Mycolactone toxin induces an inflammatory response by targeting the IL-1ß pathway: Mechanistic insight into Buruli ulcer pathophysiology.

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1ß, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1ß, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.

Epileptic syndromes: differential treatment in infants, children, and adolescents.

This paper proposes therapeutic guidelines for the management of some epileptic syndromes in infants, children, and adolescents, based on available medical literature and clinical practice in the French Community of Belgium. The guidelines address both epileptic encephalopathies (West syndrome, Lennox-Gastaut syndrome, and Dravet syndrome) and idiopathic epilepsies (typical absence seizures, epilepsy with centro-temporal spikes and juvenile myoclonic epilepsy).

Spike detection algorithm automatically adapted to individual patients applied to spike-and-wave percentage quantification.

OBJECTIVE: To report an innovative spike detection algorithm that tailors its detection to the patient. Interictal epileptiform activity quantification was accomplished in the setting of epileptic syndromes with continuous spike and waves during slow sleep, which is a time-consuming task for the EEG analysis. METHODS: The algorithm works in three steps. Firstly, a first spike detection is made with generic parameters. Secondly, the detected spikes are used to tailor the detection algorithm to the patient; and thirdly, the resulting patient-specific detection algorithm is used to analyze individual patient with high-quality detection. Therefore, the algorithm produces a patient-specific template -hence exhibiting improved performance metrics, without the need of a priori knowledge from the experts. RESULTS: The system was first evaluated for EEG of three patients, against the scoring of three EEG experts, demonstrating similar performance. Later, it was evaluated against the spike and wave percentage evaluation of another expert for 17 additional records. The difference between the two evaluations was 4.4% on average, which is almost the same as the interexpert difference (4.7%). CONCLUSIONS: We designed a fully automated and efficient spike detection algorithm, which is liable to trim down the specialist's diagnostic time.

Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa, Debre type.

OBJECTIVE: To delineate a new syndrome of brain dysgenesis and cutis laxa based on the description of 11 patients belonging to nine unrelated families recruited through an international collaboration effort. METHODS: Careful clinical assessment of patients from birth to the age of 23 years with follow-up studies ranging from 3 to 20 years. Biochemical studies of serum proteins glycosylation by isoelectric focusing and capillary zone electrophoresis were performed in 10 patients. Brain MRI studies using conventional methods were analyzed in eight patients. RESULTS: An expanded clinical spectrum of a syndrome comprising facial dysmorphia (enlarged anterior fontanelles, downward slant of palpebral fissures, prominent root of the nose), a connective tissue disorder (inguinal hernia, hip dislocation, high myopia), and neurologic impairment was defined. Early developmental delay was followed by onset of generalized seizures by the end of the first decade and a subsequent neurodegenerative course. A defect of N- or N- plus O-glycosylation of serum transferrins and ApoCIII was observed in 10 patients. An unusual cobblestone-like cortical malformation over the frontal and parietal regions was seen in eight patients and cerebellar abnormalities, including two patients with Dandy-Walker malformation, were observed in three patients. CONCLUSIONS: Our results suggest that autosomal recessive cutis laxa, Debré type, initially considered a dermatologic syndrome, is a multisystemic disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome. It might represent a metabolic cause of Dandy-Walker malformation. It is associated with a deficient N- and-O glycosylation of proteins and shares many similarities with muscle-eye-brain syndromes.

The epileptic syndromes with continuous spikes and waves during slow sleep: definition and management guidelines.

The authors propose to define the epileptic syndromes with continuous spikes and waves during slow sleep (CSWS) as a cognitive or behavioral impairment acquired during childhood, associated with a strong activation of the interictal epileptiform discharges during NREM sleep--whatever focal or generalized--and not related to another factor than the presence of CSWS. The type of syndrome will be defined according to the neurological and neuropsychological deficit. These syndromes have to be classified among the localization-related epileptic syndromes. Some cases are idiopathic and others are symptomatic. Guidelines for work-up and treatment are proposed.

Prophylaxis of the epilepsies: should anti-epileptic drugs be used for preventing seizures after acute brain injury?

In many circumstances antiepileptic drugs are used in patients who have never presented any clinical epileptic seizures. These substances are administered on the assumption of a potential risk for the patients of developing acute or delayed chronic seizures after brain injuries such as trauma, stroke, hemorrages or even neurosurgical interventions. The aim of this paper is to propose therapeutic guidelines for the management of this prophylactic attitude in epilepsy based on basic research and clinical practice in the French community in Belgium. We will distinguish between the prevention of acute (early onset-provoked) seizures and a delayed truly post-lesional (unprovoked) epilepsy. Some therapeutic goals can be achieved under the former circumstances whereas in the latter situation we all agree for the absence of any coherent antiepileptic prophylactic behaviour.

Guidelines for recognition and treatment of the psychoses associated with epilepsy.

Epilepsy and psychiatric diseases are frequent comorbidities. Psychoses in patients with epilepsy have special physiopathology and several clinical presentations and prognoses. Their treatments are also specific, according to the specific diagnosis. This paper represents the summary of a consensus meeting held in November 2003 by a Belgian French-speaking group of neurologists, neuropediatricians and psychiatrists and proposes guidelines for the recognition and treatment of those entities.

