Search PubMed⌕ Search

Biomedical subjects

S Minoshima

Publications and source records attributed to S Minoshima.

251 records · Page 14Linked to original sources
PubMed1989

The suppressive effect of cyclophosphamide on low-dose streptozotocin-induced diabetes in mice.

We found that low-dose streptozotocin (SZ)-induced diabetes in mice is suppressed by cyclophosphamide (CY) and studied the mechanisms of this suppression. Male CD-1 mice were injected intraperitoneally with SZ (40 mg/kg) for five consecutive days (group SZ). In addition, CY (200 mg/kg) was injected on the first day (group CY-1) or on days 1 and 5 (group CY-2). In group SZ, all mice developed diabetes within nine days after the first injection of SZ. Group CY-1 did not develop hyperglycemia for 14 days and group CY-2 did not develop it throughout the experimental period (40 days). Insulitis was suppressed slightly in group CY-1 and completely in group CY-2. The number of spleen cells did not change in group SZ compared with that before cyclophosphamide treatment. They decreased significantly on days 3 and 7 in both groups CY-1 and CY-2 (p less than 0.01 or p less than 0.05), but then increased significantly on days 14 and/or 21 (p less than 0.01 or p less than 0.05) compared with those before cyclophosphamide treatment. The Thy 1.2- and L3T4-positive cells increased significantly in group SZ but they decreased on days 3 and 7 in both groups CY-1 and CY-2 (p less than 0.01) compared with the controls. These results suggest that (1) this large reduction of lymphocytes at the beginning of SZ treatment may lead to the prevention of hyperglycemia and insulitis, and (2) T-cells, especially L3T4-positive cells may play an important role in the pathogenesis of this type of diabetes.

Animals↗
PubMed1988

Two independent mechanisms for escaping epidermal growth factor-mediated growth inhibition in epidermal growth factor receptor-hyperproducing human tumor cells.

Human squamous cell carcinoma cell lines often possess increased levels of epidermal growth factor (EGF) receptor. The growth of these EGF receptor-hyperproducing cells is usually inhibited by EGF. To investigate the mechanism of EGF-mediated inhibition of cell growth, variants displaying alternate responses to EGF were isolated from two squamous cell carcinoma lines, NA and Ca9-22; these cell lines possess high numbers of the EGF receptor and an amplified EGF receptor (EGFR) gene. The variants were isolated from NA cells after several cycles of EGF treatment and they have acquired EGF-dependent growth. Scatchard plot analysis revealed a decreased level of EGF receptor in these ER variants as compared with parental NA cells. Southern blot analysis and RNA dot blot analysis demonstrated that the ER variants had lost the amplified EGFR gene. One variant isolated from Ca9-22 cells, CER-1, grew without being affected by EGF. CER-1 cells had higher numbers of EGF receptor than parental Ca9-22 but similar EGFR gene copy number. Flow cytometric analysis indicated an increase in ploidy and cell volume which may give rise to the increase in receptor number per cell. The EGF receptors on both Ca9-22 and CER-1 cells were autophosphorylated upon EGF exposure in a similar manner suggesting no obvious alteration in receptor tyrosine kinase. However, very efficient down-regulation of the EGF receptor occurred in CER-1 cells. These data suggest two independent mechanisms by which EGF receptor-hyperproducing cells escape EGF-mediated growth inhibition: one mechanism is common and involves the loss of the amplified EGFR genes, and another is novel and involves the efficient down-regulation of the cell-surface receptor.

Carcinoma, Squamous Cell↗
PubMed1986

Geographutoxin II, a novel peptide inhibitor of Na channels of skeletal muscles and autonomic nerves.

