Endoscopic treatment of massive lower GI hemorrhage in two patients with ulcerative colitis.
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Adult↗
Biomedical subjects
S Nagao
Publications and source records attributed to S Nagao.
Long-term activation of the glutamatergic system associated with N-methyl-D-aspartate receptors after postischemic hypothermia in gerbils.
OBJECTIVE: The objective of this study was to investigate whether hypothermia would suppress secondary damage in the chronic postischemic stage, in terms of glutamate excitotoxicity. METHODS: Gerbils underwent 5 minutes of ischemia via bilateral common carotid artery occlusion. Seven groups were studied, as follows: 1) ischemia without treatment group; 2) intraischemic hypothermia group; 3) postischemic hypothermia group (32 degrees C for 4 h); 4) MK-801 treatment group (2 mg/kg, every other day for 1 mo); 5) postischemic hypothermia with MK-801 treatment for 1 week group (2 mg/kg, every other day); 6) postischemic hypothermia with MK-801 treatment for 1 month group (2 mg/kg, every other day); and 7) sham-treated control group. One month after ischemia, histological changes in hippocampal CA1 neurons (assessed using hematoxylin and eosin staining) and memory function (assessed using an eight-arm radial maze) were studied. Extracellular glutamate concentrations were monitored by microdialysis during ischemia and hypothermia. Staining of microglia was performed 1 week and 1 month after ischemia. RESULTS: MK-801 alone, postischemic hypothermia alone, and postischemic hypothermia with MK-801 treatment for 1 week failed to prevent ischemic neuronal damage and memory function decreases 1 month after the insult (P < 0.05 versus control). However, the postischemic hypothermia with MK-801 treatment for 1 month group exhibited significant protective effects (not significant [P > 0.05] compared with the control group). Extracellular glutamate levels for the intraischemic hypothermia group were significantly low, compared with the postischemic hypothermia group. There was no microglial activation in the postischemic hypothermia at 1 week and 1 month after ischemia groups. CONCLUSION: Postischemic hypothermia and long-term intermittent administration of MK-801 demonstrated significant neuronal protection, indicating that long-term glutamatergic activation, with changes in N-methyl-D-aspartate receptors, plays a role in neuronal damage in the chronic postischemic stage.
Animals↗
Incidence of mutation and deletion in topoisomerase II alpha mRNA of etoposide and mAMSA-resistant cell lines.
The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to VP-16 (etoposide) or mAMSA (m-amsacrine). Subsequently, a population of cells from each subline was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. Finally, 66 sublines were picked up. The frequency and nature of mutations in the topoisomerase II gene in the drug-selected cell lines were evaluated. In order to screen a large number of cell lines, an RNAse protection assay was developed and mismatches were observed in 13.6% of resistant cell lines (12% of resistant cell lines exposed to lower drug concentrations and 18.8% of resistant cell lines exposed to higher drug concentrations). Some of these mutations are located in vital regions of topoisomerase II (phosphorylation sites in the C-terminal or N-terminal, and nuclear localizing signal of topoisomerase II). Our findings suggest that mutations of topoisomerase II gene are an important and frequent mechanism of resistance to topoisomerase II inhibitors.
Amsacrine↗
Expression of drug resistance genes in VP-16 and mAMSA-selected human carcinoma cells.
The cell lines described in the present study were isolated as part of an effort to understand resistance to topoisomerase (topo) II inhibitors. To that end, 50 sublines were isolated from four human breast cancer cell lines, i.e., MCF-7, T47D, MDA-MB-231, and ZR-75B. As an initial step, a concentration that would be lethal to the majority of cells (IC99) was selected for both VP-16 and mAMSA, for each cell line. The identification of an increasing number of putative drug resistance-related proteins provided the opportunity to examine expression of the corresponding genes in the selected cell lines. Northern blot analysis revealed different responses to the selecting agents in the different cell lines. Previous studies examining expression of multidrug resistance (MDR)-1 in resistant cell lines had found undetectable levels in all cells. In the ZR-75B sublines, increased expression of MDR-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) was observed, and when the relative levels of overexpression were compared, a high correlation was found. In contrast, increased expression of MRP was observed in some of the MDA-MB-231 sublines, without a concomitant increase in cMOAT expression. Finally, in both T47D and MCF-7 sublines, increased expression of cMOAT or MRP was observed infrequently, and where it occurred, was of a much smaller magnitude. In the analysis of expression of MRP, the highest levels were found in the ZR-75B and MDA-MB-231 sublines, with lower levels in the MCF-7 and T47D clones. Similarly, differences in the expression of topo IIalpha were observed among the sublines. Although the differences in expression appear to depend on the parental cell line from which the resistant sublines were derived, a strong correlation was observed between the expression of MRP and the levels of topo IIalpha. Cell lines with low levels of MRP had lower levels of topo IIalpha, while those with high levels of MRP maintained higher levels of topo IIalpha. While a reduced topo IIalpha level was common, there did not appear to be a compensating increase in the expression of topo IIbeta or topo I or casein kinase (CK) IIalpha in any of the cell lines. While the possibility that such compensation could occur has been discussed and even reported in some cell lines, such an adaptation was not observed in the present study, suggesting that it is not common.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Hypophosphorylation of topoisomerase IIalpha in etoposide (VP-16)-resistant human carcinoma cell lines associated with carboxy-terminal truncation.
