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Epigenetic modifications, such as DNA methylation or histone deacetylation, are early events in cell tumorigenesis. The consequences of these modifications are repression of gene transcription and, notably, of tumor suppressor gene transcription. New therapeutic strategies aim to ‘normalize’ the epigenetic status of cancer cells. Histone deacetylase inhibitors (HDACi) have shown promising effects against proliferation and resistance to apoptosis of a large number of cancer cells. Vorinostat (SAHA), a hydroxamate HDACi, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of refractory cutaneous T-cell lymphoma (CTCL). However, HDACi are poorly specific, present toxicities and many have very low half-lives in the plasma. Thus, the development of new compounds is necessary in order to increase the potential of HDACi in cancer treatment. We designed an assay, based on bioluminescence resonance energy transfer (BRET) technology, to screen and characterize HDACi activity in living cells. Using our specific and reproducible BRET assay, we characterized the pharmacological properties of benzofuranone HDACi compounds for the induction of histone acetylation and performed a comparison with the properties of suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA). We defined a benzofuranone HDACi compound that induced histone acetylation at nanomolar concentrations and showed an increased duration of histone acetylation. These properties correlated with the pharmacological properties of this HDACi for the growth inhibition of cancer cells. We, thus, demonstrated the applicability of BRET technology for the screening and characterization of new HDACi compounds in living cells, and identified an interesting benzofuranone HDACi.

To investigate, using PET and H215O, brain activation abnormalities of patients with PD during motor imagery. To determine whether motor imagery activation patterns depend on the hand used to complete the task.

Regional cerebral blood flow (rCBF) was measured using PET and H215O in Parkinson's disease (PD) patients with predominantly right-sided akinetic-rigid symptoms and in control subjects during the execution of an externally cued motor task either with the left or the right hand. During the execution of the task with the left, non-akinetic, hand, cerebral activation in PD patients appeared similar to that of controls. Activated areas were the primary motor cortex, premotor cortex, parietal cortex and cerebellum. When the task was executed with the right, akinetic, hand cerebral activation in PD patients differed from that of controls subjects. The most important change was a bilateral activation of the primary motor cortex. We conclude that overactivation of primary motor cortex is asymmetrical in hemiparkinsonian patients.

In a series of 12 patients (eight women and four men, aged between 20 and 62 years), operated on for a pituitary adenoma shown to be thyrotropic by immunocytochemistry, we performed a retrospective and comparative analysis of clinical and biological data, tumor studies including immunocytochemistry with double labeling, and proliferation marker (proliferative cell nuclear antigen (PCNA) and Ki-67) detection, electron microscopy and culture. Our study leads us to confirm that thyrotropic tumors are rare (12 of 1174 pituitary adenomas: 1%). The main points arising were that: (1) high or normal plasma TSH associated with an increase in plasma alpha-subunit and high thyroid hormone levels is the best criterion for diagnosis; (2) the failure of TSH to respond to TRH or Werner's test is not a reliable criterion for diagnosis; (3) thyrotropic adenomas may be 'silent', without clinical signs of hyperthyroidism and with only slight increase in TSH, tri-iodothyronine and thyroxine concentrations; (4) mitoses and nuclear atypies are frequently detected in large tumors, which are invasive in more than 50% of cases - the first analysis of two proliferation markers (PCNA and Ki-67) bears out the relative aggressiveness of thyrotropic adenomas; (5) thyrotropic adenomas are frequently plurihormonal. Immunocytochemical double labeling, complemented by in vitro study, showed that thyrotropic tumor cells sometimes can or sometimes cannot cosecrete TSH, GH or prolactin. The pathological identification of monohormonal and plurihormonal adenomas seems to be supported by clinical and biological differences.

Pseudocyst formation is a well-recognized complication of pancreatitis. Involvement of a pseudocyst with the kidney is rare. We report an unusual case of a pancreatic pseudocyst with rupture into the renal collecting system. The surgical management of this problem is described and the world- wide experience is reviewed briefly.