Geographutoxin II (GTX II, 3 X 10(-9) to 10(-7) M) from a cone shell Conus geographus inhibited twitch responses of the isolated mouse diaphragm to direct stimulation in a dose-dependent manner. The contraction of the diaphragm induced by grayanotoxin I or veratridine was abolished by GTX II (3 X 10(-7) M), whereas the contractile response to KCI or caffeine was not affected. GTX II induced similar effects on isolated bullfrog sartorius muscles, but required higher concentrations (6 X 10(-7) to 3 X 10(-6) M). GTX II (greater than 10(-6) M) inhibited or abolished the action potential evoked in sartorius muscles markedly. In the isolated guinea pig vas deferens and ileum, GTX II caused a dose-dependent inhibition of the twitch responses to indirect nerve stimulation at concentrations of 3 X 10(-8) to 10(-6) M and 10(-7) to 10(-6) M, respectively. But the toxin had no effect on the dose contractile-response curves for norepinephrine, carbamylcholine or KCI in the vas deferens and for carbamylcholine or histamine in the ileum. GTX II (5 X 10(-8) to 10(-6) M) decreased norepinephrine release induced by veratridine from the vas deferens in a dose-dependent manner. These results suggest that GTX II blocks the voltage-sensitive Na channels in the cell membrane of skeletal muscles and autonomic nerves and these may play an important role in the mechanism of inhibitory effects of GTX II on contractile responses of these tissues to electrical stimulation.

Amino Acid Sequence↗
PubMed1982

Autonomous control of the level of methylation of methyl-accepting chemotaxis protein.

Methylation and demethylation of the methyl-accepting chemotaxis protein (MCP) was studied in vitro. The in vitro MCP methylating system showed the following characteristics. 1. Multiple bands of methylated MCP were produced. 2. The reaction could be separated into two phases: the initial phase, in which the level of methylation increased as a result of multiple methylation; and the stationary phase, in which methylation and demethylation took place at the same velocity without apparent change in the level of methylation. 3. Pulse-chase analysis of the reaction showed that MCP was demethylated preferentially at the relatively highly methylated state. 4. The behavior of MCP in this system was similar to that of MCP stimulated in vivo with attractant. Based on the above results, an autonomous control mechanism of the level of MCP methylation is discussed.

Bacterial Proteins↗
PubMed1981

An in vitro study of the methylation of methyl-accepting chemotaxis protein of Escherichia coli. Construction of the system and effect of mutant proteins on the system.

An in vitro system for the methylation of methyl-accepting chemotaxis proteins (MCP's), which have been shown to be membrane integral proteins, was constructed. The system, consisting of the membrane, the cytoplasm, and labeled S-adenosyl methionine, showed the following characteristics. 1. The methylation of MCP in the membrane required the cytoplasm. The rate of incorporation of the labeled methyl group into MCP was dependent on the amount of the cytoplasm. 2. Incorporation of the labeled methyl moiety into MCP reached a steady state, and the level of the steady state incorporation was dependent on the concentration of the cytoplasm when the concentration of the membrane protein was constant. 3. The methyl moiety which had been incorporated into MCP before the steady state could be exchanged. It was suggested that the amount of methyl group introduced into MCP was equal to that of taken from MCP. 4. The methylated MCP was demethylated faster in the presence of a methyl donor than in its absence. 5. The membranes obtained from cheX-, cheB-, and cheZ mutants were inactive in the present in vitro system even when they were mixed with the wild type cytoplasm.

Bacterial Proteins↗
PubMed1980

Studies on bacterial chemotaxis. V. Possible involvement of four species of the methyl-accepting chemotaxis protein in chemotaxis of Escherichia coli.

Chemotactic Escherichia coli contains five major methyl-accepting proteins. Three of them were identified as the product of tsr gene, tar gene and peptide elongation factor Tu. Electrophoretic analysis of sulfur-labeled proteins and methyl-labeled proteins from trg mutants, which lost the ability of chemotaxis only towards ribose, galactose and their analogs, showed that the product of trg gene was another methyl-accepting protein i.e. a methyl-accepting chemotaxis protein for ribose and galactose (trg-MCP). The last methylatable protein, named as MCP-IV, seems to be involved in chemosensory transduction (accompanying paper). Thus, it is possible that chemosensory transduction in E. coli involves four species of MCP, although no genetic evidence for MCP-IV has yet been found. A hypothesis relating a change in the methylation of MCP with a movement of ions is presented.

Bacterial Proteins↗
PubMed1980

Studies on bacterial chemotaxis. VI. Effect of cheX mutation on the methylation of methyl-accepting chemotaxis protein of Escherichia coli.

