[Shprintzen syndrome].
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Abnormalities, Multiple↗
Biomedical subjects
S Yano
Publications and source records attributed to S Yano.
Hypercalcemia induced by metastatic bone cancer in a patient with chronic renal failure.
We present a diagnostically challenging case of hypercalcemia in a 50-year-old Japanese woman with chronic renal failure due to chronic interstitial nephritis. She had a history of a radical mastectomy for breast cancer at the age of 30. Despite her chronic renal failure, serum levels of calcium and alkaline phosphatase were abnormally high, and levels of intact parathyroid hormone and of parathyroid hormone-related protein were undetectable on repeated assays. Bone scintigram revealed multiple hot lesions in the ribs, which were suggestive of bone metastases of breast cancer. After treatment with tamoxifen citrate was initiated, her serum calcium levels returned to the normal range and hot lesions were no longer evident on bone scintigraphy in 14 months. Thus, our patient's hypercalcemia was considered to be related to bone metastases of breast cancer. Physicians should be aware of existence of malignancy in the patient with chronic renal failure and hypercalcemia.
Alkaline Phosphatase↗
Four cases of anti-myeloperoxidase antibody-related rapidly progressive glomerulonephritis during the course of idiopathic pulmonary fibrosis.
We report here 4 cases of rapidly progressive glomerulonephritis (RPGN) which developed during the management of idiopathic pulmonary fibrosis. In each patient, pulmonary disease preceded the onset of nephritis by 1 to 6 years. All patients had a high titer of serum autoantibodies against myeloperoxidase (MPO-ANCA) when the diagnosis of RPGN was made. Although the association of pulmonary fibrosis with ANCA-related glomerulonephritis has been occasionally described in the past literature, the sequence of pulmonary and renal injury has not been well defined. The present report demonstrates that idiopathic pulmonary fibrosis exists as a preceding condition in some patients with MPO-ANCA-related nephritis.
Aged↗
Acetaminophen-induced immunosuppression associated with hepatotoxicity in mice.
We investigated the influence of acetaminophen (APAP), an analgesic and hepatotoxic agent, on the immune system in mice. The activity of serum glutamic-pyruvic transaminase was markedly increased by about 200 fold compared to that of the vehicle control following intraperitoneal injection of 400 mg/kg of APAP. In vivo antibody-producing responses to SRBC was significantly inhibited by APAP in a dose-dependent manner, while in vivo T cell-independent antibody-producing responses to TNP-Ficoll was not inhibited. The addition of thymocytes from APAP-treated mice suppressed the response to SRBC in vitro. Thymocyte blastogenesis following mitogenic stimulation with concanavalin A was also inhibited by injection of APAP. The delayed-type hypersensitivity response and mixed lymphocyte reaction, which are used to evaluate cell-mediated immunity, were also significantly reduced after treatment with APAP. These results indicate that APAP suppresses the humoral and cell-mediated immune responses at a dose that causes liver injury.
Acetaminophen↗
[Effects of anxiolytics on hemodynamic responses to acute microgravity environment].
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Animals↗
Apoptosis induction of human lung cancer cell line in multicellular heterospheroids with humanized antiganglioside GM2 monoclonal antibody.
The chimeric antiganglioside GM2 monoclonal antibody (MAb) KM966, which showed high effector functions such as complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC), potently suppressed growth and metastases of GM2-positive human cancer cells inoculated into mice. To further improve the therapeutic efficacy of the anti-GM2 MAb in humans, we constructed a humanized anti-GM2 MAb, KM8969. The humanized KM8969 was more efficient in supporting ADCC against GM2-positive human cancer cell lines than the chimeric KM966, whereas complement-dependent cytotoxicity was slightly reduced in the humanized KM8969. In addition, the humanized KM8969 was shown to exert potent ADCC mediated by both lymphocytes and monocytes. To investigate the effect of the humanized KM8969 on the biological function of GM2 in the condition physiologically mimicking formation and growth of cancer masses, the heterospheroids composed of normal human dermal fibroblasts and GM2-positive human lung cancer cells were developed. Interestingly, the humanized KM8969 gave rise to growth inhibition of heterospheroids without dependence of the effector functions. Morphological and immunocytochemical analysis suggested that the inhibitory effect was due to the apoptosis of GM2-positive cancer cells in the heterospheroids. The result indicates that GM2 captured by the antibody on the cell surface loses its physiological function that plays a critical role in maintaining the three-dimensional growth of cancer cells in contact with its own cells or other type of cells in a microenvironment. The humanized KM8969, which can destroy the cancer cells via blocking functional GM2 on the cell surface as well as the effector functions, would have extraordinary potential in human cancer therapy.
