NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder.

NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare, and only 1 patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report 3 additional patients with a de novo deletion encompassing NR4A2: 2 patients have deletions encompassing only NR4A2 gene and 1 patient has a deletion including NR4A2 and the first exon of GPD2. Our patients presented a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder. We suggest that NR4A2 haploinsufficiency is implicated in neurodevelopmental disorder with high penetrance.

[Association between the presence of antiphospholipid antibodies and the occurrence of autism spectrum disorder in childhood]. / Lien entre trouble du spectre autistique de l'enfant et anticorps antiphospholipides : une étude cas-témoin.

OBJECTIVES: To evaluate the association between the presence of antiphospholipid (APL) antibodies and the occurrence of autism spectrum disorder (ASD) in childhood. METHODS: A prospective, monocentric case-control study from February 2012 to August 2014 comparing the APL antibodies of children with ASD (group 1) and children without ASD (group 2). RESULTS: Group 1 consisted of 44 children with ASD defined by clinical, genetic, metabolic, and morphological criteria. Group 2 consisted of 26 control children without ASD. One of children with ASD (2.3 %) had persistent anticardiolipin (ACL) antibodies, five of them (11.4 %) had persistent APL antibodies, one of them (2.3 %) had antiannexin V (AAV) antibodies, and two of them (4.5 %) had antiphosphatidylethanolamine (APE) antibodies. Two of the control children (7.7 %) had persistent APL antibodies. None of them had persistent ACL, AAV, or APE antibodies. Comparing group 1 and 2 children, no significant difference was found between the presence and the titers of conventional and non conventional antibodies (P<0.05). Furthermore, one mother of an autistic child (3 %) had persistent APL antibodies. CONCLUSION: ASD had no significant relation with the presence of APL antibodies.

Purification from human plasma of a tetrapeptide that potentiates insulin-like growth factor-I activity in chick embryo cartilage.

Human plasma has been shown to contain a low molecular weight factor that potentiates human IGF-I stimulation of glycosaminoglycan synthesis in chick embryo cartilage. The peptide was purified and characterized by Edman degradation and electrospray mass spectrometry. The primary structure determined was: Trp-Gly-His-Glu. A homologous synthetic peptide similarly promoted matrix biosynthesis in cartilage exposed to IGF-I.

Application of preparative high-performance liquid chromatography to the purification of a fetal ovine insulin-like growth factor II: N-terminal sequence determinations using two different carriers.

A highly efficient procedure for the purification to homogeneity of an ovine fetal insulin-like growth factor II (IGF II) is described. Fetal sheep serum was used as the source material, and the bioactivity was followed throughout purification by an IGF II radioreceptor assay. Ovine IGF II was isolated by a combination of gel permeation, ion-exchange chromatography and reversed-phase high-performance liquid chromatography. The amino-terminal sequence of the first 36 amino acid residues was compared using two supports (polyethylenimine and polybrene) as carrier for protein sequencing. Ovine fetal IGF II was found to differ from human IGF II in three residues of the C-domain, with serine, isoleucine and asparagine substituted for alanine, valine and serine, respectively, at positions 32, 35 and 36. The final yield of highly purified ovine fetal IGF II was 134 micrograms, starting from 450 ml of serum.

Purification and characterization of three molecular forms of insulin-like growth factor II from human Cohn paste IV.

The somatomedins or insulin-like growth factors (IGFs) are a family of peptides present in human serum. They are bound to specific carrier proteins and are thought to mediate growth-promoting actions of human growth hormone. Starting from Cohn fraction IV of human plasma, we describe here a rapid and highly efficient procedure for the purification to homogeneity, in addition to IGF I. of three forms of insulin-like growth factor II: IGF IIA (10-12 kDa), IGF IIB (the "classical" 7.5 kDa IGF II) and IGF IIC, identified as the IGF II variant of Jansen by fast-atom bombardment mass spectrometry. The procedure is based on ion-exchange chromatography and gel permeation chromatography on Biogel P10. As judged by specific radioimmunoassay methods for IGF I and IGF II, one of the most striking advantages of this process at this stage is the yield of IGF I not contaminated by 7.5 kDa IGF II. Isoelectric focusing or chromatofocusing, which require affinity chromatography to separate proteins from the polybuffers, are not necessary in this procedure. Final purification was directly achieved by preparative, followed by analytical high-performance liquid chromatography. The N-terminal sequence of peptide IGF IIB (39 amino acids) and peptide IGF I (29 amino acids) showed total homology with those previously described by Rinderknecht and Humbel [FEBS Lett., 89 (1978) 283]. The final yields of purified human IGF I and IGF IIB were 15 and 25 micrograms, respectively, from 11 of serum. All peptides interact with specific receptors on human lymphocytes and red blood cells, and are biologically active (stimulation of 35S uptake, increasing [3H]thymidine incorporation in human and chick embryo fibroblasts).

