Helicobacter pylori (HP) has been shown to possibly be a pathogen of gastric carcinoma. HP has urease activity and produces ammonia in the stomach. In this study, the role of ammonia on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in rats. After 24 weeks pretreatment with MNNG (83 mg/l), 0.01% ammonia or tap water as a drinking water was administered for 24 weeks. The ammonia-treated rats showed a significantly higher incidence of gastric cancer (percent of animals with tumors and number of tumors per rat). Ammonia would thus appear to have an important role in HP-related human gastric carcinogenesis.

Adenocarcinoma↗

PubMed1992

Observation of a fast beta collapse during high poloidal-beta discharges in JT-60.

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Journal Article↗

PubMed1992

A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3' splice site selection.

The molecular basis of a dramatically decreased steady state level of beta-hexosaminidase beta subunit mRNA in a patient with juvenile Sandhoff disease was investigated. Nucleotide sequence analysis of the HEXB gene coding for the beta subunit revealed two single base substitutions, one in exon 2 (A to G, a known polymorphism) and the other in exon 11 (C to T). Analysis of the beta subunit mRNA species demonstrated activation of a cryptic splice site in exon 11 as well as skipping of the exon. A transfection assay using a chimeric gene containing intron 10 flanked by cDNA sequences carrying the mutation confirmed that the single base substitution located at position 8 of exon 11 inhibits the selection of the normal 3' splice site. The results demonstrate a new type of exon mutation affecting 3' splice site selection.

Adult↗

PubMed1992

DNA mutation analysis of Gaucher patients.

We evaluated 62 Gaucher patients to determine whether patients with similar phenotypes had the same DNA point mutations. Genomic DNA from these Gaucher patients was screened for the 3 most frequent single-point mutations, occurring in 69% of the 124 patient alleles, and resulting in changes in amino acids 370, 444, and 463. Many different genotypes were observed, at least one of which is present in all 3 types of Gaucher disease. No specific symptom complex could be correlated with a unique genotype. Even the more clinically homogeneous subgroups of Gaucher patients contained several genotypes. This study further emphasizes the need for caution in making clinical predictions on the basis of current genotype analysis, especially since one might not discern a fetus affected with type 2 disease by current DNA studies. The severity of involvement in type 1 disease could also not be predicted. Thus, even limiting our focus to 3 isolated common point mutations, a given genotype cannot be uniquely correlated with a specific prognosis.

Adolescent↗

PubMed1992

Effects of proton pump inhibitor on gastric mucosa hemodynamics and tissue oxygenation in anesthetized rats.

Proton pump inhibitors have been reported to have a cytoprotective action in addition to the anti-secretory action of acid. The precise mechanism, however, remains obscure. In this study, the effects of proton pump inhibitors (omeprazole and NC-1300) on gastric mucosa hemodynamics and tissue oxygenation were investigated using organ reflectance spectrophotometry in a hemorrhagic shock-reperfusion model involving anesthetized rats. Neither drug affected gastric mucosa hemodynamics nor tissue oxygenation in the basal state before hemorrhage. During the hemorrhagic shock state, however, these drugs maintained tissue oxygenation and reduced ulcer formation, although they did not show a significant effect on gastric mucosa blood volume. The results suggest that both proton pump inhibitors have an anti-ulcer action by maintaining mucosal oxygenation in addition to the anti-secretory activity of acid.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1992

Tumor necrosis factor and endotoxin in the pathogenesis of liver and pulmonary injuries after orthotopic liver transplantation in the rat.

This study examines whether tumor necrosis factor and endotoxin are involved in the pathogenesis of primary nonfunction of graft and pulmonary complication after orthotopic liver transplantation. Livers from Lewis rats were stored for either 1 or 4 hr in ice-cold Euro-Collins solution (1-hr storage and 4-hr storage group, respectively). Subsequently, donor livers were implanted orthotopically. In some experiments, anti-tumor necrosis factor antibody was administered intravenously before and immediately after the surgery into animals that received livers stored for 4 hr. Blood samples for the measurement of tumor necrosis factor and endotoxin were collected by way of an indwelling catheter placed in the suprahepatic vena cava. Serum tumor necrosis factor was elevated at all time points studied postoperatively in rats of the 4-hr storage group; however, tumor necrosis factor was not detected in the serum in the 1-hr storage group. Endotoxin was also elevated significantly in the serum of the former group compared with levels in the serum of the latter group. The peak value of endotoxin occurred 1 hr earlier than that of tumor necrosis factor, suggesting that the rise in endotoxin stimulated release of tumor necrosis factor. The histological study of livers stored for 4 hr showed substantial hepatocellular degeneration 24 hr after surgery, whereas hepatocellular damage was minimal in the 1-hr storage group. Serum ALT levels 24 hr after the operation in the 1-hr and 4-hr storage groups were 169 +/- 46 IU/L and 374 +/- 41 IU/L (mean +/- S.E.M., p less than 0.05), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗

PubMed1992

Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease.

