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Biomedical subjects

P Lefebvre

Publications and source records attributed to P Lefebvre.

At least 73 records · Page 4Linked to original sources
PubMed1997

Influences of weight, body fat patterning and nutrition on the management of PCOS.

Polycystic ovary syndrome (PCOS) is a heterogeneous clinical entity that is defined as the association of hyperandrogenism with chronic anovulation in women without specific underlying diseases of the adrenal or pituitary glands. PCOS is also associated with a metabolic disturbance (insulin resistance). The nature of the complex interrelation of obesity, insulin resistance and endocrine abnormalities in PCOS remains unresolved. However, several studies link obesity, body fat distribution and nutritional habitus with the hormonal and metabolic profiles of PCOS. Moreover, intervention studies have suggested that reducing weight and/or hyperinsulinaemia either by diet alone or by a combination of diet and drugs improves hirsutism, fertility and the hormonal and metabolic profiles of PCOS. In fact, the evaluation of nutritional factors in PCOS is helpful for the screening of metabolic abnormalities and the management of women with PCOS. A point of particular interest in the management of PCOS is that the choice of contraception remains difficult in these high cardiovascular risk women. The impact of pills with ethinyl oestradiol on weight, body fat distribution and carbohydrate metabolism in women with PCOS has not been thoroughly evaluated. The lack of prospective studies to evaluate long-term metabolic and cardiovascular tolerance necessitates care and the assessment of other hormonal possibilities.

Body Constitution↗
PubMed1997

Disruption of the glucocorticoid receptor assembly with heat shock protein 90 by a peptidic antiglucocorticoid.

Association of glucocorticoid (GR) and progesterone (PR) receptors with a set of molecular chaperones, including the 90-kDa heat shock protein (hsp90), is a dynamic process required for proper folding and maintaining these nuclear receptors under a transcriptionally inactive, ligand-responsive state. Mutational studies of the chicken hsp90 complementary DNA suggested that three regions of this protein (A, B, and Z) interact with the hormone-binding domain of GR, whereas region A is dispensable for hsp90 binding to PR. We found that this 69-amino acid region can be narrowed down to a 35-mer alpha-helical, acidic peptide, which is by itself able to inhibit hsp90 association to GR translated in vitro. The hsp90-free GR did not bind ligand, but was devoid of any specific DNA-binding activity, and higher peptide concentrations specifically inhibited the binding of activated GR to DNA. When overexpressed in cultured cells, this peptide acted as an antiglucocorticoid and inhibited the antiactivating protein-1 activity and the ligand-dependent nuclear transfer of GR. None of these effects, either in vivo and in vitro, was observed for PR. The region from residue 232 to residue 265 of hsp90 is, therefore, a domain critical for its association to GR, an association that is a prerequisite for receptor transcriptional activity. More importantly, these results demonstrate that targeting specific protein/protein interaction interfaces is a powerful means to specifically modulate nuclear receptor signaling pathways in a ligand-independent manner.

Amino Acid Sequence↗
PubMed1997

[Pneumatosis cystoides intestinalis. Diagnostic elements and therapeutic approach].

Pneumatosis cystoides intestinalis is an uncommon condition characterised by multiple gas-filled cysts within the small intestine or colonic wall. Clinical manifestations are unspecific and often found in many other abdominal diseases. To avoid unnecessary laparotomy, radiologic and endoscopic findings are essential to be known. The present case associates symptoms highly suspect of neoplasia like weight loss, rectal mass, bloody stools and tenesmus. Treatment of choice is medical. In the absence of an acute abdomen, surgery is only reserved when it is not responsive to medical treatment.

Aged↗
PubMed1997

Jean Marquet Award. Regeneration of the neurosensory structures in the mammalian inner ear.

