Tomographic imaging by coding and reconstruction

We present the various researches we made on tomographic imaging by coding and reconstruction . These works are based on two chief kinds of methods : Coding Aperture Imaging and Transaxial Tomography, each of them including theoretical studies and realization of tomographic systems for definite applications . In this paper, we mainly present the more recent studies concerning reconstruction problems from missing data, with development of an original method by "constrained natural pixels", and implementation of multislit coding in micro-imaging of laser plasmas .Nous présentons les divers travaux que nous avons réalisés sur l'imagerie tomographique par codage et reconstruction . Ces travaux sont axés sur deux grands types de méthodes : l'Imagerie par Ouverture de Codage et la Tomographie Axiale Transverse, et comprennent, pour chacune d'elles, des études théoriques et la conception de systèmes tomographiques pour des applications bien précises . Dans cet article, nous présentons essentiellement les études les plus récentes qui concernent les problèmes de reconstruction à données incomplètes, avec le développement d'une méthode originale par «pixels naturels avec contrainte», et la mise en ceuvre d'un codage par multifentes en micro-imagerie de plasmas laser

Novel STAT1 Alleles in Otherwise Healthy Patients with Mycobacterial Disease

The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)–induced gamma-activating factor–mediated immunity and interferon alpha (IFNA)–induced interferon-stimulated genes factor 3–mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor–mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3–mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding

STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis

We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency

DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice

As shown by analysis of mice and humans bearing DOCK8-inactivating mutations, DOCK8 plays a cell-autonomous role in survival of naive CD8 T cells, LFA-1 polarization toward the immune synapse, and CD8 T cell memory and recall responses following viral infection

Multiparameter Phospho-Flow Analysis of Lymphocytes in Early Rheumatoid Arthritis: Implications for Diagnosis and Monitoring Drug Therapy

The precise mechanisms involved in the initiation and progression of rheumatoid arthritis (RA) are not known. Early stages of RA often have non-specific symptoms, delaying diagnosis and therapy. Additionally, there are currently no established means to predict clinical responsiveness to therapy. Immune cell activation is a critical component therefore we examined the cellular activation of peripheral blood mononuclear cells (PBMCs) in the early stages of RA, in order to develop a novel diagnostic modality.PBMCs were isolated from individuals diagnosed with early RA (ERA) (n = 38), longstanding RA (n = 10), osteoarthritis (OA) (n = 19) and from healthy individuals (n = 10). PBMCs were examined for activation of 15 signaling effectors, using phosphorylation status as a measure of activation in immunophenotyped cells, by flow cytometry (phospho-flow). CD3+CD4+, CD3+CD8+ and CD20+ cells isolated from patients with ERA, RA and OA exhibited activation of multiple phospho-epitopes. ERA patient PBMCs showed a bias towards phosphorylation-activation in the CD4+ and CD20+ compartments compared to OA PBMCs, where phospho-activation was primarily observed in CD8+ cells. The ratio of phospho (p)-AKT/p-p38 was significantly elevated in patients with ERA and may have diagnostic potential. The mean fluorescent intensity (MFI) levels for p-AKT and p-H3 in CD4+, CD8+ and CD20+ T cells correlated directly with physician global assessment scores (MDGA) and DAS (disease activity score). Stratification by medications revealed that patients receiving leflunomide, systemic steroids or anti-TNF therapy had significant reductions in phospho-specific activation compared with patients not receiving these therapies. Correlative trends between medication-associated reductions in the levels of phosphorylation of specific signaling effectors and lower disease activity were observed.Phospho-flow analysis identified phosphorylation-activation of specific signaling effectors in the PB from patients with ERA. Notably, phosphorylation of these signaling effectors did not distinguish ERA from late RA, suggesting that the activation status of discrete cell populations is already established early in disease. However, when the ratio of MFI values for p-AKT and p-p38 is >1.5, there is a high likelihood of having a diagnosis of RA. Our results suggest that longitudinal sampling of patients undergoing therapy may result in phospho-signatures that are predictive of drug responsiveness

IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

Attending to warning signs of primary immunodeficiencies disease across the range of clinical practices

Purpose: Patients with primary immunodeficiency diseases (PIDD) may present with recurrent infections affecting different organs, organ-specific inflammation/autoimmunity, and also increased cancer risk, particularly hematopoietic malignancies. The diversity of PIDD and the wide age range over which these clinical occurrences become apparent often make the identification of patients difficult for physicians other than immunologists. The aim of this report is to develop a tool for educative programs targeted to specialists and applied by clinical immunologists. Methods: Considering the data from national surveys and clinical reports of experiences with specific PIDD patients, an evidence-based list of symptoms, signs, and corresponding laboratory tests were elaborated to help physicians other than immunologists look for PIDD. Results: Tables including main clinical manifestations, restricted immunological evaluation, and possible related diagnosis were organized for general practitioners and 5 specialties. Tables include information on specific warning signs of PIDD for pulmonologists, gastroenterologists, dermatologists, hematologists, and infectious disease specialists. Conclusions: This report provides clinical immunologists with an instrument they can use to introduce specialists in other areas of medicine to the warning signs of PIDD and increase early diagnosis. Educational programs should be developed attending the needs of each specialty.Fil: Costa Carvalho, Beatriz Tavares. Universidade Federal de São Paulo; BrasilFil: Sevciovic Grumach, Anete. Fundação ABC. Faculdade de Medicina; BrasilFil: Franco, José Luis. Universidad de Antioquia; ColombiaFil: Espinosa Rosales, Francisco Javier. Instituto Nacional de Pediatría. Unidad de Investigación en Inmunodeficiencias; MéxicoFil: Leiva, Lily E.. State University of Louisiana; Estados UnidosFil: King, Alejandra. Hospital de Niños Doctor Luis Calvo Mackenna. Unidad de Inmunología; ChileFil: Porras, Oscar. Hospital Nacional de Niños “Dr. Carlos Sáenz Herrera”; Costa RicaFil: Bezrodnik, Liliana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Oleastro, Mathias. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sorensen, Ricardo U.. State University of Louisiana; Estados Unidos. Universidad de La Frontera. Facultad de Medicina; MéxicoFil: Condino Neto, Antonio. Universidade de Sao Paulo; Brasi

The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61 %). Out of 39 familial cases from 11 families, 26 patients (67 %) from 9 families and out of 18 sporadic cases, 9 patients (50 %) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing