[A pool unlike any other].
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Child Day Care Centers↗
Biomedical subjects
F Girard
Publications and source records attributed to F Girard.
Comparison of two levels of vitamin C supplementation on antioxidant vitamin status in elderly institutionalized subjects.
The concentrations of antioxidant vitamins, particularly vitamin C, are often low in the plasma of institutionalized elderly subjects, and could explain their susceptibility to oxidative stress. However, as such low levels were not always found in home-living healthy elderly persons, the antioxidant vitamin depletion in the formers could result from environmental conditions better than aging itself. The objective of this study was therefore to verify the antioxidant vitamin status in institutionalized elderly persons and to evaluate if a low vit C supplement could be sufficient to improve the plasma vit C concentration in those subjects. This study confirms that plasma vitamin C levels are in the scurvy range in 20 elderly institutionalized subjects and significantly lower than in healthy home-living elderly persons. Beta-carotene concentrations were found marginally low but alpha-tocopherol levels were in the normal range. All three vitamins were correlated. Fifteen days on a physiological vitamin C (150 mg/day) supplementation was sufficient to restore normal vit C levels (50 mumol/l). A further pharmacological vit C administration (750 mg/day) during 30 days only allowed a marginal increase in the plasma vit C concentrations.
Aged↗
Activation of p34cdc2 protein kinase by microinjection of human cdc25C into mammalian cells. Requirement for prior phosphorylation of cdc25C by p34cdc2 on sites phosphorylated at mitosis.
Human cdc25C protein, a specific tyrosine phosphatase that activates the p34cdc2 protein kinase at mitosis, is itself a phosphoprotein that shows increased phosphorylation during the G2-M transition. In vitro, cdc25C protein is substantially phosphorylated by purified p34cdc2-cyclin B protein kinase. Of seven putative phosphorylation sites for p34cdc2 protein kinase present in human cdc25C, five are phosphorylated by p34cdc2 protein kinase in vitro, as assessed by tryptic phosphopeptide mapping and peptide sequencing. These same sites are also phosphorylated in vivo during the G2-M transition in normal mammalian fibroblasts and have been precisely mapped. The cdc25C phosphorylated in vitro by p34cdc2 protein kinase exhibits a 2-3-fold higher activity than the nonphosphorylated cdc25C, as assayed by activation of inactive cdc2 prokinase. Microinjection of purified cdc25C proteins into living fibroblasts reveals that only the phosphorylated form of cdc25 is highly effective in activating G2 cells into premature prophase in a manner similar to microinjection of purified active p34cdc2 protein kinase. Together these data show that multisite phosphorylation of cdc25C by p34cdc2-cyclin B protein kinase occurs at the G2-M transition and is sufficient to induce the autoamplification of cdc2/M-phase promoting factor necessary to drive somatic mammalian cells into mitosis.
Amino Acid Sequence↗
Localized T2 measurements using an OSIRIS-CPMG method. Application to measurements of blood oxygenation and transverse relaxation free of diffusion effect.
This work presents a new method allowing localized T2 measurements, based upon the OSIRIS scheme. A train of 180 degrees pulses is applied after the OSIRIS preparation cycle, recording directly the transverse magnetization decay. The method was verified for two nuclei, 1H and 19F, with phantoms and in vivo on rats. The accuracy of the T2 values is discussed, as well as possible applications of the OSIRIS-CPMG method to proton transverse spin relaxation measurements, free of diffusion effects, and to non-invasive in vivo blood oxygenation measurements, through the use of an emulsion of perfluorooctylbromide, a blood substitute containing fluorine.
Animals↗
Clonal analysis of human adrenocortical carcinomas and secreting adenomas.