Animals↗
Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine under anaerobic conditions by reductively activated nitro 5-deazaflavin derivatives.
Electrolytically reduced 6- and 8-nitro-5-deazaflavin derivatives have been found to interact to react specifically with guanine base by means of cyclic voltammetry. Electrolytic reductions of 6- and 8-nitro-5-deazaflavin derivatives in the presence of the 2'-deoxyguanosine under anaerobic conditions resulted in prominent formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine.
8-Hydroxy-2'-Deoxyguanosine↗
High extracellular calcium inhibits osteoclast-like cell formation by directly acting on the calcium-sensing receptor existing in osteoclast precursor cells.
Although it has recently been suggested that high extracellular calcium ([Ca(2+)](e)) inhibits osteoclast function via a calcium-sensing receptor (CaSR) in mature osteoclasts, the role of CaSR in the regulation of osteoclast formation remains unknown. The present study was performed to investigate whether osteoclast precursor cells possess CaSR and to clarify the possible role of CaSR in the regulation of osteoclast formation. Immunocytochemistry detected CaSR in osteoclast precursor cells derived from spleen cells as well as in osteoblastic MC3T3-E1 cells. The use of reverse-transcription polymerase chain reaction (RT-PCR) with CaSR-specific primers, followed by nucleotide sequencing of the amplified products, also identified CaSR transcripts in osteoclast precursor cells derived from spleen cells as well as in MC3T3-E1 cells. High [Ca(2+)](e) (3 to 5 mM) concentration dependently inhibited 1,25(OH)2D3- or human parathyroid hormone (hPTH) (1-34)-induced osteoclast-like cell (Ocl) formation from osteoclast precursor cells derived from spleen cells. Further, the CaSR agonist neomycin also concentration dependently inhibited 1,25(OH)2D3- or hPTH(1-34)-induced Ocl formation. Moreover, a calcimimetic which mimics or potentiates the effects of [Ca(2+)](e) at the CaSR NPS R-467 (1-100 microM) concentration dependently inhibited Ocl formation stimulated by 1,25(OH)2D3 or hPTH(1-34). These findings first demonstrated that osteoclast precursor cells possess CaSR very similar, if not identical, to those in the parathyroid and kidney. Furthermore, the CaSR in osteoclast precursor cells could play a key role in regulating Ocl formation by sensing local changes in [Ca(2+)](e) at the resorptive sites.
Animals↗
Combined therapy with anti-P-glycoprotein antibody and macrophage colony-stimulating factor gene transduction for multiorgan metastases of multidrug-resistant human small cell lung cancer in NK cell-depleted SCID mice.
Our aim was to determine the antimetastatic potential of anti-P-glycoprotein (P-gp) antibodies (Abs) against multidrug-resistant (MDR) human small cell lung cancer (SCLC) cells expressing P-gp. Human SCLC cells H69 (P-gp negative) and its etoposide-resistant variant H69/YP (P-gp positive) were used. H69 and H69/VP cells injected i.v. metastasized to the liver, kidneys and systemic lymph nodes of NK cell-depleted severe combined immunodeficient (SCID) mice. H69/VP cells, but not H69 cells, were resistant to treatments with vindesine. Treatment with mouse-human chimeric anti-P-gp Ab (MH162) and its mouse counterpart (MRK-16) reduced metastasis of H69/VP cells in various organs and prolonged the survival of tumor-bearing mice, although they were less effective if injected at late times (after 28 days). Treatment with another mouse anti-Pgp Ab, MRK-17, was effective only against liver metastasis. MH162 and MRK-16 efficiently induced Ab-dependent cellular cytotoxicity (ADCC) by peritoneal macrophages against H69/VP cells in vitro, but MRK-17 was less effective, in accordance with their in vivo antimetastatic potential. Gene transfection of macrophage colony-stimulating factor (M-CSF) into H69/VP cells to augment macrophage-mediated ADCC resulted in inhibition of metastasis to the liver and lymph nodes, but not kidneys. Combined treatment with a low dose of MRK-16 completely cured metastasis of M-CSF transfectant, but not of the mock transfectant. Our findings suggest that while anti-P-gp Abs had antimetastatic potential against SCLC cells expressing P-gp, combined treatment with M-CSF gene transduction to augment the therapeutic efficacy of anti-P-gp Abs may be beneficial for eradicating metastatic MDR SCLC in humans.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Purification and characterization of thermostable aspartase from Bacillus sp. YM55-1.
