[Multiple sclerosis : a neurological dysimmune inflammatory disease]. / La sclérose en plaques : une maladie neurologique dysimmunitaire inflammatoire.

Multiple sclerosis is a central nervous system autoimmune disease of the white and grey matters. Its pathophysiology is much better well known. It results from the interaction between genetic and environmental susceptibility factors. The role of EBV virus has recently been highlighted. Imaging techniques and neuropathology knowledge allow to distinguish several distinct processes responsible for focal and more diffuse inflammation. Therapeutic advances in recent years have been considerable. Different molecules and treatment sequences can be proposed to the patient with a demonstrated positive impact on the risk of disability secondary progression. Precise follow-up is a key. It requires optimal and early use of various treatments. The therapeutic choice must be guided by obtaining stabilization of the disease, both clinically and in terms of imaging, without exposing the patient to an excessive risk of side effects. Continuous and sequential treatments are available.

: La sclérose en plaques est une maladie auto-immune du système nerveux central qui concerne la substance blanche mais aussi la substance grise. Sa physiopathologie est beaucoup mieux connue. Elle résulte de l'interaction entre des facteurs génétiques de susceptibilité et environnementaux. Le rôle du virus EBV a été récemment souligné. Les techniques d'imagerie et les connaissances de neuropathologie ont permis de distinguer plusieurs processus distincts responsables d'une inflammation focale, mais également plus diffuse. Les progrès thérapeutiques des dernières années sont considérables. Différentes molécules et séquences de traitements peuvent être proposées au patient avec un impact positif démontré sur le risque de progression secondaire du handicap. La précision du suivi est un élément clé de la prise en charge. Elle requiert une utilisation optimale, et surtout précoce, des différents traitements. Le choix thérapeutique doit être guidé par l'obtention d'une stabilisation de la maladie, tant sur le plan clinique qu'en imagerie, sans exposer le patient à un risque excessif d'effets secondaires négatifs. Des traitements continus et séquentiels sont disponibles.

Understanding the Effect of Thermal Treatment on the Physico-Mechanical Properties of Light-Cured Composites for use in Indirect Restorations.

OBJECTIVES: To study the potential benefits of a post-cure thermal treatment on key physico-mechanical properties of light-cured resin-based composites for use in indirect restorations, a CAD/CAM composite block being used as control. MATERIAL AND METHODS: Six commercial composites were light-cured before being thermally treated in a furnace at 90°C during 15 minutes (CAD/CAM composite used as a control). The properties measured with or without thermal treatment were: degree of conversion, flexural strength, elastic modulus, Vickers microHardness, organic mass content and eluted and absorbed mass before and after storage in ethanol. The data were analysed using one-way ANOVA, and Weibull distributions. RESULTS: A general increase in the properties measured was observed for all materials after thermal treatment, except a general decrease in mass elution and absorption (most statistically significant: p⟨0.05). Weibull analysis showed a tendency (p⟩0.05) of increased reliability of the flexural strength after thermal treatment for all materials. CONCLUSION: The present data revealed clear physico-mechanical improvements after thermal treatment of light-cured composites. Such method could hence be beneficially used to produce indirect restorations as compared to stratifying and light-curing the same composites in situ. However, most properties of the control CAD/CAM composite were higher, but CAD/CAM technologies aren't available everywhere.

[Multiple sclerosis : therapy update]. / Actualités thérapeutiques dans la sclérose en plaques.

Multiple sclerosis is still a severe disease potentially associated with a short- or long-term disability in young adults. Since a few years therapeutic progresses are considerable. New drugs and new therapy rationale considerably improved our knowledge and patient's care. Early treatment is a key within dedicated specialized and multidisciplinary units. Clinical and neuroradiological no evidence of disease activity (NEDA) is a goal, which is more often reached. Patient's evolution and follow-up is completely changed in recent years with more efficacy.

