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12 février 2012 7 12 /02 /février /2012 21:21
Helminth parasites and the modulation of joint inflammation.

AuthorsMatisz CE, et al. Show all Journal
J Parasitol Res. 2011;2011:942616. Epub 2011 Apr 18.

Affiliation
Gastrointestinal Research Group, Department of Physiology and Pharmacology, The Calvin, Phoebe and Joan Snyder Institute of Infection Immunity and Inflammation, 1877 HSC University of Calgary, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1.

Abstract
There is an urgent need to develop better therapeutics for autoimmune and autoinflammatory diseases, of which musculoskeletal disorders such as rheumatoid arthritis are particularly prevalent and debilitating. Helminth parasites are accomplished masters at modifying their hosts' immune activity, and so attention has focused on rodent-helminth model systems to uncover the workings of the mammalian immune response to metazoan parasites, with the hope of revealing molecules and/or mechanisms that can be translated into better treatments for human autoimmune and idiopathic disorders. Substantial proof-of-principal data supporting the concept that infection with helminth parasites can reduce the severity of concomitant disease has been amassed from models of mucosal inflammation. Indeed, infection with helminth parasites has been tried as a therapy in inflammatory bowel disease, and there are case reports relating to other conditions (e.g., autism); however, the impact of infection with parasitic helminths on musculoskeletal diseases has not been extensively studied. Here, we present the view that such a strategy should be applied to the amelioration of joint inflammation and review the literature that supports this contention.
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12 février 2012 7 12 /02 /février /2012 21:14
Application of Novel PCR-Based Methods for Detection, Quantitation, and Phylogenetic Characterization of Sutterella Species in Intestinal Biopsy Samples from Children with Autism and Gastrointestinal Disturbances.

AuthorsWilliams BL, et al. Show all Journal
MBio. 2012 Jan 10;3(1). pii: e00261-11. doi: 10.1128/mBio.00261-11. Print 2012.

Affiliation
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA.

Abstract
ABSTRACT Gastrointestinal disturbances are commonly reported in children with autism and may be associated with compositional changes in intestinal bacteria. In a previous report, we surveyed intestinal microbiota in ileal and cecal biopsy samples from children with autism and gastrointestinal dysfunction (AUT-GI) and children with only gastrointestinal dysfunction (Control-GI). Our results demonstrated the presence of members of the family Alcaligenaceae in some AUT-GI children, while no Control-GI children had Alcaligenaceae sequences. Here we demonstrate that increased levels of Alcaligenaceae in intestinal biopsy samples from AUT-GI children result from the presence of high levels of members of the genus Sutterella. We also report the first Sutterella-specific PCR assays for detecting, quantitating, and genotyping Sutterella species in biological and environmental samples. Sutterella 16S rRNA gene sequences were found in 12 of 23 AUT-GI children but in none of 9 Control-GI children. Phylogenetic analysis revealed a predominance of either Sutterella wadsworthensis or Sutterella stercoricanis in 11 of the individual Sutterella-positive AUT-GI patients; in one AUT-GI patient, Sutterella sequences were obtained that could not be given a species-level classification based on the 16S rRNA gene sequences of known Sutterella isolates. Western immunoblots revealed plasma IgG or IgM antibody reactivity to Sutterella wadsworthensis antigens in 11 AUT-GI patients, 8 of whom were also PCR positive, indicating the presence of an immune response to Sutterella in some children. IMPORTANCE Autism spectrum disorders affect ~1% of the population. Many children with autism have gastrointestinal (GI) disturbances that can complicate clinical management and contribute to behavioral problems. Understanding the molecular and microbial underpinnings of these GI issues is of paramount importance for elucidating pathogenesis, rendering diagnosis, and administering informed treatment. Here we describe an association between high levels of intestinal, mucoepithelial-associated Sutterella species and GI disturbances in children with autism. These findings elevate this little-recognized bacterium to the forefront by demonstrating that Sutterella is a major component of the microbiota in over half of children with autism and gastrointestinal dysfunction (AUT-GI) and is absent in children with only gastrointestinal dysfunction (Control-GI) evaluated in this study. Furthermore, these findings bring into question the role Sutterella plays in the human microbiota in health and disease. With the Sutterella-specific molecular assays described here, some of these questions can begin to be addressed.
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12 février 2012 7 12 /02 /février /2012 21:07
State of the art; microbiology in health and disease. Intestinal bacterial flora in autism.