A membrane from Escherichia coli cheX mutants failed to accept the methyl-moiety when incubated with a cytoplasm of wild type bacteria. The possibility of reduced production of methyl-accepting chemotaxis protein (MCP) as a result of the effect of cheX mutation was considered. However, analysis of sulfur labeled proteins from cheX mutants by two-dimensional gel electrophoresis showed that the proportion of non-esterified MCP increased in cheX mutants while the total amount of MCP was not seriously affected. Thus the decreased methylation of MCP in cheX mutants, as detected by the methyl-labeling experiment, is not caused by an effect of cheX mutation on the production of MCP back-bone protein but by a defect in the device for methylation. The presence of four species of MCP's whose extent of methylation was affected by cheX mutation as well as cheB mutation was also shown by this experiment.

Chemotaxis↗
PubMedDate not supplied

Neuropsychological function and cerebral glucose utilization in isolated memory impairment and Alzheimer's disease.

We hypothesized that 20 patients with isolated memory impairment (IMI) would demonstrate [18F]-2-fluoro-2-deoxy-D-glucose utilization and a progression of neuropsychological symptoms consistent with Alzheimer's disease (AD). IMI subjects performed similarly to AD in recall and verbal fluency, but comparable to normal subjects in other areas of cognitive functioning. A positron emission tomography (PET) diagnostic index based on parietal Z-scores categorized IMI patients into normal and abnormal metabolic patterns. Ten of the original 20 IMI patients (50%) reflected PET AD abnormalities. Clinical information was available for IMI patients at three-year follow-up. Ten (50%) had converted to AD, three were found to have pseudodementia and the seven remained IMI. Of the 10 IMI patients with an originally normal PET index, three (30%) were diagnosed with AD at three years. Of the 10 with an abnormal index originally, seven (70%) converted to AD. The finding that memory deficit in IMI was as pronounced as that in AD patients is consistent with the notion that memory is an initial symptom of AD. A substantial number of the IMI patients reflected regional hypometabolism similar to AD, suggesting that IMI is likely an early stage in progressive dementia. A large percentage of IMI patients converted clinically to AD within three years of initial study, though we observed impaired memory functioning well before a clinical diagnosis of AD could be made. In addition to potential clinical utility, IMI and PET represent an opportunity to study dementia in relation to brain chemistry at a time when brain pathology is in the process of development.

Aged↗
PubMedDate not supplied

Differential diagnosis of CNS lesions in AIDS patients by FDG-PET.

OBJECTIVE: The aim of this study was to evaluate the potential of FDG-PET in the differential diagnosis of CNS lesions in patients with AIDS, particularly to differentiate between toxoplasmosis and lymphoma. MATERIALS AND METHODS: We examined 11 AIDS patients, 6 with toxoplasmosis, 1 with a tuberculoma, and 4 with a primary CNS lymphoma. The FDG uptake within the lesion was compared with the uptake in a contralateral brain area [standardized uptake value (SUV)]. RESULTS: In all subjects with cerebral infections (toxoplasmosis, tuberculoma), the SUV ratio was significantly (p < 0.05) lower than the SUV ratio in patients with lymphoma (range of 0.3-0.7 vs. 1.7-3.1) with no overlap of the uptake values. CONCLUSION: In conclusion, FDG-PET may help to characterize these lesions metabolically and play an important role in the clinical management of AIDS patients with CNS involvement.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

Preserved pontine glucose metabolism in Alzheimer disease: a reference region for functional brain image (PET) analysis.

OBJECTIVE: Our goal was to examine regional preservation of energy metabolism in Alzheimer disease (AD) and to evaluate effects of PET data normalization to reference regions. MATERIALS AND METHODS: Regional metabolic rates in the pons, thalamus, putamen, sensorimotor cortex, visual cortex, and cerebellum (reference regions) were determined stereotaxically and examined in 37 patients with probable AD and 22 normal controls based on quantitative 18FDG-PET measurements. Following normalization of metabolic rates of the parietotemporal association cortex and whole brain to each reference region, distinctions of the two groups were assessed. RESULTS: The pons showed the best preservation of glucose metabolism in AD. Other reference regions showed relatively preserved metabolism compared with the parietotemporal association cortex and whole brain, but had significant metabolic reduction. Data normalization to the pons not only enhanced statistical significance of metabolic reduction in the parietotemporal association cortex, but also preserved the presence of global cerebral metabolic reduction indicated in analysis of the quantitative data. CONCLUSION: Energy metabolism in the pons in probable AD is well preserved. The pons is a reliable reference for data normalization and will enhance diagnostic accuracy and efficiency of quantitative and nonquantitative functional brain imaging.

