Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

Are allergic multimorbidities and IgE polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis.

Allergic diseases [asthma, rhinitis and atopic dermatitis (AD)] are complex. They are associated with allergen-specific IgE and nonallergic mechanisms that may coexist in the same patient. In addition, these diseases tend to cluster and patients present concomitant or consecutive diseases (multimorbidity). IgE sensitization should be considered as a quantitative trait. Important clinical and immunological differences exist between mono- and polysensitized subjects. Multimorbidities of allergic diseases share common causal mechanisms that are only partly IgE-mediated. Persistence of allergic diseases over time is associated with multimorbidity and/or IgE polysensitization. The importance of the family history of allergy may decrease with age. This review puts forward the hypothesis that allergic multimorbidities and IgE polysensitization are associated and related to the persistence or re-occurrence of foetal type 2 signalling. Asthma, rhinitis and AD are manifestations of a common systemic immune imbalance (mesodermal origin) with specific patterns of remodelling (ectodermal or endodermal origin). This study proposes a new classification of IgE-mediated allergic diseases that allows the definition of novel phenotypes to (i) better understand genetic and epigenetic mechanisms, (ii) better stratify allergic preschool children for prognosis and (iii) propose novel strategies of treatment and prevention.

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.

DLNO/DLCO ratio evolution under targeted therapy in patients with pulmonary hypertension.

The ratio of the diffusing capacity of the lung for carbon monoxide (DLCO) and for nitric oxide (DLNO) measured simultaneously is modified in patients with precapillary pulmonary hypertension (PH). The potential impact of targeted therapy on the DLCO/DLNO ratio is unknown. Simultaneous measurements of DLNO and DLCO were performed at baseline, 3-4 month follow-up (first evaluation) and 12-month follow-up (second evaluation) after initiation of targeted PH therapies in incident cases of precapillary PH. The main outcome was the change in DLNO/DLCO ratio under treatment between baseline and the first evaluation. Twenty-nine patients were included (mean age: 66.8 years, 62.1% female). No significant change in the DLNO/DLCO ratio was found between baseline and the first evaluation. Similarly, no significant differences were noted with regard to changes in Dm or Vc, the DLNO/DLCO ratio in different patient subgroups, or in the 20 patients evaluated at the second follow-up. Within the limitations of this study, the DLNO/DLCO ratio is not useful in monitoring the response to treatment in PH.

Synthesis, calcium mobilizing, and physicochemical properties of D-chiro-inositol 1,3,4,6-tetrakisphosphate, a novel and potent ligand at the D-myo-inositol 1,4,5-trisphosphate receptor.

The synthesis of a novel and potent ligand at the D-myo-inositol 1,4, 5-trisphosphate receptor (InsP3R) is described. D-chiro-Inositol 1,3, 4,6-tetrakisphosphate (7) and L-chiro-inositol 1,3,4, 6-tetrakisphosphate (ent-7) have been synthesized from D-2, 5-di-O-benzyl-chiro-inositol and L-2,5-di-O-benzyl-chiro-inositol, respectively. The potency of binding and Ca2+ release of 7 and ent-7 were examined in L15 and Lvec cells. 7 was a full agonist at the InsP3R in both cells, and ent-7 was inactive. The results are compared to those from D-myo-inositol 1,4,5-trisphosphate (1), DL-scyllo-inositol 1,2,4-trisphosphate (2), DL-myo-inositol 1,2,4, 5-tetrakisphosphate (3), scyllo-inositol 1,2,4,5-tetrakisphosphate (4), D-myo-inositol 2,4,5-trisphosphate (5), and D-chiro-inositol 1, 3,4-trisphosphate (6). The protonation processes of 7 have also been investigated by 31P NMR titration experiments.

Synthesis, acid-base behavior, and binding properties of 6-modified myo-inositol 1,4,5-tris(phosphate)s.

myo-Inositol 1,4,5-tris(phosphate) was modified at position 6. The analogues synthesized are reported in this publication are 6-deoxy-myo-inositol 1,4,5-tris(phosphate), 6-fluoro-6-deoxy-myo-inositol 1,4,5-tris(phosphate), epi-inositol 1, 4,5-tris(phosphate), and 6-amino-6-deoxy-myo-inositol 1,4, 5-tris(phosphate). These derivatives showed poor affinity for the Ins(1,4,5)P(3) receptors. The inframolecular acid-base behavior and the cooperative effects between the phosphate groups could help explain the loss of affinity of these 6-modified analogues.

[Managements of chronic cough in general medicine and requirements of general practitioners]. / Prise en charge des toux chroniques difficiles en médecine générale et attente des médecins généralistes.

Chronic cough represents a persistent dilemma, for general practitioner (GP), inducing a lot of medical investigations. Few data are available about French GP practice and their expectancy from cough specialists. We studied management in primary care and impressions of GP of patients with chronic cough. Thirty-four patients were studied. They were mostly women, mean age was above 50 years-old, and the waste majority of patients were non-smokers. Halftime, the symptom was persistent (more than 6 months), had promoted numerous medical consultations (more than five). Drugs were prescribed since the first visit for the majority of patients, principally cough-sedation drugs, steroids and bronchodilatators. A chest radiography was realized in almost all patients. Advices were asked (with a decreasing frequency) to physicians specialized in: ear-nose-throat or respiratory, gastroenterology, allergy, or cardiology. The majority of patients were satisfied of their GP, despite persistent symptoms. From the point of the GP, chronic cough remains a relentless dilemma. Their main purpose, when they addressed their patient to a specialized physician, was to obtain an etiologic diagnosis. When they were asked "which tool will be more adequate for you in the next future?", the preferred response was "a simple etiologic algorithm". Despite persistent symptoms, inducing furthers medical consultations, the main ask from GP was to promote a simple etiologic algorithm.