PubMed Health⌕ Search

Biomedical subjects

L Leclerc

Publications and source records attributed to L Leclerc.

At least 19 recordsLinked to original sources
PubMed2004

Thyroid carcinomas involving follicular and parafollicular C cells: seventeen cases with characterization of RET oncogenic activation.

Recent studies have focused on the occurrence of concomitant medullary-papillary thyroid carcinomas (MTC-PTC). The aims of this report were to compare the frequency of occult PTC in a population with MTC versus a control population that had undergone thyroidectomies and to check whether differences could be related to particular phenotype or genotype. To achieve these goals, we determined the frequency of occult PTC among patients operated for MTC (n = 82) or undergoing total thyroidectomy mainly for goiter and/or nodules (n = 7313) between 1994-2001. We then examined the clinical, histologic, and genetic characteristics (using a bio-chemical family inquiry and screening for RET germline mutations) of patients with associated PTC-MTC. Results show a significantly higher frequency of occult PTC in MTC (14.7%) than in total thyroidectomy (6.8%; p < 0.01). Seventeen cases of MTC or bilateral C-cell hyperplasia (CCH) and separate occult PTC were identified from 16 different families. Although common RET mutations providing evidence of familial forms of MTC were identified in only 3 of 16 families, clinical and histologic features usually seen in inherited forms of MTC such as young age of occurrence, bilateral CCH or associated case in family were found in 11 of the remaining 14 patients. In conclusion, results suggest that the association of MTC-PTC is not only a coincidence. Surprisingly, 11 of 17 MTC-PTC patients exhibited clinical, histologic, and/or family features usually encountered in familial forms despite the fact that no RET defect were present. This suggests the possible involvement of another gene or uncommon abnormality of RET gene.

Adult↗
PubMed2004

A new generation of polymer nanoparticles for drug delivery.

One of the main interests of using polymer nanoparticles as drug carrier systems is to control the delivery of the drugs including their biodistribution. During the last decade, it was clearly demonstrated that surface properties of nanoparticles were the key factor which determined the in vivo fate of such a carrier. Thus, the purpose of this work was to develop a new method which allows the easy fabrication of nanoparticles with versatile surface properties using polysaccharides. This preparation was based on the use of a redox radical polymerization reaction applied for the first time to the emulsion polymerization of alkylcyanoacrylates in aqueous continuous media. The dispersion of nanoparticles was very stable. The nanoparticle surfaces were coated with polysaccharides and their characteristics can be modulated by the type and the molecular weight of the polysaccharides used during the synthesis. Interestingly the biological properties of the polysaccharide immobilized on the nanoparticle surface can be preserved opening very interesting perspectives for such nanoparticles. This method also offers a new strategy for the design of modular biomimetic nanoparticles as drug carrier systems with multiple functions. One of the applications considered in this work was to use these nanoparticles coupled with haemoglobin as an oxygen carrier.

Complement System Proteins↗
PubMed2003

[Multiple endocrine neoplasias. Recent advances in clinical and genetic diagnosis].

PURPOSE: Multiple endocrine neoplasias (MEN) are autosomal dominant inherited syndromes characterized by the association of different glandular lesions in several members of the same kindred. The main clinical features of MEN 1 include primary hyperparathyroidism, pancreatic islet cell tumors and pituitary adenomas; less common features are adrenal adenomas, thymic and bronchial carcinoid tumors, lipomas and various cutaneous lesions. The MEN 2 syndromes (MEN 2A, MEN 2B and familial medullary thyroid carcinomas) are characterized by high penetrance of medullary thyroid carcinoma and differ in their variable expression of pheochromocytoma, hyperparathyroidism and other clinical features. CURRENT KNOWLEDGE AND KEY POINTS: MEN 1 tumor suppressor gene encodes a nuclear protein, menin, which interacts with different regulation transcription factors. The MEN 2 syndromes are caused by germ-line mutations of the RET proto-oncogene, which encodes a transmembrane tyrosine kinase. Genetic testing for mutations in these 2 genes allows identification of individuals predisposed to the disease, early diagnosis, and clinical and therapeutic management. FUTURE PROSPECTS AND PROJECTS: Fundamental approach will allow a best comprehension of physiopathogenic mechanisms of these disorders and the improvement of therapeutic management.