Authors
Finegold SM.
Journal
Anaerobe. 2011 Dec;17(6):367-8. Epub 2011 Apr 16.

Affiliation
Veterans Administration Medical Center, Infectious Diseases Section (111F), Los Angeles, CA 90073, USA. sidfinegol@aol.com

Abstract
Autism of the regressive variety is selected as an example of the importance of intestinal bacterial microflora in disease other than classical infection.

Our studies have indicated that intestinal bacteria play a role in this disease since it responds to oral vancomycin, a drug that is not absorbed from the GI tract.

Pyrosequencing studies document an abnormal gut microflora in regressive autism subjects as compared to controls.

Finally, we present preliminary evidence suggesting that Desulfovibrio may play a key role in this disease.
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12 février 2012 7 12 /02 /février /2012 21:04
Maternal infection and immune involvement in autism.

Authors
Patterson PH.
Journal
Trends Mol Med. 2011 Jul;17(7):389-94. Epub 2011 Apr 7.

Affiliation
Biology Division, California Institute of Technology, Pasadena, CA 91125, USA. php@caltech.edu

Abstract
Recent studies have highlighted a connection between infection during pregnancy and the increased risk of autism in the offspring. Parallel studies of cerebral spinal fluid, blood and postmortem brains reveal an ongoing, hyper-responsive inflammatory-like state in many young as well as adult autism subjects.

There are also indications of gastrointestinal problems in at least a subset of autistic children. Work on the maternal infection risk factor using animal models indicates that aspects of brain and peripheral immune dysregulation can begin during fetal development and continue through adulthood.

The offspring of infected or immune-activated dams also display cardinal behavioral features of autism, as well as neuropathology consistent with that seen in human autism.

These rodent models are proving useful for the study of pathogenesis and gene-environment interactions as well as for the exploration of potential therapeutic strategies.
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12 février 2012 7 12 /02 /février /2012 20:58
Desulfovibrio species are potentially important in regressive autism.

Authors
Finegold SM.
Journal
Med Hypotheses. 2011 Aug;77(2):270-4. Epub 2011 May 17.

Affiliation
Infectious Diseases Section (111 F), VA Medical Center West Los Angeles, Los Angeles, CA 90073, USA. sidfinegol@aol.com

Abstract
Autism is a complex disorder with no specific diagnostic test so the disease is defined by its characteristics including cognitive defects, social, communication and behavioral problems, repetitive behaviors, unusual sensitivity to stimuli such as noise, restricted interests, and self stimulation.

The incidence of this disease has increased remarkably in recent years and was 110/10,000 children (∼1%) in multiple areas of the US in 2007. The financial burden on families and communities is enormous. In terms of predisposing factors, heredity plays a role in some subjects, but it is clear that environmental factors are also important.

Environnemental toxins can affect the immune system adversely.

Intestinal bacteria are recognized by a few investigators as potentially important and we have proposed that certain antimicrobial drugs may be a key factor in modifying the intestinal bacterial flora adversely, selecting out potentially harmful bacteria that are normally suppressed by an intact normal intestinal flora. We had felt that clostridia in the gut might be involved in autism because they are virulent organisms and spore-formers; spores would resist antibacterial agents so that when antibiotics were discontinued the spores would germinate and by toxin production or another mechanism lead to autism.

However, a recent study of ours employing the powerful pyrosequencing technique on stools of subjects with regressive autism showed that Desulfovibrio was more common in autistic subjects than in controls.

