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Sample records for primary immunodeficiencies pid

  1. Primary immunodeficiencies (PIDs) presenting with cytopenias.

    PubMed

    Notarangelo, Luigi D

    2009-01-01

    Autoimmune manifestations are increasingly being recognized as a component of several forms of primary immunodeficiencies (PID). Defects in purging of self-reactive T and B cells, impaired Fas-mediated apoptosis, abnormalities in development and/or function of regulatory T cells, and persistence of immune activation as a result of inability to clear infections have been shown to account for this association. Among autoimmune manifestations in patients with PID, cytopenias are particularly common. Up to 80% of patients with autoimmune lymphoproliferative syndrome (ALPS) have autoantibodies, and autoimmune hemolytic anemia and immune thrombocytopenia have been reported in 23% and 51% of ALPS patients, and may even mark the onset of the disease. ALPS-associated cytopenias are often refractory to conventional treatment and represent a therapeutic challenge. Autoimmune manifestations occur in 22% to 48% of patients with common variable immunodeficiencies (CVIDs), and are more frequent among CVID patients with splenomegaly and granulomatous disease. Finally, autoimmune cytopenias have been reported also in patients with combined immunodeficiency. In particular, autoimmune hemolytic anemia is very common among infants with nucleoside phosphorylase deficiency. While immune suppression may be beneficial in these cases, full resolution of the autoimmune manifestations ultimately depends on immune reconstitution, which is typically provided by hematopoietic cell transplantation.

  2. Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs).

    PubMed

    Lee, Wen-I; Huang, Jing-Long; Yeh, Kuo-Wei; Jaing, Tang-Her; Lin, Tzou-Yien; Huang, Yhu-Chering; Chiu, Cheng-Hsun

    2011-12-01

    Natural human immunity to the mycobacteria group, including Mycobacterium tuberculosis, Bacille Calmette-Guérin (BCG) or nontuberculous mycobacteria (NTM), and/or Salmonella species, relies on the functional IL-12/23-IFN-γ integrity of macrophages (monocyte/dendritic cell) connecting to T lymphocyte/NK cells. Patients with severe forms of primary immunodeficiency diseases (PIDs) have more profound immune defects involving this impaired circuit in patients with severe combined immunodeficiencies (SCID) including complete DiGeorge syndrome, X-linked hyper IgM syndrome (HIGM) (CD40L mutation), CD40 deficiency, immunodeficiency with or without anhidrotic ectodermal dysplasia (NEMO and IKBA mutations), chronic granulomatous disease (CGD) and hyper IgE recurrent infection syndromes (HIES). The patients with severe PIDs have broader diverse infections rather than mycobacterial infections. In contrast, patients with an isolated inborn error of the IL-12/23-IFN-γ pathway are exclusively prone to low-virulence mycobacterial infections and nontyphoid salmonella infections, known as Mendelian susceptibility to the mycobacterial disease (MSMD) phenotype. Restricted defective molecules in the circuit, including IFN-γR1, IFN-γR2, IL-12p40, IL-12R-β1, STAT-1, NEMO, IKBA and the recently discovered CYBB responsible for autophagocytic vacuole and proteolysis, and interferon regulatory factor 8 (IRF8) for dendritic cell immunodeficiency, have been identified in around 60% of patients with the MSMD phenotype. Among all of the patients with PIDs referred for investigation since 1985, we have identified four cases with the specific defect (IFNRG1 for three and IL12RB for one), presenting as both BCG-induced diseases and NTM infections, in addition to some patients with SCID, HIGM, CGD and HIES. Furthermore, manifestations in patients with autoantibodies to IFN-γ (autoAbs-IFN-γ), which is categorized as an anticytokine autoantibody syndrome, can resemble the relatively persistent

  3. Primary immunodeficiencies: 2009 update

    PubMed Central

    Notarangelo, Luigi D.; Fischer, Alain; Geha, Raif. S.; Casanova, Jean-Laurent; Chapel, Helen; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Hammartröm, Lennart; Nonoyama, Shigeaki; Ochs, Hans D.; Puck, Jennifer; Roifman, Chaim; Seger, Reinhard; Wedgwood, Josiah

    2009-01-01

    More than 50 years after Ogdeon Bruton’s discovery of congenital agammaglobulinemia, human primary immunodeficiencies (PIDs) continue to unravel novel molecular and cellular mechanisms that govern development and function of the human immune system. This report provides the updated classification of PIDs, that has been compiled by the International Union of Immunological Societies (IUIS) Expert Committee of Primary Immunodeficiencies after its biannual meeting, in Dublin (Ireland) in June 2009. Since the appearance of the last classification in 2007, novel forms of PID have been discovered, and additional pathophysiology mechanisms that account for PID in humans have been unraveled. Careful analysis and prompt recognition of these disorders is essential to prompt effective forms of treatment and thus to improve survival and quality of life in patients affected with PIDs. PMID:20004777

  4. [Basics of primary immunodeficiencies].

