Biomedical subjects
Publications and source records attributed to J Lebeau.
Three newly synthesised lipid peroxidation inhibitors (7, 11, 14) were evaluated for their effects on myocardial functional recovery during reperfusion after 30 min global ischemia in isolated rat hearts. The flavonoid compounds (7, 11, 14, rutin) reduce ischemia/reperfusion-induced cardiac dysfunction.
The protective effect of di-tert-butylhydroxylated flavonoids (chalcones and arylidenes) against minimally oxidized LDL (mO-LDL)-induced cytotoxicity was studied in cultured bovine aortic endothelial cells. Most of the tested compounds decreased aldehydes formation in medium containing mO-LDL, but their capacity to inhibit LDL oxidation in the cellular medium was not sufficient to totally reduce the cellular toxicity of mO-LDL. Most of the tested flavonoids improved the integrity of cells exposed to mO-LDL, whereas butylated hydroxytoluene was ineffective and quercetin worsened the toxicity of mO-LDL. Moreover these flavonoids induced an increase in GSH cellular levels and their protective effects might be because of their inability to reduce metal ion. Arylidene 6 substituted at position 7 by a hydroxyl group was the most potent compound.
A thorough knowledge of mandibular growth is necessary for proper comprehension of growth disorders and malformations affecting the lateral cranio-facial region. The growth mechanisms are complex and multifactorial, the mandible itself is subdivided into two heterogeneous and interdependent segments, as far as growth is concerned. These are the ramus and the corpus. The ramus is interacting with the middle cranial base through the TMJ and the temporo-pterygoid muscle belt. The mandibular body is interacting with the maxilla and the anterior cranial base. Its occlusal role is a function of the adaptive capacity of the alveolodental region.
Otomandibular dysplasia is a congenital malformation defined by a certain degree of temporomandibular or pterygomandibular hypoplasia. The syndrome is characterised by the variability of clinical findings, but the three major features are auricular, mandibular and maxillary hypoplasia. All the laterofacial structures may be affected. The deformity is usually unilateral but bilateral cases exist; a lot of associated malformations have been described. Multiple classification systems have been published. Some of them are very complex, but it is possible to define a simple diagnostic diagram based on ethiopathogenic data. Bilateral involvement affects predominantly the zygoma, and concerns hereditary syndromes. When the mandibular hypoplasia is evident Franceschetti or Goldenhar syndrome is suspected; otherwise Treacher-Collins syndrome is probable. Unilateral cases are not, in general, hereditary and the hypoplasia predominates on the mandible. The difference between hemifacial microsomia or mandibular dysplasia is made by the presence of associated laterofacial deformities.
Several reports suggested that steroidogenic hormones could be directly involved in the regulation of apoptosis in vitro, but whether this is due to blocking or promoting mechanism of these hormones remains controversial. However, it was shown that progesterone exhibited a protective effect against the apoptotic process during mouse mammary gland involution in vivo. In this study, we analyzed the effect of medroxyprogesterone acetate (MPA) treatment, an agonist of progesterone, on serum starvation induced apoptosis on breast cancer cell lines. Positive and negative progesterone receptor (PgR+ and PgR-) breast cancer cell lines were treated with MPA (10 nM), either in standard culture conditions or in serum-free medium to induce apoptosis. Cell survival, proliferation and apoptosis were simultaneously analyzed with the expression of apoptosis-related genes measured by a real time quantitative RT-PCR. At non cytotoxic doses, MPA protected PgR+ T47-D, MCF-7 and H466-B cell lines against serum depletion-induced apoptosis, while MPA did not protect PgR-MDA-MB-231 cells against serum depletion induced apoptosis. In PgR+ cell lines and in concordance with the protective effect, the pro-apoptotic HRK and BAK1 mRNAs were up-regulated after apoptosis induction, while they were no more induced in condition of protection against apoptosis after MPA treatment. We also observed, specifically in PgR+ cells, an up-regulation of BCLX-L and BCLX-S and a down-regulation of BCL2 mRNAs, which are specific to the MPA response and unrelated to apoptotic process. Involvement of these genes with regard to the MPA-mediated protection against apoptosis is discussed.