Anti-IgM stimulation of B cells is decreased in the presence of maternal serum as compared to control media. This inhibiting influence of maternal serum is observed during the priming of the B cells. The progression of B cells into cellular proliferation was not influenced by maternal serum. At the level of the immunoglobulin secretion, the influence of maternal serum was also shown. A significant down regulation of the IgM, no change of the IgG production, and an enhanced secretion of IgA and IgE was demonstrated in the presence of maternal serum as compared to control media. It has been suggested that the maternal IgG fraction contains a molecule partly responsible for these changes. Furthermore, the CD23 antigen is increased when B cells are stimulated in the presence of a pool of maternal IgG. All the findings concerning maternal IgG were more pronounced when retroplacental IgG was used instead of peripheral maternal IgG. This observation suggests that the factor responsible for the B cell changes is released at the fetomaternal interface.

Neoplastic Jurkat cells were submitted to a PHA stimulation test after a preincubation in maternal or nulliparous serum (10% dilution). The Il2R expression was significantly downregulated among maternal serum treated cells.Retroplacental serum was significantly more inhibitive than peripheral maternal serum (P < 0,01). The maternal IgG fractions and mostly the retroplacental IgG fraction proved to contain a factor mainly responsible for the I12R expression inhibitive property.The molecular mechanism of this phenomenon was further studied. It was shown that H7 (acting as a protein kinase inhibitor) could not influence the Il2R modulation. E.G.T.A., a calcium chelator, was not able to interfere with the inhibitive influence of maternal serum. It was suggested that the maternal serum mediated inhibition of the IL2R expression is not influenced by the hydrolysis of membrane bound phosphatidyl inositol.In contrast, pertussis toxin markedly enhanced, in a dose dependent way, the suppressive influence of maternal serum as compared to nulliparous serum. At low concentrations, pertussis toxin lost its stimulating property and retained its ability to ADP ribosylate the alpha subunit of G proteins inducing a release of adenyl-cyclase mediating cAMP synthesis.This mechanism has been further studied by the addition of dbc AMP or dbc GMP to Jurkat cells preparations stimulated by PHA. dbc AMP, in a dose-related way, induced a downregulation of the IL2R expression of stimulated neoplastic cells preincubated in nulliparous or maternal serum, dbc GMP did not influence the IL2R expression in the same experimental conditions. The maternal serum mediated cells showed the most pronounced IL2R inhibition. Finally, it was shown that the cAMP synthesis by PHA stimulated Jurkat cells was upregulated in a dose dependent way, after a previous cellular incubation in progressive concentrations of maternal serum. In contrast, among nulliparous serum pretreated cells, cAMP synthesis remained significantly lower, after a lectin stimulation, as compared to the cAMP production derived from retroplacental serum treated and stimulated cells.Taken together, these experiments suggest that the maternal serum dependent suppression of the IL2R expression is related to a protein G stimulation followed by an enhanced cAMP synthesis.

Summary: The introduction of a synthetic calcium phosphate into a biological environment is likely to result in surface-mediated chemical events. On the basis of such an assessment, we studied the chemical changes occurring in the mineral after exposure of a synthetic hydroxyapatite ceramic to bothin vivo (implantation in human) andin vitro (cell culture) conditions. A small amount of the material was phagocytized but the major remaining part behaved as a secondary nucleator as evidenced by the appearance of a newly formed mineral. Morphologically, the newly formed mineral appeared as tiny crystals precipitated and grown from the surface of the initial synthetic crystals. The density of the additional mineral increased from the periphery to the core of each biomaterial aggregate. Chemically, it was identified by IR spectroscopy as a carbonated apatitic mineral. We propose that the adsorption of biomolecules could inhibit precipitation, accounting for the increasing amount of precipitate from the periphery to the core of the aggregates.

Two infants with dysmorphism and aortic stenosis were trisomic for the distal part of 15q. Similar to seven other published cases, the facial dysmorphism was characteristic: prominent nose, narrow palpebral fissures, slight anti-mongoloïd slant, low-set ears, long upper lip, and a pronounced philtrum. Laboratory studies failed to demonstrate a gene-dose effect for the enzymes coded by chromosome 15 (PK 3 and MPI) and chromosome 21 (SOD 1).

The cytogenetic analysis of a 12-year-old retarded boy revealed a partial proximal trisomy 13, resulting from a maternal translocation t(8;13). A familial study shows this translocation in seven persons and also a Robertsonian translocation t(13q;14q) in three sons of a t(8;13) father. A review of partial proximal trisomies 13 shows a variability in the phenotypic expression.