    PubMed

    Hernández-Martínez, Claudia; Espinosa-Rosales, Francisco; Espinosa-Padilla, Sara Elva; Hernández-Martínez, Ana Rosa; Blancas-Galicia, Lizbeth

    2016-01-01

    Primary immunodeficiencies (PID) are a heterogeneous group of inherited disorders, the etiology are the defects in the development or function of the immune system. The principal PID manifestations are the infections in early age, malignancy and diseases of immune dysregulation as autoimmunity and allergy. PIDs are genetics disorders and most of them are inherited as autosomal recessive, also this group of diseases is more prevalent in males and in childhood. The antibody immunodeficiency is the PID more common in adults. The more frequent disorders are the infections in the respiratory tract, abscesses, candidiasis, diarrhea, BCGosis etc. Initial approach included a complete blood count and quantification of immunoglobulins. The delay in diagnosis could be explained due to a perception that the recurrent infections are normal process or think that they are exclusively of childhood. The early diagnosis of PID by primary care physicians is important to opportune treatment and better prognosis.

  5. Current Perspectives on Primary Immunodeficiency Diseases

    PubMed Central

    Kumar, Arvind; Teuber, Suzanne S.; Gershwin, M. Eric

    2006-01-01

    Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis. PMID:17162365

  6. PID comes full circle: applications of V(D)J recombination excision circles in research, diagnostics and newborn screening of primary immunodeficiency disorders.

    PubMed

    van Zelm, Menno C; van der Burg, Mirjam; Langerak, Anton W; van Dongen, Jacques J M

    2011-01-01

    The vast majority of patients suffering from a primary immunodeficiency (PID) have defects in their T- and/or B-cell compartments. Despite advances in molecular diagnostics, in many patients no underlying genetic defect has been identified. B- and T-lymphocytes are unique in their ability to create a receptor by genomic rearrangement of their antigen receptor genes via V(D)J recombination. During this process, stable circular excision products are formed that do not replicate when the cell proliferates. Excision circles can be reliably quantified using real-time quantitative (RQ-)PCR techniques. Frequently occurring δREC-ψJα T-cell receptor excision circles (TRECs) have been used to assess thymic output and intronRSS-Kde recombination excision circles (KREC) to quantify B-cell replication history. In this perspective, we describe how TRECs and KRECs are formed during precursor - T- and B-cell differentiation, respectively. Furthermore, we discuss new insights obtained with TRECs and KRECs and specifically how these excision circles can be applied to support therapy monitoring, patient classification and newborn screening of PID.

  7. History of Primary Immunodeficiency Diseases in Iran

    PubMed Central

    Aghamohammadi, Asghar; Moin, Mostafa; Rezaei, Nima

    2010-01-01

    Pediatric immunology came into sight in the second half of 20th century, when pediatricians and basic immunologists began to give attention to diagnosis and treatment of children with primary immunodeficiency diseases (PIDs). Understanding the genetic and mechanistic basis of PIDs provides unique insight into the functioning of the immune system. By progress in basic and clinical immunology, many infrastructural organizations and academic centers have been established in many countries worldwide to focus on training and research on the immune system and related disorders. Along with progress in basic and clinical immunology in the world, pediatric immunology had a good progress in Iran during the last 33-year period. Now, patients with PIDs can benefit from multidisciplinary comprehensive care, which is provided by clinical immunologists in collaboration with other specialists. Patients with history of recurrent and/or chronic infections suggestive of PIDs are evaluated by standard and research-based testing and receive appropriate treatment. The progress in PIDs can be described in three periods. Development of training program for clinical fellowship in allergy and immunology, multidisciplinary and international collaborative projects, primary immunodeficiency diseases textbooks, meetings on immunodeficiency disorders, improvement in diagnosis and treatment, and construction of Iranian primary immunodeficiency association, Students' research group for immunodeficiencies, Iranian primary immunodeficiency registry, and the immunological societies and centers were the main activities on PIDs during these years. In this article, we review the growth of modern pediatric immunology and PIDs status in Iran. PMID:23056678