Regeneration of the neurosensory structures in the mammalian inner ear. Motivated by the absence of treatment of neurosensory deafness apt to restore auditory function or alter the course of progressive hearing loss, we developed two different experimental strategies to approach these diseases: one is otoprotection, designed to prevent further degradation of auditory function; the other is regeneration which is defined as the replacement of hair cells in the deaf ear and their reconnection to the central nervous system through primary auditory neurons. In this paper, we summarize our data on the regeneration of auditory neurons and hair cells. Neuronal maintenance and regeneration was studied through an initial investigation of growth factors during inner development. Once the effect of various neurotrophic molecules was determined, the factors were tested on mature auditory neurons in vitro and in vivo. The hair cell regeneration was investigated on the basis of a concept derived from comparative physiology and from the study of the development of the inner ear. We showed that in young rats it is possible to induce the regeneration/repair of hair cells in the organ of Corti in cultures using retinoïc acid and transforming growth factor alpha. The clinical prospects of these findings of inner ear regeneration are discussed.

Animals↗
PubMed1997

Limited proteolysis for assaying ligand binding affinities of nuclear receptors.

The binding of natural or synthetic ligands to nuclear receptors is the triggering event leading to gene transcription activation or repression. Ligand binding to the ligand binding domain of these receptors induces conformational changes that are evidenced by an increased resistance of this domain to proteases. In vitro labeled receptors were incubated with various synthetic or natural agonists or antagonists and submitted to trypsin digestion. Proteolysis products were separated by SDS-PAGE and quantified. The amount of trypsin-resistant fragments was proportional to receptor occupancy by the ligand, and allowed the determination of dissociation constants (kDa). Using the wild-type or mutated human retinoic acid receptor alpha as a model, kDa values determined by classical competition binding assays using tritiated ligands are in agreement with those measured by the proteolytic assay. This method was successfully extended to human retinoic X receptor alpha, glucocorticoid receptor, and progesterone receptor, thus providing a basis for a new, faster assay to determine simultaneously the affinity and conformation of receptors when bound to a given ligand.

Animals↗
PubMed1996

Identification of amino acids critical for the DNA binding and dimerization properties of the human retinoic acid receptor alpha. Importance of lysine 360, lysine 365, and valine 361.

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) activate target genes by binding to retinoic acid response elements (RAREs) as heterodimeric, asymmetrical complexes, and display a high degree of cooperativity in binding to RAREs. We have examined here the effect of lysine, cysteine, arginine, histidine, and tyrosine side chain chemical modification on the DNA binding, homo- and heterodimerization properties of the full-length human retinoic acid receptor alpha (hRARalpha). Lysines are the only residues to be engaged in the dimerization with human retinoid X receptor alpha (hRXRalpha) in the absence of DNA, whereas histidines are selectively involved in the homodimerization of hRARalpha in the presence of a RARE. Arginine modification affected the DNA binding activity of each type of dimer, whereas cysteines and tyrosines were primarily involved in the homo- or heterodimerization process in the presence of the same RARE. Modified lysines, interfering with the dimerization with hRXRalpha, were identified by receptor labeling and peptide mapping. They are located in the hormone binding domain eighth heptad repeat, at positions 360 and 365. In keeping with these results, mutation of Lys360, Val361, and Lys365 diminished strongly the DNA binding activity of hRARalpha as a homodimer or a heterodimer. Our results thus provide direct evidence for the differential involvement of basic, polar, or aromatic amino acids in the DNA binding, homodimerization, and heterodimerization properties of hRARalpha. Furthermore, they demonstrate the use of distinct dimerization interfaces and identify the type of amino acids involved in these protein-protein interactions.

Amino Acid Sequence↗
PubMed1996

NT-3 and/or BDNF therapy prevents loss of auditory neurons following loss of hair cells.

Destruction of auditory hair cells results in a subsequent loss of auditory neurons. In situ hybridization and neuronal cell culture studies as well as analyses of the inner ears of neurotrophin and neurotrophin receptor gene knockout mice have shown that NT-3 and BDNF mediate both the development and survival of auditory neurons. In this study guinea pigs were exposed to the ototoxic combination of an aminoglycoside antibiotic and a loop diuretic and then received 8 weeks of intracochlear infusion of either NT-3, BDNF or NT-3 + BDNF to determine whether site-specific application of these neurotrophins could prevent the loss of auditory neurons that follows a loss of auditory hair cells. Infusion of either NT-3 or NT-3 + BDNF into the scala tympani resulted in a > 90% survival of auditory neurons while BDNF infusion yielded a 78% survival rate, compared with a 14-24% neuronal survival rate in untreated ototoxin-exposed cochleae. These results show that loss of auditory neurons that occurs subsequent to a loss of auditory hair cells can be prevented by in vivo neurotrophin therapy with either NT-3 or BDNF.