Genetic Testing↗
PubMed2001

Clinical evaluation of a new sensitive calcitonin assay: study of specificity.

BACKGROUND: Calcitonin (CT) is the most sensitive marker available for medullary thyroid carcinoma, but it lacks specificity. Procalcitonin is the precursor protein of calcitonin. Infections are known to be associated with elevations of procalcitonin. The aim of this study was to evaluate a new sensitive calcitonin assay in a large population and to study the assay specificity in two particular populations: patients with renal failure and patients hospitalized in intensive care units with a high procalcitonin level. METHODS: Using two immunometric assays (A and B) to detect only mature calcitonin, we evaluated the calcitonin level in 488 sera (46 stimulation tests) from 340 subjects. RESULTS: The clinical evaluation showed that the calcitonin concentrations obtained with the two assays were similar for all patients except those with high procalcitonin levels. Among the patients, 12% (n=13) had basal calcitonin concentrations greater than 10 pg/ml with method A and 25.7% (n=25) with kit B. No correlation was found between calcitonin and procalcitonin concentrations. CONCLUSION: The new sensitive calcitonin assay tested is very efficient especially for the low concentrations. The cross-reaction for high procalcitonin levels exists and is variable according to the kits used. The procalcitonin evaluation can help the interpretation of ambiguous calcitonin levels.

Adolescent↗
PubMed2000

Effects of 14-day spaceflight on myosin heavy chain expression in biceps and triceps muscles of the rhesus monkey.

In rats, changes in myosin expression are induced by the chronic elimination of weight-bearing activity, particularly in the postural muscles. This occurs during spaceflight and hindlimb suspension. Myosin heavy chain (MHC) changes affect fast and slow fiber types differently depending on muscle function. An increase in co-expression of different MHC within the same fiber will signal early changes in muscle fibers. In the rat soleus muscles, the spaceflight-induced increase in fast MHC expression appears to be essentially due to the enhanced or de novo synthesis of IID or IIX MHC. In response to microgravity, the expression of slow-type myosin decreases, while that of fast-type increases. There is scarce information concerning the effect of microgravity on rhesus monkeys (Macaca mulatta), especially on their upper limbs. We investigated the expression of MHC using an immunocytochemical approach to determine the nature and magnitude of the changes in biceps and triceps muscles of rhesus monkeys during the Bion 11 14-day mission.

Adaptation, Physiological↗
PubMed1999

Southeast Asian ovalocytosis in White persons.

We describe two White persons, a girl and her mother, presenting with Southeast Asian ovalocytosis. The child was evaluated for scoliosis. The red cell indices were normal but the cell counter triggered an alarm due to a high fraction of hyperdense red cells. Blood smears showed ovalocytes and ovalostomatocytes. Red cells exhibited a total lack of deformability upon osmotic gradient ektacytometry performed immediately after blood drawing. Analysis of nucleic acids and proteins ascertained a 27 nucleotide deletion, resulting in the loss of amino acids 400 to 408, and the presence in cis of the Memphis I polymorphism. The sulfate transport was diminished by more than 50%. There was no acidosis. In vitro invasion of ovalocytes by Plasmodium falciparum was decreased. The mother presented with the same hematological picture. On the whole, the condition was Southeast Asian ovalocytosis in all respects. The present kindred had ancestors who had inhabited islands in the Southwestern Indian Ocean.

Adult↗
PubMed1998

Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine.

BACKGROUND: Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management. OBJECTIVE: To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis. DESIGN AND PATIENTS: Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database. MEASUREMENTS: Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis. RESULTS: Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure was solely dependent on stage. CONCLUSION: Survival of these medullary thyroid carcinoma patients appears better than expected even in non-cured patients. Considering the strong impact of stage, the necessity for pre-operative diagnosis of MTC is obvious.

