Fièvre à répétition chez l'enfant: penser au syndrome de PFAPA [Periodic fever in children: keep in mind the PFAPA syndrome]

Les maladies autoinflammatoires font partie du diagnostic différentiel de l'état fébrile à répétition chez l’enfant. Ces maladies sont caractérisées par des poussées inflammatoires sans cause évidente. Certaines de ces maladies, comme la Fièvre méditerranéenne familiale, ont une origine génétique et nécessitent un traitement régulier pour éviter des conséquences graves à long terme. Le syndrome de PFAPA est la plus fréquente des fièvres récurrentes et son diagnostic se base sur des critères diagnostiques peu précis. Son traitement reste controversé. La prednisone en dose unique permet d'interrompre la poussée et l'amygdalectomie peut induire une rémission dans une majorité des cas. The autoinflammatory diseases should be considered in the differential diagnosis of recurrent fever in childhood. These diseases are characterized by inflammatory episodes without an evident cause. Some of these diseases, like the Familial Mediterranean Fever, have a genetic origin and need a chronic treatment to avoid severe complications on the long term. PFAPA syndrome is the most frequent cause of recurrent fever and is diagnosed based on unspecific criteria. The treatment is still controversial. One dose of Prednisone is able to interrupt the flare and tonsillectomy may induce a remission in the majority of the cases

Genetic characterization of morphologically variant strains of Paracoccidioides brasiliensis

Molecular characterization of Paracoccidioides brasiliensis variant strains that had been preserved under mineral oil for decades was carried out by random amplified polymorphic DNA analysis (RAPD). On P. brasiliensis variants in the transitional phase and strains with typical morphology, RAPD produced reproducible polymorphic amplification products that differentiated them. A dendrogram based on the generated RAPD patterns placed the 14 P. brasiliensis strains into five groups with similarity coefficients of 72%. A high correlation between the genotypic and phenotypic characteristics of the strains was observed. A 750 bp-RAPD fragment found only in the wild-type phenotype strains was cloned and sequenced. Genetic similarity analysis using BLASTx suggested that this RAPD marker represents a putative domain of a hypothetical flavin-binding monooxygenase (FMO)-like protein of Neurospora crassa.

Sexueller Missbrauch bei Kindern und Jugendlichen- Aufdeckung, Untersuchung und Erstbetreuung [Sexual abuse of female children and adolescents--detection, examination and primary care].

Epidemiological studies show a prevalence of sexual abuse experience among girls from 14-33%. Although indicators of abuse are unspecific, the combination of several findings may be indicative: Somatic signs may be sexually transmitted diseases, vulvovaginal complaints. Psychosocial nonsexual indicators are abrupt behavioural changes, running away from home, eating disorders. Psychosexual signs are hypersexualisation of the language and behaviour, disturbed body image and gender identity. Indirect evidence of abuse is given not only in cases of old vaginal and anal lesions but also in situations, where deep tears of the hymen in the typical localization at the posterior part can be found. The workup and care for children in whom there is suspicion of abuse but no clear evidence asks for highly competent professionals in a multidisciplinary cooperation including pediatric gynecologists, child psychiatrists, children-protection groups and other specialists to avoid on one hand unjustified destabilisation or even destruction of familial structures but to assure on the other hand, that the child victims are treated and followed after in a short and long term comprehensive medical and psychosocial care.

Analysis of the cytolytic T lymphocyte response of melanoma patients to the naturally HLA-A*0201-associated tyrosinase peptide 368-376.

The human tyrosinase gene codes for two distinct antigens that are recognized by HLA-A*0201-restricted CTLs. For one of them, tyrosinase peptide 368-376, the sequence identified by mass spectrometry in melanoma cell eluates differs from the gene-encoded sequence as a result of posttranslational modification of amino acid residue 370 (asparagine to aspartic acid). Here, we used fluorescent tetrameric complexes ("tetramers") of HLA-A*0201 and tyrosinase peptide 368-376 (YMDGTMSQV) to characterize the CD8+ T-cell response to this antigen in lymphoid cell populations from HLA-A2 melanoma patients. Taking advantage of the presence of significant numbers of tetramer-positive CD8+ T cells in tumor-infiltrated lymph node cells from a melanoma patient, we derived polyclonal and monoclonal tyrosinase peptide 368-376-specific CTLs by tetramer-guided flow cytometric sorting. These CTLs efficiently and specifically lysed HLA-A*0201- and tyrosinase-positive melanoma cells. As assessed with tyrosinase peptide variants, the fine antigen specificity of the CTLs was quite diverse at the clonal level. Flow cytometric analysis of PBMCs stained with tetramers showed that tyrosinase peptide 368-376-specific CD8+ T cells were hardly detectable in peripheral blood of melanoma patients. However, significant numbers of such cells were detected after short-term stimulation of CD8+ lymphocytes with tyrosinase peptide 368-376 in 6 of 10 HLA-A2 melanoma patients. Taken together, these findings emphasize the significant contribution of the natural tyrosinase peptide 368-376 to the antigenic specificities recognized by the tumor-reactive CTLs that may develop in HLA-A2 melanoma patients.