OBJECTIVES: Adrenocortical tumours in man are characterized mainly on biochemical, anatomical and histological grounds which establish their secretory pattern and, with some uncertainty, their benign or malignant nature. To study further these tumours and eventually to shed some light on their pathogenesis, we determined their clonal composition. METHODS: Clonal composition was determined by X-chromosome inactivation analysis on tumour and leucocyte DNA using three markers: M27 beta, phospho-glycero-kinase (PGK) and hypoxanthine-phosphoribosyl transferase (HPRT) with 88, 33 and 27% heterozygosity rates respectively. PATIENTS: Clonal analysis was performed on 25 tumours from 19 heterozygous female patients: four had a carcinoma, 14 had a single secreting adenoma, and one had autonomous bilateral macronodular hyperplasia with Cushing's syndrome (seven adenomas examined). RESULTS: The malignant tumours had patterns indicative of monoclonality. The single adenomas displayed contrasting results with patterns indicative of monoclonality in eight cases, and patterns indicative of polyclonality in six cases; monoclonal adenomas were larger and had a higher prevalence of nuclear pleomorphism than the apparently polyclonal adenomas. In the patient with bilateral macronodular hyperplasia, different clonal patterns were present in different adenomas: whereas a clear monoclonal pattern was observed in the three adenomas of the right gland, in which the active X-allele was not always the same, in two interpretable adenomas of the left gland, a moderately skewed pattern suggested a partial monoclonal component. CONCLUSIONS: These data show that adrenocortical carcinomas are monoclonal and suggest that adenomas may arise from a single cell or from more than one cell under the putative action of local growth factors. In adenomas, which until now had appeared homogeneous, this genetic heterogeneity may reflect different pathophysiological mechanisms or it may represent different stages of a common multistep process exceptionally occurring in a single patient with bilateral macronodular hyperplasia.
Adenoma↗
Rearrangements at the 11p15 locus and overexpression of insulin-like growth factor-II gene in sporadic adrenocortical tumors.
Little is known about the pathophysiology of sporadic adrenocortical tumors in adults. Because loss of heterozygosity at the 11p15 locus has been described in childhood tumors, particularly, in adrenocortical tumors, associated with the Beckwith-Wiedemann syndrome and because insulin-like growth factor-II (IGF-II) is a crucial regulator of fetal adrenal growth, we looked for structural analysis at the 11p15 locus and IGF-II gene expression in 23 sporadic adrenocortical adult tumors: 6 carcinomas (5 with Cushing's syndrome and 1 nonsecreting) and 17 benign adenomas (13 with Cushing's syndrome, 1 pure androgen secreting, and 3 nonsecreting). Twenty-one patients were informative at the 11p15 locus, and six (four carcinomas and two adenomas) of them (28.5%) exhibited 11p15 structural abnormalities in tumor DNA (five, an uniparental disomy and one, a mosaicism). In a single case that could be further studied, a paternal isodisomy was observed. Very high IGF-II mRNA contents were detected in seven tumors (30%; 5 of the 6 carcinomas and 2 of the 17 adenomas). They were particularly found in tumors with uniparental disomy at the 11p15 locus. Overall, a strong correlation existed between IGF-II mRNA contents and DNA demethylation at the IGF-II locus. These data show that genetic alterations involving the 11p15 locus were highly frequent in malignant tumors, but found only in rare adenomas. These results in combination with evidence for overexpression of IGF-II from the 11p15.5 locus suggest that abnormalities in structure and/or expression of the IGF-II gene play a role as a late event of a multistep process of tumorigenesis.
Adenoma↗
Environmental exposure to cadmium and human birthweight.
Fetal toxicity of cadmium (Cd) is well documented in rodents. However, little information is available regarding the human fetus. To investigate the effect of low levels of Cd on the human placenta and the consequences on birthweight, we conducted a study of 102 mothers and their newborns in an obstetrical care unit. Placental and hair samples were collected at delivery to determine Cd concentrations. The main finding of this study was the relationship between a decrease in birthweight and an increase of newborn hair Cd which varied in the presence of placental calcification. In cases of parenchymal calcifications, placental Cd levels were higher (Wilcoxon test, P < 0.05) and newborn hair Cd levels were lower (Wilcoxon test, P < 0.01) than in the absence of calcification. These relationships remained significant even after taking into account smoking habits and gestational age. In the presence of calcification, an increase in the level of Cd in newborn hair was related to a decrease in birthweight which was independent of placental Cd concentration (rpartial = -0.49, P < 0.01). In the absence of calcification, a decrease in birthweight was observed for the upper values of newborn hair Cd (r = -0.44, P < 0.05 when Cd > or = 0.3 ppm). The difference in birthweight between infants in the first and last quartiles of newborn hair Cd was 472 g in cases of calcifications and 122 g in the absence of calcification. Other placental parameters were not significantly related to placental Cd concentration.