Adult↗
PubMed1998

Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine.

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.

Adult↗
PubMed1998

Effect of a 14-day spaceflight on dystrophin associated proteins complex in rat soleus muscle.

One of the most obvious effects of hypokinesia and hypodynamia is muscular atrophy. Changes in myosin expression are induced by the chronic elimination of the weight-bearing activity, particularly in the postural muscles, which occur during spaceflight and hindlimb suspension. Other morphological changes, such as the remodeling of myotendinous junction, are also induced by this reduction in mechanical stress. Moreover, the transversal interface between the cytoskeleton and the extracellular matrix of the muscle fiber can also be modified by the functional demand imposed on muscle. Dystrophin and its associated proteins appear to be essential for the stability of this interface and the deletion of one of these proteins results in a pathological phenotype. Changes in their expression appears to be induced by muscle disuse. We have quantified the changes in the expression of dystrophin and associated proteins induced by a 14-day spaceflight.

Animals↗
PubMed1998

[Early therapeutic management of patients genetically predisposed to medullary thyroid cancer].

STUDY: The aim of our study was to study therapeutic results after thyroidectomy in patients positive for predictive genetic analysis and with preoperative calcitonin (CT) response to pentagastlin (Pg) < 150 pg/ml. MATERIAL AND METHODS: 36 patients (13 F, 23 M) were selected: 13 F-MTC from 8 families, 22 MEN 2A from 15 families and 1 MEN 2B. They were positive for direct RET mutation analysis. CT was assayed by immunoradiometric method before and after Pg. Pg test results before and after thyroidectomy, age at operation and histologic results were analysed. RESULTS: Mean preoperative peak CT was 82.5 +/- 34.0 pg/ml (22-133): among these 36 patients preoperative basal and peak CT were normal in 16 and 2 patients respectively. F-MTC and MEN 2A patients were different according to their preoperative peak CT levels (58.1 +/- 24.0 vs 97.6 +/- 31.3) pg/ml, p < 0.01) and age at thyroidectomy (20.4 +/- 10.5 vs 11.6 +/- 7.6 years, p < 0.01 by Mann-Whitney test). Total thyroidectomy was performed in all patients at a mean age of 14.8 +/- 9.8 years (2.5-41.7) and was associated with lymph node dissection in 30 cases. The 2 F-MTC patients with normal preoperative peak CT levels had bilateral C-cell hyperplasia (CCH) associated with uni or bilateral micro-MTC. Other patients had uni or bilateral micro MTC except 4 who had isolated CCH without carcinoma. The age of two MEN-2A and 1 MEN 2B patients with micro-MTC ranged from 2.5 to 4.7 yr. Micro MTC was present in 100% of MEN-2A cases after the age of 10 yr. There were no lymph nodes metastases. During postoperative survey, the last PG tests (n = 33) were performed 27.5 months (1-92) after thyroidectomy: peak CT values were always < 10 pg/ml. IN CONCLUSION: Thyroidectomy should be performed at a very young age in RET mutation carriers, regardless of the plasma CT values. This choice is justified in NEM-2A and NEM-2B patients but must be discussed in F-MTC families with less aggressive forms of the disease.

Adolescent↗
PubMed1996

Heme-CO binding to tryptophan-containing calmodulin mutants.

The binding of heme-CO to genetically engineered calmodulin containing a single tryptophan residue has been studied. A tryptophan residue was integrated at one of five positions: 26 or 62 of the N-terminal, 81 in the central helix, or 99 or 135 of the C-terminal. As for the wild type, the mutant calmodulins bind four molecules of heme-CO with an average affinity of 1 microM. (i) Homotropic effect. The quenching of the tryptophan fluorescence by energy transfer to the hemes indicates that there is no preference between the N- or C-terminal pockets for heme binding. The quenching is less than expected for a binomial distribution of four sites. This could indicate a lower energy transfer rate due to a specific orientation factor. The weak quenching as a function of the number of hemes bound may also reveal a cooperativity in the heme binding; the data can be simulated assuming two pairs of sites, where each pocket shows a cooperative binding for two hemes. (ii) Heterotropic effect. As observed for the wild type, addition of melittin does not displace the hemes from the mutant calmodulins; the affinity of heme-CO for the calmodulin.melittin complex is higher than that for calmodulin alone. The affinity of heme-CO for native calmodulin is also higher in the presence of trifluoperazine.

