Cardiopathies congénitales de l'âge adulte: nouvelle population de patients, prise en charge multidisciplinaire [Adults with congenital heart diseases: a growing population, a multidisciplinary approach].

Untill recently, congenital heart disease was considered as a childhood's disease. With improvement in pediatric survival, adults with a congenital heart disease (ACHD) represent an emerging group of patients who need specialized medical care. In 2010, the ESC published newguidelines on global and specific management of adults with congenital heart disease. ACHD centers organize appropriate medical care for these patients, promote specialist training and national scientific research in collaboration with other national ACHD centers.

Proteomic analysis of cytokine induced proteins in human intestinal epithelial cells: implications for inflammatory bowel diseases.

A role for cytokine regulated proteins in epithelial cells has been suggested in the pathogenesis of inflammatory bowel diseases (IBD). The aim of this study was to identify such cytokine regulated targets using a proteomic functional approach. Protein patterns from (35)S-radiolabeled homogenates of cultured colon epithelial cells were compared before and after exposure to interferon-gamma, interleukin-1beta and interleukin-6. Proteins were separated by two-dimensional polyacrylamide gel electrophoresis. Both autoradiographies and silver stained gels were analyzed. Proteins showing differential expression were identified by tryptic in-gel digestion and mass spectrometry. Metabolism related proteins were also investigated by Western blot analysis. Tryptophanyl-tRNA synthetase, indoleamine-2,3-dioxygenase, heterogeneous nuclear ribonucleoprotein JKTBP, interferon-induced 35kDa protein, proteasome subunit LMP2 and arginosuccinate synthetase were identified as cytokine modulated proteins in vitro. Using purified epithelial cells from patients, overexpression of indoleamine-2,3-dioxygenase, an enzyme involved in tryptophan metabolism, was confirmed in Crohn's disease as well as in ulcerative colitis, as compared to normal mucosa. No such difference was found in diverticulitis. Potentially, this observation opens new avenues in the treatment of IBD.

Mass spectrometry for the evaluation of cardiovascular diseases based on proteomics and lipidomics.

The identification and quantification of proteins and lipids is of major importance for the diagnosis, prognosis and understanding of the molecular mechanisms involved in disease development. Owing to its selectivity and sensitivity, mass spectrometry has become a key technique in analytical platforms for proteomic and lipidomic investigations. Using this technique, many strategies have been developed based on unbiased or targeted approaches to highlight or monitor molecules of interest from biomatrices. Although these approaches have largely been employed in cancer research, this type of investigation has been met by a growing interest in the field of cardiovascular disorders, potentially leading to the discovery of novel biomarkers and the development of new therapies. In this paper, we will review the different mass spectrometry-based proteomic and lipidomic strategies applied in cardiovascular diseases, especially atherosclerosis. Particular attention will be given to recent developments and the role of bioinformatics in data treatment. This review will be of broad interest to the medical community by providing a tutorial of how mass spectrometric strategies can support clinical trials.

Sémiologie de l'atteinte bronchique en scanner [Bronchial diseases: CT imaging features].

Multidetector row computed tomography (MDCT) is the imaging modality of reference for the diagnosis of bronchiectasis. MDCT may also detect a focal stenosis, a tumor or multiple morphologic abnormalities of the bronchial tree. It may orient the endoscopist towards the abnormal bronchi, and in all cases assess the extent of the bronchial lesions. The CT findings of bronchial abnormalities include anomalies of bronchial division and origin, bronchial stenosis, bronchial wall thickening, lumen dilatation, and mucoid impaction. The main CT features of bronchiectasis are increased bronchoarterial ratio, lack of bronchial tapering, and visibility of peripheral airways. Other bronchial abnormalities include excessive bronchial collapse at expiration, outpouchings and diverticula, dehiscence, fistulas, and calcifications.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: prevention and management of invasive infections in neonates and children caused by Candida spp.