Predictive markers of intrinsic radiosensitivity in healthy individuals are needed in monitoring their occupational or environmental radiation exposure and may predict a patient's response to radiotherapy. Ionizing radiation can induce a large spectrum of DNA lesions, but under optimal DNA repair conditions, the principal residual lesions of importance are misrepaired double-strand breaks. The micronucleus (MN) assay represents a useful test in measuring radiosensitivity since it reflects non-repaired DNA breaks at the time of cell division. Spontaneous and radiation-induced MN vary greatly between individuals, and little is known about the molecular mechanisms of this variability. DNA repair and apoptosis processes are involved in the cellular response to radiation-induced DNA damage, and variation in gene expression related to these cellular pathways could be linked to individual radiosensitivity. In this study we analysed by real-time quantitative RT-PCR the basal expression of 12 genes involved both in DNA repair and apoptosis in a series of blood samples obtained from 32 healthy male donors. Relationships between basal RNA expressions and MN frequency and distribution per bi-nucleated cell were studied after ex vivo irradiation of total blood samples. Our results indicate that the variability of mRNA gene expression among the 32 subjects appears to be of the same magnitude or higher than that found for spontaneous or radiation-induced MN frequency and that RAD51 gene expression is negatively correlated with radiation-induced MN frequency.
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The wide diversity of bilateral facial clefts makes it most difficult to assess surgical success, particularly in terms of long-term outcome. The aim of this work was to examine the rationale for the current protocol used for cleft surgery at the Grenoble University Hospital. In a first group of 28 children, a 3-step surgical protocol was applied. The first two steps were performed between 4 and 8 months with at least 3 months between each procedure. Skoog's unilateral cheilo-rhino-uranoplasty was used, associated with a periosteal tibial graft. The third step, performed between 10 and 12 months, was for staphylorraphy. Outcome was analyzed at 15 years and evidenced the deleterious effect of excessive and asymmetrical premaxillary scars, of the 2-step cheiloplasty and of columella lengthenings from the lip. The frequency of secondary revision of the superior labial vestibule and the medial labial tubercule (43%) was considered to be high; this procedure should be re-examined as should be osteotomy (32% revision). Palatine closure, acquired in 82% of the cases and premaxillary stability, achieved in 86%, would appear to favor use of the periosteal tibial graft. The osteogenic capacity of this graft tissue was less satisfactory after a second harvesting (from the same tibia three months later). These results have led us to modify our protocol, favoring early and total closure of the bony palate and continued use of the periosteal tibial graft. We now use the following operative protocol: premaxillary alignment using an active orthopedic plate at 2 months, lip adhesion associated with staphylorraphy and passive palatine contention plate at 3 months, definitive bilateral cheilo-uranoplasty associated with a single periosteal graft at 7 months. The preliminary results with this protocol in a group of 12 children have shown better quality scars, more harmonious maxillary arches, an excellent occlusion of the deciduous dentition, and preservation of the positive results obtained with the periosteal tibial graft.
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Epidemiological evidence suggests an inverse relationship between dietary intake of flavonoids and cardiovascular risk. The biological activities of flavonoids are related to their antioxidative effects, but they also can be mutagenic, due to the prooxidant activity of the catechol pattern. To prevent these problems, we synthesized new flavonoids where one or two di-tert-butylhydroxyphenyl (DBHP) groups replaced catechol moiety at position 2 of the benzopyrane heterocycle. Two DBHP moieties can also be arranged in an arylidene structure or one DBHP fixed on a chalcone structure. Position 7 on the flavone and arylidene or position 4 on the chalcone was substituted by H, OCH(3), or OH. New structures were compared with quercetin and BHT in an LDL oxidation system induced by Cu(II) ions. Arylidenes and chalcones had the best activities (ED(50) = 0.86 and 0.21) compared with vitamin E, BHT, and quercetin (ED(50) = 10.0, 7. 4, and 2.3 microM). Activity towards stable free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) was measured by log Z and ECR(50) parameters. Synthesized flavones proved to be poor DPPH radical scavengers, the activity increasing with the number of DBHP units. In contrast, arylidenes and chalcones were stronger DPPH radical scavengers (log Z > 3, 0.3 < ECR(50) < 2.12) than BHT (log Z = 0.75, ECR(50) = 12.56) or quercetin (log Z = 2.76, ECR(50) = 0.43). Unlike quercetin, synthesized compounds neither chelated nor reduced copper, proving that these new flavonoids had no prooxidant activity in vitro.