Therapeutic issues in women with epilepsy.

Approximately 20% of people with epilepsy are of childbearing potential and about 3 to 5 births per thousand will be to women with epilepsy. Both epilepsy and antiepileptic drugs can cause specific problems in women and embryos (less than 8 weeks of gestational age) or foetuses (more than 8 weeks of gestational age). The aim of this paper is to discuss therapeutic issues for the management of women with epilepsy: initiation of antiepileptic therapy, contraception, pregnancy, breast feeding and menopause. Some fertility issues are also discussed.

A new crystalline phase of nitric acid dihydrate.

The crystal structure of a new high-temperature phase of nitric acid dihydrate, HNO(3).2H(2)O, has been determined at 225 K by single-crystal X-ray diffraction. The H atom of the nitric acid is delocalized to one water molecule, leading to an association of equimolar NO(3)(-) and H(5)O(2)(+) ionic groups. The asymmetric unit contains two molecules of HNO(3).2H(2)O. The two independent molecules are related by a pseudo-twofold c axis, by a translation of 0.54 (approximately (1/2)) along b, with a mean atomic distance difference of 0.3 A, except for one H atom of the water molecules (1.5 A), because of their different orientations in the two molecules. The two independent molecules, linked by strong hydrogen bonds, are arranged in layers. These layers are linked by weaker hydrogen bonds oriented approximately along the c axis. A three-dimensional hydrogen-bond network is observed.

[Daltonism and the genetics of aging]. / Le daltonisme et la génétique du vieillissement.

In order to test whether mutations giving rise to color vision deficiencies are more frequently inherited from older fathers, an exhaustive screening of births in the Namur region has allowed to isolate a sample of 225 descending sons of maternal grandfathers who were older than 45 years at their daughter's birth. The incidence of color vision defects was compared between this set of cases and three control groups totalling 959 boys from independent families. While these comparisons were not conclusive, we propose new hypotheses concerning the population dynamics of color vision deficiencies. Neomutations in X-linked pigment genes may be a marker of the overall genetic load borne by the X chromosome. Selection against such loaded X chromosomes may occur in the second generation, either in the course of embryogenesis, or during female gametogenesis. The future assessment of these novel hypotheses relies on the arbitration of molecular genetics.

Niosomes as carriers of radiopaque contrast agents for X-ray imaging.

Non-ionic surfactant vesicles (niosomes) are considered as carriers of iobitridol, a diagnostic agent used for X-ray imaging. The niosomes, with a diameter between 150 and 175 nm, are prepared using the film-hydration method followed by sonication. These vesicles were obtained with appropriate mixtures of D-alpha tocopheryl polyethylene glycol 1000 succinate, polyoxyethylene glycol 4000 stearate, sorbitan monostearate, cholesterol and dicetylphosphate. Methods allowing the increase of the rate of encapsulation and the stability of the vesicles were carried out. In addition to the study of the formulation of the vesicles, the physico-chemical and morphological properties of the vesicles have been studied.

Physical, chemical, and biological evaluations of P760: a new gadolinium complex characterized by a low rate of interstitial diffusion.

An original gadolinium chelate, termed P760, which diffuses through the vascular endothelium but at a much lower rate than nonspecific agents (NSA), is described. P760 is a gadolinium macrocyclic compound based on a DOTA structure that is substituted by hydrophilic bulky groups branched on the amino-carboxylic residues. The molecular weight is 5293, and the molecular volume, measured by light scattering, is 30 times higher (11.5 nm3) than that of gadolinium (Gd)-DOTA (0.38 nm3). The increase in molecular volume and weight has two consequences: a) higher relaxivity (r1; 24.7 mM-1.s-1 compared with 3.4 mM-1.s-1 for Gd-DOTA at 20 Mhz, 37 degrees C); and b) a lengthening of its transport rate through the endothelium. P760 presents a peculiar pharmacokinetic profile: at early times post injection, the blood concentrations are higher than those of Gd-DOTA, but after 20 minutes, the blood concentrations are equal for the two compounds. The body clearances of the products are identical (i.e., glomerular filtration rate). P760 molecules are large enough to have a restricted diffusion through the endothelium but, conversely, small enough to pass freely through the glomerular membrane. This limited extravasation has been observed in rabbits by magnetic resonance angiography or in investigations of tumor permeability. Further experimental imaging studies are needed to define the clinical interest of such properties.

[The head nurse faced with nurses' rites of passages]. / Le cadre face aux rites de passages des soignants.

The caregivers, faced with a death, have repetitive and meaningless attitudes. The concept of rite, developed by Pierre CAZE-NEUVE, reveals that a rite can be characterized by three elements: stereotyped, repetitive and meaningless. The passage rite is made up of three steps: separation, margin and aggregation. The passage rites are defence mechanisms installed by the caregivers to fight against an element which they do not master, the death of a patient. The role of the head nurse can come in three forms: a protection role in order to give caregivers good working conditions, an attention faced with the limits of the rite as well as a vigilance faced with negative rites.