Birth Weight↗
The MO15 gene encodes the catalytic subunit of a protein kinase that activates cdc2 and other cyclin-dependent kinases (CDKs) through phosphorylation of Thr161 and its homologues.
Phosphorylation of Thr161, a residue conserved in all members of the cdc2 family, has been reported to be absolutely required for the catalytic activity of cdc2, the major regulator of eukaryotic cell cycle. In the present work, we have purified from starfish oocytes a kinase that specifically activates cdc2 in a cyclin-dependent manner through phosphorylation of its Thr161 residue. Our most highly purified preparation contained only two major proteins of apparent M(r) 37 and 40 kDa (p37 and p40), which could not be separated from each other without loss of activity. The purified kinase was found to phosphorylate not only cdc2, but also cdk2 and a divergent cdc2-like protein from Caenorhabditis, in chimeric complexes including both mitotic and G1/S cyclins. Extensive microsequencing of p40 did not reveal any convincing homology with any known protein. In contrast, p37 is the starfish homologue of the M015 gene product, a kinase previously cloned by homology probing from a Xenopus cDNA library. As expected, immunodepletion of the MO15 protein depleted Xenopus egg extracts of CAK (cdk-activating kinase) activity, which was recovered in immunoprecipitates. Taken together, the above results demonstrate that MO15 is a gene conserved throughout evolution (at least from echinoderms to vertebrates) that encodes the catalytic subunit of a protein kinase that activates cdc2-cdks complexes through phosphorylation of Thr161 (or its homologues).
Adenosine Triphosphate↗
Validity of hair cadmium in detecting chronic cadmium exposure in general populations.
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Adult↗
Potentiation of the classic ovine corticotrophin releasing hormone stimulation test by the combined administration of small doses of lysine vasopressin.
OBJECTIVE: To assess the corticotrophic response to ovine corticotrophin releasing hormone (CRH) with the lowest dose of lysine vasopressin able to induce both the greatest stimulation and the lowest degree of side-effects. SUBJECTS: Fourteen healthy young adult males. DESIGN: Increasing intravenous doses (either 0, 0.03, 0.1, 0.3, or 1 IU) of lysine vasopressin, infused over 20 minutes, combined with a bolus of 100 micrograms ovine CRH. MEASUREMENT: Radioimmunoassay of plasma ACTH, lipotrophin hormones and cortisol levels. RESULTS: (1) Responses to stimulation tests were evaluated as the area under the curves of plasma levels versus sample times, from 0 to 120 minutes after injection or start of perfusion (six subjects). The lowest dose of lysine vasopressin that induced an additional stimulation in the CRH-stimulated ACTH response was 0.3 IU. The combination of 1 IU lysine vasopressin with CRH doubled values of the area under the curve for the ACTH. Lysine vasopressin alone (0.3 and 1 IU) failed to stimulate ACTH responses. (2) The combined test (100 micrograms CRH and 1 IU lysine vasopressin) was carried out on eight additional control subjects. From a mean basal level of 23 +/- 5.6 (SEM), plasma ACTH peaked to 104.5 +/- 8 ng/l (23.0 +/- 1.8 pmol/l) as early as 20-30 minutes after the start of injection. When repeated after a two-week interval, the combined test induced identical stimulation in a given subject. Results of lipotrophin hormone determinations roughly paralleled those of ACTH. However the effects on cortisol levels were less clear. Subjects injected with CRH experienced slight facial flush. Following the 1 IU lysine vasopressin dosage, side-effects were reduced to skin pallor. No changes in heart-rate or blood-pressure were observed. CONCLUSIONS: Under these conditions, the combination of 100 micrograms CRH with 1 IU lysine vasopressin constitutes a powerful test for direct assessment of the pituitary reserve and therefore can be employed as a routine investigational tool.