  8. Primary immunodeficiencies associated with eosinophilia.

    PubMed

    Navabi, Behdad; Upton, Julia Elizabeth Mainwaring

    2016-01-01

    Eosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia. A retrospective PubMed, and Google Scholar search using the terms "eosinophilia" and "every individual PID" as classified by Expert Committee of the International Union of Immunological Societies with the limit of the English language was performed. Results were assessed to capture case(s) which reported eosinophilia in the context of PID conditions. Absolute eosinophil counts (AEC) were retrieved from manuscripts whenever reported. In addition to the typical PID conditions described with eosinophilia, we document that MHC class II deficiency, CD3γ deficiency, STAT1 deficiency (AD form), Kostmann disease, cyclic neutropenia, TCRα deficiency, Papillon-Lefevre syndrome, CD40 deficiency, CD40L deficiency, anhidrotic ectodermal dysplasia with immune deficiency, ataxia-telangiectasia, common variable immunodeficiency disorders (CVID), Blau syndrome, CARD9 deficiency, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA), chronic granulomatous disease, MALT1 deficiency and Roifman syndrome have been noted to have elevated eosinophils. Severe eosinophilia (>5.0 × 10(9)/L) was reported in Omenn syndrome, Wiskott Aldrich syndrome, ADA deficiency, autoimmune lymphoproliferative syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked, STAT3

  9. Attentiveness of pediatricians to primary immunodeficiency disorders

    PubMed Central

    2012-01-01

    Background Primary immunodeficiency (PID) is a cluster of serious disorders that requires special alertness on the part of the medical staff for prompt diagnosis and management of the patient. This study explored PID knowledge and experience among pediatricians of wide educational backgrounds, practicing in the United Arab Emirates (UAE). Method A self-administered questionnaire was used to determine the competency of pediatricians in their knowledge of PID disorders. This study questionnaire included questions on PID signs and symptoms, syndromes associated with immunodeficiency, screening tests, interpreting laboratory tests and case management. The participants were 263 pediatricians of diverse education working in the 27 governmental hospitals in all regions of UAE. Results The overall performance of the pediatricians did not differ based on their age, gender, origin of certification, rank, or years of experience. Of the 50 questions, 20% of pediatricians answered correctly <60% of the questions, 76% answered correctly 60 to 79% of the questions, and 4% answered correctly ≥80% of the questions. Seventeen of the 19 PID signs and symptoms were identified by 55 to 97%. Four of 5 syndromes associated with immunodeficiency were identified by 50 to 90%. Appropriate screening tests were chosen by 64 to 96%. Attention to the laboratory reference range values as function of patient age was notably limited. Conclusions There was a noteworthy deficiency in PID work-up. Therefore, implementing effective educational strategies is needed to improve the competency of pediatricians to diagnose and manage PID disorders. PMID:22846098

  10. [Innate immunity primary immunodeficiencies and infections].

    PubMed

    Duchamp, M; Miot, C; Bustamante, J C; Picard, C

    2016-07-01

    The diagnosis of primary immunodeficiency diseases (PIDs) is important for the early and adaptive care of patients and their families. Among the various known PIDs, a number of them concern the innate immune system, which involve a set of cells and mechanisms involved in the host defense by a nonspecific and fast response. The majority of patients with innate immunity defects have a predisposition to one isolated type of infection (bacterial, viral, or fungal), dependent on the genetic defect involved. This article describes the different PIDs involving innate immunity and the immunological investigations allowing for their diagnosis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  11. Family Physician Perspectives on Primary Immunodeficiency Diseases

    PubMed Central

    Orange, Jordan S.; Seeborg, Filiz O.; Boyle, Marcia; Scalchunes, Christopher; Hernandez-Trujillo, Vivian

    2016-01-01

    Primary immunodeficiency diseases (PIDs) include over 250 diverse disorders. The current study assessed management of PID by family practice physicians. The American Academy of Allergy, Asthma, and Immunology Primary Immunodeficiency Committee and the Immune Deficiency Foundation conducted an incentivized mail survey of family practice physician members of the American Medical Association and the American Osteopathic Association in direct patient care. Responses were compared with subspecialist immunologist responses from a similar survey. Surveys were returned by 528 (of 4500 surveys mailed) family practice physicians, of whom 44% reported following ≥1 patient with PID. Selective immunoglobulin A deficiency (21%) and chronic granulomatous disease (11%) were most common and were followed by significantly more subspecialist immunologists (P < 0.05). Use of intravenously administered immunoglobulin and live viral vaccinations across PID was significantly different (P < 0.05). Few family practice physicians were aware of professional guidelines for diagnosis and management of PID (4 vs. 79% of subspecialist immunologists, P < 0.05). Family practice physicians will likely encounter patients with PID diagnoses during their career. Differences in how family practice physicians and subspecialist immunologists manage patients with PID underscore areas where improved educational and training initiatives may benefit patient care. PMID:27066486

  12. Gene Therapy for Primary Immunodeficiencies

    PubMed Central

    Rivat, Christine; Santilli, Giorgia; Gaspar, H. Bobby

    2012-01-01

    Abstract For over 40 years, primary immunodeficiencies (PIDs) have featured prominently in the development and refinement of human allogeneic hematopoietic stem cell transplantation. More recently, ex vivo somatic gene therapy using autologous cells has provided remarkable evidence of clinical efficacy in patients without HLA-matched stem cell donors and in whom toxicity of allogeneic procedures is likely to be high. Together with improved preclinical models, a wealth of information has accumulated that has allowed development of safer, more sophisticated technologies and protocols that are applicable to a much broader range of diseases. In this review we summarize the status of these gene therapy trials and discuss the emerging application of similar strategies to other PIDs. PMID:22691036