We subsequently confirmed this with pilot cultural and real-time PCR studies and found siblings of autistic children had counts of Desulfovibrio that were intermediate, suggesting possible spread of the organism in the family environment.

Desulfovibrio is an anaerobic bacillus that does not produce spores but is nevertheless resistant to aerobic and other adverse conditions by other mechanisms and is commonly resistant to certain antimicrobial agents (such as cephalosporins) often used to treat ear and other infections that are relatively common in childhood.

This bacterium also produces important virulence factors and its physiology and metabolism position it uniquely to account for much of the pathophysiology seen in autism.

If these results on Desulfovibrio are confirmed and extended in other studies, including treatment trials with appropriate agents and careful clinical and laboratory studies, this could lead to more reliable classification of autism, a diagnostic test and therapy for regressive autism, development of a vaccine for prevention and treatment of regressive autism, tailored probiotics/prebiotics, and important epidemiologic information.


Therapy and epidemiology of autism--clostridial spores as key elements.
Pyrosequencing study of fecal microflora of autistic and control children.
Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois, June 12-13, 2000.
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12 février 2012 7 12 /02 /février /2012 20:53
Gut microbiota and pediatric disease.

AuthorsIebba V, et al. Show all Journal
Dig Dis. 2011;29(6):531-9. Epub 2011 Dec 12.

Affiliation
Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, Rome, Italy. valerio.iebba@uniroma1.it

Abstract
BACKGROUND: Researchers have made every effort to assess the role of gut microbiota in pediatric diseases like inflammatory bowel disease (IBD), celiac disease, asthma, allergy, and autism. The leading hypothesis is that an altered microbial composition is present (other than the presence of a specific pathogen) and that it could be involved in the pathogenesis or progression of such disorders.

METHODS: Cultural, molecular, metabolomic, and metagenomic approaches are trying to define the pediatric gut microbiota imbalances in different diseases.

RESULTS AND CONCLUSION: In pediatric IBD, a marked increase in aerobes and facultative anaerobes was found, along with an increase in Enterobacteriaceae members (Escherichia coli). In both pediatric IBD and celiac disease (Th1-mediated disorders), higher bacterial cell counts were observed, jointly with a general gain of biodiversity. A preponderance of Bacteroidetes and a parallel decrease of Firmicutes was also reported in IBD, celiac disease and autism. Contrarily, dietary changes due to Western lifestyles increase Firmicutes populations and lower short-chain fatty acids production, possibly exposing 'developed' children to the infectious challenge (Escherichia and Shigella spp.). Lactobacillus and Bifidobacterium species could be protective agents for atopic diseases, while Clostridia, Enterobacteriaceae, and staphylococci can be associated with an increased risk of such Th2-mediated disorders. In the brain-gut axis view, gut microbiota could also play a role in autism.

Copyright © 2011 S. Karger AG, Basel.
PMID 22179208 [PubMed - in process]
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12 février 2012 7 12 /02 /février /2012 20:48
Microbiology of regressive autism.

AuthorsFinegold SM, et al. Show all Journal
Anaerobe. 2011 Dec 22. [Epub ahead of print]

Affiliation
Infectious Diseases Section (111 F), VA Medical Center WLA, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA; Department of Microbiology, Immunology and Molecular Genetics, UCLA School of Medicine, Los Angeles, CA, USA; Department of Medicine, UCLA School of Medicine, Los Angeles, CA, USA.

Abstract
This manuscript summarizes some of our earlier work on the microbiology of autism subjects' stool specimens, as compared with stools from control subjects. Our most recent data indicating that Desulfovibrio may play an important role in regressive autism is also presented. In addition, we present information on antimicrobial susceptibility patterns of Desulfovibrio using the CLSI agar dilution susceptibility technique. In addition, we summarize data from our earlier studies showing the impact of various antimicrobial agents on the indigenous bowel flora. This shows that penicillins and cephalosporins, as well as clindamycin, have a major impact on the normal bowel flora and therefore might well predispose subjects to overgrowth of such organisms as Clostridium difficile, and of particular importance for autism, to Desulfovibrio.