Since defects in molecular mechanisms controlling DNA repair, cell cycle checkpoint and apoptosis could modify cellular sensitivity to DNA damaging agents, we have conducted a multiparametric molecular analysis for better understanding the regulation pathways leading to cell survival or cell death after irradiation. Using a human lymphoblastoid cell line, we have analysed, following gamma irradiation (0.5, 1, 2, 4, 8, 16 and 32 Gy, at 0.5, 24, 48 and 72 h after treatment), the correlation between proliferation, cell cycle analysis, apoptosis and micronuclei frequency with the expression of TP53, WAF1, DNA LIGASE 1, PCNA, BAX, BLC-2, BAK, DAD1, ICH1-Long and -Short forms mRNAs. We have found that whereas TP53, BAK, ICH1-Short form, and DAD1 were expressed at constant levels, WAF1, PCNA, BAX were up-regulated, ICH1-Long form, DNA LIGASE 1, and BCL-2 were down-regulated. These modifications of expression were significantly correlated with doses, survival, proliferation, cell cycle delays, and apoptosis. A positive correlation of WAF1 and BAX, and a borderline negative correlation with BCL-2 expressions were observed with micronuclei frequency for doses ranging from 0.5 to 4 Gy. In conclusion, our data clearly demonstrate that gene expression profiling, which is easier and more rapid to conduct than the assessments of classical phenotypic responses, could be useful to improve knowledge concerning pathways involved in cellular response to irradiation, knowing that such biomarkers could constitute tools to assess radio-sensitivity/radio-resistance. Oncogene (2000) 19, 916 - 923.
Functional tests are needed to assess the quality of reconstructive surgery after treatment of intraoral cancers. Quality of Life tests are subjective and Cinefluoroscopy is a demanding and non-comparative procedure. We develop here a method to test the capacity of patients to maximize use of their articulatory space. We recorded a corpus of sounds. These sounds were analyzed with classical signal processing procedures. By comparison with a non-distorded sound database, it was possible to evaluate speech disorders, localize the defect, and provide a guide for rehabilitation. This method is an objective, reproductible, and comparative measurement tool.
Why initially normal wound healing sometimes shifts toward an impaired cicatrization is poorly understood. Collagen gels with incorporated fibroblasts constitute valuable in vitro models to study mechanisms of connective tissue reorganization. Such 1-week-old, partially contracted normal dermal equivalents were treated with concentrations of TGF-beta1 ranging from 1 to 10 ng/ml. The cytokine was applied in a single dose or four times at regular intervals, over a 2-week period. Dose-dependent activation of fibroblasts was observed after treatment. The cytokine induced a myofibroblastic transformation of dermal cells, significantly enhanced the process of dermal contraction, and stimulated synthesis of such proteins as cellular fibronectin, tenascin and smooth-muscle actin. Our approach is more informative than models using pathological or pretreated dermal cells, since it demonstrates newly induced modulation of fibrotic transformation in an initially normal dermal equivalent. This in vitro assay will enable us to study mechanisms involved in the shift between normal and impaired fibrotic transformation during wound healing.
Pregnant females appear to have an increased chromosomal sensitivity to gamma-irradiation. This hypersensitivity was found to parallel the increase of gestation hormone amounts [M. Ricoul, L. Sabatier, B. Dutrillaux, Increased chromosome radiosensitivity during pregnancy, Mutat. Res. 374(1997) 73-78]. An in vitro experiment was developed to study the effect of progesterone. We performed irradiations of whole blood from normal human donors and chromosome were analysed in first generation metaphases. By comparison to untreated controls, all cultures in which progesterone was added around the 24th h of culture exhibited an increased frequency of chromosome rearrangements, principally dicentrics and rings, which confirms the role of progesterone in the results of in vivo studies. BrdU incorporation studies suggested that progesterone was particularly efficient just before the entry into S-phase, which corresponds to the G1/S transition period. Cultures with an increased frequency of chromosome breakage had a slightly higher mitotic index than controls. It is suggested that progesterone may stimulate DNA repair in cells which reached the end of G1-phase with unrepaired breaks. This would allow the cells to enter the S-phase and survive, although some illegitimate repair leads to chromosome rearrangements, visible at the following metaphase.