La sclérose en plaques (SEP) reste une maladie grave du système nerveux central (SNC), potentiellement responsable d'un handicap, physique ou non, à moyen et long termes, chez des adultes jeunes. Les progrès thérapeutiques au cours des dernières années ont été considérables grâce à l'avènement de nouvelles molécules, mais aussi, et peut-être surtout, de schémas thérapeutiques nettement plus performants. Les progrès des connaissances en immunologie ont eu un impact majeur dans ce domaine. La prise en charge précoce des patients au sein d'unités intégrées et multidisciplinaires est une étape essentielle qui permet de guider l'utilisation rationnelle des médicaments. L'obtention d'une stabilité clinique et neuroradiologique est un défi qui est, de plus en plus souvent, relevé avec un bénéfice majeur pour les patients.

Management of adverse renal events related to alemtuzumab treatment in multiple sclerosis: a Belgian consensus.

Alemtuzumab is a humanized monoclonal antibody indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis with active disease. Multiple sclerosis (MS) patients treated with alemtuzumab are at increased risk for autoimmune adverse events (thyroid disorders, immune thrombocytopenia, and renal disease). The use of alemtuzumab has been associated with the development of renal immune-mediated adverse events in 0.3% of patients in clinical trials in MS, which generally occurred within 39 months of the last administration. Both anti-GBM disease and membranous nephropathy have been associated with the use of alemtuzumab. Early detection is necessary to allow for early diagnosis and prevent adverse renal and patient outcomes. Through the implementation of the risk minimization measures, patients can be diagnosed, and treated if needed, early allowing for generally favorable outcomes. This important goal can be reached through health care professional and patient education, careful analysis of the monthly lab tests, and close collaboration between the patient, neurologist, and the nephrologist. This article presents the consensus of Belgian MS specialists and nephrologists on the practicalities of diagnosis, management, and treatment of alemtuzumab-associated renal adverse events based on good clinical practice.

Corticosteroids in the management of acute multiple sclerosis exacerbations.

Multiple sclerosis (MS) is an autoimmune, inflammatory demyelinating disease of the central nervous system characterized in the majority of the patients by a relapsing-remitting disease course. For decades high-dosage corticosteroids (CS) are considered the cornerstone in the management of acute MS relapses. However, many unanswered questions remain when it comes to the exact modalities of CS administration. In this review on behalf of the Belgian Study Group for MS we define the efficacy of CS in reducing MS-related morbidity and examine whether the effect is different according to type of CS, route of administration, cumulative dosage, timing of initiation and disease course. We also review the use of CS in combination with other MS treatments and during pregnancy and lactation. Furthermore, we delineate the relevant adverse events due to a pulse CS regimen and present a decision tree that can be used when treating MS relapses in clinical practice.

[Is this cerebral cavernoma the cause of a Parkinsonian syndrome?]. / Le cas clinique du mois. Ce cavernome cérébral est-il la cause d'un syndrome parkinsonien?

We report the case of a patient presenting with an akineto-rigid syndrome of the left hemibody whose etiological exploration by magnetic resonance imaging showed the presence of a cavernoma located in the right lenticular region. The interest of this situation is to establish if there is a pathophysiological link between such symptoms and the lesion revealed by the MRI.

The antimalarial ferroquine: from bench to clinic.

Ferroquine (FQ, SSR97193) is currently the most advanced organo-metallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocene-containing compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.

A role for CD4+ and CD8+ cells and not for CD25+ cells in the control of Plasmodium berghei Anka blood stage parasites in rats.

In previous studies of the infection of rats by P. berghei Anka, we have shown that primary blood stage infection induced the expansion of CD4+ T cells and CD8+ T cells in adult resistant rats while the number of CD4+CD25+ cells was found to be higher in young susceptible rats. In this work, the respective contribution of each cell population was determined in young and adult rats treated with monoclonal antibodies. Down-regulation of surface CD25 molecules, including those expressed by CD4+ cells did not significantly enhance the capacity of young rats to control the development of erythrocytic stages or modify the course of infection in adult infected rats. However, we observed a significant loss of protection when adult rats were treated with anti-CD4 mAb (W3/25) with higher blood parasitemia levels and approximately 50% of rats succumbed to infection. More importantly and in contrast to earlier studies performed in mice, we found a significant increase in blood parasite levels and a significant delay in parasite clearance in adult rats treated with anti-CD8 mAb OX8, known to deplete CD8+ cells. These results suggest that CD8+ cells play a critical role in the development of immune responses in rats to control the replication of blood stage parasites.