Adrenocorticotropic Hormone↗
Plasma immunoreactive joining peptide in man: a new marker of proopiomelanocortin processing and corticotroph function.
Joining Peptide (JP) is a 30 amino acid fragment separating the N-terminal peptide and ACTH within their common polypeptide precursor POMC. Using antibody Jamie directed against the C-terminal amidated residue Glu-NH2 we studied the molecular weight forms and the variations of plasma immunoreactive (IR)-JP in man under various physiological, pharmacological, and pathological conditions. In 21 plasma samples from patients with ACTH hypersecretory syndromes from pituitary and nonpituitary tumors, IR-JP had the same elution pattern on Sephadex G-75 showing a predominant, if not single, peak corresponding to a mol wt of 7000 as expected for a JP-homodimer. Normal male volunteers at 0800 h had plasma IR-JP values ranging from undetectable (< 6 pmol/L) to 28 pmol/L; all values were suppressed by the overnight 1 mg dexamethasone test. Plasma IR-JP had circadian variations and responded to the metyrapone test in a manner strictly similar to that of ACTH and lipotropins (LPHs). One hundred and fifteen plasma samples covering a large range of pathological ACTH values (from 10(0) to 10(4) pmol/L) were also assayed by the JP and LPH RIAs. All three immunoreactivities strongly correlated with each other with a molar ratio close to 1:1. Discrepancies were observed in two situations where both IR-JP and IR-LPH were much higher than ACTH: they occurred in some patients with the ectopic ACTH syndrome and in all patients with chronic renal failure; they are explained by the further degradation of ACTH into corticotropin-like intermediary lobe peptide in the first case, by the prolonged plasma half-life of JP and LPH, compared to that of ACTH, in the second case. These data show that JP is a normal end-product of POMC processing in man which circulates in blood mainly as a homodimer. It provides yet another marker of the overall corticotroph function and may be used to unravel abnormal POMC processing in some nonpituitary tumors.
Adrenocorticotropic Hormone↗
Evaluation of acromegaly by measurement of 24-hourly urinary growth hormone excretion.
Twenty-four hourly urinary growth hormone excretion (24-h uGH) has been quantified using a combination of ultrafiltration and conventional immunoradiometric assay. Twenty-four hourly uGH was measured in 20 normal adults and in 42 patients with acromegaly (9 untreated, 28 treated but with above-normal IGF-I levels, and 5 treated and cured). The means and ranges were as follows: 3.7 (1-9) ng/24 h for normals and 160 (40-540), 66 (2-380) and 5.2 (4-8) ng/24 h for the three groups of acromegalic patients, respectively. Ten patients with pituitary adenomas without acromegaly had 24-h uGH within the normal range. Twenty-four hourly uGH therefore gives a clear differentiation between controls and untreated patients. Log-transformed values for subjects with acromegaly showed significant correlations between 24-h uGH and levels of IGF-I (r = 0.63, p < 0.01), fasting plasma GH (r = 0.92, p < 0.001) and plasma GH after glucose loading (r = 0.85, p < 0.001). Twenty-four hourly uGH was also determined in three acromegalic patients before and during SMS 201-995 therapy. Twenty-four hourly uGH reflected the corresponding changes in mean levels for hourly sampling over 12 h of plasma GH and IGF-I and in clinical signs after 3-6 months of therapy. The results of this study indicate that 24-h uGH is an accurate indicator of GH secretion in acromegalic patients and could therefore be used both in diagnosis and in monitoring the progress of therapy in these patients.
Acromegaly↗
[Cushing syndrome in children].