  13. Skin manifestations in primary immunodeficient children.

    PubMed

    Al-Herz, Waleed; Nanda, Arti

    2011-01-01

    Skin manifestations are prevalent in primary immunodeficiency disorders (PID). In a large proportion of patients, they manifest as presenting signs and serve as important factors for the early diagnosis of PID. Only a few studies describing the spectrum of skin disorders in PID are available. The objective of the current study was to determine the prevalence and characteristics of skin manifestations in children with PID. Participants were 128 pediatric patients with PID (aged <16 years) registered prospectively over 6 years. Skin manifestations were observed in 61 patients (48%), and those manifestations were the presenting features in 50 (39% of total PID and 82% of those with skin lesions). Skin infections were the most prevalent manifestations, seen in 39 patients (30%), followed by eczemas in 24 (19%). Skin infections were significantly more prevalent in those with congenital defects in phagocyte number, function, or both, as well as in those with well-defined immunodeficiencies. Although widely present in all participants with PID, eczema was a consistent feature (100%) in patients with hyper IgE syndrome and Wiskott-Aldrich syndrome (WAS). Erythroderma of infancy with diffuse alopecia was seen exclusively in patients with severe combined immunodeficiency disorders, telangiectasia in patients with ataxia telangiectasia, and partial albinism with silvery gray hair in those with Chediak-Higashi syndrome. Autoimmune skin manifestations were observed in 6% of reported cases of PID. This study highlights the importance of awareness of skin manifestations of PID to assist in the early diagnosis and management of these disorders. © 2011 Wiley Periodicals, Inc.

  14. Primary Immunodeficiencies: “New” Disease in an Old Country

    PubMed Central

    Lee, Pamela P W; Lau, Yu-Lung

    2009-01-01

    Primary immunodeficiency disorders (PIDs) are rare inborn errors of the immune system. Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying infections, autoimmunity, lymphoproliferation, allergy and cancer. Over 150 PID syndromes were characterized in the past 60 years, with an ever growing list of new entities being discovered. Because of their rarity, multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights into the phenotypic and genetic diversities of PIDs. In this article, we summarize our research findings on PIDs in Chinese population in the past 20 years. Close collaboration among various immunology centers, cross-referrals and systematic data analysis constitute the foundation for research on PIDs. Future directions include establishment of a national PID registry, raising awareness of PIDs and securing sufficient resources for patient care and scientific research. PMID:20003815

  15. Prevalence of primary immunodeficiency in Korea.

    PubMed

    Rhim, Jung Woo; Kim, Kyung Hyo; Kim, Dong Soo; Kim, Bong Seong; Kim, Jung Soo; Kim, Chang Hwi; Kim, Hwang Min; Park, Hee Ju; Pai, Ki Soo; Son, Byong Kwan; Shin, Kyung Sue; Oh, Moo Young; Woo, Young Jong; Yoo, Young; Lee, Kun Soo; Lee, Kyung Yil; Lee, Chong Guk; Lee, Joon Sung; Chung, Eun Hee; Choi, Eun Hwa; Hahn, Youn Soo; Park, Hyun Young; Kim, Joong Gon

    2012-07-01

    This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

  16. Primary immunodeficiency update I: Syndromes associated with eczematous dermatitis

    PubMed Central

    Pichard, Dominique C.; Freeman, Alexandra F.; Cowen, Edward W.

    2015-01-01

    In the past decade, the availability of powerful molecular techniques has accelerated the pace of discovery of several new primary immunodeficiencies (PID) and revealed the biologic basis of other established PID. These genetic advances, in turn, have facilitated more precise phenotyping of associated skin and systemic manifestations and provide a unique opportunity to better understand the complex human immunologic response. These continuing medical education articles will provide an update of recent advances about PID that may be encountered by dermatologists through their association with eczematous dermatitis, infectious, and non-infectious cutaneous manifestations. Part I will discuss new primary immunodeficiencies that have an eczematous dermatitis. Part II will focus on primary immunodeficiencies that greatly increase susceptibility to fungal infection and the noninfectious presentations of PID. PMID:26282794

  17. Thirty years of primary immunodeficiencies in Turkey.

    PubMed

    Sanal, Ozden; Tezcan, Ilhan

    2011-11-01

    Turkey, with its population of some 75 million, has a high rate of consanguineous marriages. Because the majority of the primary immunodeficiencies (PIDs) are inherited as autosomal recessive (AR) forms, the high consanguinity rate leads to a high prevalence of PID diseases in Turkey. The first pediatric immunology division was established in 1972, since then over 10 other immunology divisions have been established in different cities. Approximately 4,000 patients with possible PID are referred to these centers annually. The percentages of some of the major immunodeficiency groups and individual disease numbers among these patients differ somewhat in comparison with Western countries, likely because the relative incidences of PIDs with AR inheritance and of rare diseases are higher. These characteristics of the patient population, and our determination of differences in disease presentation and unusual features, have led us to undertake studies in collaboration with various centers in Western countries. These collaborations have contributed to the identification of the genes responsible for some rare immunodeficiencies, to the resolution of the genetic heterogeneity underlying conventional phenotypes, and to the description of new clinical phenotypes.

