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Biomedical subjects

J Simon

Publications and source records attributed to J Simon.

At least 271 records · Page 15Linked to original sources
PubMed1995

Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting beta-cells.

In the beta TC3 insulin-secreting beta-cell line, glucose rapidly induces the tyrosine phosphorylation of the 97-kDa insulin receptor beta-subunit. Phosphorylation is transient, with fourfold stimulation by 2 min and subsequent dephosphorylation to basal levels by 10-15 min. Elevating the extracellular KCl concentration equipotently initiates receptor phosphorylation. Preventing insulin secretion with 1 mumol/l epinephrine or by removing extracellular Ca2+ blocks the effect. In the absence of glucose-induced secretion, exogenous insulin also stimulated insulin receptor autophosphorylation transiently and with an ED50 of 4 x 10(-9) mol/l. In addition, functional insulin-like growth factor I (IGF-I) receptors are also expressed by these beta-cells, as indicated by IGF-I-induced receptor tyrosine phosphorylation (ED50 = 5 x 10(-9) mol/l) and also by detection of hybrid insulin/IGF-I receptor autophosphorylation at 10(-7) mol/l IGF-I. Both glucose and insulin stimulate the tyrosine phosphorylation of the insulin receptor substrate (IRS) IRS-1 and increase by two- to fivefold the rapid association of IRS-1 with the 85-kDa alpha-subunit of the phosphatidylinositol-3-kinase, as determined by co-immunoprecipitation assays. These results demonstrate that in these beta-cells, glucose-induced insulin secretion activates the beta-cell surface insulin receptor tyrosine kinase and its intracellular signal transduction pathway, suggesting a new autocrine mechanism for the regulation of beta-cell function.

Animals↗
PubMed1995

Localization of P2X purinoceptor transcripts in the rat nervous system.

We used transcript-specific oligonucleotides to examine the localization in the rat nervous system of the corresponding mRNAs for the two P2X purinoceptor genes cloned recently from the rat vas deferens and PC12 cells. PC12 P2X purinoceptor mRNA was labeled in the olfactory tubercle, striatum, hypothalamus, hippocampus, dentate gyrus, amygdala, cortex, and cerebellum, whereas the vas deferens P2X purinoceptor-specific probes labeled the cerebellum and, at lower levels of expression, the striatum, hippocampus, and cortex. Both types of P2X purinoceptor transcript were found on cell bodies in the nodose and superior cervical ganglia. The presence of these two purinoceptor transcripts in the brain was confirmed by polymerase chain reaction. Two partial cDNAs, identical to sections of the PC12 or vas deferens P2X purinoceptor coding sequences, were amplified from neonatal brain and cerebellum poly(A)+ RNA, respectively. These findings are in broad agreement with earlier Northern blot studies on the PC12 P2X purinoceptor mRNA but differ from those for the vas deferens P2X purinoceptor mRNA, which had not previously been detected in adult brain. This difference is attributed to the low levels seen in the adult compared with the neonate and to the greater sensitivity of the methods used in the present study. The neonate medial habenula had low levels of transcripts for the PC12 but none for the vas deferens P2X purinoceptor. Because pharmacologically the recombinant PC12 P2X purinoceptor differs from the functional purinoceptor in the medial habenula, these results suggest the existence of other, unidentified, P2X purinoceptors in the rat nervous system.

Adenosine Triphosphate↗
PubMed1994

Human t(4;11)(q21;q23) acute lymphoblastic leukemia in mice with severe combined immunodeficiency.