Published by Elsevier Ltd.
PMID 22202440 [PubMed - as supplied by publisher]
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12 février 2012 7 12 /02 /février /2012 20:43
Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis.

AuthorsSaadoun D, et al. Show all Journal
N Engl J Med. 2011 Dec 1;365(22):2067-77.

Affiliation
Université Pierre et Marie Curie Université Paris 06, Paris, France.

Comment in
N Engl J Med. 2011 Dec 1;365(22):2129-31.
Abstract
BACKGROUND: Patients with vasculitis induced by the hepatitis C virus (HCV) have reduced levels of regulatory T cells (Tregs). Resolution of HCV infection correlates with cure of vasculitis and the recovery of Treg levels. We reasoned that interleukin-2, a cytokine that promotes Treg survival and function, could be beneficial for patients with vasculitis that is resistant to HCV therapy.

METHODS: We investigated the safety and immunologic effects of the administration of low-dose interleukin-2 in a prospective open-label, phase 1-phase 2a study. Ten patients with HCV-induced vasculitis that was refractory to conventional antiviral therapy, rituximab therapy, or both and who were not receiving glucocorticoid or immunosuppressant therapy, received one course of interleukin-2 (1.5 million IU per day) for 5 days, followed by three 5-day courses of 3 million IU per day at weeks 3, 6, and 9. Both the safety of the treatment and its effectiveness were evaluated, the latter by monitoring the Treg response and the clinical signs of HCV vasculitis.

RESULTS: No adverse events reached a level higher than grade 1. The treatment did not induce effector T-cell activation, vasculitis flare, or increased HCV viremia. We observed a reduction in cryoglobulinemia in 9 of 10 patients and improvement of vasculitis in 8 of 10. Administration of low-dose interleukin-2 was followed by an increase in the percentage of CD4+, CD25(high), forkhead box P3 (FOXP3+) Tregs [E(max) (maximum value)÷baseline value×100=420%] with potent suppressive activity in all subjects and by a concomitantly decreased proportion of marginal-zone B cells. Transcriptome studies of peripheral-blood mononuclear cells revealed that interleukin-2 induced a global attenuation of the signatures for inflammation and oxidative stress mediators.