Invasive candidiasis (IC) is a relatively common syndrome in neonates and children and is associated with significant morbidity and mortality. These guidelines provide recommendations for the prevention and treatment of IC in neonates and children. Appropriate agents for the prevention of IC in neonates at high risk include fluconazole (A-I), nystatin (B-II) or lactoferrin ± Lactobacillus (B-II). The treatment of IC in neonates is complicated by the high likelihood of disseminated disease, including the possibility of infection within the central nervous system. Amphotericin B deoxycholate (B-II), liposomal amphotericin B (B-II), amphotericin B lipid complex (ABLC) (C-II), fluconazole (B-II), micafungin (B-II) and caspofungin (C-II) can all be potentially used. Recommendations for the prevention of IC in children are largely extrapolated from studies performed in adults with concomitant pharmacokinetic data and models in children. For allogeneic HSCT recipients, fluconazole (A-I), voriconazole (A-I), micafungin (A-I), itraconazole (B-II) and posaconazole (B-II) can all be used. Similar recommendations are made for the prevention of IC in children in other risk groups. With several exceptions, recommendations for the treatment of IC in children are extrapolated from adult studies, with concomitant pharmacokinetic studies. Amphotericin B deoxycholate (C-I), liposomal amphotericin B (A-I), ABLC (B-II), micafungin (A-I), caspofungin (A-I), anidulafungin (B-II), fluconazole (B-I) and voriconazole (B-I) can all be used.

Oral insecticidal activity of root colonizing Pseudomonas fluorescens CHA0: a biocontrol agent with potential to control plant pests and diseases

The application of microbial biocontrol agents for the control of fungal plant diseases and plant insect pests is a promising approach in the development of environmentally benign pest management strategies. The ideal biocontrol organism would be a bacterium or a fungus with activity against both, insect pests and fungal pathogens. Here we demonstrate the oral insecticidal activity of the root colonizing Pseudomonas fluorescens CHA0, which is so far known for its capacity to efficiently suppress fungal plant pathogens. Feeding assays with CHA0-sprayed leaves showed that this strain displays oral insecticidal activity and is able to efficiently kill larvae of three important insect pests. We further show data indicating that the Fit insect toxin produced by CHA0 and also metabolites controlled by the global regulator GacA contribute to oral insect toxicity.

Genes associated with retinitis pigmentosa and allied diseases are frequently mutated in the general population.

BACKGROUND: Retinitis pigmentosa and other hereditary retinal degenerations (HRD) are rare genetic diseases leading to progressive blindness. Recessive HRD are caused by mutations in more than 100 different genes. Laws of population genetics predict that, on a purely theoretical ground, such a high number of genes should translate into an extremely elevated frequency of unaffected carriers of mutations. In this study we estimate the proportion of these individuals within the general population, via the analyses of data from whole-genome sequencing. METHODOLOGY/PRINCIPAL FINDINGS: We screened complete and high-quality genome sequences from 46 control individuals from various world populations for HRD mutations, using bioinformatic tools developed in-house. All mutations detected in silico were validated by Sanger sequencing. We identified clear-cut, null recessive HRD mutations in 10 out of the 46 unaffected individuals analyzed (∼22%). CONCLUSIONS/SIGNIFICANCE: Based on our data, approximately one in 4-5 individuals from the general population may be a carrier of null mutations that are responsible for HRD. This would be the highest mutation carrier frequency so far measured for a class of Mendelian disorders, especially considering that missenses and other forms of pathogenic changes were not included in our assessment. Among other things, our results indicate that the risk for a consanguineous couple of generating a child with a blinding disease is particularly high, compared to other genetic conditions.

Real-time PCR for type-specific identification of herpes simplex in clinical samples: evaluation of type-specific results in the context of CNS diseases.

BACKGROUND: HSV-1 and HSV-2 cause CNS infections of dissimilar clinico-pathological characteristics with prognostic and therapeutic implications. OBJECTIVES: To validate a type-specific real-time PCR that uses MGB/LNA Taqman probes and to review the virologico-clinical data of 25 eligible patients with non-neonatal CNS infections. RESULTS: This real-time PCR was evaluated against conventional PCR (26 CSF and 20 quality controls), and LightCycler assay (51 mucocutaneous, 8 CSF and 32 quality controls) and culture/immunofluorescence (75 mucocutaneous) to assess typing with independent methods. Taqman real-time PCR detected 240 HSV genomes per ml CSF, a level appropriate for the management of patients, and provided unambiguous typing for the 104 positive (62 HSV-1 and 42 HSV-2) out the 160 independent clinical samples tested. HSV type diagnosed by Taqman real-time PCR predicted final diagnosis (meningitis versus encephalitis/meningoencephalitis, p<0.001) in 24/25 patients at time of presentation, in contrast to clinical evaluation. CONCLUSIONS: Our real-time PCR, as a sensitive and specific means for type-specific HSV diagnosis, provided rapid prognostic information for patient management.