Mice with severe combined immunodeficiency (SCID) were injected intravenously with primary bone marrow blasts from 12 children with newly diagnosed t(4;11)(q21;q23) acute lymphoblastic leukemia (ALL). Blasts from eight patients caused overt disseminated leukemia, whereas blasts from the other four patients produced occult leukemia that was detectable only by the polymerase chain reaction (PCR) technique. Only one patient among eight whose blasts caused disseminated leukemia in SCID mice remains alive and disease-free at 48.4 months postdiagnosis. In contrast, three of the other four patients whose blasts did not cause overt leukemia in SCID mice remain alive and disease-free at 6.1, 23.6, and 35.9 months, respectively. Thus, the occurrence of overt leukemia in SCID mice may be a predictor of patients' disease-free survival. The described SCID mouse model system may prove useful for designing more effective treatment strategies against therapy-refractory t(4;11) ALL.

Adolescent↗
PubMed1994

Childhood acute myeloid leukemia in mice with severe combined immunodeficiency.

Primary bone marrow blasts from 4 children with t(8;21) acute myeloid leukemia (AML), 6 children with inv(16) AML, and 2 children with t(9;11) AML were injected intravenously or transplanted under the kidney capsule of sublethally irradiated mice with severe combined immunodeficiency (SCID). Leukemic cells from all AML patients infiltrated the SCID mouse thymus, suggesting that the thymic microenvironment supports the survival and growth of human AML blasts. Blasts from 1 of 4 t(8;21) AML patients and 4 of 6 inv(16) AML patients caused histopathologically detectable disseminated leukemia. Blasts from the remaining patients produced disseminated occult leukemia that was only detected by polymerase chain reaction. Occurrence of histopathologically detectable disseminated leukemia was dependent on intravenous injection of leukemic cells; none of the mice challenged with an inoculum transplanted under the kidney capsule developed overt leukemia. No obvious association was noted between occurrence of leukemia in SCID mice and clinical or laboratory features presented by patients, including age, sex, or leukocyte count at diagnosis. To our knowledge, this study is the first to show that leukemic blasts from children with newly diagnosed AML, especially inv(16) AML, can cause disseminated human leukemia in SCID mice without exogenous cytokine support. The SCID mouse model system may prove particularly useful for designing more effective treatment strategies against childhood AML.

Adolescent↗
PubMed1994

[Continuous non-invasive blood pressure monitoring in the diagnosis of pacemaker syndrome].

The drop in blood pressure coinciding with the atrioventricular dyssynchrony plays an important role in the genesis of pacemaker syndrome. The diagnosis is often based on continuous blood pressure recording. Formerly the continuous blood pressure monitoring could only be performed by invasive methods. The authors demonstrate the feasibility of a new non invasive continuous blood pressure recorder, the Finapres 2300, by presenting illustrative case reports. The authors recommend more widespread use of non invasive haemodynamic monitoring for the diagnosis of pacemaker syndrome.

Aged↗
PubMed1994

[Alcohol and health--friend or foe?].