CONCLUSIONS: The trial showed that low-dose interleukin-2 was not associated with adverse effects and led to Treg recovery and concomitant clinical improvement in patients with HCV-induced vasculitis, an autoimmune condition. (Funded by the French Agency for Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT00574652.).
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12 février 2012 7 12 /02 /février /2012 20:20
En 1982, Ian Carr médecin anatomopathologiste canadien rapporta dans le Lancet les troubles psychiatriques et neurologiques sévères observés chez sa fille Jane avant que ne soit découverte sa maladie de Hodgkin. Il proposa le terme de syndrome d’Ophélie en référence aux troubles psychiatriques présentés par Ophélie  à la suite du dépit amoureux provoqué par la conduite d’Hamlet dans la fameuse œuvre éponyme de Shakespeare. La lecture de cet article publié dans la rubrique « personal paper » est à conseiller à tous les amateurs de belles lettres. C’est  un exemple malheureusement rare de littérature médicale où le malade est décrit dans sa vie quotidienne avec ses interrogations  et ses émotions et non pas comme un complexe de gènes, d’images ou de biomarqueurs.
« We  walked and visited the small islands ; and  she was  her quaint, cool, remote self, with  the infinite promise  of  femininity lurking around the corner of her  smile ».
Cette jeune fille avait donc présenté un tableau clinique subaigu sévère associant une perte de mémoire, une  dépression et des hallucinations. A cette époque, l’origine de l’encéphalite limbique était incertaine (métastases, papovavirus) mais le mécanisme paranéoplasique avait été déjà évoqué. Ian carr avait ainsi suggéré que la tumeur primitive secrétait une substance douée d’un effet neurotransmetteur.
Depuis cette description, la connaissance de la physiopathologie de l’encéphalite limbique a beaucoup progressé mais la plume médicale s’est asséchée. Un article  récemment publié dans Lancet Neurology   fait la synthèse des avancées dans ce domaine. L’encéphalite limbique liée à des anticorps anti  récepteurs NMDA  est la plus fréquente et peut se manifester par un état psychotique suivi de crises d’épilepsie, d ‘un état catatonique, d’une désintégration du langage, de mouvements anormaux et d’une dysautonomie. Une série de près de 400 cas a été ainsi publiée. Dans 58 % des cas, un tératome ovarien est retrouvé et une immunothérapie peut entrainer une amélioration dans 75 % des cas. Le traitement peut être orienté par la mise en évidence d’une synthèse intrathécale de ces anticorps. Plus récemment, on a identifié des anticorps dits anti canaux potassiques (VGKC) dirigés contre des protéines associées leucine-rich glioma inactivated 1 (LGI1) et  contactin-associated protein-like 2 (CASPR2).
Dans ce cas, les manifestations encéphaliques peuvent être précédées de troubles du comportement en sommeil paradoxal  ou d’insomnie réalisant un syndrome de Morvan. D’autres anticorps ont été aussi décrits dirigés contre le récepteur GABA B et la glutamic acid decarboxylase. Mais 30 ans après peut-on expliquer ce qui est arrivé à Jane ? Les anticorps probablement coupables ont été, de fait, récemment identifiés puisqu’une équipe a mis en évidence chez des patients avec une encéphalite et une maladie de Hodgkin des anticorps dirigés contre les récepteurs mGlu5 (récepteurs glutamate) chez 2 patients.
Ainsi, la chimiothérapie et la radiothérapie ont-ils aidé Jane à triompher du Hodgkin, limitant la production des anticorps et lui évitant le sort d’Ophélie. 
“When  we  came  back  she  remembered  what  she  had  been doing  the  day  before.  Not  just  a  straw  in  the  wind  but  bending branches.  It  went  on. More  chemotherapy. The  snow  went and the instant prairie summer  came. Day  by  day she was remembering  more  and  more.”


Dr Christian Geny

Carr I : The Ophelia syndrome: memory loss in Hodgkin's disease. Lancet. 1982 ; 1 : 844-5.
Graus F et coll. : CNS autoimmunity: new findings and pending issues. The Lancet Neurology, 2012; 11: 17 - 19,
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12 février 2012 7 12 /02 /février /2012 13:11
Dans un contexte où jusqu’à 25 % des patients ayant une maladie de Kawasaki (MK) non traitée, et 5 % de ceux dont la MK a été traitée, développent des anévrysmes coronariens, une étude californienne a évalué la contribution des séquelles coronariennes de la MK méconnue à l’ischémie myocardique des adultes jeunes.

LB. Daniels et coll. ont passé en revue les dossiers médicaux des patients âgés de moins de 40 ans ayant eu, entre 2005 et 2009, dans 4 hôpitaux de San Diego, une coronarographie pour suspicion d’ischémie myocardique, et inclus 233 adultes (73 % d’hommes), dont la médiane d’âge était de 36 ans.

Parmi ces patients, 16 avaient des anévrysmes coronariens, et après analyse des antécédents compatibles avec une MK, et des facteurs de risque traditionnels de maladie coronarienne, la maladie de Kawasaki est apparue possiblement ou très probablement en cause dans la survenue de l’ischémie myocardique chez 5,6 % des patients.


Dr Julie Perrot Publié le 10/02/2012

Daniels LB et coll. : Prevalence of Kawasaki disease in young adults with supected myocardial ischemia. American Heart Association (AHA) Scientific Sessions (Orlando) : 12-16 novembre 2011.


Syndrome de Kawasaki

[?] Qu'est-ce que c'est ?

C'est une maladie inflammatoire fébrile liée à un dysfonctionnement immunitaire.

