A homozygous contiguous gene deletion in chromosome 16p13.3 leads to autosomal recessive osteopetrosis in a Jordanian patient

Human malignant autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. Mutations in the CLCN7 gene are responsible not only for a substantial portion of ARO patients, but also for other forms of osteopetrosis characterized by different severity and inheritance. The lack of a clear genotype/phenotype correlation makes genetic counselling a tricky issue for CLCN7-dependent osteopetrosis. Here we characterize the first homozygous interstitial deletion in 16p13.3, detected by array Comparative Genomic Hybridization (a-CGH) in an ARO patient of Jordanian origin. The deletion involved other genes beside CLCN7, while the proband displayed a classic ARO phenotype; however her early death did not allow more extensive clinical investigations. The identification of this novel genomic deletion involving a large part of the CLCN7 gene is of clinical relevance, especially in prenatal diagnosis, and suggests the possibility that this kind of mutation has been underestimated so far. This data highlights the need for alternative approaches to genetic analysis also in other ARO-causative genes

International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide

Transplacental Passage of Interleukins 4 and 13?

The mechanisms by which prenatal events affect development of adult disease are incompletely characterized. Based on findings in a murine model of maternal transmission of asthma risk, we sought to test the role of the pro-asthmatic cytokines interleukin IL-4 and -13. To assess transplacental passage of functional cytokines, we assayed phosphorylation of STAT-6, a marker of IL-4 and -13 signaling via heterodimeric receptor complexes which require an IL-4 receptor alpha subunit. IL-4 receptor alpha−/− females were mated to wild-type males, and pregnant females were injected with supraphysiologic doses of IL-4 or 13. One hour after injection, the receptor heterozygotic embryos were harvested and tissue nuclear proteins extracts assayed for phosphorylation of STAT-6 by Western blot. While direct injection of embryos produced a robust positive control, no phosphorylation was seen after maternal injection with either IL-4 or -13, indicating that neither crossed the placenta in detectable amounts. The data demonstrate a useful approach to assay for transplacental passage of functional maternal molecules, and indicate that molecules other than IL-4 and IL-13 may mediate transplacental effects in maternal transmission of asthma risk

Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome

Background: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS). Objective: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified. Methods: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2R229Q/R229Q (Rag2R229Q) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt. Results: We show that memory/activated T cells from patients with OS and from the Rag2R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad TH1/TH2/TH17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2R229Q mice results in increased frequency of Ccr4+ splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by TH1 effector T cells. Conclusions: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS

Predictors of linkage to care following community-based HIV counseling and testing in rural Kenya

Despite innovations in HIV counseling and testing (HCT), important gaps remain in understanding linkage to care. We followed a cohort diagnosed with HIV through a community-based HCT campaign that trained persons living with HIV/AIDS (PLHA) as navigators. Individual, interpersonal, and institutional predictors of linkage were assessed using survival analysis of self-reported time to enrollment. Of 483 persons consenting to follow-up, 305 (63.2%) enrolled in HIV care within 3 months. Proportions linking to care were similar across sexes, barring a sub-sample of men aged 18–25 years who were highly unlikely to enroll. Men were more likely to enroll if they had disclosed to their spouse, and women if they had disclosed to family. Women who anticipated violence or relationship breakup were less likely to link to care. Enrolment rates were significantly higher among participants receiving a PLHA visit, suggesting that a navigator approach may improve linkage from community-based HCT campaigns.Vestergaard Frandse

Symptoms and management of cow's milk allergy: perception and evidence

IntroductionThe diagnosis and management of cow's milk allergy (CMA) is a topic of debate and controversy. Our aim was to compare the opinions of expert groups from the Middle East (n = 14) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (n = 13).MethodsThese Expert groups voted on statements that were developed by the ESPGHAN group and published in a recent position paper. The voting outcome was compared.ResultsOverall, there was consensus amongst both groups of experts. Experts agreed that symptoms of crying, irritability and colic, as single manifestation, are not suggestive of CMA. They agreed that amino-acid based formula (AAF) should be reserved for severe cases (e.g., malnutrition and anaphylaxis) and that there is insufficient evidence to recommend a step-down approach. There was no unanimous consensus on the statement that a cow's milk based extensively hydrolysed formula (eHF) should be the first choice as a diagnostic elimination diet in mild/moderate cases. Although the statements regarding the role for hydrolysed rice formula as a diagnostic and therapeutic elimination diet were accepted, 3/27 disagreed. The votes regarding soy formula highlight the differences in opinion in the role of soy protein in CMA dietary treatment. Generally, soy-based formula is seldom available in the Middle-East region. All ESPGHAN experts agreed that there is insufficient evidence that the addition of probiotics, prebiotics and synbiotics increase the efficacy of elimination diets regarding CMA symptoms (despite other benefits such as decrease of infections and antibiotic intake), whereas 3/14 of the Middle East group thought there was sufficient evidence.DiscussionDifferences in voting are related to geographical, cultural and other conditions, such as cost and availability. This emphasizes the need to develop region-specific guidelines considering social and cultural conditions, and to perform further research in this area

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content.

Mutations of the recombinase Activating Genes 1 and 2 (RAG1, RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment, however high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- NK cells have a mature phenotype, reduced fitness and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT

Controlo químico de infestantes

Uma planta é considerada infestante quando nasce espontaneamente num local e momento indesejados, podendo interferir negativamente com a cultura instalada. As infestantes competem com as culturas para o espaço, a luz, água e nutrientes, podendo atrasar e prejudicar as operações de colheita, depreciar o produto final e assegurarem a reinfestação nas culturas seguintes. Dado o modo de propagação diferenciado das diversas espécies de infestantes, com as anuais a propagarem-se por semente e as perenes ou vivazes a assegurarem a sua propagação através de órgãos vegetativos (rizomas, bolbos, tubérculos, etc.), assim, também o seu controlo quer químico, quer mecânico terá que ser diferenciado, ou seja, para controlar infestantes anuais será suficiente destruir a sua parte aérea, enquanto para controlar infestantes perenes teremos que destruir os seus órgãos reprodutivos. O controlo de infestantes poderá ser químico, através da utilização de herbicidas, ou mecânico pela utilização de alfaias agrícolas, tais como a charrua de aivecas, a charrua de discos, a grade de discos, o escarificador e a fresa. Quando a técnica utilizada na instalação das culturas é a sementeira directa, o controlo das infestantes terá que ser obrigatoriamente químico, enquanto se o recurso à mobilização do solo for a técnica mais utilizada (sistema de mobilização tradicional ou sistema de mobilização reduzida), o controlo das infestantes tanto poderá ser químico como mecânico. Neste trabalho iremos abordar apenas, o controlo químico de infestantes

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