Animals↗
PubMed1996

Picosecond geminate recombination of CO to the complexes calmodulin*heme-CO and calmodulin*heme-CO*melittin.

Picosecond CO recombination kinetics have been measured after photodissociation of the artificial complexes calmodulin*heme-CO and calmodulin*heme-CO*melittin. These systems show an enhancement of the geminate fraction of kinetics relative to unbound heme-CO, due in part to fast geminate kinetics (tau=50ps for the initial phase), as well as a decrease in the rate of migration of CO away from the binding site. This indicates that calmodulin provides a complete pocket around the heme group. Rather than competing with the hemes for binding to calmodulin, the melittin seems to act as a cap to further enclose the hemes; melittin increases the affinity of calmodulin for heme-CO, but only weakly affects the CO recombination kinetics.

Amino Acid Sequence↗
PubMed1995

Protection by lazaroids of the erythrocyte (Ca2+, Mg2+)-ATPase against iron-induced inhibition.

The calmodulin-stimulated (Ca2+, Mg2+)-ATPase (calmodulin-ATPase) of the erythrocyte membrane is susceptible to oxidative stress induced by heme and non-heme iron. There is a time-and concentration-dependent inhibition of the calmodulin-ATPase activity when the erythrocyte membranes are treated with either iron or hemin. In the present study, the calmodulin-ATPase has been used as a model system to evaluate the protective effects of a vitamin E analog (U83836E) and two 21-aminosteroids (U74500A and U74389G) against calmodulin-ATPase inhibition induced by iron and hemin. The drugs, lazaroids from Upjohn, can significantly protect the enzyme against iron-induced inhibition and also causes a decrease in the formation of thiobarbituric acid reactive species, with an IC50 of 0.4 microM for the drug U83836E and 4 microM for the drug U74500A. The 21-aminosteroid U74389G does not restore iron-inhibited calmodulin-ATPase activity under similar conditions. At higher concentrations (> 100 microM) all three drugs inhibit the calmodulin-ATPase activity. None of the drugs tested can restore hemin-inhibited calmodulin-ATPase activity.

Antioxidants↗
PubMed1995

Heme as an optical probe for studying the interactions between calmodulin and the Ca(2+)-ATPase of the human erythrocyte membrane.

The heme group was used as an optical probe to study the interactions between calmodulin and its targets: the peptide melittin and the enzyme Ca(2+)-ATPase. As already reported, melittin when present in Tris buffer binds hemin-CN which quenches the tryptophan fluorescence. Addition of calmodulin restores the fluorescence significantly accompanied by a blue shift. We show here that the recovery of fluorescence is very slow and takes about 120 min to become constant. In a hydrophobic buffer, the fluorescence spectrum of melittin is already shifted with a peak at 335 nm and intensity almost 2-fold relative to a similar concentration of melittin in Tris buffer. The quenching of tryptophan fluorescence is lesser in this buffer and further addition of calmodulin fails to restore the fluorescence. This indicates the absence of binding of calmodulin to melittin in hydrophobic conditions. Under similar conditions of hydrophobicity, hemin-CN quenches about 35% of the tryptophan fluorescence of the Ca(2+)-ATPase. The subsequent addition of calmodulin restores about half of the quenched fluorescence. The interaction of calmodulin with the Ca(2+)-ATPase even under hydrophobic conditions suggests its high specificity for the enzyme which may be expected for a physiological target.

Calcium-Transporting ATPases↗
PubMed1994

Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock.

