Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.

Parameter estimation for uncertain systems based on fault diagnosis using Takagi-Sugeno model.

The paper addresses a systematic procedure to deal with state and parameter uncertainty estimation for nonlinear time-varying systems. A robust observer with respect to states, inputs and perturbations is designed, using a Takagi-Sugeno (T-S) approach with unknown premise variables. Tools of the linear automatic to the nonlinear systems are applied, using the Linear Matrix Inequalities optimization. The observer estimates the uncertainties, the states and minimizes the effect of external disturbances on the estimation error. The uncertainties are modelled in a polynomial way which allows considering the uncertainty estimation as a fault detection problem. The residual sensitivity to faults while maintaining robustness according to a noise signal is handled by H∞/H- approach. The method performance is illustrated using the three-tank system.

Studies on the in vitro genotoxicity of baytubes, agglomerates of engineered multi-walled carbon-nanotubes (MWCNT).

The increasing production and expanding application of nanoparticles in multiple aspects of life necessitate reliable safety assessment. In this context we here report on the evaluation of the potential genotoxicity of baytubes, i.e. agglomerates of multi-walled carbon-nanotubes (MWCNT). Testing for chromosome aberrations was done in V79 cells and for gene mutations in the Salmonella microsome test. Baytubes were formulated in deionised water at 10 mg/ml and treated with ultrasound for 30 min at 25 degrees C. Particle size distribution was determined under the incubation conditions in the in vitro studies. In the chromosome aberration test V79 cells (OECD TG 473) were exposed in the absence or presence of S9 mix for 4 h to concentrations of 2.5, 5 and 10 microg/ml of baytubes (visible from concentration of 5 microg/ml and higher). Harvest was 18 h after the beginning of the treatment. In addition, cells treated with 10 microg/ml were harvested 30 h after the beginning of the treatment. An additional experiment was performed using continuous treatment at 2.5, 5 and 10 microg/ml for 18 h (no S9 mix) with subsequent harvest. Under these conditions and in the concentration range tested there were no cytotoxic and no clastogenic effects. In the Salmonella microsome (Ames) test (OECD TG 471) concentrations up to 5000 microg/plate were tested in Salmonella typhimurium (strains TA 1535, TA 100, TA 1537, TA 98 and TA 102) in the absence or presence of S9 mix. Under these conditions and in the concentration range tested there were no bacteriotoxic and no mutagenic effects.

Linear mass balance equilibration: a new approach for an old problem.

Interval analyses are well known in the mathematics literature but have found few applications in control engineering. Based on the interval concept, we present here a methodology for data reconciliation and mass balance equilibration which is a very classical problem in mineral and chemical engineering. Indeed, this problem is solved with the view of inequality constraints which allows us to represent measurements by interval without particular knowledge and hypothesis about the density probability function of the measurement errors. As a main result, the paper gives a set of solutions for the reconciled data under an interval form and not only one solution as is the case with classical approaches.

[Diffuse sclerosing osteomyelitis of the mandible and SAPHO syndrome]. / Ostéomyélite sclérosante diffuse mandibulaire et syndrome de SAPHO.

BACKGROUND: Diffuse sclerosing osteomyelitis of the mandible (DSOM) and SAPHO (synovitis, acne, palmo-plantar pustulosis and psoriasis, hyperosteosis, osteitis) syndrome are not commonly associated. SAPHO has not been described to date in the stomatology and maxillo-facial surgery literature in French. Were report here a homogeneous series of 12 patients with DSOM. MATERIAL AND METHODS: All patients had mandibular osteitis. RESULTS: Five patients with multifocal osteitis wre considered to present SAPHO syndrome because of the associated skin lesions. One patient with a unique focus of mandibular osteitis and palmo-plantar pustulosis probably had early-stage SAPHO syndrome. The diagnosis in the other cases was diffuse sclerosis osteitis of the mandible. DISCUSSION: We compared our series with those reported in the literature, emphasizing diagnostic and therapeutic difficulties. Diffuse sclerosing osteomyelitis of the mandible should be distinguished from microbial osteitis. Early diagnosis is required to avoid successive and unnecessary dental avulsions. There is a possible link between DSOM and SAPHO and all patients should have a complete work-up including whole-body scintigraphy to search for other foci. A biopsy is indicated to rule out malignancy. Nonsteroidal antiinflammatory drugs can improve patient comfort in this particularly long syndrome. Although the efficacy is demonstrated, surgery and antibiotics can only delay relapse for a few months.

A novel route to preussomerins via 2-arylacetal anions.

[reaction--see text] Dimerization of salicylaldehydes provided 6H,12H-6,12-epoxydibenzo[b, f][1,5]dioxocins in multigram quantities. Deprotonation-allylation of the benzylic acetals followed by further functionalization of the diallyl derivative and double Friedel-Crafts cyclization gave a novel preussomerin analogue which possessed the full carbon skeleton of the natural products.