La cause de ce syndrome adéno-cutanéo-muqueux est inconnue mais semble d'origine immunitaire car il y a de nombreuses similitudes avec la périartérite noueuse. Il semble s'agir d'une inflammation des vaisseaux secondaire à une réaction hyper-immune vis-à-vis d'agressions variées (infectieuses, toxiques, etc ) agissant comme stimulus antigéniques.

Peut-être existe-t-il un terrain génétique prédisposant, ce qui expliquerait la fréquence de l'affection en Asie (Japon).

[?] Les signes de la maladie

Ce diagnostic est évoqué chez un enfant de moins de 5 ans devant une fièvre élevée qui persiste une ou deux semaines malgré les antipyrétiques et les antibiotiques, avec une altération de l'état général.

D'autres symptômes sont souvent associés

Une conjonctivite bilatérale ;
Une pharyngite avec langue framboisée ;
Une stomatite ;
Une chéilite douloureuse (les lèvres sont rouges et fissurées) ;
Une rhinite, une toux discrète ;
Un érythème palmo-plantaire apparaît dès le 4° jour de la maladie avec des oedèmes du dos des mains et des pieds ;
Une éruption cutanée ;
Des maux de tête.
Une desquamation apparaît vers la 2° ou 3° semaine d'évolution à la jonction ongle-pulpe du doigt et de l'orteil.

Des ganglions cervicaux sont fréquents.

Des douleurs articulaires, une diarrhée, des douleurs abdominales, des nausées, des vomissements sont possibles.

Des signes neurologiques sont parfois mis en évidence : méningite lymphocytaire, encéphalite, hypertension intracrânienne.

Un léger ictère traduit l'atteinte hépatique.

Le risque est cardiaque : myocardite, péricardite et atteinte des artères coronaires (infarctus du myocarde) dominent le pronostic.

Le bilan biologique montre un syndrome inflammatoire non spécifique :

hyperleucocytose avec polynucléose, vitesse de sédimentation (VS) très élevée, C réactive protéine (CRP) augmentée, fibrine augmentée, hyper alpha 2 globulinémie etc...On peut noter une anémie, une augmentation du nombre de plaquettes (thrombocytose) et des IgE.

[?] Complications

Sans complication, l'évolution est favorable en 3 semaines environ.

Ce sont les complications cardiaques qui grèvent le pronostic : myocardite, péricardite et surtout l'atteinte des artères coronaires pouvant provoquer à tout moment une mort subite, des troubles du rythme cardiaque, une insuffisance cardiaque aiguë, un infarctus du myocarde etc...

Les facteurs de gravité seraient :

L'âge inférieur à 1 ans ;
Le sexe masculin ;
La fièvre très prolongée ;
La vitesse de sédimentation très élevée ;
La thrombocytose élevée ;
L'augmentation importante et prolongée des IgE.
1,5% des enfants décèdent pendant la convalescence par rupture d'anévrisme coronaire ou infarctus du myocarde.

[?] Diagnostic différentiel

Leptospirose ictéro-hémorragique ;
Scarlatine ;
Eruption allergique ;
Maladie de Still (polyarthrite chronique juvénile) ;
Collagénose etc.
[?] Traitement

L'hospitalisation s'impose.

Les échographies cardiaques sont renouvelés pour dépister les anévrismes des artères coronaires.

Les veinoglobulines sont utilisées en première intention.

Les corticoïdes auraient un effet sur la fièvre mais plusieurs spécialistes les déconseillent.

Les antiagrégants plaquettaires (Aspirine) sont prescrits en cas de forte thrombocytose.

Les anticoagulants sont parfois nécessaires.

La chirurgie cardiovasculaire peut s'avérer obligatoire (pontage aortocoronarien) en cas d'infarctus du myocarde.

La surveillance après la phase aiguë s'impose pendant plusieurs mois.

La maladie donne une immunité acquise et les récidives sont exceptionnelles.

Dr Lyonel Rossant, Dr Jacqueline Rossant-Lumbroso.
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