atrophy was seen in the brainstem. A marked hypointensity was seen along the rim of the brain structures including brainstem, cerebellum, sylvian fissures and the medial temporal lobes on MR T 2-weighted images. This hypointensity was also found at the edges of the third and fourth ventricles. These findings were regarded as haemosiderin deposit. By using oxygen-15, PET was carried out repeatedly with ten-year interval. In the initial PET study, both cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) were mildly decreased in the cerebellar hemispheres and the occipital cortices. The follow-up PET study revealed a progressive reduction of CMRO2 in the brainstem, cerebellar hemispheres and temporal cortices including the hippocampus in which the haemosiderin deposition was marked on MRI, whereas the reduction of CBF was not advanced as compared with CMRO2. It was suggested that the progressive reduction of CMRO2 in the brain sites where the haemosiderin deposition was observed on MRI reflected the clinical course of neurological deterioration.
Brain↗
[A case of aortic coarctation presenting with Brown-Séquard syndrome due to radicular artery aneurysm].
We report a case of aortic coarctation who showed a Brown-Séquard syndrome due to the aneurysm of the anterior radicular artery. A 71-year-old right-handed hypertensive woman was admitted to the Research Institute for Brain and Blood Vessels because of subarachnoid hemorrhage in 1984. No aneurysm was detected even on the four-vessel cerebral angiography. However, the left subclavian artery was occluded associated with the coarctation. In 1997, she complained of numbness of the right lower extremity, which gradually expanded to the back and the right upper extremity. On neurological examination, she exhibited a mild weakness of the right lower extremity and a dissociated sensory disturbance below the level of C5. The cervical MRI showed a space occupying lesion at the level of C4. The right vertebral angiography revealed an aneurysm of the left anterior radicular artery at the level of C4, which compressed the spinal cord. Previously only a few cases of an aortic coarctation associated with the radicular artery aneurysm were reported in our country. The age of onset of this case was older than in the previous cases, and the location of the aneurysm was higher than those of the previous cases. Probably due to the occlusion of the left subclavian artery, the transverse collateral circulation was produced from the right to the left anterior radicular arteries at the level between C2 and C5, causing a radicular artery aneurysm in this patient.
Aged↗
[Usefulness of myocardial scintigraphy with 99mTc-tetrofosmin for diagnosis in 2 cases of acute coronary syndrome].
Patients with acute coronary syndrome require accurate diagnosis and treatment. We found that emergency myocardial scintigraphy with 99mTc-tetrofosmin was useful for diagnosis in 2 patients with acute coronary syndrome. The first patient was a 66-year-old man, who was hospitalized with chest discomfort at rest. Blood tests, electrocardiography, and echocardiography revealed no unusual findings. Myocardial scintigraphy with 99mTc-tetrofosmin disclosed moderately reduced uptake extending from the anterior wall to the apex. Coronary arteriography revealed 75% stenosis of the left main trunk. He was diagnosed as having unstable angina pectoris and coronary bypass surgery was performed. The second patient was a 61-year-old man, who was hospitalized with chest discomfort. Slight leukocytosis and flat T waves in leads V5 and V6 on electrocardiogram were detected, but echocardiographic findings were not abnormal. Myocardial scintigraphy with 99mTc-tetrofosmin revealed a defect in the posterolateral wall. Coronary arteriography showed total obstruction of #14, and a diagnosis of acute myocardial infarction was established. PTCA of #14 was performed to achieve reperfusion.
Aged↗
[Flow cytometric analysis of helper T cell subsets (Th1 and Th2) in healthy adults].
To estimate frequency of T helper (Th) 1, Th2, and other related subsets in T cells among healthy Japanese, we determined the frequencies of interferon (IFN)-gamma- and/or interleukin (IL)-4-producing cells in stimulated peripheral blood lymphocytes (PBL) from 51 healthy adults of various ages by three-color flow cytometry using FITC-labeled anti-IFN-gamma, PE-conjugated anti-IL-4, and peridinin chlorophyll protein (PerCP)-labeled anti-CD4 or anti-CD3 antibody. As a result, proportions (mean +/- SD) of IFN-gamma-single positive (conveniently called Th1), IL-4-single positive (Th2), and double-positive cells (Th0) in CD4+ PBL, and homologous cell populations in CD3+ PBL (Th1 type, Th2 type, and Th0 type cells) were 21.3 +/- 8.2%, 2.7 +/- 1.1%, 1.9 +/- 1.0%, 39.5 +/- 13.5%, 1.7 +/- 0.8%, and 1.8 +/- 1.0%, respectively. Percentages of Th1 and Th2 were roughly consistent with those reported previously. Proportions of Th1, Th2, Th1 type, and Th2 type cells were found to increase with the age, whereas there were no significant difference in sex at least in 20s. Furthermore, positive correlation was seen between Th1 and Th1 type (r = 0.79), Th2 and Th2 type (r = 0.87), and Th0 and Th0 type (r = 0.86). Frequencies of these subsets in each donor were maintained at substantially the same levels for at least 3 months, suggesting existence of particular and stable Th1/Th2 balance among healthy individuals. As reported, 6 patients with atopic dermatitis examined in this study showed significantly lower frequencies of Th1 (11.0 +/- 2.5%) as compared with healthy donors (p < 0.01), implying usefulness of the immune test.