Data reconciliation with uncertain models

Data reconciliation has proven to be an effective technique for providing frequent, accurate and consistent "best estimates" of plant operation data. However, in almost all the proposed techniques until today, the mathematical model of the process has been considered as exact. In point of fact, this hypothesis is uncommon and frequently the models used are uncertain. This paper proposes a new technique of data reconciliation which is able to exploit the knowledge about the uncertainties of the model with regard to which the reconciliation is done. It leads to the solution of a classical quadratic optimisation problem subject to constraints. The originality of the proposed technique is to use penalty functions for solving this problem and to weight each constraint with regard to their uncertainties.

Imbalanced "memory" T lymphocyte subsets and analysis of dendritic cell precursors in the peripheral blood of adult patients with Langerhans cell histiocytosis.

OBJECTIVES: To investigate the phenotype of lymphocytes and dendritic cell precursors in the peripheral blood of adult patients with histiocytosis X. METHODS: Data were obtained on patients with histiocytosis X treated in La Pitié-Salpetrière Hospital. Peripheral blood mononuclear cells from 10 patients (4 with unifocal and 6 with disseminated disease) were studied by flow cytometry. A method was set up to detect circulating Langerhans cells, dendritic cells and their precursors. RESULTS: An abnormal repartition of "memory" T lymphocyte subsets was observed, with a significant decrease of CD4CD45RO and CD8CD45RO and a reciprocal increase of CD4CD45RA "naive" cells, while CD4+ cells displaying the accessory molecule CD28 were decreased in some patients. These abnormalities disappeared in vitro after triggering of the CD3 and CD28 molecules in the absence of antigen presenting cells, hence demonstrating that there was no constitutive defect in the capacity of CD4+ and CD8+ T cells to convert from the CD45RO- to the CD45RO+ isoform. Langerhans cells were undetectable in the peripheral blood, and dendritic cells and their precursors were present in normal proportions (0.5 +/- 0.2% and 2.8 +/- 1.2%, respectively), but the latter were more numerous (4% and 6% of the PBMC) in the two patients with the more severe form of the disease. CONCLUSIONS: We found in these patients some T lymphocyte phenotype abnormalities which suggest alterations in antigen-driven activation processes. The number of dendritic precursor cells was not consistently elevated in the peripheral blood from histiocytosis X patients.

[Anesthesia for hand surgery in patients with bullous epidermolysis]. / Anesthésie pour chirurgie de la main chez des patients atteints d'épidermolyse bulleuse.

Epidermolysis bullosa is a rare genetic disease, characterized by the formation of bullae in the skin and squamous epithelium following minimal trauma. The majority of surgical indications specific to this disease concern autosomal recessive dystrophic epidermolysis bullosa (RDEB). Hand surgery is one of the fields of surgery involved. The cicatricial course of the lesions results in retraction and pseudosyndactylization of the fingers, sometimes leading to complete destruction of the hand. Since 1988, we have treated 23 patients, including 11 children under the age of 8 years and weighing less than 20 kg. 185 procedures were performed by two anaesthetists, using regional plexus blocks in 157 cases and general anaesthesia in only 28 cases. This series is comparable in number, to that reported by the London team, which prefers general anaesthesia. Regional anaesthesia has been previously used, but only following general anaesthetic induction. Our approach, based on the experience of a hand surgery center, is in marked opposition with this standard paediatric approach. Regional anaesthetic techniques, particularly in the upper limb, present many advantages in addition to their feasibility in small children: efficacy, simplicity, postoperative analgesia, and outpatient comfort. In the context of the specificities and difficulties encountered in the management of these patients suffering from epidermolysis bullosa, the authors demonstrate the value of first-line regional anaesthesia, even in very young children (less than 3 years). The presence of a parent in the operating room is a valuable aid, which is still insufficiently used, but which should be used with conviction for the benefit of all concerned.

[Anesthesia for hand surgery in patients with epidermolysis bullosa]. / Anesthésie pour chirurgie de la main chez des patients atteints d'épidermolyse bulleuse.

OBJECTIVE: To report on the anaesthetic management with axillary block of patients suffering from recessive dystrophic epidermolysis bullosa (RDEB), undergoing repetitive surgery of the hand. STUDY DESIGN: Retrospective analysis of a case series. PATIENTS: Twenty-two patients, including 11 children less than 8-year-old and with a body weight under 20 kg, treated since 1988, were considered. METHODS: For surgery, including usually three stages at a 7-day interval, an axillary block was placed when feasible, after oral premedication midazolam (0.1-0.2 mg.kg-1) with a 25 gauge needle in patients of less than 30 kg of body weight and 22 gauge beyond. The local anaesthetic mixture included 2% lidocaine (5-10 mg.kg-1) and 0.5% bupivacaine (2-3 mg.kg-1). A catheter for repetitive injections had not been inserted. For children less than 10-year-old a parent was present in the theater during all the course of operation. RESULTS: Between 1988 and 1995, 22 patients underwent 160 operative interventions on 54 hands. Regional anaesthesia was used in 142 cases, including 140 axillary and 2 interscalene blocks. General anaesthesia was only required in 20 cases, either alone or associated with regional anaesthesia. The success rate of axillary blocks was 98%. DISCUSSION: For surgery of the hand in patients with RDEB, we switched in 1988 from general anaesthesia with ketamine to axillary block, even in young children, as it is closer to the no-touch principle, which is essential to prevent from blistering. In comparison to general anaesthesia, regional anaesthesia raises neither the problems of airway and vascular access, nor those of instrumental monitoring. The main factors of success with regional anaesthesia are technical skills, expertise in the management of patients with RDEB and parental presence in the operating room which makes the procedure less stressful for children.