A thermostable aspartase was purified from a thermophile Bacillus sp. YM55-1 and characterized in terms of activity and stability. The enzyme was isolated by a 5-min heat treatment at 75 degrees C in the presence of 11% (w/v) ammonium sulfate and 100 mM aspartate, followed by Q-Sepharose anion-exchange and AF-Red Toyopearl chromatographies. The native molecular weight of aspartase determined by gel filtration was about 200,000, and this enzyme was composed of four identical monomers with molecular weights of 51,000 determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Unlike Escherichia coli aspartase, the enzyme was not activated by the presence of magnesium ion at alkaline pH. At the optimum pH, the Km and Vmax were 28.5 mM and 700 units/mg at 30 degrees C and 32.0 mM and 2200 units/mg at 55 degrees C, respectively. The specific activity was four and three times higher than those of E. coli and Pseudomonas fluorescens enzymes at 30 degrees C, respectively. Eighty percent of the activity was retained after a 60-min incubation at 55 degrees C, and the enzyme was also resistant to chemical denaturants; 80% of the initial specific activity was detected in assay mixtures containing 1.0 M guanidine hydrochloride. The purified enzyme shared a high sequence homology in the N-terminal region with aspartases from other organisms.
Amino Acid Sequence↗
Substrate recognition by Ca2+/Calmodulin-dependent protein kinase kinase. Role of the arg-pro-rich insert domain.
Mammalian Ca2+/CaM-dependent protein kinase kinase (CaM-KK) has been identified and cloned as an activator for two kinases, CaM kinase I (CaM-KI) and CaM kinase IV (CaM-KIV), and a recent report (Yano, S., Tokumitsu, H., and Soderling, T. R. (1998) Nature 396, 584-587) demonstrates that CaM-KK can also activate and phosphorylate protein kinase B (PKB). In this study, we identify a CaM-KK from Caenorhabditis elegans, and comparison of its sequence with the mammalian CaM-KK alpha and beta shows a unique Arg-Pro (RP)-rich insert in their catalytic domains relative to other protein kinases. Deletion of the RP-domain resulted in complete loss of CaM-KIV activation activity and physical interaction of CaM-KK with glutathione S-transferase-CaM-KIV (T196A). However, CaM-KK autophosphorylation and phosphorylation of a synthetic peptide substrate were normal in the RP-domain mutant. Site-directed mutagenesis of three conserved Arg in the RP- domain of CaM-KK confirmed that these positive charges are important for CaM-KIV activation. The RP- domain deletion mutant also failed to fully activate and phosphorylate CaM-KI, but this mutant was indistinguishable from wild-type CaM-KK for the phosphorylation and activation of PKB. These results indicate that the RP-domain in CaM-KK is critical for recognition of downstream CaM-kinases but not for its catalytic activity (i.e. autophosphorylation) and PKB activation.
Amino Acid Sequence↗
Monocyte chemoattractant protein-1 gene modification of multidrug-resistant human lung cancer enhances antimetastatic effect of therapy with anti-P-glycoprotein antibody in SCID mice.
Distant metastases and multidrug resistance are critical problems in the therapy of human small cell lung cancer (SCLC). In this study, we investigated whether transduction of the monocyte chemoattractant protein-1 (MCP-1) gene into multidrug-resistant (MDR) human lung cancer cells affected the formation of metastases or their inhibition by the anti-P-glycoprotein (P-gp) monoclonal antibody (MAb) MRK16. MDR human SCLC (H69/VP) cells were transduced with the human MCP-1 gene inserted into the expression vector BCMGSNeo. MCP-1 gene transduction had no effect on drug sensitivity, the expression of surface antigens or the in vitro proliferation of H69/VP cells. Using the metastatic model of NK cell-depleted SCID mice, H69/VP cells transduced with the MCP-1 gene were inoculated intravenously (i.v.) and formed metastatic colonies in the liver, kidneys and lymph nodes, similar to those formed by parent or mock-transduced cells. However, systemic treatment of the mice with MRK16 reduced the metastases of H69/VP cells in the liver, kidneys and lymph nodes, and was significantly more effective in inhibiting the metastases of MCP-1 producing H69/VP than those of mock-transduced cells. MCP-1 gene transduction significantly prolonged the survival of tumor-bearing mice treated with MRK16. Our findings suggest that local production of MCP-1 in the tumor site increases the anti-P-gp antibody-dependent cell-mediated cytotoxicity, and the MCP-1 gene-induced modification of MDR human SCLC cells thereby enhances the antimetastatic effect of therapy with anti-P-gp antibody. Thus, the accumulation of effector cells in the tumor site is a very important factor in the therapy using the anti-P-gp antibody.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Heterogeneity of multiorgan metastases of human lung cancer cells genetically engineered to produce cytokines and reversal using chimeric monoclonal antibodies in natural killer cell-depleted severe combined immunodeficient mice.