Aged↗
PubMedDate not supplied

Effects of yohimbine on cerebral blood flow, symptoms, and physiological functions in humans.

OBJECTIVE: Increases in adrenergic activity are associated with stress, anxiety, and other psychiatric, neurological, and medical disorders. To improve understanding of normal CNS adrenergic function, CBF responses to adrenergic stimulation were determined. METHODS: Using PET, the CBF changes after intravenous yohimbine, an alpha2-adrenoreceptor antagonist that produces adrenergic activation, were compared with placebo in nine healthy humans. Heart rate, blood pressure, Paco2, plasma catecholamines, and symptom responses were also determined. RESULTS: Among nonscan variables, yohimbine produced significant symptom increases (including a panic attack in one subject), a decrease in Paco2 due to hyperventilation, increases in systolic and diastolic blood pressure, and a trend toward a significant norepinephrine increase. Among scan results, yohimbine produced a significant decrease in whole-brain absolute CBF; regional decreases were greatest in cortical areas. Medial frontal cortex, thalamus, insular cortex, and cerebellum showed significant increases after normalization to whole brain. Medial frontal CBF change was correlated with increases in anxiety. A panic attack produced an increase instead of a decrease in whole-brain CBF. Factors potentially contributing to the observed CBF changes were critically reviewed. Specific regional increases were most likely due in large part to activation produced by adrenergically induced anxiety and visceral symptoms. CONCLUSIONS: This study supports the relationship of anxiety and interoceptive processes with medial frontal, insular, and thalamic activation and provides a baseline for comparison of normal yohimbine-induced CNS adrenergic activation, adrenergically-based symptoms, and other markers of adrenergic function to stress, emotion, and the adrenergic pathophysiologies of various CNS-related disorders.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Reduction of regional cerebral blood flow and cognitive impairment in patients with Alzheimer's disease: evaluation of an observer-independent analytic approach.

The aim of the study was to evaluate an observer-independent semiquantitative analysis of brain imaging by single-photon emission computed tomography (SPECT) in patients with Alzheimer's disease (AD). Patients (n = 45, mean age 70 +/- 11 years) with a clinical diagnosis of AD according to NINCDS/ADRDA criteria were examined by 99mTc-ethylcysteine dimer SPECT. Following anatomic normalization and data extraction using three-dimensional stereotactic surface projection, a pixelwise comparison of ECD uptake was performed with the reference values of 10 cognitive intact controls of comparable age. The global relative decrease of cerebral blood flow in cortical association areas showed a significant inverse association with the overall level of cognitive functioning as assessed with the Mini Mental State Examination and with the cognitive section (CAMCOG) of the Cambridge Mental Disorders of the Elderly Examination. There were significant region-specific associations between left temporoparietal perfusion deficit and language performance and between right temporoparietal regional cerebral blood flow reduction and praxis. The results suggest that this observer-independent analysis of SPECT data provides a valid assessment of the pattern and severity of cortical perfusion abnormalities in patients with AD.

Adult↗
PubMedDate not supplied

Change of cerebral glucose metabolism by antineoplastic drug.

To estimate change of cerebral glucose metabolism by anticancer drugs, positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) was performed in 11 patients with malignancies who did not show neurological symptoms. In a patient treated with intravenous high-dose methotrexate (HD-MTX) and intrathecal MTX, apparent decrease of glucose metabolism was observed. HD-MTX and intrathecal MTX may cause cerebral glucose metabolism disorder primarily. Cerebral glucose metabolism was also mildly reduced by chemotherapy with drugs other than MTX and by radiotherapy outside the brain, with a corresponding change of blood data. It may reflect a psychosomatic change in whole body.

Aged↗