  18. Utility of Next Generation Sequencing in Clinical Primary Immunodeficiencies

    PubMed Central

    Raje, Nikita; Soden, Sarah; Swanson, Douglas; Ciaccio, Christina E.; Kingsmore, Stephen F.; Dinwiddie, Darrell L.

    2015-01-01

    Primary immunodeficiencies (PIDs) are a group of genetically heterogeneous disorders that present with very similar symptoms, complicating definitive diagnosis. More than 240 genes have hitherto been associated with PIDs, of which more than 30 have been identified in the last 3 years. Next generation sequencing (NGS) of genomes or exomes of informative families has played a central role in the discovery of novel PID genes. Furthermore, NGS has the potential to transform clinical molecular testing for established PIDs, allowing all PID differential diagnoses to be tested at once, leading to increased diagnostic yield, while decreasing both the time and cost of obtaining a molecular diagnosis. Given that treatment of PID varies by disease gene, early achievement of a molecular diagnosis is likely to enhance treatment decisions and improve patient outcomes. PMID:25149170

  19. Primary immunodeficiency diseases worldwide: more common than generally thought.

    PubMed

    Bousfiha, Ahmed Aziz; Jeddane, Leïla; Ailal, Fatima; Benhsaien, Ibtihal; Mahlaoui, Nizar; Casanova, Jean-Laurent; Abel, Laurent

    2013-01-01

    Primary immunodeficiency diseases (PIDs) comprise at least 176 hereditary disorders that are thought to be individually and collectively rare. The actual prevalence and incidence of PIDs remains unclear, but recent epidemiologic studies have suggested that PIDs are more common than generally thought. Based on these studies, we attempted to estimate the worldwide prevalence and incidence of PIDs. Using data from registries and two recent epidemiologic surveys estimating the frequencies of PIDs, we extrapolated the frequencies reported for certain countries to the populations of continents and of the world. Our upper estimates suggest that six million people may be living with a PID worldwide, whereas only 27,000-60,000 have been identified to date (all national registries and the Jeffrey Modell Centers Network, respectively). For Europe, our upper estimate was 638,000 cases, and 15,052 cases are currently registered (2.27 %). In Africa, up to 902,631 people may have a PID, whereas only 1,016 cases are currently registered. We also found that PIDs were prevalent not only in children, but also in adults, who were strongly underrepresented in registries. Specific, dedicated epidemiologic studies are required, to obtain more realistic statistics for PIDs and to increase the awareness of physicians and public health systems about these diseases. Furthermore, the field of PIDs is continually growing, and this is likely to lead to a revision of the definition of these conditions, potentially increasing estimates of their impact on both adults and children, at the population level.

  20. Primary immunodeficiency in the neonate: Early diagnosis and management.

    PubMed

    Walkovich, Kelly; Connelly, James A

    2016-02-01

    Many primary immunodeficiencies (PIDs) manifest in the neonatal period but can be challenging to diagnose and manage optimally. In part, the difficulty stems from the natural immaturity of the neonatal immune system that may mask immune deficits and/or complicate interpretation of clinical findings and laboratory assays. The great diversity of PIDs--from innate immune system defects to those that impact the humoral and/or cellular components of the adaptive immune system--and the rapid rate at which new PIDs are being discovered makes it challenging for practitioners to stay current. Moreover, recent appreciation for immune deficiencies that lead to autoinflammation and autoimmunity have broadened the spectrum of neonatal PID, adding additional complexity to an already intricate field. This article serves to highlight the deficiencies in the neonatal immune system, while providing a review of the more common PIDs that present in the neonate and guidelines for diagnosis and supportive care.

  1. Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

    PubMed Central

    Al-Herz, Waleed; Bousfiha, Aziz; Casanova, Jean-Laurent; Chatila, Talal; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Franco, Jose Luis; Gaspar, H. Bobby; Holland, Steven M.; Klein, Christoph; Nonoyama, Shigeaki; Ochs, Hans D.; Oksenhendler, Erik; Picard, Capucine; Puck, Jennifer M.; Sullivan, Kate; Tang, Mimi L. K.