METHODS: Estrone (E1), estradiol (E2), testosterone (T), FSH, and LH levels were daily measured during a ten day period in 50 critically ill patients (38 men, 12 post-menopausal women). Patients were separated into four groups: A) no circulatory failure, no sepsis, B) sepsis syndrome without circulatory failure, C) circulatory failure without sepsis syndrome, D) septic shock. Results of hormonal measurements were compared 1) among the 4 groups, 2) between male and female patients, 3) between septic and nonseptic patients. The potential for the infusion of the vasoactive drug dobutamine to induce sex hormonal changes was documented in ten additional septic shock patients by measuring cortisol, E1, and T at base-line and after dobutamine infusion. Changes in active renin and plasma renin activity (PRA) were used as indirect witness of the dobutamine-induced beta 2-stimulation. RESULTS: A dramatic increase in E1 and E2 levels was observed in women of groups B and D, and only in male patients of group D. In the septic patients, estrogen levels peaked at days 1 and 2 and trended to normal from day 6 after the onset of sepsis, while FSH and LH decreased. No difference was found between survivors and non-survivors. Whatever the group, male patients had low T levels throughout the study. Dobutamine induced a significant increase in active renin levels and a decrease in the regression slope between renin and PRA. Cortisol levels remained normal. No significant change in E1 and T was observed after dobutamine. CONCLUSIONS: High estrogen levels were specifically observed in patients with sepsis and septic shock, either males or females. Decreased LH and FSH levels were consistent with the negative feed-back effect of high estrogen levels on pituitary secretion. Circulating T levels were decreased in all male patients. We found no correlation between sequential estrogen levels and outcome. These levels were not modified by a dobutamine-induced beta-2 stimulation.

Adult↗
PubMed1993

Interaction of heme with amphiphilic peptides: use of hemin-CN to probe the interaction of calmodulin with its target peptides.

UNLABELLED: The interaction of heme with several amphiphilic peptides has been studied by absorption and fluorescence spectroscopy. The binding can be followed by the changes in the absorption spectrum of the heme group or by the decrease in the peptide tryptophan fluorescence due to energy transfer to the heme. Despite their small size, ranging from 26 residues for melittin to 14 for mastoporan, a high affinity for heme-CO and hemin-CN (Kd < 100 nM) may be observed. Spectral shifts in the absorption peaks and appreciable geminate recombination after photodissociation of CO from the complex peptide-heme-CO suggest the formation of a heme pocket, as for the natural heme proteins. APPLICATION: hemin-CN can be used as a probe for the interaction of calmodulin with these target peptides. Amphiphilic peptides such as melittin bind to calmodulin with a high (nM) affinity. While both the peptide and calcium-bound calmodulin bind heme-CO, only the peptide binds hemin-CN. These interactions permit studies of the competition between hemin-CN and calmodulin for binding to the peptide: while hemin-CN quenches the melittin tryptophan fluorescence, addition of calmodulin to the [melittin*hemin-CN] complex displaces the hemin-CN and the melittin tryptophan fluorescence is recovered.

Amino Acid Sequence↗
PubMed1993

Heme binding to calmodulin, troponin C, and parvalbumin, as a probe of calcium-dependent conformational changes.

Heme-CO binds to the active (calcium-bound) form of calmodulin (CaM), but not to the inactive form. Despite a similarity in structure of another calcium-binding protein, skeletal muscle troponin C, both the affinity and the spectral red-shift of the absorption of the heme group are greatly decreased for troponin C relative to calmodulin. Parvalbumin, another calcium-binding protein, shows a twofold greater affinity for heme-CO relative to CaM. Unlike calmodulin and troponin C, the affinity of parvalbumin for heme-CO is even greater in the absence of calcium. The affinity of the tryptic and thrombic fragments of CaM for heme-CO are decreased relative to the entire calmodulin. The binding of heme-CO is specific as demonstrated by the discrimination of the calmodulin, troponin C, and parvalbumin pockets. The interaction of heme-CO with active (calcium-bound) CaM is rapid (ms) as determined by stopped flow measurements. No difference in kinetics was observed for mixing inactive (calcium free) CaM with a solution of [heme-CO plus calcium], indicating that the calcium-binding step and subsequent change in protein conformation are rapid.

Animals↗