In pediatric patients, endogenous Cushing syndrome is an infrequent condition almost always due to one of two conditions. 1) Adrenal gland tumors account for 70% of Cushing syndromes in young pediatric patients. They cause rapidly progressive hypercorticism not due to increased ACTH production (elevated plasma and urine cortisol levels, very low ACTH and LPH levels unchanged by dexamethasone, metyrapone or CRH). Imaging techniques determine the side and spread of the tumor and look for metastases. Following surgical removal, patients with indicators of malignant disease (tumor weight above 30 g, extracapsular spread or metastases, independently from pathological data) are given op'DDD. 2) Cushing disease occurs in peripubertal patients and causes overweight with delayed statural gain. ACTH production is increased (positive dexamethasone suppression test and provocative metopirone and CRH tests) as a result of a pituitary adenoma which should be looked for by magnetic resonance imaging and whose removal ensures recovery in 50% of cases. Other therapeutic tools include op'DDD, radiation to the pituitary, and bilateral adrenalectomy as the last resort given the high risk of post-adrenalectomy pituitary tumor (50% of pediatric patients). Other causes are exceedingly rare: primary nodular hyperplasia of the adrenal glands and production of ACTH by a nonpituitary tumor. Corticosteroid treatment is the most common cause of Cushing syndrome in children.
Adolescent↗
Aryl hydrocarbon hydroxylase activity in human placenta and threatened preterm delivery.
Induction of aryl hydrocarbon hydroxylase (AHH) activity in the placenta has been well documented. This enzyme may be induced by a variety of Polycyclic Aromatic Hydrocarbons (PAHs) and the AHH inducibility is associated with harmful effects of environmental chemicals. Toxic effects of PAHs in tissues such as placenta have been demonstrated to be due to their metabolites, epoxides, which interact with DNA. Thus, environmental PAHs may be related to its alterations in fetal development. Founded on these findings the PAH metabolites could interfere with the normal course of the pregnancy and may be an aborticide, a teratogen or a carcinogen. We hypothesize that low increased activity of placental Aryl Hydrocarbon Hydroxylase (AHH) may be an important determinant of human fetotoxicity. The present investigation was designed to examine the possible implications of PAH exposure at environmental exposure levels on the normal course of the pregnancy using AHH induction as an indicator of PAH exposure. Threatened Preterm Delivery (TPD) was used as an index of problems in the normal course of pregnancy. A group of forty pregnancies at term with TPD was compared with eighty controls for placental AHH induction. Macroscopic placental examination was also performed. A significant increase in prevalence of placental AHH induction with TPD was shown (Odds-Ratio = 2.8; 95% confidence bounds [1.3-6.2]; chi 2 = 6.7 p < 0.01). No such increases were found associated with placental pathology. When taking into account the group of placenta without basal plate calcifications, the significant increase in prevalence of placental AHH induction with TPD above mentioned was greatly increased (Odds-Ratio = 8.9; 95% confidence bounds [2.4-32.9]; chi 2 = 11.1 p < 0.001) controlling for gestational age. The increase in prevalence of placental AHH induction with TPD disappeared when taking into account the subgroup with basal plate or parenchyma calcifications. It is hypothesized that the high estrogen and progesterone at term may explain these associations.
Adult↗
Scanning secondary ion analytical microscopy with parallel detection.
The secondary ion microscope described here allows to obtain the simultaneous registration of chemical and isotopic distribution maps of several elements composing the sample. The instrument has been specially designed to optimize both sensitivity and selectivity; bombardment with primary Cs+ ions to increase the ionization yields of negative secondary ions, efficient collection of secondary ions at the target surface, matching of the secondary ion beam etendue with the acceptance of the mass spectrometer working at high mass resolution, spectrometer with parallel detection capabilities. The probe diameter can be made as low as 30 nm and ion induced electron images registered at the same time as ion images. Presently, four ion micrographs are obtained simultaneously over a field of view up to 20 x 20 micro m2 containing up to 512 x 512 pixels. Examples are shown with an ion probe diameter of 0.1 microm.
Breast Neoplasms↗
Placental aryl hydrocarbon hydroxylase activity and placental calcifications.