Acute oxygen sensing in heme oxygenase-2 null mice.

Hemeoxygenase-2 (HO-2) is an antioxidant enzyme that can modulate recombinant maxi-K(+) channels and has been proposed to be the acute O(2) sensor in the carotid body (CB). We have tested the physiological contribution of this enzyme to O(2) sensing using HO-2 null mice. HO-2 deficiency leads to a CB phenotype characterized by organ growth and alteration in the expression of stress-dependent genes, including the maxi-K(+) channel alpha-subunit. However, sensitivity to hypoxia of CB is remarkably similar in HO-2 null animals and their control littermates. Moreover, the response to hypoxia in mouse and rat CB cells was maintained after blockade of maxi-K(+) channels with iberiotoxin. Hypoxia responsiveness of the adrenal medulla (AM) (another acutely responding O(2)-sensitive organ) was also unaltered by HO-2 deficiency. Our data suggest that redox disregulation resulting from HO-2 deficiency affects maxi-K(+) channel gene expression but it does not alter the intrinsic O(2) sensitivity of CB or AM cells. Therefore, HO-2 is not a universally used acute O(2) sensor.

Enhanced production of indole-3-acetic acid by a genetically modified strain of Pseudomonas fluorescens CHA0 affects root growth of cucumber but does not improve protection of the plant against Pythium root rot

The biocontrol strain CHA0 of Pseudomonas fluorescens produces small amounts of indole-3-acetic acid via the tryptophan side chain oxidase and the tryptophan transaminase pathways. A recombinant plasmid (pME3468) expressing the tryptophan monooxygenase pathway was introduced into strain CHA0; this resulted in elevated synthesis of indole-3-acetic acid in vitro, especially after addition of -tryptophan. In natural soil, strain CHA0/pME3468 increased fresh root weight of cucumber by 17-36%, compared to the effect of strain CHA0; root colonization was about 106 cells per g of root. However, both strains gave similar protection of cucumber against Pythium ultimum. In autoclaved soil, at 6×107 cells per g of root, strain CHA0 stimulated growth of roots and shoots, whereas strain CHA0/pME3468 caused root stunting and strong reduction of plant weight. These results are in agreement with the known effects of exogenous indole-3-acetic acid on plant roots and suggest that in the system examined, indole-3-acetic acid does not contribute to the biocontrol properties of strain CHA0.

Enzymatic activity, ultrastructure and function in ganglia infected with a neurotropic virus.

This chapter attempts to answer the questions, how do the viruses reach the neurons, what are the alterations that they impose on the neuronal machinery, and what are the consequences of these alterations on the function of the infected neurons? The virus used for this research was the pseudorabies. Pseudorabies virus is transported from the eye to the superior cervical ganglion by retrograde axonal flow. In the sympathetic neurons, the virus induces an increased protein synthesis and tyrosine 3-monooxygenase activity, a transsynaptic increased activity of the cholineacetyltransferase and a great rise in the acetylcholine content. The virus also causes an abnormal spontaneous electrophysiological activity, which also seems to be of presynaptic origin, despite the fact that the virus never crossed the synaptic cleft.

Fab antibodies capable of blocking T cells by competitive binding have the identical specificity but a higher affinity to the MHC-peptide-complex than the T cell receptor.