    2014-01-01

    We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases. PMID:24795713

  2. Neutropenia in primary immunodeficiency

    PubMed Central

    Sokolic, Robert

    2016-01-01

    Purpose of review Neutropenia is a feature of several primary immunodeficiency diseases (PIDDs). Because of the diverse pathophysiologies of the PIDDs and the rarity of each disorder, data are often lacking, leading to the necessity of empiric treatment. Recent developments in the understanding of neutropenia in several of the PIDDs make a review of the data timely. Recent findings The category of severe congenital neutropenia continues to expand. Mutations in G6PC3 have been identified as the cause of neutropenia in a minority of previously molecularly undefined cases. Recent advances have broadened our understanding of the pathophysiology and the clinical expression of this disorder. A possible function of the C16orf57 gene has been hypothesized that may explain the clinical overlap between Clerucuzio-type poikiloderma with neutropenia and other marrow diseases. Plerixafor has been shown to be a potentially useful treatment in the warts, hypogammaglobulinemia, infection, and myelokathexis syndrome. Investigations of patients with adenosine deaminase deficient severe combined immunodeficiency have identified neutropenia, and particularly susceptibility to myelotoxins, as a feature of this disorder. Granulocyte-colony stimulating factor is the treatment of choice for neutropenia in PIDD, whereas hematopoietic cell transplantation is the only curative option. Summary The number of PIDDs associated with neutropenia has increased, as has our understanding of the range of phenotypes. Additional data and hypotheses have been generated helping to explain the diversity of presentations of neutropenia in PIDDs. PMID:23196894

  3. Evolving Gene Therapy in Primary Immunodeficiency.

    PubMed

    Thrasher, Adrian J; Williams, David A

    2017-05-03

    Prior to the first successful bone marrow transplant in 1968, patients born with severe combined immunodeficiency (SCID) invariably died. Today, with a widening availability of newborn screening, major improvements in the application of allogeneic procedures, and the emergence of successful hematopoietic stem and progenitor cell (HSC/P) gene therapy, the majority of these children can be identified and cured. Here, we trace key steps in the development of clinical gene therapy for SCID and other primary immunodeficiencies (PIDs), and review the prospects for adoption of new targets and technologies. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  4. Frequency and clinical manifestations of patients with primary immunodeficiency disorders in Iran: update from the Iranian Primary Immunodeficiency Registry.

    PubMed

    Rezaei, Nima; Aghamohammadi, Asghar; Moin, Mostafa; Pourpak, Zahra; Movahedi, Masoud; Gharagozlou, Mohammad; Atarod, Lida; Ghazi, Bahram Mirsaeid; Isaeian, Anna; Mahmoudi, Maryam; Abolmaali, Kamran; Mansouri, Davoud; Arshi, Saba; Tarash, Naser Javaher; Sherkat, Roya; Akbari, Hedayat; Amin, Reza; Alborzi, Abdolvahab; Kashef, Sara; Farid, Reza; Mohammadzadeh, Iraj; Shabestari, Mehrnaz Sadeghi; Nabavi, Mohammad; Farhoudi, Abolhassan

    2006-11-01

    Primary immunodeficiency disorders (PID) are a heterogeneous group of diseases, characterized by an increased susceptibility to infections. A total of 930 patients (573 males and 357 females) are registered in Iranian PID Registry (IPIDR) during three decades. Predominantly antibody deficiencies were the most common (38.4%), followed by congenital defects of phagocyte number and/or function (28.3%), other well-defined immunodeficiency syndromes (17.7%), combined T- and B-cell immunodeficiencies (11.0%), complement deficiencies (2.4%), and diseases of immune dysregulation (2.3%). Common variable immunodeficiency was the most frequent disorder (20.8%), followed by chronic granulomatous disease, ataxia-telangiectasia, btk deficiency, selective IgA deficiency, and T-B-severe combined immunodeficiency. The frequency of other PID disorders was less than 50 in number (<5%). There is an increasing trend in recognition of more PID in the recent years. Construction of such registry is not only important for its epidemiological aspect but also for its role in increasing the physician's knowledge about such disorders.

  5. Primary immunodeficiency update II: Syndromes associated with mucocutaneous candidiasis and non-infectious cutaneous manifestations

    PubMed Central

    Pichard, Dominique C.; Freeman, Alexandra F.; Cowen, Edward W.

