Biomedical subjects
Publications and source records attributed to P Chatelain.
This review focuses on the action of somatomedins IGF-1 and IGF-2, and in particular the role of IGF-1 in cell multiplication and differentiation. A brief overview is given of the factors controlling IGF-1 flow rate expression in the tissues. Factors influencing IGF-1 plasma levels, i.e. age, and insufficiency or excess of growth hormone, are discussed.
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Genetic determination as well as prospective analysis of islet cell autoantibodies and autoantibodies to insulin were conducted in a population of 479 first degree relatives of 174 Type 1 (insulin-dependent) diabetic patients. Analysis of HLA haplotypes within families illustrated the high frequency of DR3 and DR4 alleles with preferential transmission from parent to both affected and unaffected offspring. DR4 was preferentially associated with DQw3.2 (TA10-) in 60/73 (82.2%) patients and 101/127 (79.5%) relatives. Relatives have been followed for a period of 800 subject-years. Twenty-two out of 430 relatives (5.1%) were found islet cell antibodies (ICA-IgG) positive. Seven sera with low titres became negative 6 months later at two different determinations. Fifteen sera ICA-IgG and ICA-protein A positive with high titres remained positive thereafter. Half of the ICA positive relatives were also found insulin autoantibodies (IAA) positive. All but 3 ICA negative relatives did not have IAA in their sera. Analysis of IAA specificity with competition experiments indicated that most antibodies recognised epitopes shared between human and pork insulins while four were specific for human insulin determinants. Analysis of class I and class II HLA antigen distribution indicated no particular allelic restriction in antibody positive individuals. Metabolic status of antibody positive relatives was determined with oral and intravenous charge of glucose. Two haplo-identical DR3-DQw2 brothers became diabetic during the study. One child and one mother both with DR4-DQw3.2 became intolerant to glucose. Each of these relatives had high titre ICA prior to metabolic deterioration.(ABSTRACT TRUNCATED AT 250 WORDS)
A solid-phase low-ionic strength salt antiglobulin test (LISS-SPAT) has been developed using a microplate coated with dried sera as a solid phase. Before coating, the in vitro C3d fragment generation was activated by adding heat-aggregated immunoglobulin. The LISS-SPAT was compared with low-ionic strength conventional antiglobulin test (LISS-AGT) and also with a test using polybrene or papain microplates. When detecting the IgG and IgM antierythrocyte antibodies the reaction was developed in the same way in LISS-SPAT and LISS-AGT. In routine work, the LISS-SPAT provides a fast, reliable, handy and inexpensive screening of antibodies. This method appears to be an additional method to the papain and polybrene tests in microplates.
Using primary culture of steroidogenic cells in vitro, in serum-free chemically defined medium, strong evidence has been provided for actions of IGF-I on the differentiation of immature Leydig cells and on the maintenance of a differentiated function of mature adrenocortical cells. These data point to the steroidogenic cells as a target for IGF-I action. They also add further evidence for a role of IGF-I in the differentiation process. These actions can be of importance in normal physiological situations as well as in abnormal conditions where IGF-I is decreased, such as hypopituitarism and malnutrition.
Terminally radioiodinated fatty acid analogs are of potential use for the noninvasive delineation of regional alterations of fatty acid metabolism by gamma imaging. Since radioactivity from extracted iodine-123 heptadecanoic acid [( 123I]HDA) is released from the myocardium in form of free radioiodide (123I-) the present study was performed to determine whether deiodination of [123I]HDA is related to free fatty acid metabolism. Myocardial production of free radioiodide was measured in rat hearts in vitro and in vivo both under control conditions and after inhibition of fatty acid oxidation. In isolated rat hearts perfused at constant flow with a medium containing [123I]HDA, release of 123I- was markedly reduced during cardioplegia and pharmacologic inhibition of mitochondrial fatty acid transfer with POCA by 67% (p less than 0.005) and 72% (p less than 0.005), respectively. In fasted rats in vivo, 1 min after i.v. injection of [123I]HDA, 51 +/- 5% of myocardial radioactivity was recovered in the aqueous phase, containing free iodide, of myocardial lipid extracts. Aqueous activity was significantly decreased in fed (20 +/- 2%; p less than 0.002) and POCA pretreated (30 +/- 3.7%; p less than 0.05) animals exhibiting reduced oxidation of [14C]palmitate. Thus, deiodination of [123I]HDA was consistently reduced during inhibition of fatty acid oxidation in vitro and in vivo. The results apply to the interpretation of myocardial clearance curves of terminally radioiodinated fatty acid analogs.