[Diabetic peripheral neuropathy]. / La neuropathie diabétique périphérique.

Peripheral neuropathy is a very frequent consequence of diabetes mellitus. Its clinical expression is quite variable. A specific therapy is sometimes necessary. Early diagnosis of diabetic neuropathy is a cornerstone of patient's follow-up. Differential diagnosis of diabetic neuropathy is sometimes difficult from another type of neuropathy or a focal, even systemic, disease. It is mandatory to know how a diabetic neuropathy may express. Pathophysiological mechanisms involved in diabetic neuropathy are complex and interrelated. Hyperglycaemia alone, even mild or moderate, vascular disorders and dysimmune factors may be combined to induce axonal injury. Glycaemic control is the cornerstone of effective treatment for neuropathy associated with diabetes. Specific pain control and therapies of autonomic disturbances are regularly required.

[Somatosensory evoked potentials: clinical applications in peripheral neuropathies]. / Intérêt des potentiels evoqués somesthésiques dans l'exploration des neuropathies périphériques.

Somatosensory evoked potentials (SSEP) offer a reliable measurement of peripheral and central sensory conduction through the stimulation of mixed or purely sensitive nerves. If their interest is well known for the evaluation of central pathologies (cerebral or spinal), their precise indication and application field in peripheral neuropathies remains unclear. Some specific diseases, like lumbar or cervical radiculopathies or brachial plexopathies, have been extensively studied and large series have been reported in the literature. Relative sensitivity and specificity of SSEPs and electroneuromyography (ENMG) is a matter of debate for specific peripheral nerve affections. We present a practical approach in which SSEPs and ENMG data are integrated toward a better diagnosis. Clinical histories are exposed as an illustrative demonstration of specific interest for combined SSEPs and ENMG in the patient's functional evaluation and follow-up.

In vitro and in vivo antimalarial activity of ferrochloroquine, a ferrocenyl analogue of chloroquine against chloroquine-resistant malaria parasites.

Previous studies have shown that ferrochloroquine (FQ) exhibited an antimalarial activity against Plasmodium spp. The present work confirmed this activity, described the curative effect on P. vinckei and investigated the FQ toxicity in vitro and in vivo. The in vitro and in vivo growth inhibition of P. falciparum and P. berghei N, respectively, showed that FQ antimalarial activity was 1.5-10 times more potent than chloroquine. FQ completely inhibited the in vivo development of both chloroquine-susceptible and resistant P. vinckei strains and protected mice from lethal infection at a dose of 8.4 mg kg(-1) day(-1) given for 4 days subcutaneously or orally. This curative effect was 5-20 times more potent than chloroquine, according to the strains' resistance to chloroquine. At this curative dose, no clinical changes were observed in mice up to 14 days after the last administration. Nevertheless, the acute toxicity and lethality of ferrochloroquine seemed to be dependent on gastric surfeit. The FQ security index determined in vitro confirmed that it might be a promising compound.

Novel ferrocenic artemisinin derivatives: synthesis, in vitro antimalarial activity and affinity of binding with ferroprotoporphyrin IX.

Following our search for novel compounds with high antimalarial activity, a series of artemisinin (QHS) derivatives containing a ferrocenic nucleus was prepared and tested in vitro against Plasmodium falciparum strains. Two new metallocenic derivatives (1 and 3) were found as potent as QHS. All compounds showed a capacity to bind with ferroprotoporphyrin IX. A decrease in the Soret band absorbance of ferroprotoporphyrin IX, resulting from the addition of different drugs concentrations, was shown. The association stoichiometry of compounds to ferroprotoporphyrin IX appears to be 1:2 at equilibrium, with an intermediate 1:1 complexation. These results appear to strengthen the role of adducts between artemisinin derivatives and heme in generation of artemisinin radicals. Such interaction of artemisinin ferrocenyl derivatives with ferroprotoporphyrin IX and its biological significance could form a basis in future drug development.

Use of cartilage grafts for closure of cleft palate fistulae.