[Evolution of in vivo and in vitro tests during specific immunotherapy against hymenoptera venoms]. / Evolution des tests in vivo et in vitro au cours de l'immunothérapie spécifique au venin d'hyménoptère.

In this study, on a population of 26 patients with systemic reactions after hymenoptera stings, different immunobiological tests have been used to confirm the sensitivity to hymenoptera venom. These 26 patients were divided into two groups according to the stage of their immunotherapy: group 1 (n = 8) included all assessments from day 0 (before IT) and group 2 (n = 16) the assessments at 1 and 2 years during IT. In general, there was a good correlation between skin tests, RAST and histamine release. The results show that the IgE level seems to be more informative than histamine release and that measurement of the specific IgE level is more sensitive with Allerbio allergen compared with other allergens. However these preliminary results must be confirmed on a statistically significant number of patients. HL by Agf is less sensitive than that done with Ags.

[Respective roles of high and low molecular weight serum growth factors in the metabolism of proteoglycans and other cartilage macromolecules]. / Rôles respectifs des facteurs de croissance sériques de haut et faible poids moléculaire dans le métabolisme des protéoglycannes et d'autres macromolécules du cartilage.

35S radiolabeling allowed an evaluation to be made of neosynthesized macromolecules in chick embryo cartilage cultures. Activities for growth factors of high (serum retentate) or low (ultrafiltrate below 1,000) molecular weight (MW) were assessed in pelvic cartilage explants and in corresponding incubation media. In the absence of growth factor, 35S was mostly incorporated in glycosaminoglycans (GAGs) as regards the medium and for cartilage, in guanidinium chloride unextractable material. In retentate-enriched medium, 35S incorporation was enhanced in all cartilage GAGs while in the medium, stimulation essentially occurred in macromolecules other than GAGs. Low MW growth factors exclusively enhanced cartilage levels of macromolecules which were insoluble in guanidinium chloride. In the medium, these factors did not display any significant effect. These results indicate that human serum growth factors with high and low MW possess different metabolic targets at the cellular level.

[Role of food allergy in atopic dermatitis]. / Rôle de l'allergie alimentaire dans la dermatite atopique.

Food allergy is one of the main causes of atopic dermatitis. Its frequency was established at 41.3% in our study. Eggs, cows milk and wheat were the foods most often responsible for DA. Proof by elimination-reintroduction is the best diagnostic criterion in food allergy, leading to suppression of the food if its nutritional importance permits this. This food suppression leads to 84% clinical improvement of DA.

[Significance of anti-gluten IgA levels for detection and monitoring of celiac disease]. / Intérêt du dosage des IgA antigluten comme test de dépistage et de suivi de la maladie coeliaque.

Diagnosis of coeliac disease rests in jejunal biopsy. This is recognised as a traumatic examination which today may perhaps be replaced by a biological test produced by Pharmacia in which the anti-gluten IgA is measured by the ELISA method. The sensitivity of the test reaches 100% and the specificity to 96%. This biological test makes it possible to follow the development of the coeliac illness under diet, since the anti-gluten IgA diminishes significantly, often to the normal level.

[Local and general experimental anti-anaphylactic effect of 554 L, a synthetic antihistaminic]. / Effet antianaphylactique expérimental, général et local du 554 L, hypohistaminémiant de synthèse.

554 L, a synthetic histamine depressant, was first made in September 1956. In spite of the age of this compound, it seemed to us that it may be of interest to examine it for possible experimental general and localised bronchial antianaphylactic activity. In the first experiments, the results showed an anti-anaphylactic effect in guinea pigs that had been sensitised to cow milk. The second study proved that there was an anti-anaphylactic effect locally on the bronchii by an aerosol of 554 L or Hypostamine on guinea pigs that were sensitive to OVA. These results may produce development of this old compound in delayed release and aerosol presentations.

[Cell-mediated immunity using anti-influenza vaccine (AIV) and an immunostimulant (R)]. / Etude de l'immunité à médiation cellulaire du vaccin antigrippal (VAG) et d'un immuno-stimulant (R).

21 infected asthmatics were involved in this study, divided into three groups: Group 1 (G1): 7 subjects who received Ribomunyl. Group 2 (G2): 7 subjects who received anti-influenza vaccine, replaced on the 8th day by Ribomunyl. Group 3 (G3): 7 subjects who received the anti-influenza vaccine. Every patient had a IMC assessment on days 0, 8 and 30 that was composed of: 1. An RE test to show the Ly T11 receptors. 2. A study of the lymphocyte sub-populations CD3, CD4 and CD8, that respectively exhibit the LyT, T-helper and T-suppressor receptors. 3. Lymphocyte function was studied by stimulation of the lymphocytes by lectins, PHA (Ly T), Con A (Ly Ts) PKWM (Ly 8): by TB co-operation). 4. Measurement of total IgE. Only the lymphocyte stimulation tests by lectins showed a significantly raised response in the subjects of G1, who received Ribomunyl. IAV and Ribomunyl (G2) or IAV alone (G3) showed lymphocytes responses that were statistically less than G1. It seemed as though the IAV retarded the Ribomunyl response in IMC. The RE test and the study of the sub-populations did not show any significant differences between the groups. No differences between the total IgE levels could be seen in the groups. This study indicates the possibilities in the treatment of super-infected asthmatics with Ribomunyl alone, since the anti-influenza vaccine had a tendency to retard cell-mediated immunity.