Adult↗
Distinct roles for DH and PH domains in the Lbc oncogene.
Members of the Dbl-homology (DH) family of proteins promote guanine nucleotide exchange on Rho GTPases. Lbc, which specifically acts on Rho but not Rac or Cdc42, was isolated as a transforming oncogene and is composed of a DH and a Pleckstrin-homology (PH) domain. We show here that the Lbc DH domain alone is capable of stimulating new DNA synthesis in quiescent fibroblasts and Rho-dependent actin stress fiber assembly. However, the PH domain is required for subcellular localization of Lbc along actin stress fibers and for efficient transformation of NIH3T3 cells. The results show that, in contrast to other Dbl-homology proteins, the PH domain of Lbc is dispensable for activation of Rho in vivo. The PH domain-dependent subcellular localization of Lbc may, however, be important for growth factor activation of endogenous Lbc and for oncogenic transformation.
3T3 Cells↗
Promoter structure of the MxA gene that confers resistance to influenza virus.
The human MxA protein is one of the interferon-inducible proteins that inhibits multiplication of influenza virus and other viruses. To clarify the control mechanism of its expression, we prepared a series of mutant MxA promoters and identified a 30 nucleotides long cis-acting interferon-responsive element by transient transfection assay. Its nucleotide sequence is somewhat similar to that of ISRE (interferon-stimulated response element), suggesting that the regulation of MxA mRNA synthesis is under the control of some ISRE binding factor such as ISGF-3 (interferon-stimulated gene factor-3).
Antiviral Agents↗
Solution structure of midkine, a new heparin-binding growth factor.
Midkine (MK) is a 13 kDa heparin-binding polypeptide which enhances neurite outgrowth, neuronal cell survival and plasminogen activator activity. MK is structurally divided into two domains, and most of the biological activities are located on the C-terminal domain. The solution structures of the two domains were determined by NMR. Both domains consist of three antiparallel beta-strands, but the C-terminal domain has a long flexible hairpin loop where a heparin-binding consensus sequence is located. Basic residues on the beta-sheet of the C-terminal domain form another heparin-binding site. Measurement of NMR signals in the presence of a heparin oligosaccharides verified that multiple amino acids in the two sites participated in heparin binding. The MK dimer has been shown to be the active form, giving signals to endothelial cells and probably to neuronal cells. We present a head-to-head dimer model of MK. The model was supported by the results of cross-linking experiments using transglutaminase. The dimer has a fused heparin-binding site at the dimer interface of the C-terminal domain, and the heparin-binding sites on MK fit the sulfate group clusters on heparin. These features are consistent with the proposed stronger heparin-binding activity and biological activity of the dimer.
Amino Acid Sequence↗
Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6.
Gas6, a product of a growth arrest-specific gene 6, potentiates proliferation of vascular smooth muscle cells and prevents cell death of vascular smooth muscle cells. It has been also demonstrated that Gas6 is a ligand of receptor tyrosine kinases Axl, Sky, and Mer. Gas6 contains gamma-carboxyglutamic acid residues, which are found in some blood coagulation factors and mediate the interaction of the coagulation factors with negatively charged phospholipid. In this study, we clarified that Gas6 specifically bound to phosphatidylserine and the binding was dependent on Ca2+ and gamma-carboxyglutamic acid residues. Furthermore, we found that U937 cells, which express Gas6 receptor on their surfaces, adhered to phosphatidylserine-coated enzyme-linked immunosorbent assay (ELISA) plate only in the presence of Gas6 and Ca2+. U937 cells also bound to ELISA plate coated with phosphatidylinositol, but the binding was independent of Gas6 and Ca2+. On the other hand, U937 cells did not adhere to phosphatidylcholine- or phosphatidylethanolamine-coated ELISA plate even in the presence of Gas6 and Ca2+. These findings suggest that Gas6 may play a role in recognition of cells exposing phosphatidylserine on their surfaces by phagocytic cells, which is supposed to be one of the mechanisms for clearing dying cells.
Animals↗
Adrenergic control of the force-frequency and relaxation-frequency relations in patients with hypertrophic cardiomyopathy.