3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis.

Serine concentrations were markedly decreased in the cerebrospinal fluid of two brothers with congenital microcephaly, profound psychomotor retardation, hypertonia, epilepsy, growth retardation, and hypogonadism. The youngest boy also had congenital bilateral cataract. Magnetic resonance imaging of the brain showed evidence of dysmyelination. Plasma serine as well as plasma and cerebrospinal fluid glycine concentrations were also decreased but to a lesser extent. Treatment with oral serine in the youngest patient significantly increased cerebrospinal fluid serine and abolished the convulsions. In fibroblasts of both patients, a decreased activity was demonstrated of 3-phosphoglycerate dehydrogenase, the first step of serine biosynthesis (22% and 13% of the mean control value). This is an unusual disorder as the great majority of aminoacidopathies are catabolic defects. It is a severe but potentially treatable inborn error of metabolism that has not been previously reported in man.

Nitrogen metabolism in rumen and whole digestive tract of lactating dairy cows fed grass silage.

Effects of wilting of grass prior to ensiling on OM intake, ruminal digestibility, efficiency of bacterial protein synthesis, and amount and composition of duodenal N fraction were examined using four lactating Holstein cows. Direct-cut or wilted grass silages were fed for ad libitum intake and supplemented with 5.0 or 5.3 kg of concentrate, respectively. Milk yield was 18.1 and 21.2 kg/d with direct-cut versus wilted silage, and milk protein and fat contents were 2.63 and 4.60% with direct-cut versus 2.75 and 4.27% with wilted silage, respectively. Wilting of the grass (from 17 to 38% DM) increased OM intake but had no effect on ruminal digestibility. Total N flow and amounts of different AA in proximal duodenum were increased, and the difference was principally of bacterial origin. The efficiency of bacterial protein synthesis in rumen was related to dilution rate of liquid phase and to the time devoted to ruminating. These results indicate that the passage of bacterial protein to the lower digestive tract is a key factor for improving the assimilation of the soluble N fraction of grass silage and that this phenomenon is related to chewing activity.

Campomelic syndrome: manifestations in a 20 week fetus and case history of a 5 year old child.

We report on 2 unusual cases of the campomelic syndrome, the first being a fetus in whom the diagnosis was suspected in the 18th week and confirmed sonographically at 20 weeks. The second case concerns a 5 year old 46, XY girl with an exceptional longevity and a relatively favorable evolution.

Regional brain blood flow in congenital dysphasia: studies with technetium-99m HM-PAO SPECT.

Congenital dysphasia is a developmental speech disorder not explained by deafness, phonation disorder, mental retardation, neurologic lesion, or psychiatric disease. The existence of brain lesions has often been postulated but conventional investigations fail to demonstrate any cerebral abnormality. By means of [99mTc]hexamethyl-propyleneamine oxime (HM-PAO) brain single photon emission computed tomography (SPECT) we have studied 14 children suffering from congenital dysphasia. The brain computed tomographic scan was normal in all cases. In two patients with expression impairment the SPECT study demonstrated a hypoperfusion in the inferior frontal convolution of the left hemisphere, involving the Broca's area. In nine of 12 patients with global dysphasia (deficits in both comprehension and expression), SPECT study showed two hypoperfused areas: an abnormality in the left temporoparietal region and a hypoactivity in the upper and middle areas of the right frontal lobe. These results suggest that congenital dysphasia could be due, like acquired aphasia, to specific impairment of the language cerebral areas and that brain SPECT studies with [99mTc]HM-PAO could be useful for a better comprehension of the physiopathology of these disorders.

Apparent digestibility of nitrogen in rumen and whole tract of Friesian cattle fed direct-cut and wilted grass silages.

Spring grass consisting of Lolium perene L. (81%), Poa pratensis L. (9%), and annual weeds (5%) was stored as direct-cut or as wilted silage and used in feeding trials to determine the effects of wilting on N utilization. Six mature Friesian cattle, fitted with rumen and simple duodenal cannulae, were fed the silages for ad libitum intake in a crossover design consisting of two 49-d periods. Wilting increased intake of organic matter and decreased ruminal apparent digestibility or organic matter and whole tract apparent digestibilities of organic matter, NDF, and total N. Rumen degradability of silage N was increased by wilting (.7 vs. .67). Direct-cut silage, in comparison with wilted silage, provide (g/d) less N intake (232 vs. 286) and lower duodenal flows of total N (215 vs. 293), non-NH3 N (202 vs. 280), microbial N (111 vs. 177), and total amino acids (1056.8 vs. 1342.7). Duodenal flows of NH3 N and undegraded N were not different between silages. Efficiency of bacterial N synthesis in rumen was higher for wilted than for direct-cut silage (32.3 vs. 21.4 g N/kg organic matter apparently digested in rumen). It was concluded that wilting increase silage intake, rumen bacterial synthetic efficiency, and duodenal flow of non-NH3 N in cattle.