The status of chemical elements in the blood plasma of children with autism spectrum disorder in Tunisia: a case-control study.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders defined by a deficit in social interactions and the presence of restricted and stereotypical behaviors or interests. The etiologies of autism remain mostly unknown. Many genetic and environmental factors have been suspected. Among these environmental factors, exposure to several chemical elements has been previously studied. The purpose of this study was to compare the levels of trace elements in the blood plasma of children with ASD with typically developed children (TDC). The participants in this study consisted of 89 children with ASD (14 girls and 74 boys) and 70 TD children (29 girls and 41 boys). The levels of 33 chemical elements have been analyzed by inductively coupled plasma spectrometry (ICP-MS). We detected significant differences in the levels of eight elements between the two groups, among which there were three rare earth elements (REEs): Eu, Pr, and Sc (p = 0.000, p = 0.023, and p < 0.001 respectively); four heavy metals: Bi, Tl, Ti, and V (p = 0.004, p < 0.001, p = 0.001, and p = 0.001 respectively); and one essential element: Cu (p = 0.043). Children with ASD had higher levels of Er, Pr, Sc, Bi, Tl, Ti, and V, and lower levels of Cu in comparison with the TD group. The children exposed to passive smoking had lower levels of lead (Pb) compared with children without exposure (p = 0.018). Four elements (Cr, Er, Dy, and Pr) were negatively correlated to the severity of ASD. The level of Cu was significantly associated with autistic children's behavior (p = 0.014). These results suggest that children with ASD might have abnormal plasma levels of certain chemical elements (including Er, Pr, Sc, Bi, Tl, Ti, and V, and Cu), and some of these elements might be associated with certain clinical features.

Nanoparticulate adjuvants and delivery systems for allergen immunotherapy.

In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of allergic diseases. However, current allergen immunotherapy shows limitations concerning the long-term efficacy and safety due to local side effects and risk of anaphylaxis. Thus, effective and safe vaccines with reduced dose of allergen have been developed using adjuvants. Nevertheless, the use of adjuvants still has several disadvantages, which limits its use in human vaccines. In this context, several novel adjuvants for allergen immunotherapy are currently being investigated and developed. Currently, nanoparticles-based allergen-delivery systems have received much interest as potential adjuvants for allergen immunotherapy. It has been demonstrated that the incorporation of allergens into a delivery system plays an important role in the efficacy of allergy vaccines. Several nanoparticles-based delivery systems have been described, including biodegradable and nondegradable polymeric carriers. Therefore, this paper provides an overview of the current adjuvants used for allergen immunotherapy. Furthermore, nanoparticles-based allergen-delivery systems are focused as a novel and promising strategy for allergy vaccines.

Delta-like 1/fetal antigen-1 (Dlk1/FA1) is a novel regulator of chondrogenic cell differentiation via inhibition of the Akt kinase-dependent pathway.

Delta-like 1 (Dlk1, also known as fetal antigen-1, FA1) is a member of Notch/Delta family that inhibits adipocyte and osteoblast differentiation; however, its role in chondrogenesis is still not clear. Thus, we overexpressed Dlk1/FA1 in mouse embryonic ATDC5 cells and tested its effects on chondrogenic differentiation. Dlk1/FA1 inhibited insulin-induced chondrogenic differentiation as evidenced by reduction of cartilage nodule formation and gene expression of aggrecan, collagen Type II and X. Similar effects were obtained either by using Dlk1/FA1-conditioned medium or by addition of a purified, secreted, form of Dlk1 (FA1) directly to the induction medium. The inhibitory effects of Dlk1/FA1 were dose-dependent and occurred irrespective of the chondrogenic differentiation stage: proliferation, differentiation, maturation, or hypertrophic conversion. Overexpression or addition of the Dlk1/FA1 protein to the medium strongly inhibited the activation of Akt, but not the ERK1/2, or p38 MAPK pathways, and the inhibition of Akt by Dlk1/FA1 was mediated through PI3K activation. Interestingly, inhibition of fibronectin expression by siRNA rescued the Dlk1/FA1-mediated inhibition of Akt, suggesting interaction of Dlk1/FA1 and fibronectin in chondrogenic cells. Our results identify Dlk1/FA1 as a novel regulator of chondrogenesis and suggest Dlk1/FA1 acts as an inhibitor of the PI3K/Akt pathways that leads to its inhibitory effects on chondrogenesis.

Immunoglobulin-E reactivity to wine glycoproteins in heavy drinkers.