Amiodarone is a potent antianginal and antiarrhythmic drug which affects the lipid dynamics. The influence of amiodarone ionization on the lipid transition temperature and enthalpy associated to the liquid crystalline to gel state transition was studied in multilamellar vesicles (MLV) of dipalmitoylphosphatidylcholine (DPPC) by differential scanning measurements (DSC) at different pH. These data were correlated with the calculated number of charged amiodarone molecules inserted into the lipid vesicles. The procedure of calculation requires the knowledge of the intrinsic ionization constant of amiodarone and the area occupied per amiodarone molecule in the close packed state; it can be applied successfully to water insoluble amphiphilic molecules. Only the ionized form of amiodarone molecule destabilizes the lipid matrix organisation whereas no effect was observed with the uncharged form. This destabilizing effect could be explained in terms of a modification of the drug structure induced by its ionization state or in terms of its distribution in the lipid matrix, as an isolated molecule or assembled in clusters depending on its ionization state.
This work was performed to study phospholipid metabolism in isoproterenol-induced ischemic heart and the possible protective effect of amiodarone (Am) and chlorpromazine (CPZ). Heart weight increased 24 h after subcutaneous injection of isoproterenol (40 mg/kg) whereas myocardial phospholipid content and creatine kinase activity decreased without modification of the cholesterol content. The phospholipid content was significantly correlated with creatine kinase activity (P less than 0.001). Phosphatidylcholine, phosphatidylethanolamine and cardiolipin decreased significantly (P less than 0.001) in the isoproterenol group whereas the lysophosphatidylcholine and lysophosphatidylethanolamine content increased. The lysophosphatidylcholine/phosphatidylcholine and lysophosphatidylethanolamine/phosphatidylethanolamine ratios consequently increased to a significant degree (P less than 0.01) suggesting indirectly the activation of phospholipases A in the ischemic myocardium. Free fatty acid content increased, indicating hydrolysis of phosphatidylcholine, phosphatidylethanolamine, lysophosphatidylcholine and lysophosphatidylethanolamine. Intravenous injection of Am (20 mg/kg) or intraperitoneal injection of CPZ (30 mg/kg) prior to isoproterenol injection provided complete protection against phospholipid depletion and against increase of the lysophosphatidylcholine/phosphatidylcholine and lysophosphatidylethanolamine/phosphatidylethanolamine ratios which returned to control values. Neither substance had any effect on the heart weight increase due to an edematous and inflammatory process. The total protection by both substances against phospholipid depletion was not sufficient to prevent the creatine kinase activity decrease. The improved phospholipid degradation in the ischemic myocardium is discussed in relation to the in vitro inhibitory effect of Am or CPZ on phospholipases A activity.