In previous studies, we discovered a growth inhibitory factor (GIF) that was abundant in normal human brain, but greatly reduced in Alzheimer's disease (AD) brain. Molecular cloning of a full-length cDNA for human GIF revealed that the GIF had striking homology to metallothioneins. Furthermore, it was determined that the GIF gene was on chromosome 16, as are the metallothionein genes. GIF, in contrast to metallothioneins, was found to be expressed exclusively in the nervous system. The GIF protein produced by Escherichia coli harboring the GIF cDNA in a prokaryotic expression vector inhibited the growth of neonatal rat cortical neurons. These results indicate that GIF is a new member of the metallothionein family with distinct tissue-specific expression and functions. Northern blot analysis revealed that expression of the GIF mRNA is drastically decreased in AD brains. The result raises the possibility that down-regulation of the GIF gene in AD brain plays an important role in the pathogenesis of AD.

Alzheimer Disease↗

PubMed1992

Bimodal regulation of protein phosphorylation by a ganglioside in rat brain membrane.

Whether or not a ganglioside influences the protein phosphorylation in the rat brain membrane fraction was investigated. Phosphorylation of the 72 kDa protein was significantly affected by the addition of 80 nM GQ1b in vitro, which is far below the reported concentration of gangliosides that affects protein phosphorylation in the neuronal membrane fraction. This action of GQ1b was bimodal: it being not only stimulatory as to the incorporation of phosphate into the 72 kDa protein on incubation of 20 sec, but also as to the release of phosphate from or breakdown of the 72 kDa protein on incubation for more than 5 min. Eighty nM GQ1b did not noticeably affect ATPase in the same fraction. These results suggest that the transphosphorylation of the 72 kDa protein is affected by the interaction of GQ1b with either the responsible enzymes or the 72 kDa protein as a substrate.

Adenosine Triphosphatases↗

PubMed1992

A quantitative approach to technetium-99m hexamethylpropylene amine oxime.

A non-invasive, simple method for the quantitative evaluation of brain perfusion is presented using intravenous radionuclide angiography with technetium-99m hexamethylpropylene amine oxime (99mTc-HM-PAO). Graphical analysis was employed for the evaluation of the unidirectional influx constant (ku) of the tracer from the blood to the brain. The ku values were standardized to provide objective and comparable values, brain perfusion indices (BPI), among studied subjects by setting the ratio of ROIbrain size to ROIaorta size at 10. The whole-brain BPI values for the normal control subjects showed a significant negative correlation with advancing age (r = -0.632, P = 0.0204, n = 13). The mean of the whole-brain BPI of 7.0 (SD = 1.4) in 20 patients with cerebrovascular disorders was significantly lower than that of 10.6 (SD = 1.5) in 13 normal control subjects. The BPI measurements showed only minimal intra- and interobserver variability. Changes of the ratio of ROIaorta size and ROIbrain size did not significantly influence the BPI values. Hemispherical BPI values in 19 subjects (n = 38) showed highly significant correlations with the hemispherical mean cerebral blood flow values obtained from Xenon-133 single photon emission tomography (SPET) (r = 0.926, P = 0.0001 for the early picture method and r = 0.932, P = 0.0001 for the sequential picture method). This technique is easy to apply as an adjunct to SPET and may be helpful in the quantitative evaluation of brain perfusion in routine clinical studies.

Adult↗

PubMed1992

Interferon gamma but not tumor necrosis factor alpha decreases susceptibility of human renal cell cancer cell lines to lymphokine-activated killer cells.

Human renal cell cancer (RCC) cell lines, ACHN and KRC/Y, with or without exposure to cytokines, were examined for their susceptibility to lymphokine-activated killer (LAK) cells. Flow-cytometric analysis demonstrated constitutional expression of class I antigen on both cell lines, which was enhanced by interferon alpha (IFN alpha), IFN gamma and tumor necrosis factor alpha (TNF alpha). A 4-h 51Cr-release cytotoxicity assay demonstrated that pretreatment of both cell lines with IFN gamma or IFN alpha, but not with TNF alpha, decreased their susceptibility to LAK cells. IFN gamma also decreased susceptibility to natural killer cells in a 16-h 51Cr-release cytotoxicity assay. IFN gamma treatment decreased the susceptibility of ACHN cells in a dose-dependent manner. "Cold"-target competition assay clearly showed that IFN gamma- but not TNF alpha-pretreated cells compete less effectively than do untreated target cells. Pretreatment with IFN gamma, however, increased expression of intercellular adhesion molecule-1 (ICAM-1) to a degree comparable to that with TNF alpha. Northern blot analyses using a 520-base-pair ICAM-1 cDNA as a probe demonstrated that more 3.3-kb mRNA is expressed in IFN gamma- and TNF alpha-pretreated cells. These results suggest that IFN gamma-treated RCC cell lines may reduce their ability to be recognized by LAK cells, and that IFN-induced protection of RCC cell lines against LAK cells may depend upon a mechanism independent of the expression of class I antigens or ICAM-1 on tumor cells.