BACKGROUND: The association of alcohol with a number of diseases, accidents, traffic and word injuries, psychoses, degenerative nervous processes and some organ malignities is known and has been proved. An exception is formed by population studies providing evidence of a reduced risk of development of ischaemic heart disease, incl. mortality from the latter. Our population has a high beer consumption: In the West Bohemian region the consumption is 180-200 l of beer per head per year. We were concerned with the problem of the influence of this consumption on the prevalence of IHD, myocardial infarction and some tumours and the general mortality of middle-aged men. METHODS AND RESULTS: The investigation started in 1976 comprised 3758 men aged 40-50 years. On account of manifest disease 171 subjects were eliminated and in the general evaluation after 12 years another 192 subjects could not be included. The final analysis was made in 3395 men, mean age 44.6 +/- 3.6 years, BMI 27.0 +/- 3.2, mean systolic pressure 133.1 +/- 18 mm Hg (17.74 +/- 2.4 kPa), mean diastolic pressure 83.2 +/- 10.7 mm Hg (11.0 +/- 1.5 kPa) and mean serum cholesterol values 5.69 +/- 0.99 mmol/l. A BMI above 29 was recorded in a total of 835 men (23.6%), systolic pressure above 160 mm Hg (21.23 kPa) in 302 men, diastolic pressure higher than 90 mm Hg (11.98 kPa) in 1004 (28.4%); serum cholesterol above 6.7 mmol/l was recorded in 491 (13.9%) of the examined subjects, regular smoking was admitted by 1915 (54.1%) and regular alcohol intake by 1815 (51.3%) of the investigated subjects. The mean follow-up period was 10.73 years. For statistical analysis multiple logistic regression was used and the relative risk expressed as the "odds ratio" (OR) standardized for a number of variables known to influence in a comprehensive way selected final indicators. Approximately 50% of the men were smokers and consumed alcohol. Regular alcohol intake was associated with a significantly lower risk (odds ratio 0.87). The significant difference was, however, not found when the data were standardized for age, blood pressure, family-history and leisure activities. Separate assessment of the relative risk of alcohol for fatal and non-fatal acute myocardial infarction and for the total mortality rate revealed the following risks (expressed as OR and 95% confidence limit in parentheses: OR for fatal infarction = 0.85 (0.44-1.64), not significant), OR for non-fatal infarction = 0.84 (0.60-1.17) and OR for the general mortality = 0.89 (0.68-1.17): both the latter values are at the borderline of statistical significance (p = 0.05-0.1). When smokers drink regularly, they have a significantly lower risk of non-fatal infarctions (but not fatal infarctions!). This effect is not found in non-smokers. The relative risk for the development of tumours in smokers-drinkers is insignificantly elevated, OR = 1.55 (0.89-2.75). The largest number of malignities was lung cancer. Regular smokers who drink alcohol have a treble risk of developing lung cancer, as compared with abstainers: OR = 2.96 (1.07-8.23) a statistically significant increase. CONCLUSIONS: From the investigation it is apparent that regular alcohol intake reduces the rate of all coronaries in middle-aged men, but this protective effect applies only to non-fatal myocardial infarctions, in particular in smokers. No effect on the general mortality was proved. However, there was evidence of a positive association between alcohol intake and lung cancer. Alcohol potentiates (3x) the relative risk of development of lung cancer in smokers.

Adult↗
PubMed1994

Enhancer point mutation results in a homeotic transformation in Drosophila.

In Drosophila, the misexpression or altered activity of genes from the bithorax complex results in homeotic transformations. One of these genes, abd-A, normally specifies the identity of the second through fourth abdominal segments (A2 to A4). In the dominant Hyperabdominal mutations (Hab), portions of the third thoracic segment (T3) are transformed toward A2 as the result of ectopic abd-A expression. Sequence analysis and deoxyribonuclease I footprinting demonstrate that the misexpression of abd-A in two independent Hab mutations results from the same single base change in a binding site for the gap gene Krüppel protein. These results establish that the spatial limits of the homeotic genes are directly regulated by gap gene products.

Animals↗
PubMed1994

Characterization of insulin receptors in chicken kidneys: effect of nutritional status.

In chickens, the kidneys actively contribute to gluconeogenesis. A cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK) is present in this tissue but is absent in liver. Cytosolic renal PEPCK is nutritionally and hormonally controlled which indicates a likely contribution of insulin in the control of this enzyme (and other renal functions). The present studies characterize renal insulin receptors in the chicken. The effects of the following nutritional conditions were examined: fed, 48 hr fasted, and 24 hr refed following a 48-hr fast. PEPCK activity was increased by the 48-hr fast and returned to normal after refeeding. Specific binding of 125I-insulin to renal membranes was time-, temperature-, and protein-dependent. Unlabeled insulin was more potent than IGF-1 in inhibiting 125I-insulin binding; the ratio of potencies for insulin and IGF-1, however, was dependent upon the nutritional state. Insulin binding was significantly higher (P < 0.05) following 48 hr fasting and lower (P < 0.05) following refeeding compared to ad libitum feeding. Receptor affinity was similar irrespective of the nutritional state. Solubilized and wheat germ agglutinin purified renal insulin receptors were devoid of ATPase activity in contrast to hepatic receptors. The sizes of alpha- and beta-subunits of renal receptors were similar to those of hepatic receptors: 135 and 95 kDa, respectively. Insulin-stimulated autophosphorylation of the beta-subunit was decreased, although not significantly, by prolonged fasting. Phosphorylation of artificial substrate: poly(Glu-Tyr) 4:1 was significantly decreased by the 48-hr fast at high insulin concentrations (10 and 100 nM). Kinase activities of renal insulin receptors from fed or refed chickens were very similar. In conclusion, typical insulin receptors are present in chicken kidneys. These receptors exhibit a regulation at the level of their number and kinase activity in a fashion similar to that found for hepatic receptors. The present results suggest a role for insulin in chicken renal function.