Molecular detection and identification of zygomycetes species from paraffin-embedded tissues in a murine model of disseminated zygomycosis: a collaborative European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) evaluation.

The present study was performed to assess the interlaboratory reproducibility of the molecular detection and identification of species of Zygomycetes from formalin-fixed paraffin-embedded kidney and brain tissues obtained from experimentally infected mice. Animals were infected with one of five species (Rhizopus oryzae, Rhizopus microsporus, Lichtheimia corymbifera, Rhizomucor pusillus, and Mucor circinelloides). Samples with 1, 10, or 30 slide cuts of the tissues were prepared from each paraffin block, the sample identities were blinded for analysis, and the samples were mailed to each of seven laboratories for the assessment of sensitivity. A protocol describing the extraction method and the PCR amplification procedure was provided. The internal transcribed spacer 1 (ITS1) region was amplified by PCR with the fungal universal primers ITS1 and ITS2 and sequenced. As negative results were obtained for 93% of the tissue specimens infected by M. circinelloides, the data for this species were excluded from the analysis. Positive PCR results were obtained for 93% (52/56), 89% (50/56), and 27% (15/56) of the samples with 30, 10, and 1 slide cuts, respectively. There were minor differences, depending on the organ tissue, fungal species, and laboratory. Correct species identification was possible for 100% (30 cuts), 98% (10 cuts), and 93% (1 cut) of the cases. With the protocol used in the present study, the interlaboratory reproducibility of ITS sequencing for the identification of major Zygomycetes species from formalin-fixed paraffin-embedded tissues can reach 100%, when enough material is available.

Ophtalmologie. Thérapie génique des rétinopathies héréditaires: premiers résultats [Gene therapy for hereditary eye diseases: where are we?]

Les résultats préliminaires de trois essais cliniques de thérapie génique d'une forme agressive de rétinite pigmentaire (l'amaurose congénitale de Leber) ont prouvé que le traitement des maladies dégénératives de la rétine par transfert de gène peut être sûr et efficace pour rétablir une fonction visuelle. Il faudra encore attendre les résultats à long terme de ces études pour que soit définitivement validée cette approche thérapeutique. Dans l'intervalle, il importe de se préparer à son introduction en ophtalmologie de façon à la rendre accessible à nos malades. Pratiquement cela revient à promouvoir: 1) le recrutement; 2) la caractérisation du phénotype et du génotype des sujets atteints et 3) la constitution d'un registre des rétinopathies héréditaires. Recently, preliminary results of three clinical gene therapy trials for early onset retinitis pigmentosa--Leber congenital amaurosis--suggested that treating this degenerative retinal disease by gene transfection can be safe and efficient to restore a visual function. The definitive validation of this therapeutic approach depends on the long-term results. The forthcoming availability of gene therapy in ophthalmology prompts the implementation: of 1) recruitment, 2) phenotyping and genotyping of affected patients, 3) and creation of a hereditary retinopathy registry.

The effect of ethanol on fat storage in healthy subjects.