In transplant rejection, graft versus host or autoimmune diseases T cells are mediating the pathophysiological processes. Compared to unspecific pharmacological immune suppression specific inhibition of those T cells, that are involved in the disease, would be an alternative and attractive approach. T cells are activated after their T cell receptor (TCR) recognizes an antigenic peptide displayed by the Major Histocompatibility Complex (MHC). Molecules that interact with MHC-peptide-complexes in a specific fashion should block T cells with identical specificity. Using the model of the SSX2 (103-111)/HLA-A*0201 complex we investigated a panel of MHC-peptide-specific Fab antibodies for their capacity blocking specific T cell clones. Like TCRs all Fab antibodies reacted with the MHC complex only when the SSX2 (103-111) peptide was displayed. By introducing single amino acid mutations in the HLA-A*0201 heavy chain we identified the K66 residue as the most critical binding similar to that of TCRs. However, some Fab antibodies did not inhibit the reactivity of a specific T cell clone against peptide pulsed, artificial targets, nor cells displaying the peptide after endogenous processing. Measurements of binding kinetics revealed that only those Fab antibodies were capable of blocking T cells that interacted with an affinity in the nanomolar range. Fab antibodies binding like TCRs with affinities on the lower micromolar range did not inhibit T cell reactivity. These results indicate that molecules that block T cells by competitive binding with the TCR must have the same specificity but higher affinity for the MHC-peptide-complex than the TCR.

The systemic administration of oleoylethanolamide exerts neuroprotection of the nigrostriatal system in experimental Parkinsonism.

Oleoylethanolamide (OEA) is an agonist of the peroxisome proliferator-activated receptor α (PPARα) and has been described to exhibit neuroprotective properties when administered locally in animal models of several neurological disorder models, including stroke and Parkinson's disease. However, there is little information regarding the effectiveness of systemic administration of OEA on Parkinson's disease. In the present study, OEA-mediated neuroprotection has been tested on in vivo and in vitro models of 6-hydroxydopamine (6-OH-DA)-induced degeneration. The in vivo model was based on the intrastriatal infusion of the neurotoxin 6-OH-DA, which generates Parkinsonian symptoms. Rats were treated 2 h before and after the 6-OH-DA treatment with systemic OEA (0.5, 1, and 5 mg/kg). The Parkinsonian symptoms were evaluated at 1 and 4 wk after the development of lesions. The functional status of the nigrostriatal system was studied through tyrosine-hydroxylase (TH) and hemeoxygenase-1 (HO-1, oxidation marker) immunostaining as well as by monitoring the synaptophysin content. In vitro cell cultures were also treated with OEA and 6-OH-DA. As expected, our results revealed 6-OH-DA induced neurotoxicity and behavioural deficits; however, these alterations were less severe in the animals treated with the highest dose of OEA (5 mg/kg). 6-OH-DA administration significantly reduced the striatal TH-immunoreactivity (ir) density, synaptophysin expression, and the number of nigral TH-ir neurons. Moreover, 6-OH-DA enhanced striatal HO-1 content, which was blocked by OEA (5 mg/kg). In vitro, 0.5 and 1 μM of OEA exerted significant neuroprotection on cultured nigral neurons. These effects were abolished after blocking PPARα with the selective antagonist GW6471. In conclusion, systemic OEA protects the nigrostriatal circuit from 6-OH-DA-induced neurotoxicity through a PPARα-dependent mechanism.

Preference, specificity and cheating in the arbuscular mycorrhizal symbiosis.

Arbuscular mycorrhizal symbioses are mutualistic interactions between fungi and most plants. There is considerable interest in this symbiosis because of the strong nutritional benefits conferred to plants and its influence on plant diversity. Until recently, the symbiosis was assumed to be unspecific. However, two studies have now revealed that although it can be largely unspecific with the fungal community composition changing seasonally, in certain ecosystems it can also be highly specific and might potentially allow plants to cheat the arbuscular mycorrhizal network that connects plants below ground.