We describe the results of using a free cartilage graft in the closure of cleft palate fistulae in 14 patients with a mean follow-up of 8.6 months. Complete closure of the fistula was achieved in 11 patients (79%), with partial closure in the remaining three patients. This technique is simple, causes relatively little discomfort, involves little tissue dissection and can be performed as a day-case procedure. The success rate is comparable with or better than other methods, and we consider it the treatment of choice for small cleft palate fistulae.

Synthetic ferrocenic mefloquine and quinine analoguesas potential antimalarial agents.

A few years ago we proposed a strategy for the synthesis of new ferrocene-chloroquine analogues replacing the carbon chain of chloroquine by hydrophobic ferrocenyl moieties. Now, this strategy has been applied to the antimalarial amino-alcohols class to afford new potentially active analogues of mefloquine and quinine bearing a substituted ferrocenic group. The pathway used for the synthesis of the mefloquine analogues includes the coupling of an aminomethyl substituted ferrocene carboxaldehyde with a lithio quinoline compound. On the other hand, the synthesis of quinine analogues was ensured by the 'inverse' reaction of a lithio aminomethyl ferrocene with a quinoline carboxaldehyde. The configurations of each diastereoisomer were unambiguously determined by spectroscopic data. The mechanistic interpretations were fully discussed. Ferrocenyl analogues of mefloquine and quinine exhibited a lower antimalarial activity than mefloquine and quinine themselves. Comparing optical isomers, those isomers dissimilar to ferrocenyl derivatives presented better antimalarial activities than those similar to ferrocenyl.

Molecular cloning, expression analysis and iron metal cofactor characterisation of a superoxide dismutase from Toxoplasma gondii.

A genomic region of 12 kb encompassing the gene encoding the superoxide dismutase (SOD) of Toxoplasma gondii has been cloned. The gene contains four exons of 121, 42, 381 and 59 bp which are separated by three introns of 321, 202, and 577 bp, respectively. The open reading frame can be translated into a protein of 201 amino acids with a molecular mass of 22.6 kDa. Alignment indicated that it is a FeSOD, a type only found in bacteria, protozoa and chloroplast of higher plants. Recombinant SOD was expressed in a Escherichia coli double mutant lacking both MnFeSOD and FeSODs. The presence of iron as metal cofactor was confirmed by measurements of iron by absorption mass spectrometry and electron paramagnetic resonance studies. Semi-quantitative reverse transcribed polymerase chain reaction experiments showed a similar amount of SOD transcripts in two developmental stages of T. gondii. Antibodies raised against the purified recombinant protein detected SOD protein in both bradyzoite and tachyzoite forms suggesting this SOD might be essential for the intracellular growth of both developmental stages. Southern blot analysis indicated that SOD occured as a single copy gene in T. gondii genome.

Analysis of genetic diversity at the iron-containing superoxide dismutase locus in Plasmodium falciparum wild isolates.

In order to investigate the genetic diversity of iron-containing superoxide dismutase (FeSOD) from Plasmodium falciparum, a potential anti-malarial therapeutic target, we cloned and sequenced Plasmodium FeSOD from 26 blood samples from non-infected patients. Fifteen clones had the same nucleotide sequence as that of the FeSOD gene of the P. falciparum strain HB3 cultivated in vitro. The other 11 clones presented mutations responsible for punctual amino acid changes which did not modify key residues for the function or the structure of the enzyme. The high sequence conservation between FeSOD from the isolates confirms that this enzyme could represent a therapeutic target.

Cloning and characterization of iron-containing superoxide dismutase from the human malaria species Plasmodium ovale, P. malariae and P. vivax.

The iron-containing superoxide dismutase (FeSOD) gene from three human malaria species, namely Plasmodium ovale, P. malariae and P. vivax, was amplified by polymerase chain reaction, cloned and then sequenced. Comparisons of their deduced amino acid sequences with that of the FeSOD from P. falciparum revealed a very low polymorphism at the FeSOD locus in human malaria species. One P. ovale and the P. vivax FeSOD genes presented the same nucleotide sequence as that of the P. falciparum strain HB3 whereas the second P. ovale and the P. malariae genes exhibited two punctual mutations. These mutations did not affect the function and structure of the enzyme. The FeSOD polymorphism was so low that no phylogenetic relationship among human malaria species could be proposed, but this conservative structure strengthened the potentiality of this enzyme as a possible target for antimalarial drugs.