The recent immunological literature has described the existence of a retroplacental serum factor being responsible for the downregulation of the MHC Class II antigen expression. In this report, the same property has been found in peripheral maternal serum. the HLA Class II modulating activity is however diminished in the presence of peripheral maternal serum as compared to retroplacental serum suggesting that the IA like inhibiting factor is released at the fetomaternal interface.After a three-day incubation period of unrelated lymphocytes in a maternal serum pool, it was shown that the HLA Dr., the HLA Dp., and more significantly, the HLA Dq. molecules were modulated. When third party lymphocytes were stimulated by Candidine or unrelated mononuclear cells in the presence of retroplacental serum, only the cellular subpopulation belonging to the CD4+ subset showed an HLA Dq. downregulation. the molecular constituents of the MHC Class II antigen expression characterizing cells belonging to other subsets remained unchanged. When the same stimulation assay was performed in the presence of a control medium (nulliparous serum), no changes concerning the MHC Class II molecular constituents were observed.When unrelated mononuclear cells were PHA stimulated in the presence of maternal and nulliparous serums, the HLA Dq. expression of the Cd8' subset showed a significant downregulation in the maternal serum mediated stimulation assay as compared to the control stimulation test. the molecular expression of the HLA Class II antigen related to the other subpopulations (CD4+, CD3+) stimulated by a mitogenic lectin remained unchanged.It is suggested that these molecular MHC Class 11 modulations are due to a factor included in the maternal IgG reaction. Retroplacental IgG contains the highest concentration of this factor.

Although hydroxyapatite(HA), a synthetic calcium phosphate, is used in restoring bone defects associated with periodontal diseases, its specific effect on the periodontal ligament fibroblast population during the regeneration process is unclear. To determine the cellular events occurring in the presence of HA, human periodontal ligament fibroblasts (HPLF) were isolated and maintained in culture. The specificity of the cells was evidenced by their morphology, deposition of extracellular matrix components, and alkaline Phosphatase (ALP) activity (as a marker of osteoblastic differentiation of HPLF). Phase‐contrast investigations revealed morphological alterations of cells in contact with HA particles. Transmission electron microscopy demonstrated the phagocytotic process of HPLF toward HA particles. Moreover, the presence of HA particles was significantly related to an increase in the protein synthesis activity and a decrease in the proliferation and ALP‐specific activity of HPLF. These results provide new information on the phenotypic expression of HPLF, which is comparable to that of osteoblastic cells. A subpopulation of HPLF may be influenced by the presence of HA to undergo transient dedifferentiation prior to redifferentiating into osteoblasts. This process may be important as a means by which HA acts as an osteoconductive material. This experimental study improves our understanding of the cellular processes which occur during healing and regeneration of periodontal defects after implantation of biomaterials. J Periodontol 1997;68:158–165.

There is a characteristic decrease in glucose metabolism in associative frontal and temporo-parietal cortices of patients suffering from Alzheimer's disease (AD). The decrease in metabolism might result from local neuronal loss or from a decrease of synaptic activity. We measured in vivo [11C]methionine accumulation into proteins with positron emission tomography (PET) to assess cortical tissue loss in AD. Both global regional activity and compartmental analysis were used to express [11C]methionine accumulation into brain tissue. Glucose metabolism was measured with [18F]fluorodeoxyglucose and autoradiographic method. Combined studies were performed in 10 patients with probable AD, compared to age-matched healthy volunteers. There was a significant 45% decrease of temporo-parietal glucose metabolism in patients with AD, and frontal metabolism was lowered in most patients. Temporo-parietal metabolism correlated to dementia severity. [11C]methionine incorporation into temporo-parietal and frontal cortices was not significantly decreased in AD. There was no correlation with clinical symptoms. Data suggest that regional tissue loss, assessed by the decrease of [11C]methionine accumulation, is not sufficient to explain cortical glucose hypometabolism, which reflects, rather, reduced synaptic connectivity.