[Antihistaminic or anti-degranulating activity of pregnancy serum]. / Activité anti-histaminique ou anti-dégranulante de sérum de grossesse.

From observation of women who had anaphylactic accidents to hymenoptera venoms, with positive histamine release, we have noticed that these same patients lose their histamine release during pregnancy. Measurement of histamine release to pollens confirms the existence of a histaminase, which develops from the third month of the pregnancy and which is the origin of the loss of histamine release. This study makes eliminates a possible anti-degranulation ability of pregnancy sera.

[Comparative study of ELISA and RIA technics for the detection of specific IgG4]. / Etude comparative des méthodes ELISA et RIA pour le dosage des IgG4 spécifiques.

The assay of IgG4 was done by an ELISA method that has been perfected in our laboratory over two years, or by the RIA (Pharmacia technique). Assay of IgG4 is an objective element in the control of specific immunotherapy (IT) to hymenoptera venoms and grass pollens. There is an excellent correlation between the two techniques of ELISA and RIA, that shows an increase in IgG4 titre after around 3 to 4 years of IT.

[Cell-mediated immunity in antibiotic therapy]. / Etude de l'immunité à médiation cellulaire au cours de l'antibiothérapie.

Should antibiotic therapy required in the treatment of acute infection be administered frequently in patients at risk with clinical conditions involving recurrent superinfection? The results of our ongoing investigations initiated in 1967 and the present study indicate that macrolides, particularly erythromycin depress the host defense system. In contrast in a study performed in subjects treated for 8 days using cell-immunity tests, we found that cefaclor and amoxicillin may have an enhancing effect on host defenses.

[Determination of specific IgE by chemiluminescence. The IgE DHS-CLA system]. / Etude du dosage des IgE spécifiques par chimiluminescence. Système DHS.CLA IgE.

The DHS-CLA IgE system (MAST immunosystems) allows simultaneous determination of specific IgE for 35 different allergens. The method here described is compared with RAST and results are in good agreement with allergic etiology. CLA testing appears to be a good alternative when anamnesis does not permit a clear diagnostic orientation.

[Determination of histamine]. / Dosages de l'histamine.

Introduction of the radio-immunological technique (IMMUNOTECH, Marseille) for the measurement of histamine will in the future facilitate measurement of this mediator and this will be specially interesting during provocation tests for food and drug allergies and for histamine release in anaphylactic accidents caused by hymenoptera venom. The technique is more sensitive than that of the automated fluorimetric analysis.

[Determination of specific IgG4 in allergy]. / Intérêt du dosage des IgG4 spécifiques dans l'allergie.

Measurement of the titre of specific IgG4 by the ELISA method may provide objective assistance to the control of specific immunotherapy (IS) to hymenoptera venom and grass pollens. A marked increase of the specific IgG4 titre in the first 3 months of IS or a titre already raised before the start of IS correlated with poor clinical results. Specific IgG4 can not be considered to be a diagnostic indicator in food allergy since we have frequently found this type of antibody in control subjects. Specific IgG4 in food allergy expresses a mucosal marker rather than a pathological reaction.

[ImmunoComb--reliability and reproducibility]. / ImmunoComb fiabilité et reproductibilité.

ImmunoComb is a solid phase in vitro immunological test for the measurement of serum or plasma total IgE. The technique was compared with PRIST for measurement of total IgE. The study also included reproducibility, on a test serum dilution both on a complete plate and plate sections. Statistically the conclusion is that ImmunoComb is a colourimetric test that gives the exact total IgE titre with good reproducibility. Use of a photometer greatly improves the sensitivity of assessing the results.

Isolation and characterization of a low molecular weight growth-promoting factor from human plasma.

A low molecular weight growth factor (LMW-GF) enriched preparation was purified from human plasma after ultrafiltration or gel filtration by means of molecular sieving chromatography low pressure reversed phase chromatography (LP-RPLC) and electrophoresis. Purification was monitored by a biological assay testing the capacity of the fractions to enhance the sulfation activity of the somatomedins/insulin-like growth factors on chick embryo cartilage. Analysis of its chemical nature show that it is hydrophilic, stable to heat, resistant to most of the proteases but that it is degraded by acid hydrolysis or carboxypeptidase Y action. UV absorption spectrum and ion-exchange chromatographic retention behavior support the hypothesis that the most purified active preparation includes a peptide structure. The presence of sugar is suggested by concanavalin A binding experiments. The fact that the purification fractions also enhance thymidine uptake by other cell lines (fibroblasts, activated lymphocytes) widens the role of such small plasma molecules in the field of growth factor activities.