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To assess whether myocardial lipid metabolism is altered in the "stunned" myocardium we have studied the metabolism of (1-14C)-palmitate during reperfusion in a modified rat heart preparation. Hearts were perfused retrogradely at a physiological flow rate (2 ml/min) in a non-recirculating system with erythrocyte-enhanced Krebs-Henseleit buffer containing albumin 0.4 mM, glucose 11 mM, palmitate 0.4 mM and trace amounts of (1-14C)-palmitate. Left ventricular pressure was measured by a latex balloon in the left ventricular cavity. Control hearts were perfused at constant flow for 120 min. To achieve reversible ischaemic damage, myocardial perfusion was reduced by 95% for 40 min, followed by reperfusion at the control flow rate for 60 min (reperfusion group). For comparison, irreversible damage was produced by calcium free perfusion (calcium paradox group). In the reperfusion group, the developed pressure was severely depressed 5 min after reperfusion to 23% of the value in the control group (p less than 0.05) but recovered to 84% (NS) at 60 min. In the calcium paradox group, mechanical activity ceased completely without recovery. Myocardial uptake of (1-14C)-palmitate in the reperfusion group was similar to the control experiments for the entire reperfusion period, whereas a marked depression was observed in the calcium paradox group. 14CO2 production was severely depressed at the onset of reperfusion in both the reperfusion and calcium paradox group to 42% (p less than 0.05) and 29% (p less than 0.05) respectively. In contrast to the calcium paradox group, 14CO2 production in the reperfusion group recovered progressively to 70% (NS) of the control value during the 60 min of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Extracellular matrices (ECM) have been reported to enhance epithelial cell attachment and proliferation as well as to induce differentiation in vitro. Since ECM components are physiological constituents of the dermoepidermal basement membrane, we studied the growth and differentiation of human keratinocytes on ECM in order to determine the benefits of culturing epidermal epithelial cells (keratinocytes) on reconstituted basement membranes. Disaggregated epidermal cells were grown in primary and subcultures in liquid medium; the attachment of the cells was greatly enhanced by ECM and noted within the first few hours after seeding; cells formed small islets that reached confluence within 2-12 days depending upon the plating density and the type of culture (primary or passages). Histological and ultrastructural cross-sections of the cultures clearly indicated that a multilayered epithelium can be obtained including a basal cell layer, several intermediate cell layers with cytoplasmic organelles, intermediate size filaments, desmosomes, and keratohyaline granules, and an upper layer of anucleated cells. Using immunofluorescence, both pemphigus and pemphigoid (basal membrane zone) antigens were expressed. The keratin pattern noted indicated that these epithelia differentiate and keratinize but do not express a complete program of keratinization, a finding usually noted when cells are grown submersed. These data show that ECM favor epidermal cell proliferation and differentiation and suggest that they may be used to obtain large amounts of epidermal equivalent suitable for grafting and/or in vitro studies.
Using primary culture in a chemically defined medium of somatic testicular cells from immature pig, we were able to demonstrate synthesis and secretion of Somatomedin-C/Insulin-Like Growth Factor 1 (Sm-C/IGF-1) by Sertoli cells, a process that is stimulated by Fibroblast Growth Factor (FGF). The presence of IGF type 1 receptor was demonstrated on Sertoli cells. Sm-C/IGF-1 stimulates and potentiates the effects of FGF on both cell multiplication and secretion of plasminogen activator. The presence of both IGF type 1 and insulin receptors was also documented on immature Leydig cells. Pre-incubation of immature Leydig cells for 48 hours with Sm-C/IGF-1 resulted in a dramatic dose-dependent increment of both the LH receptor number and steroidogenic response to LH as well as a clear stimulation of DNA synthesis. These data provide new important insights on the role played by Sm-C, a growth and differentiating factor, on the maturation of the male gonad endocrine function.
Twenty patients with a chronic total coronary artery occlusion were studied before and 1 to 48 months (mean 9) after successful recanalization by angioplasty and compared with a group of 20 normal subjects. Before angioplasty, 19 of these 20 patients had angina. Collateral vessels to the distal part of the occluded vessel were visible in all 20 patients. A previous myocardial infarction was documented in 14 patients (9 with a Q wave and 5 with a non-Q wave infarction). At the time of follow-up, three patients were symptomatic: one had unstable angina and two had a positive stress test. The follow-up angiogram showed a significant restenosis in six patients and reocclusion in two. The mean ejection fraction had improved slightly from 59 +/- 11% to 63 +/- 9% (p less than 0.05). Left ventricular wall motion synchronism was studied using two variables for 128 shortening segments: the "time of peak contraction" and the "time of peak relaxation," as obtained from biharmonic Fourier transformation for each segment. Their respective standard deviations reflect the synchronism of contraction and relaxation. The mean standard deviations of the two variables expressed in degrees of one cardiac cycle (360 degrees) were respectively: 5.5 +/- 0.4 degrees for the time of peak contraction and 6.0 +/- 0.5 degrees for the time of peak relaxation in the 20 normal subjects, 11.7 +/- 1.7 degrees and 23.0 +/- 3.0 degrees before recanalization and 9.6 +/- 1.8 degrees and 12.5 +/- 2.2 degrees at follow-up in the group of 20 patients. These values were significantly higher (p less than 0.05) in the patients than in the normal group.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of human somatomedin C/insulin-like growth factor I(SM-C/IGF-1) and human growth hormone (hGH) on colony formation by erythroid precursor cells (CFU-E and BFU-E) from children's bone marrow or blood was studied by methylcellulose cloning assay. We found that physiological concentrations of IGF-1, but not of hGH, stimulated erythropoiesis in vitro in the presence of erythropoietin, as demonstrated by the increased activity of a cytosolic enzyme of the heme pathway (uroporphyrinogen I synthase). The results suggest that IGF-I could be involved in the regulation of erythroid differentiation.