[Simplified locoregional anesthetic technique for the surgery of the thumb]. / Technique d'anesthésie locorégionale simplifiée pour la chirurgie du pouce.

Finger surgery is a frequent procedure, of short duration unless in case of major trauma, and often performed in emergency circumstances. In order to improve this type of treatment, we have developed distal blockade techniques. The double innervation in the thumb requires two punctures; a) dorsal, in order to block the superficial branch of the radial nerve; b) palmar, through the flexor tendon sheath, allowing the blockade of the digital nerves, outing from the median nerve. We use bupivacaine 0.5% without adrenaline, which offers high quality anaesthesia and analgesia. This technique can be used outside the operating room, in emergency or X-ray rooms. It allows thumb anaesthesia, either alone for short duration or in an addition to a plexus blockade whose effect in the radial nerve area would be insufficient.

[Adenomatoid odontogenic tumor. A case with an unusual mandibular site]. / La tumeur odontogène adénomatoïde. Une observation à localisation mandibulaire inhabituelle.

An adenomatoid odontogenic tumor located in the mandible was studied in a 28 year-old woman. The clinical, histological and ultrastructural characteristics of this rare tumor are described out and the histogenesis is discussed.

Controlled clinical investigation of acute analgesic activity of nimesulide in pain after oral surgery.

A double-blind study was conducted to determine the dose-effect relationship of nimesulide and to compare the acute analgesic activity of this agent with that of placebo and niflumic acid. Patients undergoing extraction of an impacted third molar were randomised into 4 groups (nimesulide 100mg; nimesulide 200mg; niflumic acid 250mg and placebo). They were instructed to take their allocated treatment after the onset of pain, and to record the pain severity and relief during the following 6 hours. 134 patients were evaluated. There were significant differences between groups for each time of observation/efficacy parameter (Kruskal-Wallis test). Pairwise comparison (Duncan's test) showed that all 3 active medications were significantly different from the placebo. No substantial differences were found between any of the active treatments. Analogous results were obtained when the amount of rescue drug used (paracetamol) was compared. More positive judgements were reported by patients treated with an active compound than by those taking placebo.

[Local anesthesia of the finger through the flexor tendon sheath]. / Anesthésie locale digitale par la gaine des fléchisseurs.

A series of 350 cases of local anaesthesia of the finger using the flexor tendon sheath is reported. The patients were ranked ASA 1 or 2 and the youngest was 12 months old. This technique was used for day case surgery, such as nail trauma and tumours, wound exploration, tumour and cyst removal, tenolysis and neurolysis. The needle was inserted on the palmar aspect of the metacarpophalangeal joint, into the digital flexor tendon of the corresponding finger. Thereafter the needle was withdrawn very slightly in order to inject the local anaesthesia solution within the sheath, and not the tendon. The volumes were respectively 1 ml in children and 3 to 4 ml in adults of either 2% lignocaine or 0.5% bupivacaine without adrenaline. As palmar injections are painful a freezing spray solution was used prior to insertion of the needle. There was no anaesthesia of the dorsal digital nerves, as opposed to the findings of the author of the first series. This technique, which can be qualified as being easy and reliable, could be a valuable alternative for the ring or interdigital blocks, which carry a significant risk of vascular and neurological complications.

[Nerve sheath myxoma. A case involving the maxillary sinus]. / Myxome des gaines nerveuses. A propos d'un cas siégeant dans le sinus maxillaire.

A myxoma of nerve sheaths involving the maxillary sinus was observed in a 12 year-old boy. The tumour, necrotic and calcified in this central area, was detected by a radiological opacity. In this periphery, the histological features were characteristic, showing lobules surrounded by fibrous tissue. In these lobules, spindle-shaped or stellate tumour cells were scattered in an abundant "myxomatous" matrix. The child is in good health fifteen months after surgical treatment. The histogenesis of this rare tumor is discussed in relation to this case and to those cases previously reported in the literature.

[Early auditory evoked potentials in normal sheep and in sheep with trypanosomiasis]. / Potentiels évoqués auditifs précoces chez le mouton sain et chez le mouton trypanosomé.

In human and animal clinics, the early auditory potential has been used for a long time in the detection of lesions through the internal auditory way in the cerebral trunk. The aim of this work tries to determine if this non invasive test is apt to show up and to follow the evolution of lesions at the level of auditory way in the cerebral trunk of sheep with trypanosomiasis. According to the human technic, the list of the early auditory potential was realized against ten healthy sheep and ten sheep with trypanosomiasis (Trypanosoma brucei brucei) at the nervous phase. No significant anomalies exist in the sheep with trypanosomiasis. The results are discussed.