The human OGG1 gene encodes a DNA glycosylase activity catalysing the excision of the mutagenic lesion 7,8-dihydro-8-oxoguanine from oxidatively damaged DNA. The OGG1 gene was localized to chromosome 3p25, a region showing frequent loss of heterozygosity (LOH) in lung and kidney tumours. In this study, we have analysed by RT-PCR the expression of OGG1 in 25 small cell lung cancers, in 15 kidney carcinomas and the 15 normal kidney counterparts. The results show that OGG1 messenger RNA can be detected in all tumours tested and that no significant difference was observed in the level of expression between normal and tumoral kidney tissues. Denaturing gradient gel electrophoresis (DGGE) was used to screen this series of human tumours for alterations in the OGG1 cDNA. The study revealed homozygous mutations in three tumours, two from lung and one from kidney. Sequencing analysis of the mutants identified a single base substitution in each of the three cases: two transversions (GC to TA and TA to AT) and one transition (GC to AT). All three substitutions cause an amino acid change in the hOgg1 protein. For the mutant kidney tumour, the normal tissue counterpart shows a wild-type profile. These results suggest a role for OGG1 mutations in the course of the multistage process of carcinogenesis in lung or kidney.
OBJECTIVE: The authors report the case of an 83-year-old patient with a benign oncocytoma of the inferior eyelid. DESIGN: INTERVENTIONal case report. INTERVENTION: Treatment consisted of a large orbital exenteration followed by reconstruction with a pedicled temporalis muscle flap. MAIN OUTCOME MEASURES: Histologic evaluation and clinical follow-up were measured. RESULTS: After a year of follow-up, there was no sign of local recurrence. CONCLUSIONS: Oncocytomas, even if benign, must be considered as very aggressive tumors and treated accordingly.
A local wound infection developed in a 42-year-old female patient after replacement of ascending aorta, aortic arch and supra-aortic vessels, following aortic dissection. Because of the high risk of infection due to the vascular prosthesis and its location at the upper part of the sternum, a right pectoral muscular flap, detached from the humerus and vascularized by medial perforators originating from the internal mammary artery, was isolated. The postoperative course was uneventful and the patient remains well 16 months after the operation.
For pituitary adenomas surgery, rhinoseptal transsphenoidal approach is used in 98 to 99% of the cases. Although this approach is fitting for microadenomas and the majority of macroadenomas, some of them develop extensions in the nasal fossas, the posterior cranial fossa, the suprasellar region, or into the cavernous sinus and will require other approaches. For the superior routes, the frontopterional approach gives good control of the suprasellar region, the anterior and middle base of the skull. The tumor dissection is performed inside the concavity of the chiasm and between the internal carotid artery and the optic nerve (optico-carotid approach). The frontopterional approach is used for superolateral extensions, especially in the lateral fissure. The bifrontal basal inter hemispheric approach, through a medial frontal bone flap tangential to the base, gives a good route to the suprasellar region and behind the dorsum, and also for tumors extended in the third ventricle in case of prefixed chiasm. For the inferior routes, the participation of ENT or craniofacial surgeons is a great help. The transfacial or transethmoidal approach performs a hollowing of the nasal fossas and gives a large interorbital tunnel adapted for tumors extended in the rhinopharynx and the ethmoid. The Le Fort I maxillary osteotomy offers also a large approach for adenomas extending in the rhinopharynx. The transcavernous approach from Dolenc, for adenomas progressing in the cavernous sinus requires a long and difficult procedure. The progression of some adenomas in many directions may require a combined approach in one or two procedures.