BACKGROUND: Exercise-induced enhancement of the force-frequency and relaxation-frequency relations has been studied in conscious animals but not in intact diseased human hearts. METHODS AND RESULTS: We evaluated left ventricular (LV) isovolumic contraction (dP/dt(max)) and relaxation (tau) during atrial pacing and dynamic exercise in 13 patients with nonobstructive hypertrophic cardiomyopathy (HCM) and 7 control subjects to investigate the influence of exercise on the force-frequency and relaxation-frequency relations. Group A consisted of 6 patients in whom the heart rate (HR)-dP/dt(max) relation was markedly enhanced during exercise (88+/-30%) compared with during pacing (34+/-15%). Group B consisted of 7 patients in whom the HR-dP/dt(max) relation showed similar enhancement during exercise (28+/-7%) and atrial pacing (28+/-11%). There was no difference in the HR-tau (derivative method [TD] and pressure half-time method [T(1/2)]) relation between pacing and exercise in groups A and B. Both the mean maximal wall thickness and the hypertrophy score in group B were greater than in group A (27+/-5 versus 19+/-2 mm and 7+/-1 versus 5+/-1 points, respectively; both P<.01). There was no difference in the LV peak systolic pressure, end-diastolic pressure, or the plasma level of catecholamines at baseline, at 50 W of exercise, and at peak pacing between groups A and B. The HR-dP/dt(max) relation in the control group was markedly enhanced during exercise (80+/-27%) compared with during pacing (32+/-14%). The HR-tau relation in the control group was enhanced during exercise (TD, 35+/-9%; T(1/2), 34+/-8%) compared with during pacing (TD, 12+/-7%; T(1/2), 14+/-7%). CONCLUSIONS: Exercise-induced enhancement of the relaxation-frequency relation was inhibited in all HCM patients, regardless of the degree of LV hypertrophy. The patients without exercise-induced enhancement of the force-frequency relation had more severe LV hypertrophy than the patients with the enhancement, indicating that the adrenergic control of the force-frequency relation may, at least in part, depend on the severity of LV hypertrophy or the stage of HCM.
Adult↗
Direct actions of anticholinesterases on the neuronal nicotinic acetylcholine receptor channels.
Recent studies have suggested that anticholinesterases including organophosphates and carbamates act directly on the nicotinic acetylcholine receptor (AChR) channel. We performed whole-cell and single-channel patch-clamp experiments to elucidate the mechanism of action of anticholinesterases on the nicotinic AChR in rat clonal phaeochromocytoma (PC12) cells. Neostigmine and carbaryl showed a biphasic effect; enhancement and suppression of carbachol-induced whole-cell currents. The currents induced by 100 microM carbachol was enhanced by the first co-application with 10 or 100 microM neostigmine, and the current was eventually suppressed below the control level during repeated co-applications. The decay phase of current was accelerated by neostigmine. Carbaryl at 0.1 microM greatly potentiated the carbachol-induced current, and at higher concentrations (0.3-3 microM), current was suppressed. In single-channel experiments, these compounds increased the short closures or gaps during channel opening without changing the single-channel conductance. Mean open time and burst duration were decreased in the presence of neostigmine and carbaryl. These results indicate that neostigmine and carbaryl directly block the nicotinic AChR channel.
Acetylcholine↗
Misery perfusion with preserved vascular reactivity in Alzheimer's disease.
To elucidate the hemodynamic pathophysiology underlying Alzheimer's disease (AD), cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction fraction (OEF) were measured with positron emission tomography in 10 patients with probable AD and in 20 age-matched normal volunteers. By the 15O intravenous bolus injection method, CBF was measured during resting state, CO2 inhalation (hypercapnia) and hyperventilation (hypocapnia), and the vascular reactivity (VR) was estimated by comparing the CBF changes (delta CBF%/PaCO2 mmHg) in the hyper- or hypocapnic to the resting state. By the 15O2 single-breath method or 15O steady-state method, CMRO2 and OEF were measured during resting state. Based on 26 regions of interest, local CBF, CMRO2 and OEF were compared statistically between the two groups. As compared with the control group, the mean CBF and CMRO2 decreased to as low as 77.0% and 88.4% of the normal values, respectively, while the mean OEF increased by 12.1% (p < 0.05) in AD patients. These changes were most pronounced in the supramarginal and superior temporal gyri. There was no focal change in VR in the AD group, and no significant difference was seen in VR to either hyper- or hypocapnia between AD and control groups. The results may suggest a vascular involvement, possibly at the capillary level, that might cause a relative misery perfusion syndrome accompanied by preserved vascular reactivity in AD.
Adult↗
Dynamic FDG-PET study in probable Alzheimer's disease.
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Adult↗
G-proteins are involved in riluzole inhibition of high voltage-activated calcium channels in rat dorsal root ganglion neurons.
Effects of riluzole on high voltage-activated (HVA) calcium channels of rat dorsal root ganglion neurons were studied using the whole-cell patch-clamp technique. Riluzole at 30 microM inhibited the HVA currents. The onset and offset of riluzole inhibitory effect were slow usually taking more than 3 min. Riluzole inhibition of the HVA currents was abolished and partially reduced by addition of 500 microM GDP-beta-S and 1 mM N-ethylmaleimide, respectively, to the pipette solution. Pre-treatment with pertussis toxin or application of depolarizing pre-pulses did not affect riluzole's inhibitory effect on the HVA currents. Riluzole inhibition of the HVA currents was also blocked by internal application of 50 microg/ml protein kinase A inhibitory peptide. It was concluded that pertussis toxin-insensitive G-proteins and protein kinase A may be involved in riluzole inhibition of the HVA currents.
Animals↗