Topoisomerase IIalpha is a target for many chemotherapeutic agents in clinical use. To define mechanisms of resistance and regions crucial for the function of topoisomerase IIalpha, drug-resistant cell lines have been isolated following exposure to topoisomerase II poisons. Two resistant sublines, T47D-VP and MCF-7-VP, were isolated from human carcinoma cell lines following exposure to 300 or 500 ng / ml etoposide (VP-16). Cytotoxicity studies confirmed resistance to etoposide and other topoisomerase II poisons. KCl-sodium dodecyl sulfate (K-SDS) precipitation assays using intact cells showed reduced DNA-topoisomerase II complex formation following VP-16 or amsacrine (m-AMSA). RNAse protection analysis identified a deletion of 200 base pairs in the topoisomerase IIalpha cDNA of T47D-VP and rising dbl quote, left (low)AA insertion" in the topoisomerase IIalpha cDNA of MCF-7-VP. Reduced topoisomerase IIalpha mRNA and protein levels were observed in both cell lines. It was somewhat surprising to find that nuclear extracts from T47D-VP and MCF-7-VP cells had comparable topoisomerase II activity to that of parental cells. Analysis of the extent of phosphorylation demonstrated that topoisomerase IIalpha from the resistant cells was relatively hypophosphorylated compared to that of parental cells. In these cell lines, hypophosphorylation secondary to loss of a portion of the C-terminal domain of topoisomerase IIalpha mediated the restored activity, despite a fall in topoisomerase IIalpha mRNA and protein, and this resulted in cross resistance to topoisomerase II poisons.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Antiproliferative constituents in the plant 8. Seeds of Rhynchosia volubilis.
The MeOH extract of the seeds of Rhynchosia volubilis (Leguminosae) showed antiproliferative activity against human gastric adenocarcinoma [MK-1, 50% growth inhibition (GI50): 25 microg/ml], human uterus carcinoma (HeLa, GI50: 30 microg/ml), and murine melanoma (B16F10, GI50: 8 microg/ml) cells. Bioactivity-guided fractionation resulted in the isolation of gallic acid methylester (1), gallic acid (2), 7-O-galloylcatechin (3), 1,6-di-O-galloylglucose (4), 1-O-galloylglucose (5), and trigalloylgallic acid (6), and their antiproliferative activity was estimated. All showed much stronger inhibition against B16F10 cell growth than against HeLa and MK-1 cell growth. Compound 2 and its tetramer (6) with a free carboxyl group showed higher activity than those which did not have a free carboxyl group. In relation to the gallic acid tetramer (6), two gallic acid dimers (ellagic acid and dehydrodigallic acid) and trimers (tergallic acid dilactone and flavogallonic acid dilactone) were tested for their activity, and compared with those of the isolates.
Animals↗
Adenovirus-mediated gene transfer into tumors: evaluation of direct readministration of an adenoviral vector into subcutaneous tumors of immunocompetent mice.
Because systemic administration of adenoviruses appears to be limited by their immunogenicity, we examined the feasibility of intratumoral administration of adenoviruses. Direct intratumoral administration of adenoviruses resulted in efficient but transient transgene expression. When adenoviruses were readministered directly into tumors, re-expression of the transgene was achieved. Transgene expression induced by the adenoviral readministration was, however, markedly weaker than that induced by the initial administration. Furthermore, intratumoral readministration of adenoviruses elicited profound humoral and cellular immune responses to adenoviruses. These results may have important implications for efficacy considerations when adenoviral vectors are used for clinical cancer gene therapy.