Induction of aryl hydrocarbon hydroxylase (AHH) activity in the placenta as a result of maternal exposure to polycyclic aromatic hydrocarbons contained in cigarette smoke has been well documented. Furthermore, calcifications are more prevalent in the placentas of pregnant smokers than in those of non-smokers. The present study examines whether this latter relationship could be explained by the induction of AHH activity in the placenta. AHH levels were determined at birth in 141 unselected pregnant women admitted for delivery. Macroscopic placental examination was performed for vascular lesions, abnormalities of placental shape, of the cord and parameters of placental maturity such as basal and parenchymatous calcifications. Significant increases in the prevalence of calcifications of the placental basal plates and parenchyma with the induction of placental AHH were found. A similar significant association between smoking and AHH activation was also observed. These findings remained unchanged when controlling for smoking status assessed both by questionnaire and presence of cotinine in mother's urine. Moreover, the apparent association between smoking 'factor' and calcifications disappeared when controlling for AHH induction. Therefore, the association between smoking and placental calcifications previously related could be mediated by the AHH induction.
Aryl Hydrocarbon Hydroxylases↗
cdc25 is a nuclear protein expressed constitutively throughout the cell cycle in nontransformed mammalian cells.
A family of proteins homologous to the cdc25 gene product of the fission yeast bear specific protein tyrosine phosphatase activity involved in the activation of the p34cdc2-cyclin B kinase. Using affinity-purified antibodies raised against a synthetic peptide corresponding to the catalytic site of the cdc25 phosphatase, we show that cdc25 protein is constitutively expressed throughout the cell cycle of nontransformed mammalian fibroblasts and does not undergo major changes in protein level. By indirect immunofluorescence, cdc25 protein is found essentially localized in the nucleus throughout interphase and during early prophase. Just before the complete nuclear envelope breakdown at the prophase-prometaphase boundary, cdc25 proteins are redistributed throughout the cytoplasm. During metaphase and anaphase, cdc25 staining remains distributed throughout the cell and excludes the condensed chromosomes. The nuclear locale reappears during telophase. In light of the recent data describing the cytoplasmic localization of cyclin B protein (Pines, J., and T. Hunter. 1991. J. Cell Biol. 115:1-17), the data presented here suggest that separation in two distinct cellular compartments of the cdc25 phosphatase and its substrate p34cdc2-cyclin B may be of importance in the regulation of the cdc2 kinase activity.
Amino Acid Sequence↗
Molecular diagnosis of Turner's syndrome.
Turner's syndrome is a common disorder which occurs in around 1/3000 live births in girls. Diagnostic use of polymorphic DNA markers for the X chromosome could help to reduce the number of time consuming karyotype analyses needed. The M27 beta probe maps on the X chromosome to Xcen-Xp11-22 and in 83% of female subjects detects heterozygosity with multiallelic polymorphism. In Southern blotting, a single X chromosome yields a single hybridisation band. In this study, genomic DNA was extracted from leucocytes of 49 patients with Turner's syndrome (karyotypes: 45,XO, n = 29; 45,XO/46,XX, n = 4; 46,Xi(Xq), n = 1; 45,XO/46,Xi(Xq), n = 4; 45,XO/46,Xr(X), n = 4; 45,XO/46,XY, n = 4; 46,XXp-, n = 3), digested with EcoRI or HindIII, and analysed by Southern blotting. The molecular data for each patient were compared with DNA controls (homozygous 46,XX, heterozygous 46,XX and 46,XY DNA). A single band of reduced intensity compared to homozygous 46,XX control DNA was seen in 41 cases. Two hybridisation bands of different intensities were seen in four patients, in one of whom mosaicism was suspected on the basis of molecular analysis, despite a 45,XO karyotype. In four cases, Turner's syndrome failed to be detected: one 45,XO/46,XX mosaicism with only 4% of 45,XO cells and three distal Xp deletions. DNA analysis appears to be a useful and rapid tool in screening for Turner's syndrome and could be an alternative to cytogenetic analysis in diagnosing the disorder when severe growth retardation or delayed puberty are not accompanied by a Turner phenotype.
Blotting, Southern↗