A videodensitometric method for quantification of aortic regurgitation which requires neither measurement of cardiac output nor determination of enddiastolic and endsystolic left ventricular volumes has been developed. The injection of 20 ml of contrast medium into the left ventricle is digitally recorded at 25 images s-1 during 20 s using an equipment for digital subtraction angiography (Digitron 2, Siemens). The Digitron computes 2 'time dilution curves' (TDC) from the unsubtracted image sequence, for 2 regions of interest drawn around the angiographic enddiastolic and endsystolic left ventricular silhouettes. Enddiastolic and endsystolic points of the TDC are then entered into a VAX-750 computer, which calculates the ejection fraction (EF), the forward ejection fraction (FEF) and the regurgitant fraction (RGF). This is performed by a complex fitting algorithm based on a physical model of the washout process of contrast medium, which reconstructs the two best enddiastolic and endsystolic baselines in the washout parts of the two TDC. The EF, FEF and RGF obtained in 9 regurgitant and 11 nonregurgitant patients have been compared with the corresponding values EFv, FEFv and RGFv obtained by a conventional technique (Cardiogreen and biplane LV area-length volumetry). Regression analysis yielded: EF = 0.88 X EFv (regression line forced through the origin), r = 0.77, FEF = 0.76 X FEFv + 3, r = 0.96, RGF = 0.94 X RGFv + 5, r = 0.98 (v stands for volumetry).
The effects of reperfusion on the myocardial accumulation of neutrophils and their role in the extent of injury were investigated in a canine preparation with a 3 hr coronary occlusion followed by 21 hr of reperfusion. The left anterior descending coronary artery (LAD) was permanently occluded in group 1 and reperfused after 3 hr in four others (groups 2 to 5). All but group 5 received lidocaine (1 mg/min over 8 hr). A critical stenosis was produced and left in place at reperfusion only in group 2. In groups 1 and 2, 111In-labeled autologous neutrophils were injected at the time of coronary occlusion. Group 4 animals were rendered leukopenic 2 hr before the coronary ligature and throughout the experiment by injection of an antineutrophil rabbit serum. Quantification of the radioactivity by digitized scintigraphy of the heart slices revealed an 80% (p less than .05) increase in neutrophil accumulation in the infarct region after reperfusion (group 2) as compared with permanent occlusion (group 1). Gamma counting of myocardial tissue samples showed that the neutrophil accumulation ratio in the subendocardial central zone of the infarct was increased five times (p less than .05) by reperfusion, whereas no difference was evident in the subepicardium. Infarct size and myocardial area at risk were not statistically different among the five groups. However LAD flow in the leukopenic group (group 4) was significantly higher (p less than .05) 30 min after reperfusion (40.0 +/- 5 ml/min) when compared with the preocclusion value (21.7 +/- 4 ml/min). In contrast, in a parallel experiment without leukopenia (group 3), LAD flow after reperfusion did not differ from the preocclusion value.(ABSTRACT TRUNCATED AT 250 WORDS)
Idiopathic PRL deficiency was detected in a parturient woman with otherwise normal pituitary function. This PRL disorder first became manifest postpartum when she had no milk production, and oral metoclopramide failed to raise her serum PRL levels. Her second pregnancy occurred spontaneously after 3 yr of attempts to conceive. During the pregnancy, her serum PRL concentration was very low, varying from 4.5-7.8 ng/ml, and the puerperium was again characterized by alactogenesis. During normal menstrual cycles and after iv GnRH, TRH, metoclopramide, and insulin tolerance tests, serum PRL was only rarely detectable by RIA, at very low concentrations. Bioassay results confirmed the PRL deficiency. The results confirm that PRL is necessary for puerperal lactation and suggest that it is needed for normal ovarian function. The present data also suggest that the maternal pituitary is the main source of serum PRL during pregnancy, and the decidua has only a minor contribution in this respect.