Neuroplasticity of inhibitory control

Executive control refers to a set of abilities enabling us to plan, control and implement our behavior to rapidly and flexibly adapt to environmental requirements. These adaptations notably involve the suppression of intended or ongoing cognitive or motor processes, a skill referred to as "inhibitory control". To implement efficient executive control of behavior, one must monitor our performance following errors to adjust our behavior accordingly. Deficits in inhibitory control have been associated with the emergènce of a wide range of psychiatric disorders, ranging from drug addiction to attention deficit/hyperactivity disorders. Inhibitory control deficits could, however, be remediated- The brain has indeed the amazing possibility to reorganize following training to allow for behavioral improvements. This mechanism is referred to as neural and behavioral plasticity. Here, our aim is to investigate training-induced plasticity in inhibitory control and propose a model of inhibitory control explaining the spatio- temporal brain mechanisms supporting inhibitory control processes and their plasticity. In the two studies entitled "Brain dynamics underlying training-induced improvement in suppressing inappropriate action" (Manuel et al., 2010) and "Training-induced neuroplastic reinforcement óf top-down inhibitory control" (Manuel et al., 2012c), we investigated the neurophysiological and behavioral changes induced by inhibitory control training with two different tasks and populations of healthy participants. We report that different inhibitory control training developed either automatic/bottom-up inhibition in parietal areas or reinforced controlled/top-down inhibitory control in frontal brain regions. We discuss the results of both studies in the light of a model of fronto-basal inhibition processes. In "Spatio-temporal brain dynamics mediating post-error behavioral adjustments" (Manuel et al., 2012a), we investigated how error detection modulates the processing of following stimuli and in turn impact behavior. We showed that during early integration of stimuli, the activity of prefrontal and parietal areas is modulated according to previous performance and impacts the post-error behavioral adjustments. We discuss these results in terms of a shift from an automatic to a controlled form of inhibition induced by the detection of errors, which in turn influenced response speed. In "Inter- and intra-hemispheric dissociations in ideomotor apraxia: a large-scale lesion- symptom mapping study in subacute brain-damaged patients" (Manuel et al., 2012b), we investigated ideomotor apraxia, a deficit in performing pantomime gestures of object use, and identified the anatomical correlates of distinct ideomotor apraxia error types in 150 subacute brain-damaged patients. Our results reveal a left intra-hemispheric dissociation for different pantomime error types, but with an unspecific role for inferior frontal areas. Les fonctions exécutives désignent un ensemble de processus nous permettant de planifier et contrôler notre comportement afin de nous adapter de manière rapide et flexible à l'environnement. L'une des manières de s'adapter consiste à arrêter un processus cognitif ou moteur en cours ; le contrôle de l'inhibition. Afin que le contrôle exécutif soit optimal il est nécessaire d'ajuster notre comportement après avoir fait des erreurs. Les déficits du contrôle de l'inhibition sont à l'origine de divers troubles psychiatriques tels que l'addiction à la drogue ou les déficits d'attention et d'hyperactivité. De tels déficits pourraient être réhabilités. En effet, le cerveau a l'incroyable capacité de se réorganiser après un entraînement et ainsi engendrer des améliorations comportementales. Ce mécanisme s'appelle la plasticité neuronale et comportementale. Ici, notre but èst d'étudier la plasticité du contrôle de l'inhibition après un bref entraînement et de proposer un modèle du contrôle de l'inhibition qui permette d'expliquer les mécanismes cérébraux spatiaux-temporels sous-tendant l'amélioration du contrôle de l'inhibition et de leur plasticité. Dans les deux études intitulées "Brain dynamics underlying training-induced improvement in suppressing inappropriate action" (Manuel et al., 2010) et "Training-induced neuroplastic reinforcement of top-down inhibitory control" (Manuel et al., 2012c), nous nous sommes intéressés aux changements neurophysiologiques et comportementaux liés à un entraînement du contrôle de l'inhibition. Pour ce faire, nous avons étudié l'inhibition à l'aide de deux différentes tâches et deux populations de sujets sains. Nous avons démontré que différents entraînements pouvaient soit développer une inhibition automatique/bottom-up dans les aires pariétales soit renforcer une inhibition contrôlée/top-down dans les aires frontales. Nous discutons ces résultats dans le contexte du modèle fronto-basal du contrôle de l'inhibition. Dans "Spatio-temporal brain dynamics mediating post-error behavioral adjustments" (Manuel et al., 2012a), nous avons investigué comment la détection d'erreurs influençait le traitement du prochain stimulus et comment elle agissait sur le comportement post-erreur. Nous avons montré que pendant l'intégration précoce des stimuli, l'activité des aires préfrontales et pariétales était modulée en fonction de la performance précédente et avait un impact sur les ajustements post-erreur. Nous proposons que la détection d'erreur ait induit un « shift » d'un mode d'inhibition automatique à un mode contrôlé qui a à son tour influencé le temps de réponse. Dans "Inter- and intra-hemispheric dissociations in ideomotor apraxia: a large-scale lesion-symptom mapping study in subacute brain-damaged patients" (Manuel et al., 2012b), nous avons examiné l'apraxie idémotrice, une incapacité à exécuter des gestes d'utilisation d'objets, chez 150 patients cérébro-lésés. Nous avons mis en avant une dissociation intra-hémisphérique pour différents types d'erreurs avec un rôle non spécifique pour les aires frontales inférieures.