Lung cancer is a major cause of cancer deaths, most of which can be attributed to distant multiorgan metastases. To examine the cellular and molecular mechanisms of lung cancer metastasis to distant organs, we have established novel models of human lung cancer (small cell and non-small cell lung cancer) metastasis in natural killer cell-depleted severe combined immunodeficient (SCID) mice. We investigated whether local production of the cytokines responsible for regulation of macrophage function at tumor growth sites affects the pattern of lung cancer metastasis in distant organs. Several lung cancer cell lines were genetically engineered to produce human macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (MCP-1), and their metastatic potentials were assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for the liver and lymph nodes, but not the kidneys. In contrast, MCP-1 gene-modified lung cancer cells and their parent cells had identical metastatic potentials. These findings indicate a possible role for cytokines and suggest that lung cancer has metastatic heterogeneity. Examining ways of controlling human lung cancer metastases, we investigated the antimetastatic effect of chimeric monoclonal antibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162 and KM966, respectively). Both MAbs, when given on days 2 and 7, inhibited the development of distant metastases of lung cancer in a dose-dependent fashion. Combined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transduction caused complete inhibition of metastasis of H69/VP cells. The antimetastatic effect of these MAbs in vivo was mainly due to an antibody-dependent cell-mediated cytotoxicity reaction mediated by mouse macrophages. These findings suggest that the mouse-human chimeric MAb in combination with cytokine gene transduction may be useful for the eradication of lung cancer metastases in humans.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Associations between different status of myocardial ischemia and ischemia-related negative or positive epicardial U-waves: observations during coronary angioplasty.
This study examined the relationships between the polarity of the U wave on intracoronary electrocardiogram (ECG) and the status of myocardial ischemia during angioplasty. The ECG features of ischemia-related U waves were also evaluated. Among 63 patients with intracoronary ECGs adequate for analysis of U waves, there were 26 patients showing a change of the U wave to a negative direction and 18 patients showing a change to a positive direction from baseline to coronary occlusion. Among these patients, 10 of the former showed a distinct change in polarity of the U wave from positive to negative (group A), and 7 of the latter patients showed the opposite change (group B). Patients in group B had a higher incidence of prior myocardial infarction (86% vs 30%; P < .05), presence of an abnormal Q wave on intracoronary ECG (71% vs 20%; P < .05), poor wall motion in the angioplasty-related area (100% vs 30%; P < .01), and lower left ventricular ejection fraction (55.7% +/-8.1% vs 66.6% +/- 4.5%; P < .01) than patients in group A. The remaining patients (other than groups A and B) showing U wave change in a negative (n = 16) or positive (n = 11) direction presented with similar features to those in groups A or B, respectively. The ECG features of several types of ischemia-related U wave were determined by analysis of intracoronary ECG obtained from the patients in groups A and B. In group A, the Bazett-corrected Q (positive U) interval measured at baseline (myocardial state; near normal) was significantly shorter than the Q-(negative U) interval measured during coronary occlusion (acute ischemia) (0.518 +/- 0.031 s vs 0.579 +/- 0.046 s; P < .01). In group B, the Q-(negative U) interval measured at baseline (chronic ischemia) was longer than the Q-(positive U) interval measured during angioplasty (acute-on-chronic ischemia) (0.582 +/- 0.034 s vs 0.501 +/- 0.027 s; P < .001). Thus, intracoronary ECG recorded during angioplasty in the present study revealed physiologic U wave, two types ("acute" and "chronic") of ischemia-related negative and one type ("pseudonormal") of ischemia-related positive U waves, each of which appeared in a different status of myocardial ischemia and possessed characteristic ECG features in its appearance.
Adult↗
The relevance of TH1 and TH2 cells in immediate and nonimmediate reactions to gelatin-containing vaccine.