Adenoviridae↗
[Chemotherapy for gliomas based on the expression levels of drug resistant genes].
Drug resistance, which often occurs during chemotherapy, is still a great obstacle to the success of human malignancy treatment. Among many possible mechanisms of drug resistance (biological, biochemical, kinetic or pharmacological), both typical and atypical multidrug-resistance (MDR) have been extensively studied. We picked up MDR-1, MXR, MRP1, MRP2, TopoII alpha, MGMT, and GST-pi as drug-resistant gene, based on experimental data and previous reports. Expression of these genes were measured in 14 malignant glioma specimens by reverse transcription polymerase chain reaction assay. We chose anticancer drugs for each patient, based on results of drug resistant gene expression to acquire good response to drugs. Though our follow-up periods are not long enough to analyze the results of our chemotherapy, 78% (7/9) of our glioma patients who were treated with our chemotherapy are free from tumor progression. The assays, which measure the expression of drug resistant genes, are necessary to allow rapid detection of the drug-sensitivity to chemotherapy in malignant glioma patients.
Adult↗
Altered topoisomerase IIalpha and multidrug resistance-associated protein levels during drug selection: adaptations to increasing drug pressure.
To understand resistance to topoisomerase II inhibitors, we used four cancer cell lines (ZR-75B, MDA-MB-231, T47D, and MCF-7) and performed a single-step selection process to isolate 50 clones resistant to topoisomerase II inhibitors. Of these, 26 were isolated with VP-16 and 24 with mAMSA. Sixteen of these isolates (four from each cell line; two selected with VP-16 and two with mAMSA) were further exposed to higher drug concentrations. Characterization of the resistant sublines revealed the adaptation that occurs with increasing drug concentration during in-vitro selections. Reduced topoisomerase IIalpha mRNA level was observed in the majority of the initial isolates. This reduction was accompanied by a decrease in topoisomerase II activity. Other isolates showed increased levels of multidrug resistance-associated protein (MRP). With advancing resistance, MRP expression was increased further, concomitantly with some recovery in topoisomerase IIalpha expression and topoisomerase II activity. In these sublines, high levels of resistance were attained as a result of synergism between the reduced topoisomerase IIalpha levels and MRP overexpression. These results extend previous studies demonstrating how cellular adaptation to increasing drug pressure utilizes more than one mechanism. Reduced expression of topoisomerase IIalpha occurs early in the selection process. MRP overexpression can occur early or can help to confer high levels of resistance. In the latter case, MRP overexpression allows some recovery of topoisomerase II activity without loss of high drug resistance.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A novel mutation of the McLeod syndrome gene in a Japanese family.
McLeod syndrome is a rare X-linked hematologic and neuromuscular disorder manifested by chorea, myopathy, cardiomyopathy, areflexia, hyperCKemia, and acanthocytosis. Only four mutations have been reported in the gene responsible for McLeod syndrome. We report a novel gene mutation in a Japanese family. Direct sequencing of the PCR-amplified genomic DNA revealed the mutation was a single C-nucleotide insertion at codon 151 in exon 2 of the XK gene, which resulted in a 3'-frameshift. Study of family members revealed that the patient's mother was a manifesting carrier heterozygous for this mutation.
DNA Mutational Analysis↗
Immunomodulation with FK506 around the time of intravenous re-administration of an adenoviral vector facilitates gene transfer into primed rat liver.
Although adenoviruses are an attractive vehicle for gene transfer into tissues including various tumors, in vivo adenoviral administration elicits a neutralizing antibody response which eliminates or substantially reduces the efficacy of subsequent treatments. Transiently immunosuppressive strategies at the time of initial adenoviral exposure have shown to prevent the formation of neutralizing antibodies and permit the successful adenoviral readministration in animals. Initial treatment in humans may, however, correspond to adenoviral readministration into animals, because the exposure to wild-type adenoviruses is common in humans. In the present study, we infused Adex1CAlacZ adenoviruses carrying the lacZ gene into the tail vein of rats, and examined whether a transient treatment with the immunosuppressant FK506 around the time of i.v. readministration of adenoviruses could induce the re-expression of the lacZ gene in animals primed with adenoviruses. Although i.v. infusion of adenoviruses carrying the lacZ gene resulted in transiently high levels of transgene expression in rat liver, i.v. reinfusion of adenoviruses failed to induce detectable levels of transgene expression. Conversely, when animals were treated transiently with FK506 around the time of adenoviral reinfusion, development of neutralizing antibodies and antigen-specific T cell proliferation in response to adenoviral reinfusion were significantly suppressed, and re-expression of the transgene was achievable.