Carcinoma, Renal Cell↗

PubMed1992

Mechanism of gastric mucosal damage induced by ammonia.

The mechanism for Helicobacter pylori-induced gastric mucosal injury remains obscure. H. pylori has high urease activity to produce ammonia from urea in the stomach. In this study, the effects of ammonia on (a) gastric mucosal integrity, (b) gastric mucosal hemodynamics, (c) mucosal cellular viability, (d) mitochondrial respiration, and (e) energy metabolism of gastric mucosal were investigated. Ammonia (pH 10.3) at concentrations of greater than 125 mmol/L caused acute macroscopic gastric mucosal lesions in a dose-dependent manner, whereas glycine-NaOH buffer (pH 10.3) or ammonium chloride (pH 4.5) did not. The decrease in energy charge preceded the occurrence of gastric mucosal lesions, but ammonia caused no change in mucosal hemodynamics. Oxygen consumption of isolated cells and mitochondria of gastric mucosa was inhibited by ammonia dose-dependently. The present results indicate that ammonia impairs mitochondrial and cellular respiration and energy metabolism and that ammonia decreases mucosal cell viability, leading subsequently to mucosal damage.

Ammonia↗

PubMed1992

Inhibitory period following motor potentials evoked by magnetic cortical stimulation.

Following motor potentials evoked (MEPs) by magnetic cortical stimulation, there is a transient suppression of muscle action potentials (inhibitory period). We recorded MEPs, the inhibitory period, V1 waves and F waves from the abductor pollicis brevis muscle in 20 normal subjects and in 17 patients with spastic hyperreflexia due to cerebral infarction. The duration of the inhibitory period increased in correspondence with increasing stimulus intensity and did not necessarily depend on the amplitude of the MEPs. The duration of the inhibitory period elicited by a twin coil, which can stimulate the motor cortex locally, was shorter than by a single coil. The mean duration of the inhibitory period was significantly shorter in patients with spastic hyperreflexia than in normal subjects, and it correlated with the amplitude of F waves. The effects of the inhibitory period on V1 waves were different from its effects on F waves in one patient with large V1 and F waves. The amplitudes of V1 waves recorded during the inhibitory period were approximately 30-50% of the maximal amplitude of V1 waves, but F waves were not smaller. The inhibitory period is probably caused primarily by central inhibitory mechanisms.

Action Potentials↗

PubMed1992

A novel glycosignaling system: GQ1b-dependent neuritogenesis of human neuroblastoma cell line, GOTO, is closely associated with GQ1b-dependent ecto-type protein phosphorylation.

Previously, we reported that ganglioside GQ1b specifically promoted neuritogenesis of human neuroblastoma cells (GOTO), and also that is specifically stimulated the phosphorylation of several cell surface proteins on the same cells. To disclose the relationship between the two events, we examined them using a novel protein kinase inhibitor, K-252b, which is a derivative of K-252a and cannot pass through cell membrane. K-252b inhibited the GQ1b-dependent neuritogenesis as well as the GQ1b-stimulated phosphorylation. This suggests the direct coupling between the two cell events and the occurrence of a new biosignal transduction system.

Carbazoles↗

PubMed1992

Overproduction of voltage-dependent Na+ channels in the developing brain of genetically seizure-susceptible E1 mice.

We used E1 mice, a ddY mouse-derived, autosomal mutant strain and a model of hereditary sensory-precipitated epilepsy, to test the hypothesis that epileptic susceptibility may be associated with the activity of voltage-dependent ion channels. We examined the saxitoxin binding capacity of the receptor site 1 of the Na+ channel alpha-subunit, the expression activity of the Na+ channel mRNA, the veratridine-induced 22Na+ influx in the brain synaptosomes, and the regional distribution of Na+ channels in the brain. Compared with control ddY mice, in E1 mice which have not experienced seizures, the number of Na+ channels in the brain synaptosomes increased by approximately 20% starting at the fourth postnatal week through the adult stage as determined by [3H]saxitoxin binding assay. Northern blot hybridization analysis showed excess expression of Na+ channel mRNA (by 30-40%) coincidentally with Na+ channel increases. Regional analysis using the saxitoxin binding assay demonstrated approximately 1.3-fold denser distribution of Na+ channels in the cortex and cerebellum but not the hippocampus and midbrain including thalamus of E1 mice compared to ddY mice. Scatchard plot analysis for saxitoxin binding in the cortex of E1 mouse brains revealed higher maximum binding capacity (Bmax) values (ddY, 4.43 +/- 0.28 pmol/mg protein; E1, 5.43 +/- 0.25 pmol/mg protein) without a change in Kd (ddY, 1.05 +/- 0.03 nM; E1, 1.03 +/- 0.01 nM). Lastly, veratridine-evoked 22Na+ influx, sensitive to tetrodotoxin, was increased approximately 45% in the cortical synaptosomes in six-week-old E1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