N-glycans from plant and invertebrate allergens can induce extensive immunoglobulin-E (IgE) cross-reactivity in vitro. IgE antibodies against these N-glycans, also termed cross-reactive carbohydrate determinants or CCDs, are prevalent in alcohol drinkers. This study investigated the prevalence and biological significance of IgE antibodies to N-glycans from wine glycoproteins in heavy drinkers. A structured questionnaire, skin prick tests, serum IgE levels, IgE-immunoblotting to wine extracts, and basophil activation tests were used to characterize 20 heavy drinkers and 10 control subjects. Eleven heavy drinkers (55%) showed IgE binding to proteins in wine extracts. The proteins were identified by mass spectrometry as grape-derived vacuolar invertase and thaumatin-like protein. Immunoblot reactivity was closely associated with the presence of IgE to CCDs and was inhibited by preincubation with a glycoconjugate containing bromelain-type N-glycans. The same conjugate, CCD-bearing allergens, and wine extracts activated basophils in patients with high-titer CCD-specific IgE but not in healthy controls. There was no relationship between immunoblot reactivity and consumption of any specific type of wine. No patient reported symptoms of hypersensitivity to Hymenoptera venom, food, or wine. In conclusion, heavy drinkers frequently show IgE reactivity to the N-glycans of wine glycoproteins. Glycans and wine glycoprotein extracts can induce basophil activation in sensitized alcoholics. The clinical significance of these findings remains to be elucidated.

Prevalence and severity of renal dysfunction among 1062 heart transplant patients according to criteria based on serum creatinine and estimated glomerular filtration rate: results from the CAPRI study.

Chronic kidney disease (CKD) is staged on the basis of glomerular filtration rate; generally, the MDRD study estimate, eGFR, is used. Renal dysfunction (RD) in heart transplant (HT) patients is often evaluated solely in terms of serum creatinine (SCr). In a cross-sectional, 14-center study of 1062 stable adult HT patients aged 59.1±12.5 yr (82.3% men), RD was graded as absent-or-mild (AoM), moderate, or severe (this last including dialysis and kidney graft) by two classifications: SCr-RD (SCr cutoffs 1.6 and 2.5 mg/dL) and eGFR-RD (eGFR cutoffs 60 and 30 mL/min/1.73 m2). SCr-RD was AoM in 68.5% of patients, moderate in 24.9%, and severe in 6.7%; eGFR-RD, AoM in 38.6%, moderate in 52.2%, severe in 9.2%. Among patients evaluated <2.7, 2.7-6.2, 6.2-9.5 and >9.5 yr post-HT (the periods defined by time-since-transplant quartiles), AoM/moderate/severe RD prevalences were <2.7, SCr-RD 74/21/5%, eGFR-RD 47/47/6%; 2.7-6.2, SCr-RD 73/22/5%, eGFR-RD 37/56/7%; 6.2-9.5, SCr-RD 69/24/7%, eGFR-RD 37/54/9%; >9.5, SCr-RD 58/32/10%, eGFR-RD 32/52/16%. The prevalence of severe RD increases with time since transplant. If the usual CKD stages are appropriate for HT patients, the need for less nephrotoxic immunosuppressants and other renoprotective measures is greater than is suggested by direct SCr-based grading, which should be abandoned as excessively insensitive.

Allergen immunotherapy with nanoparticles containing lipopolysaccharide from Brucella ovis.

The adjuvant and protective capacity against anaphylactic shock of the association between rough lipopolysaccharide of Brucella ovis (LPS) coencapsulated with ovalbumin (OVA), as a model allergen, in Gantrez AN nanoparticles was investigated. Several strategies were performed in order to study the adjuvant effect of the LPS either encapsulated or coating the nanoparticles. OVA, as well as LPS, was incorporated either during the manufacturing process (OVA-encapsulated or LPS-encapsulated nanoparticles, respectively) or after the preparation (OVA-coated or LPS-coated nanoparticles, respectively). After the administration of 10 microg of OVA incorporated in the different formulations, all the nanoparticles, with or without LPS, were capable of amplifying the immune response (IgG(1) and IgG(2a)). However, in a model of sensitized mice to OVA, the formulation with OVA and LPS-entrapped inside the nanoparticles administered intradermally in three doses of 3 microg of OVA each was the only treatment that totally protected the mice from death after a challenge with an intraperitoneal injection of OVA. In contrast, the control group administered with OVA adsorbed onto a commercial alhydrogel adjuvant showed 80% mortality. These results are highly suggestive for the valuable use of Gantrez nanoparticles combined with rough LPS of B. ovis in immunotherapy.