BACKGROUND: Ethanol can account for up to 10 percent of the energy intake of persons who consume moderate amounts of ethanol. Its effect on energy metabolism, however, is not known. METHODS: We studied the effect of ethanol on 24-hour substrate-oxidation rates in eight normal men during two 48-hour sessions in an indirect-calorimetry chamber. In each session, the first 24 hours served as the control period. On the second day of one session, an additional 25 percent of the total energy requirement was added as ethanol (mean [+/- SD], 96 +/- 4 g per day); during the other session, 25 percent of the total energy requirement was replaced by ethanol, which was isocalorically substituted for lipids and carbohydrates. RESULTS: Both the addition of ethanol and the isocaloric substitution of ethanol for other foods reduced 24-hour lipid oxidation. The respective mean (+/- SE) decreases were 49.4 +/- 6.7 and 44.1 +/- 9.3 g per day (i.e., reductions of 36 +/- 3 percent and 31 +/- 7 percent from the oxidation rate during the control day; P less than 0.001 and P less than 0.0025). This effect occurred only during the daytime period (8:30 a.m. to 11:30 p.m.), when ethanol was consumed and metabolized. Neither the addition of ethanol to the diet nor the isocaloric substitution of ethanol for other foods significantly altered the oxidation of carbohydrate or protein. Both regimens including ethanol produced an increase in 24-hour energy expenditure (7 +/- 1 percent with the addition of ethanol, P less than 0.001; 4 +/- 1 percent with the substitution of ethanol for other energy sources, P less than 0.025). CONCLUSIONS: Ethanol, either added to the diet or substituted for other foods, increases 24-hour energy expenditure and decreases lipid oxidation. Habitual consumption of ethanol in excess of energy needs probably favors lipid storage and weight gain.

Les hépatopathies auto-immunes et leurs traitements [Auto-immune liver diseases and their treatment]

There are three main types of auto-immune liver disease, auto-immune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. In the case of auto-immune hepatitis, prednisone therapy, with or without azathioprine, can improve quality of life and halt progression to cirrhosis. If there is no response or if the therapy is poorly tolerated, mycophenolate mofetil or cyclosporin should be considered. Ursodeoxycholic acid (UDCA), at a dosage of 13 to 15 mg/kg/day slows the progression of fibrosis in patients with primary biliary cirrhosis. Pruritus may be treated with cholestyramine, rifampicin or opiate antagonists. Ursodeoxycholic acid at a dosage of 20 to 30 mg/kg/day will slow the evolution of fibrosis.

Circulating soluble CR1 (CD35). Serum levels in diseases and evidence for its release by human leukocytes.

C receptor type 1 (CR1, CD35) is present in a soluble form in plasma (sCR1). Soluble CR1 was measured with a specific ELISA assay in normal individuals and in patients with different diseases. The mean serum concentration of sCR1 in 31 normal donors was 31.4 +/- 7.8 ng/ml, and was identical in plasma. An increase in sCR1 was observed in 36 patients with end-stage renal failure on dialysis (54.8 +/- 11.7 ng/ml, p &lt; 0.0001), and in 22 patients with liver cirrhosis (158.3 +/- 49.9 ng/ml, p &lt; 0.0001). The mean sCR1 levels dropped from 181 +/- 62.7 to 52.1 +/- 24.0 ng/ml (p &lt; 0.001) in nine patients who underwent liver transplantation, and was 33.5 +/- 7.3 in 10 patients with functioning renal grafts, indicating that the increase in sCR1 was reversible. Soluble CR1 was elevated in some hematologic malignancies (&gt; 47 ng/ml), which included B cell lymphoma (12/19 patients), Hodgkin's lymphoma (4/4), and chronic myeloproliferative syndromes (4/5). By contrast, no increase was observed in acute myeloid or lymphoblastic leukemia (10) or myeloma (5). In two patients with chronic myeloproliferative syndromes, sCR1 decreased rapidly after chemotherapy. The mean concentration of sCR1 was not significantly modified in 181 HIV-infected patients at various stages of the disease (34.8 +/- 14.4 ng/ml), and in 13 patients with active SLE (38.3 +/- 19.6 ng/ml), although in both groups the number of CR1 was diminished on E. There was a weak but significant correlation between sCR1 and CR1 per E in HIV infection and SLE (r = 0.39, p &lt; 0.0001, and r = 0.60, p &lt; 0.03 respectively). In vitro, monocytes, lymphocytes, and neutrophils were found to release sCR1 into culture supernatants. In vivo, sCR1 was detected in the serum of SCID mice populated with human peripheral blood leukocytes. The sCR1 levels correlated with those of human IgG (r = 0.97, p &lt; 0.0001), suggesting synthesis of sCR1 by the transferred lymphocytes. The mechanisms underlining the increased levels of sCR1 and its biologic consequences remain to be defined.