Animals↗
PubMed1994

Corticosterone-induced insulin resistance is not associated with alterations of insulin receptor number and kinase activity in chicken kidney.

Chicken renal insulin receptors have been recently characterized; their number and kinase activities vary in response to altered nutritional status. In the present study, the effect of chronic corticosterone treatment was examined in 5-week-old chickens. The development of an insulin resistance following corticosterone was suggested after 1 and 2 weeks of treatment by a significant increases in plasma insulin levels (1.63 +/- 0.13 vs 0.56 +/- 0.14 ng insulin/ml in controls) and in renal cytosolic phosphoenolpyruvate carboxykinase activity (17.2 +/- 0.8 vs 13.7 +/- 0.7 nm/mn/mg tissue in controls). No significant changes were present at the level of insulin receptor number and kinase activity. Therefore, in kidney and, as previously observed, in muscles, corticosterone can induce insulin resistance at postreceptor steps in the cascade of events leading to insulin action.

Animals↗
PubMed1994

[3H]dynorphin1-8 binding sites in frog (Rana esculenta) brain membranes.

Opioid binding sites specific for [3H]dynorphin1-8 were characterized in the particulate membrane fraction of frog (Rana esculenta) brain. The degradation of the radioligand during the assay was prevented by the use of a broad spectrum of peptidase inhibitors. The binding of [3H]dynorphin1-8 to frog brain membranes was stereoselective, reversible, saturable, and displaceable by a series of opioid ligands including dynorphin1-13, bremazocine, levorphanol and naloxone. The specific binding of [3H]dynorphin1-8 can be significantly inhibited by Na+ ions and/or guanine nucleotides confirming the agonist property of the ligand in vitro. A single set of high affinity opioid binding sites with a Kd approximately 7.5 nM is present in the membranes. The maximum density of binding sites (Bmax approximately 1.1 pmol [3H]dynorphin1-8 per mg protein) was considerably higher than such sites in guinea-pig brain. In addition, comparison with binding of tritiated opioid peptides selective for the mu- and delta-types of opioid receptor showed that in the frog brain most of the sites labelled by [3H]dynorphin1-8 are kappa-sites and that this is a rich source of such sites.

Amino Acid Sequence↗
PubMed1994

Magnetic auditory source imaging in macaque monkey.

We recorded magnetic auditory evoked fields from the left hemisphere of a 2-year-old 3.4 kg Macaca nemestrina monkey. Three separate components were isolated from each of three data sets with latencies of approximately 22 ms, 46 ms, and 130 ms after stimulus onset. The 46 ms latency component had clear extrema values and was selected for localization. Field values from 21 recording points were used to estimate the 3-D source location of the 46 ms latency component, termed the M46. High resolution MR images of the brain provided information for correlation of neuroanatomic structure with source location. The neuroanatomic source was found to lie in the superior aspect of the temporal lobes bilaterally. We believe the M46 is the macaque analog of the human M100. Recording of auditory evoked fields in nonhuman primates offers a valuable animal model for studying neurophysiology of human magnetoencephalographically (MEG) determined auditory sources.

Acoustic Stimulation↗
PubMed1994

Auditory sensory gating, hippocampal volume, and catecholamine metabolism in schizophrenics and their siblings.