Adenoviridae↗
Dynamic characteristics and adaptability of reflex eye movements of Fyn-kinase-deficient mice.
Fyn-kinase is expressed widely in the entire brain, including the cerebellum. Fyn-kinase-deficient mice are known to exhibit hypersensitivity to ethanol. To evaluate the cerebellar functions of Fyn-kinase, we examined the dynamic characteristics of the horizontal optokinetic response (HOKR) and vestibulo-ocular reflex (HVOR) and its adaptability in Fyn-kinase-deficient mice. The HOKR was induced by sinusoidal oscillation of a checkered screen and the HVOR was induced by sinusoidal oscillation of a turntable in darkness. The HOKR gains of mutant mice were higher than those of the wild-type mice, and the HVOR phases of mutant mice were less advanced than those of the wild-type mice. However, no difference was noted in the adaptability of the HOKR induced by 1 h of sustained screen oscillation between the mutant and wild-type mice. The cerebellar functions appear to be unaffected by Fyn-kinase knockout.
Animals↗
Subdural applications of NO scavenger or NO blocker to the cerebellum depress the adaptation of monkey post-saccadic smooth pursuit eye movements.
We examined pharmacologically whether cerebellar long-term depression (LTD) may play a role in the adaptation of smooth pursuit eye movements in two Macaca fuscata, which were trained to pursue a target moving in the horizontal plane in a 3 degrees step-10 deg/s ramp mode. The monkeys showed small catch-up saccades followed by 6-8 deg/s post-saccadic pursuit movements. Adaptation of the post-saccadic pursuit velocity was induced by repetition of acceleration of the target to 20 deg/s after the catch-up saccades. Injections of 0.1 mM hemoglobin or 20 mM NG-monomethyl-L-arginine solution into the subdural space above the paraflocculus-flocculus scarcely affected the post-saccadic pursuit velocity, but markedly depressed its adaptation. These observations suggest that cerebellar LTD may underlie the adaptation of smooth pursuit.
Animals↗
Effects of hypothermia on intracranial hemodynamics and ischemic brain damage-studies in the rat acute subdural hematoma model.
Brain ischemia is the leading pathophysiological mechanism in the development of secondary brain damage after subdural hematoma (SDH). Hypothermia has been used as the effective neuroprotective treatment in clinical and laboratory studies of ischemic brain injury. In this study, we have examined the rat acute SDH model to assess the effect of hypothermia upon intracranial hemodynamics and also upon ischemic brain injury 4 hours after the induction of hematoma. Moderate hypothermia (32 degrees C) did not affect the intracranial pressure nor cerebral perfusion pressure, and it significantly reduced cortical brain edema formation underneath the hematoma (80.88 +/- 0.17%; p < 0.01) compared with the normothermic control group (81.65 +/- 0.52%). This reduction in brain edema formation was comparable to the result of MK-801 (2 mg/kg) treatment (80.95 +/- 0.35%; p < 0.01). Ischemic brain damage detected by H-E staining was also significantly reduced in the hypothermia and MK-801 treated groups (59.1 +/- 12.3 mm3 and 66.4 +/- 13.8 mm3; p < 0.01 and p < 0.05) compared with the normothermic control group (86.6 +/- 20.7 mm3). In conclusion, the present study demonstrates that hypothermia is a potent neuroprotective method and an inhibition of the glutamate excitotoxic process may contribute the protective mechanisms of hypothermia in this rat acute SDH model.
Animals↗
Protective effect of mild hypothermia on symptomatic vasospasm: a preliminary report.
Mild hypothermia (32-34 degrees C of brain temperature) was used for brain protection in patients with progressive ischemic neurological deficits associated with severe cerebral vasospasm and who did not respond to medical treatment or intravascular angioplasty. Results showed that 2 of 3 patients in Hunt & Kosnik grade I to III and 2 patients who underwent delayed operation on day 5 and 9 each and had ischemic neurological deficits made good recovery with this treatment. Favourable outcome was obtained in 4 of 9 patients in grade IV and V. Mild hypothermia is thought to provide brain protection in critical ischemia due to severe cerebral vasospasm and can lengthen therapeutic time to employ angioplasty and intraarterial Papaverin infusion.