What can spike train distances tell us about the neural code?

Time scale parametric spike train distances like the Victor and the van Rossum distancesare often applied to study the neural code based on neural stimuli discrimination.Different neural coding hypotheses, such as rate or coincidence coding,can be assessed by combining a time scale parametric spike train distance with aclassifier in order to obtain the optimal discrimination performance. The time scalefor which the responses to different stimuli are distinguished best is assumed to bethe discriminative precision of the neural code. The relevance of temporal codingis evaluated by comparing the optimal discrimination performance with the oneachieved when assuming a rate code.We here characterize the measures quantifying the discrimination performance,the discriminative precision, and the relevance of temporal coding. Furthermore,we evaluate the information these quantities provide about the neural code. Weshow that the discriminative precision is too unspecific to be interpreted in termsof the time scales relevant for encoding. Accordingly, the time scale parametricnature of the distances is mainly an advantage because it allows maximizing thediscrimination performance across a whole set of measures with different sensitivitiesdetermined by the time scale parameter, but not due to the possibility toexamine the temporal properties of the neural code.

Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.

Regulation of catecholamine release and tyrosine hydroxylase in human adrenal chromaffin cells by interleukin-1beta: role of neuropeptide Y and nitric oxide.

Adrenal chromaffin cells synthesize and secrete catecholamines and neuropeptides that may regulate hormonal and paracrine signaling in stress and also during inflammation. The aim of our work was to study the role of the cytokine interleukin-1beta (IL-1beta) on catecholamine release and synthesis from primary cell cultures of human adrenal chromaffin cells. The effect of IL-1beta on neuropeptide Y (NPY) release and the intracellular pathways involved in catecholamine release evoked by IL-1beta and NPY were also investigated. We observed that IL-1beta increases the release of NPY, norepinephrine (NE), and epinephrine (EP) from human chromaffin cells. Moreover, the immunoneutralization of released NPY inhibits catecholamine release evoked by IL-1beta. Moreover, IL-1beta regulates catecholamine synthesis as the inhibition of tyrosine hydroxylase decreases IL-1beta-evoked catecholamine release and the cytokine induces tyrosine hydroxylase Ser40 phosphorylation. Moreover, IL-1beta induces catecholamine release by a mitogen-activated protein kinase (MAPK)-dependent mechanism, and by nitric oxide synthase activation. Furthermore, MAPK, protein kinase C (PKC), protein kinase A (PKA), and nitric oxide (NO) production are involved in catecholamine release evoked by NPY. Using human chromaffin cells, our data suggest that IL-1beta, NPY, and nitric oxide (NO) may contribute to a regulatory loop between the immune and the adrenal systems, and this is relevant in pathological conditions such as infection, trauma, stress, or in hypertension.

Invasive candidiasis as a cause of sepsis in the critically ill patient.

Invasive fungal infections are an increasingly frequent etiology of sepsis in critically ill patients causing substantial morbidity and mortality. Candida species are by far the predominant agent of fungal sepsis accounting for 10% to 15% of health-care associated infections, about 5% of all cases of severe sepsis and septic shock and are the fourth most common bloodstream isolates in the United States. One-third of all episodes of candidemia occur in the intensive care setting. Early diagnosis of invasive candidiasis is critical in order to initiate antifungal agents promptly. Delay in the administration of appropriate therapy increases mortality. Unfortunately, risk factors, clinical and radiological manifestations are quite unspecific and conventional culture methods are suboptimal. Non-culture based methods (such as mannan, anti-mannan, β-d-glucan, and polymerase chain reaction) have emerged but remain investigational or require additional testing in the ICU setting. Few prophylactic or pre-emptive studies have been performed in critically ill patients. They tended to be underpowered and their clinical usefulness remains to be established under most circumstances. The antifungal armamentarium has expanded considerably with the advent of lipid formulations of amphotericin B, the newest triazoles and the echinocandins. Clinical trials have shown that the triazoles and echinocandins are efficacious and well tolerated antifungal therapies. Clinical practice guidelines for the management of invasive candidiasis have been published by the European Society for Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of North America.