Animals↗
PubMed1996

Effects of neurotrophins on early auditory neurones in cell culture.

During the first week of postnatal development, the innervation of the organ of Corti changes from an immature to an adult pattern. Dissociated cell cultures of early postnatal spiral ganglia were used to investigate the effects of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) on maturing auditory neurones. BDNF was the most potent stimulator of neuritogenesis, NT-3 provided the strongest support for neuronal survival, while NGF supported limited neuritogenesis, and only at pharmacological levels. These findings suggest that both BDNF and NT-3 participate in the postnatal maturation of cochlear innervation and that NGF is most probably not involved in this process.

Animals↗
PubMed1996

Thrombopoietin-stimulated ex vivo expansion of human bone marrow megakaryocytes.

The effect of thrombopoietin (TPO) on megakaryocytopoiesis (MKP) has been mainly studied using clonogenic assays in murine systems. In this study, we evaluated MKP in liquid culture using human bone marrow cells. While interleukin 3 (IL-3) and stem cell factor (SCF) are potent activators of TPO-stimulated MKP in the murine system, only IL-3 exhibited synergistic activity with TPO in cultures of human bone marrow. The IL-3 effect on TPO-stimulated megakaryocyte (MK) proliferation, expressed as the absolute number of MKs per seeded CD34+ cell, was more pronounced with purified CD34+ cell (8 +/- 1.6 SE versus 2.8 +/- 0.7 SE in the presence and absence of IL-3, respectively) than with mononuclear cells (MNC) (16 +/- 2.8 SE versus 11 +/- 2.0 SE). This effect of IL-3 on TPO-stimulated MK proliferation was due to a general proliferation of all cell types since the relative frequency of MKs (32.1 +/- 3 SE and 55.8 +/- 3 SE in MNC and CD34+ cells, respectively) was not affected by IL-3. The effect of TPO alone, TPO + IL-3, TPO + SCF, and TPO + IL-3 + SCF on MK proliferation was examined in MNC and CD34+ cultures. Greater numbers of MK per seeded CD34+ were observed in MNC compared to CD34+ cultures under all conditions except when TPO was added with both IL-3 and SCF. The enhancing effect of MNC was also observed on MK ploidy in the presence of TPO and IL-3. While proliferation and ploidy increase with TPO concentration in the murine system, they are inversely related in the human system. A significant 2.5-fold enhancement of TPO-induced MK proliferation was observed when purified CD34+ cells were cultured in inserts separated from human bone marrow stroma, indicating that soluble stimulatory factors are released from the stroma. These observations will be useful for ex vivo expansion of MKs to treat post-transplant or chemotherapy-associated thrombocytopenia.

Animals↗
PubMed1996

Mechanical properties of the diabetic waxy skin.

BACKGROUND: In some diabetic patients, the skin of the hands has a waxy appearance. OBJECTIVE: To study subclinical skin stiffening in diabetic patients using a noninvasive, in vivo suction device measuring skin extensibility and elasticity. Skin thickness was also measured by high-resolution ultrasonography. METHODS: Evaluations were made on the dorsum of the hands and on the volar aspect of the forearms. RESULTS: In type 1 diabetic patients, the extensibility of skin was decreased while values of thickness and elasticity were increased. These alterations were most prominent on the hands. Similar modifications, although less pronounced, were also found in type 2 diabetic subjects. CONCLUSION: The reported biomechanical changes indicate the presence of subclinical skin stiffening in many patients with diabetes mellitus. Such noninvasive biometrological evaluations could be used for monitoring, rating and correlating some diabetes-associated disorders.

Adolescent↗