Brain Ischemia↗
Expression of DNA topoisomerase I, IIalpha, and IIbeta in human brain tumors.
We investigated the expression of DNA topoisomerase I (Topo I), IIalpha (Topo IIalpha), and IIbeta (Topo IIbeta) mRNA using reverse transcription-polymerase chain reaction (RT-PCR) assay in 31 human brain tumors, and examined the relationship between DNA topoisomerase mRNA expression and Topo IIalpha and MIB-1 positive index (PI) as a cell proliferation marker. Topo IIalpha mRNA was expressed in 11 of 31 cases, and Topo I and IIbeta were each expressed in 18 of 31 cases. A significant correlation was seen between the MIB-1 PI and Topo IIalpha PI (P < 0.001). The cases with overexpression of Topo IIalpha mRNA had significantly high MIB-1 and Topo IIalpha PI (P < 0.0001). There was no significant correlation between Topo I and IIbeta mRNA expression and MIB-1 PI. We concluded that it was useful as a cell proliferation marker to analyze the expression of Topo IIalpha mRNA using RT-PCR in human brain tumors.
Adult↗
DNA topoisomerase IIalpha protein and mRNA expression in intracranial meningiomas.
We examined the expression of DNA topoisomerase IIalpha (Topo IIalpha) immunohistochemically using a monoclonal antibody and compared its proliferative potential [MIB-1 labeling index (LI)] and recurrence to verify the possible influence of Topo IIalpha on the progress of meningiomas. The reverse transcription-polymerase chain reaction (RT-PCR) assay was also performed to evaluate the expression of Topo IIalpha mRNA. Formalin-fixed, paraffin-embedded tissue sections of 52 meningiomas (18 meningothelial types, 16 fibrous types, 4 transitional types, 4 psammomatous types, 1 angiomatous type, 1 secretory type, 5 atypical types, and 3 anaplastic types) were used for immunostaining. The Topo IIalpha labeling index (LI) was 1.4 +/- 1.9% (mean +/- SE) in benign meningiomas and 4.5 +/- 1.6% in atypical or anaplastic meningiomas, representing significant differences between them (P < 0.0001). RT-PCR assay revealed that Topo IIalpha mRNA expression was associated with Topo IIalpha LI. A significant correlation was seen between Topo IIalpha LI and MIB-1 LI (r = 0.517; P < 0.01). Recurrence was significantly more frequent in patients with more than 1.5% of Topo IIalpha LI than in those with 1.5% or less (P < 0.005). In conclusion, Topo IIalpha protein and mRNA expression correlated with clinical malignancy and the potential for predicting the regrowth of meningiomas.
Adult↗
Niravoline, a selective kappa-opioid receptor agonist effectively reduces elevated intracranial pressure.
To ascertain the effects of niravoline (RU 51599, a selective kappa-opioid receptor agonist) on elevated intracranial pressure with mass lesion, the authors experimentally induced intracranial hypertension in cats by progressive inflation of an extradural balloon with physiological saline at the constant rate of 0.5 ml/h for 2.5 h. After 2.5 h, inflation was discontinued, but the balloon remained inflated for an additional 3 h. Immediately after cessation of balloon inflation and while the balloon remained expanded, the control group (n = 8) received ringer's lactate solution only. In the treatment group (n = 8), each cat was treated with an intravenous administration of niravoline at a dose of 1.0 mg/kg immediately after the cessation of balloon inflation and every hour for 3 h in post-inflation period (three injections total). Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), electroencephalogram (EEG), pupil size, blood gasses and pH, plasma osmolality and electrolytes, and brain water content were studied in both groups. Compared with the untreated group, niravoline treatment produced significant decreases in ICP and significant increases in CPP at 1, 2, and 3 h post-inflation in the presence of an extradural mass lesion. Brain water content was significantly reduced both in the compressed and contralateral hemispheres following niravoline treatment. No significant changes were observed in plasma osmolality and systemic arterial blood pressure following niravoline administration. The results from this present study provide further evidence that niravoline is effective in reducing elevated intracranial pressure, brain water content, and maintaining an adequate cerebral perfusion pressure even in the presence of an extradural mass lesion. Niravoline may offer a new therapeutic modality in head-injury patients with an acute intracranial, expanding mass lesion by providing a safer extended time-period until the mass can be surgically evacuated.
Analysis of Variance↗