Schizophrenia may result from the concerted action of several pathophysiological factors. This pilot study compared the distribution of measurements of three such putative factors in 11 schizophrenics and their siblings: a neurophysiological deficit in auditory sensory gating, diminished hippocampal volume, and increased catecholamine metabolism. Abnormal auditory sensory gating was found in all schizophrenics in the 11 families studied and in 8 of their 20 siblings. Compared with the schizophrenics, the clinically unaffected siblings with abnormal auditory gating had larger hippocampal volume. There was no similar difference for the siblings with normal gating. The siblings with abnormal auditory gating also had lower homovanillic acid levels than the other siblings. The data suggest that a familial neuronal deficit, identified by diminished sensory gating, may be a necessary, but not sufficient factor in the pathogenesis of schizophrenia. Individuals with this deficit are generally clinically unaffected, except for schizophrenics, who also have other abnormalities, such as diminished hippocampal volume and increased catecholamine metabolism.

Acoustic Stimulation↗
PubMed1994

Auditory M100 component 1: relationship to Heschl's gyri.

This study was designed to localize the neuroanatomic generator of the 100 ms latency magnetic auditory evoked field (EF) component (M100) activated by an unattended tone pip. Magnetic EFs in response to 25 ms duration, 90 dB, 1 kHz tone pips were recorded from both hemispheres of nine normal adults, five males and four females, using a seven-channel second-order gradiometer. The source of the M100 was estimated, with confidence intervals, by a least squares based inverse solution algorithm. Magnetic resonance (MR) images of the brain were acquired with a 1.5 T system using a standard head coil. The superior temporal gyri (STG) were manually segmented from 1.7 mm thick coronal images, and the superior surfaces were then rendered from the 3-D volume data. Translation and rotation matrices were identified to locate the magnetoencephalography (MEG) determined sources within the reconstructed STGs. This population of 18 STGs in 9 individuals demonstrated two transverse gyri in 4 of 9 left hemispheres, and 5 of 9 right hemispheres. All 9 left hemisphere M100 sources were in or included Heschl's gyrus(i) in the confidence intervals. Seven of the 9 included Heschl's gyrus(i) on the right: the remaining two, both males, had sources slightly anterior to Heschl's gyrus(i). We conclude that all M100 source location estimates were compatible with an auditory koniocortex source in or adjacent to Heschl's gyri.

Adult↗
PubMed1994

Altered phospholipid fatty acid content and metabolism in heart cell cultures from newborn spontaneously hypertensive rats.

Genetic hypertension has been proposed to be associated with impaired lipid metabolism. To investigate whether lipid metabolism is altered in young rats of the spontaneously hypertensive Okamoto strain (SHR), we have compared the phospholipid fatty acid content and metabolism in cultured heart myocytes and fibroblasts from SHR and normotensive Wistar-Kyoto (WKY) newborn rats. The phospholipid-bound fatty acid profile and metabolism were altered in SHR cardiomyocytes and unchanged in SHR fibroblasts. In SHR myocytes, the fatty acid composition of the phospholipid fraction was modified, with a lowered proportion of linoleic (P < .05) and eicosapentaenoic acid (P < .001), resulting in a decreased polyunsaturated to saturated fatty acid ratio (1.16 +/- 0.08 in SHR v 1.44 +/- 0.08 in WKY, P < .02). The metabolism of radioactive arachidonate (C20:4) and linoleate (C18:2) also differed between SHR and WKY myocytes. Their release was increased (P < .004 and .05 for C20:4 and C18:2, respectively). The labeled phospholipid species also differed between the two strains, suggesting an altered phospholipid turnover in SHR. This study demonstrates modifications of phospholipid fatty acid profile and metabolism in spontaneously contractile cardiac cells from newborn prehypertensive SHR, in the absence of neural, hormonal, and hemodynamic influences.

Animals↗