    2015-01-01

    Several primary immunodeficiencies (PID) have recently been described which confer elevated risk of fungal infections as well as non-infectious cutaneous manifestations. In addition, immunological advances have provided new insights into our understanding of the pathophysiology of fungal infections in established PID. We reviewed PID that present with an eczematous dermatitis in Part I. In Part II, we will discuss updates on PID associated with fungal infections and their biological basis in PID as well as non-infectious cutaneous manifestations. PMID:26282795

  6. Hematopoietic stem cell transplantation for primary immunodeficiency diseases.

    PubMed

    Slatter, Mary A; Cant, Andrew J

    2011-11-01

    Hematopoietic stem cell transplantation (HSCT) is now highly successfully curing a widening range of primary immunodeficiencies (PIDs). Better tissue typing, matching of donors, less toxic chemotherapy, better virus detection and treatment, improved supportive care, and graft-versus-host disease prophylaxis mean up to a 90% cure for severe combined immunodeficiency patients and a 70-80% cure for other PIDs given a matched unrelated donor, and rising to 95% for young patients with specific PIDs, such as Wiskott-Aldrich syndrome. Precise molecular diagnosis, detailed data on prognosis, and careful pre-HSCT assessment of infective lung and liver damage will ensure an informed benefit analysis of HSCT and the best outcome. It is now recognized that the best treatment option for chronic granulomatous disease is HSCT, which can also be curative for CD40 ligand deficiency and complex immune dysregulation disorders.

  7. [Replacement therapy with subcutaneous immunoglobulin in primary immunodeficiency in children].

    PubMed

    Pac, Małgorzata

    2011-06-01

    Primary antibody deficiency (PAD) is the most common form of primary immunodeficiency (PID), and presents up to 60-70% of PID. The hallmark of PAD are low antibody level and recurrent infections. Patients require life-long immunoglobulin replacement therapy. Now they can be treated either with intravenous (IVIG) or subcutaneous (SCIG) immunoglobulin. The last one is indicated in patients with unacceptable adverse reactions to the intravenous immunoglobulin preparations, with poor vein access or willing to improve the quality of their life. Several data and clinical trials proved that SCIG therapy is at least as safe and efficacious as IVIG to prevent infections in patients with PAD.

  8. Adverse events following immunization in patients with primary immunodeficiencies.

    PubMed

    Sarmiento, Juan David; Villada, Fabio; Orrego, Julio Cesar; Franco, Jose Luis; Trujillo-Vargas, Claudia M

    2016-03-18

    Adverse events following immunization (AEFI) requires special consideration in patients with primary immunodeficiency diseases (PID) because they may represent a "red flag" for the initial diagnosis and may cause disease complications. Therefore, the definition of appropriate vaccination schemes is a major issue in PID. The aim of this study is to describe the AEFI in a cohort of PID patients. Medical records from 379 PID patients were included. AEFI severity was classified according to the WHO 1999 guidelines. Causality was assessed using the Clinical Immunization Safety Assessment (CISA) 2009 criteria. Evidence of AEFI was found in 26 medical records and represented a total of 29 reactions. Most of the AEFI were observed in patients with idiopathic hypogammaglobulinemia (IHG), chronic granulomatous disease (CGD) and severe combined immunodeficiency (SCID), representing 10, 4 and 4 cases, respectively. A total of 21 reactions were associated with replicative vaccines, 7 of which were serious cases related to Bacille Calmette-Guérin (BCG). BCG was also the vaccine more often associated with definitive AEFI in PID. In addition to BCG-related complications, seizures were the most serious AEFI among PID patients. Our study included a large cohort of PID patients and confirmed an increased risk of serious AEFI in these populations. The design and implementation of neonatal screening strategies for the early detection of congenital lymphopenias and other PID are urgently needed to avoid serious complications of the BCG vaccine usually applied immediately after birth. Our findings also support the use of the acellular pertussis vaccine to minimize the appearance of seizures in PID patients vaccinated with diphtheria, pertussis and tetanus (DPT). Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies.

    PubMed

    Bousfiha, Aziz; Jeddane, Leïla; Al-Herz, Waleed; Ailal, Fatima; Casanova, Jean-Laurent; Chatila, Talal; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Franco, Jose Luis; Gaspar, H Bobby; Holland, Steven M; Klein, Christoph; Nonoyama, Shigeaki; Ochs, Hans D; Oksenhendler, Eric; Picard, Capucine; Puck, Jennifer M; Sullivan, Kathleen E; Tang, Mimi L K

    2015-11-01

    There are now nearly 300 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. For each of these five categories, a growing variety of phenotypes are ascribed to Primary Immunodeficiency Diseases (PID), making PIDs a rapidly expanding field of medicine. The International Union of Immunological Societies (IUIS) PID expert committee (EC) has published every other year a classification of these disorders into tables, defined by shared pathogenesis and/or clinical consequences. In 2013, the IUIS committee also proposed a more user-friendly, phenotypic classification, based on the selection of key phenotypes at the bedside. We herein propose the revised figures, based on the accompanying 2015 IUIS PID EC classification.