BACKGROUND: The immune mechanism of gelatin allergy, especially the participation of TH1 and TH2 cells and their cytokine secretion, has not been investigated. OBJECTIVE: We investigated the characteristics of T lymphocytes from patients allergic to gelatin-containing vaccine by secondary in vitro stimulation of circulating mononuclear cells with gelatin. METHODS: We studied 8 children with a history of immediate-type reactions and 8 with nonimmediate-type reactions after inoculation of gelatin-containing vaccine. The expression of IFN-gamma (TH1 ), IL-2 (TH1 ), IL-4 (TH2 ), and IL-13 (TH2 ) mRNA was examined semiquantitatively by using a reverse transcriptase PCR. IgE antibody to bovine gelatin was measured with the fluorometric ELISA system, and gelatin-specific T-cell responses were detected by an in vitro lymphocyte proliferation assay. RESULTS: Patients with an immediate reaction all had gelatin-specific IgE antibody, whereas others did not. However, all patients exhibited positive T-lymphocyte responses specific to gelatin. Lymphocytes from subjects with nonimmediate-type reactions generally expressed very weak or sometimes no IFN-gamma, IL-2, or IL-13 genes and especially no IL-4 gene. On the other hand, the lymphocytes of subjects with immediate-type reactions significantly expressed not only IL-4 and IL-13 but also IFN-gamma and IL-2 mRNA. CONCLUSION: Our observations suggest that both gelatin-specific TH2 and TH1 responses are involved in the pathogenesis of the immediate reaction to gelatin. The gelatin-specific IL-4 and/or IL-13 responses consistently observed in patients with an immediate reaction may be associated with the production of gelatin-specific IgE antibody.
Animals↗
A case of cimetidine-induced acute tubulointerstitial nephritis associated with antineutrophil cytoplasmic antibody.
We present a case of acute tubulointerstitial nephritis (ATIN) that developed in a 63-year-old man who had been taking cimetidine for treatment of a gastric ulcer. The constellation of clinical, laboratory, and histopathologic findings suggested drug-induced ATIN. Of interest, the patient had antineutrophil cytoplasmic antibody (ANCA) in his sera, reactive with myeloperoxidase, elastase, and lactoferrin. Prominent renal histological features included marked plasmacyte infiltration into the renal interstitium. Withdrawal of cimetidine resulted in complete resolution of renal findings, and the titers of ANCA concomitantly declined. Thus, cimetidine may have played a causative role in the development of ANCA-associated ATIN.
Anti-Ulcer Agents↗
Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa.
We have previously elucidated the opiate-like action of mitragynine, an active principle isolated from the Thai medicinal plant Mitragyna speciosa. In the present study, effects of the related compound, mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and on its binding affinity in the guinea pig brain membranes were studied. Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum and mouse vas deferens contractions in a concentration-dependent manner. In the ileum, the effective concentration is in an nM order, being nearly equivalent to reported concentrations of the micro-opioid receptor agonist [D-Ala2, Met-Phe4, Gly-ol5] enkephalin (DAMGO), and is 100- and 20-fold smaller than those of mitragynine and morphine, respectively. In the vas deferens, it is 35-fold smaller than that of morphine. The inhibitory action of mitragynine pseudoindoxyl in the ileum was antagonized by the non-selective opioid receptor antagonist naloxone and the micro-receptor antagonist naloxonazine. It was also antagonized by the delta-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at micro- and delta-receptors, respectively. However, the affinity at kappa-receptors was negligible. The present study demonstrates that mitragynine pseudoindoxyl, a novel alkaloid structurally different from other opioid agonists, acts on opioid receptors, leading to a potent inhibition of electrically stimulated contraction in the ileum through the micro-receptors and in mouse vas deferens through delta-receptors.
Analgesics↗
Bronchocentric granulomatosis due to Aspergillus terreus in an immunocompetent and non-asthmatic woman.
This is the first report of bronchocentric granulomatosis due to Aspergillus terreus in a healthy and non-asthmatic 74-year-old Japanese woman. Following identification of the fungus, oral itraconazole therapy was begun after intrabronchial infusion of amphotericin B. No recurrence has occurred after treatment for 24 months. We should consider the possibility of bronchocentric granulomatosis including Aspergillus terreus, when an intrabronchial lesion is found even in a healthy and non-asthmatic person. Oral itraconazole after intrabronchial infusion of amphotericin B seems to be effective in such cases.
Aged↗