Background and objective. This interim report from the Syst-Eur trial investigated the level of blood pressure control achieved during the double-blind period in patients followed in general practices. Methods. In the Syst-Eur trial elderly patients (60 years or older) with isolated systolic hypertension were randomized to either active or placebo treatment. Active treatment consisted of nitrendipine combined with enalapril and/or hydrochlorothiazide to reduce systolic pressure to Results. This analysis was restricted to patients of general practitioners who had been followed for at least 12 months. The placebo (N = 204) and active treatment (N = 217) groups had similar characteristics at randomization. At one year, the difference in sitting pressure between the two treatment groups was 10 mmHg systolic and 4 mmHg diastolic. Fewer patients remained on monotherapy in the placebo than in the active treatment group and on placebo the second and third line medications were started earlier. Nitrendipine tablets were discontinued in 10 patients on placebo and in 21 patients assigned to active treatment (P Conclusions. A significant blood pressure reduction can be achieved and maintained in older patients with isolated systolic hypertension followed by general practitioners. Whether this blood pressure reduction results in a clinically meaningful decrease of cardiovascular complications is under investigation. Keywords. Antihypertensive treatment, general practice, isolated systolic hypertension, randomized clinical trial.

A retroplacental serum factor responsible for the downregulation of the MHC class II antigen expression has been described [1]. We found that maternal serum had the same property. The HLA class II modulating activity is however diminished in the presence of maternal serum as compared to retroplacental serum suggesting that the IA like inhibiting factor is released at the fetomaternal interface. After a 3-day incubation period of unrelated lymphocytes and mononuclear cord blood cells in a maternal serum pool, it was shown that the HLADr, the HLADp, and more significantly, the HLADq molecules were modulated. This phenomenon was more pronounced among cord blood cells. When third party lymphocytes and mononuclear cord blood cells were stimulated by Candidine or unrelated mononuclear cells in the presence of retroplacental serum, only the cellular subpopulation belonging to the CD4+subset showed an HLADq downregulation. The molecular constituents of the MHC class II antigen expression characterizing cells belonging to other subsets remained unchanged. When the same stimulation assay was performed in the presence of a control medium (nulliparous serum), we found no changes in the MHC class II molecular constituents. When unrelated mononuclear cells and mononuclear cord blood cells were PHA stimulated in the presence of maternal and nulliparous serum, the HLADq expression of the CD8+subset showed a significant downregulation in the maternal serum mediated stimulation assay as compared to the control stimulation test. The molecular expression of the HLA class II antigen related to the other subpopulation (CD4+, CD3+) stimulated by a mitogenic lectin remained unchanged. It is suggested that these molecular MHC class II modulations are due to a factor included in the maternal IgG reaction. Retroplacental IgG contains the highest concentration of this factor.

Rapid diagnosis and treatment of ethylene glycol poisoning can be challenging and is critical for reducing the morbidity and the mortality of this intoxication. Cases from our center were retrospectively reviewed. From the 12 cases of ethylene glycol poisoning found since 2007, we present here three with significant toxicity and requiring critical care.

Valider un programme de réduction des risques et des dommages (RdR-D) dédié aux ChemSexeurs (usagers de substances psychoactives [SPA] en contexte sexuel) et aux Slameurs (injecteurs de psychostimulants dans ce même contexte), basé sur l’analyse des SPA collectées sur deux années en montrant l’apport de l’analyse pour l’usager.

Présenter les résultats préliminaires de la validation d’un programme de réduction des risques et des dommages (RDR-D) dédié aux chemsexeurs (usagers de substances psychoactives [SPA] en contexte sexuel) et aux slameurs (injecteurs de psychostimulants dans ce même contexte), basé sur l’analyse des produits.

Le suivi toxicocinétique consiste à mesurer au cours du temps l’évolution des concentrations sanguines d’un ou plusieurs toxiques, chez un patient hospitalisé secondairement à une intoxication volontaire ou non. Les paramètres pharmacocinétiques sont modifiés lors d’intoxications, par différents mécanismes (retard d’absorption, saturation du métabolisme et/ou de l’élimination, interactions médicamenteuses…), d’où l’intérêt de mesurer les concentrations plasmatiques.

OSTEOGENIC sarcomas attached to bone tissue have been reported in animals of different species. In 1936, Brues1described a case of spontaneous osteogenic sarcoma in the jaw of a three-year-old grey rabbit. Barrett et al. reported an osteogenic sarcoma attached to the left femur of a C3H female mouse2. Osteogenic sarcomas have also been induced by radio-isotopes such as radium-226, strontium-90, calcium-45 (ref. 3) and strontium-89 (ref. 4). One case of osteogenic neoplasm arising from muscle tissue has been reported in man5. This tumour found in the thigh muscle had developed over a period of ten years and was believed to have followed an abscess in the muscle.