Gantrez AN nanoparticles as an adjuvant for oral immunotherapy with allergens.

The aim of this study was to investigate the adjuvant properties of oral-administered Gantrez AN nanoparticles with ovalbumin (as allergen model) and, in some cases, lipopolysaccharide of Brucella ovis as immunomodulator. For this purpose, BALB/c mice were administered by oral gavage with OVA nanoparticles and both Th1 and Th2 markers (IgG2a and IgG1, respectively) were enhanced. On the other hand, these carriers administered by oral route were able to protect a model of sensitized mice to ovalbumin from anaphylactic shock. These results are highly suggestive for the valuable use of Gantrez nanoparticles in oral immunotherapy with allergens.

[New pathophysiological concepts on aspirin hypersensitivity (Widal syndrome); diagnostic and therapeutic consequences]. / Nouvelles données pathophysiologiques sur l'hypersensibilité à l'aspirine (syndrome de Widal); conséquences diagnostiques et thérapeutiques.

Hypersensitivity to aspirin usually takes the form of a clinical syndrome combining chronic rhinitis, nasal polyposis and asthma attacks that are exacerbated by aspirin or other non steroidal anti-inflammatory drugs (NSAIDs). This syndrome, first described by Widal in 1922, is very frequent: it affects nearly 15% of asthmatic patients and is usually associated with severe and sometimes fatal asthma. In other instances, hypersensitivity to NSAIDs manifests in the form of skin lesions, such as urticaria and angioedema. Until recently, the pathophysiological mechanism of NSAID hypersensitivity was somewhat mysterious. The fact that the main mediators involved are sulfidoleukotrienes (LTC4, LTD4, LTE4) and that the drugs responsible all inhibit cyclooxygenase-1 (COX-1), pointed to a pharmacogenetic abnormality of arachidonic acid metabolism. An immunopharmacological study of basophil activation (detected by flow cytometry), sulfidoleukotriene production in the presence of NSAIDs in vitro, and other related studies reviewed here have revealed that: a) basophils from patients with the Widal syndrome are hyperactivated in a non specific manner, probably related to chronic inflammation in the skin or airways; b) these hyperactive basophils produce increased amounts of sulfidoleukotrienes but decreased amounts of PGE2 when exposed to NSAIDs in vitro. These observations led to the development of an in vitro diagnostic test which, in many cases, can replace challenge tests. The pathogenic mechanism of the Widal syndrome now appears to involve the combined effects of chronic inflammation (causing non specific cellular hyper-reactivity, particularly of mast cells, basophils and eosinophils) and a pharmacogenetic abnormality of arachidonic acid metabolism in response to NSAIDs. This leads to sulfidoleukotriene overproduction and to a decrease in the anti-inflammatory prostaglandin PGE2. This concept is compatible with the onset and outcome of most cases of the Widal syndrome, and provides a therapeutic rationale.

Anaphylactic reaction after artificial insemination.

BACKGROUND: Bovine seroalbumin is known as an allergen for human beings, but reactions to it in an artificial insemination procedure are much rarer. We report a case of anaphylaxis after intrauterine insemination (IUI) in which sensitization to bovine serum albumin (BSA) is demonstrated. OBJECTIVE: Report the allergy evaluation performed in a patient who suffered a severe reaction immediately after an IUI procedure. METHODS: A 33-year-old woman was referred because of an anaphylactic reaction after a second trial of IUI. She developed pruritus, abdominal pain, nausea and vomiting, bronchospasm, and generalized urticaria. She had an atopic medical history of pollen allergy and sensitization to cat epithelium. She had never had trouble with minor surgery and she usually uses latex material. She had never received heterologous sera before. Her husband's semen for the IUI was processed in a standard fluid medium called upgraded INRA B 2 (Laboratoires CCD, Paris, France), which contains amino acids, lipids, vitamins, BSA, penicillin, and streptomycin in addition to inorganic salts. RESULTS: Skin prick tests with the medium and BSA 10 mg/mL were positive. In vitro studies demonstrated an immunoglobulin E binding protein of 60 to 65 kDa and mast cells and basophil activation (CD63 expression) against BSA contained in the medium. Cutaneous and challenge tests with penicillin and streptomycin were negative. CONCLUSIONS: We consider the BSA in the semen culture medium to be the factor which triggered the anaphylactic reaction. This case supports the authors who state that media free from heterologous proteins should be used for human application, especially on atopic patients, to avoid sensitization.