  10. Antibiotic resistance in patients with primary immunodeficiency disorders versus immunocompetent patients.

    PubMed

    Mohammadinejad, Payam; Ataeinia, Bahar; Kaynejad, Kimia; Zeinoddini, Atefeh; Sadeghi, Bamdad; Hosseini, Mohammad; Rezaei, Nima; Aghamohammadi, Asghar

    2015-01-01

    We aimed to investigate the antimicrobial susceptibility among bacterial isolates of patients with primary immunodeficiency disorders (PID) in comparison with immunocompetent patients. Patients' antibiotic sensitivity profiles were extracted from their medical records. In order to compare the antibiotic sensitivity profiles of PID patients with immunocompetent patients, the results of antibiograms of patients who did not have a known or suspected immunodeficiency and were hospitalized during the same period were obtained and used as control subjects. A total number of 257 isolates were obtained from 86 PID patients. Antimicrobial susceptibilities of several organisms isolated from PID patients were significantly lower compared to that of immunocompetent patients. Antibiotic resistance seems to be higher among PID patients compared to immunocompetent patients. This indicates a need for further investigations for the possible factors responsible for antibiotic resistance in PID patients.

  11. Mortality in primary immunodeficient patients, registered in Iranian primary immunodeficiency registry.

    PubMed

    Mir Saeid Ghazi, Bahram; Aghamohammadi, Asghar; Kouhi, Ali; Farhoudi, Abolhassan; Moin, Mostafa; Rezaei, Nima; Shahriar Doost, Parisa; Movahedi, Masoud; Gharagozlou, Mohammad; Pourpak, Zahra; Arshi, Saba; Yazdani, Fereshteh; Atarod, Lida; Mohammad Zadeh, Iraj; Bazargan, Nasrin; Ahmadi Afshar, Akefeh; Mahmoudi, Maryam; Tahaei, Amir

    2004-03-01

    Primary immunodeficiencies (PID) are a group of disorders, characterized by an unusual susceptibility to infections. Delay in diagnosis results in increased morbidity and mortality in affected patients. The purpose of this study was to determine the mortality rate of Iranian immunodeficient patients referred to Children Medical Center Hospital affiliated to Tehran University of Medical Sciences over a period of 20 years.In this study, records of 235 (146 males, 89 females) patients with immunodeficiency who were diagnosed and followed in our center, during 22 years period (1979-2001) were reviewed. The diagnosis of immunodeficiency was based on the standard criteria. The cause of death was determined by review of death certificates.Antibody deficiency was the most common diagnosis made in our patients. The overall five-year survival rate was 22.7% in our studied patient group; this was greatest in antibody deficiency. During the 22 year period of study, 32 patients died. As some of the patients could not be located, the true mortality rate ranged between 13.6% and 17.5%. The main leading cause of death were lower respiratory tract involvement in 14 cases (44%). The most common pathogenic microorganisms causing fatal infections were psudomonas and staphylococcus in 9 cases (28.1%) followed by E. coli in 7 (21.9%), tuberculosis in 13 (40.6%) and salmonella in 1 (3.1%).Based on our study, delay in diagnosis in patients with PID results in tissue and organ damage and several complications. Mortality and morbidity are increased in undiagnosed patients.

  12. Primary immunodeficiencies underlying fungal infections

    PubMed Central

    Lanternier, Fanny; Cypowyj, Sophie; Picard, Capucine; Bustamante, Jacinta; Lortholary, Olivier; Casanova, Jean-Laurent; Puel, Anne

    2014-01-01

    Purpose of review We review the primary immunodeficiencies underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors. Recent findings An increasing number of primary immunodeficiencies are being shown to underlie fungal infectious diseases in children and young adults. Inborn errors of the phagocyte NADPH oxidase complex (chronic granulomatous disease), severe congenital neutropenia and leukocyte adhesion deficiency type I confer a predisposition to invasive aspergillosis and candidiasis. More rarely, inborn errors of IFN-γ immunity underlie endemic mycoses. Inborn errors of IL-17 immunity have recently been shown to underlie chronic mucocutaneous candidiasis, whereas inborn errors of CARD9 immunity underlie deep dermatophytosis and invasive candidiasis. Summary Chronic mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, deep dermatophytosis, pneumocystosis, and endemic mycoses can all be caused by primary immunodeficiencies. Each type of infection is highly suggestive of a specific type of primary immunodeficiency. In the absence of overt risk factors, single-gene inborn errors of immunity should be sought in children and young adults with these and other fungal diseases. PMID:24240293

  13. Latin American challenges with the diagnosis and treatment of primary immunodeficiency diseases.

    PubMed

    Costa-Carvalho, Beatriz; González-Serrano, Maria; Espinosa-Padilla, Sara; Segundo, Gesmar

    2017-05-01

    diagnosis of primary immunodeficiency diseases (PID) is still a challenge in many countries in Latin America (LA), especially those that face social and economic problems. The creation of a society was fundamental to combine efforts that resulted in an effective educational program, establishment of a registry and a network to improve diagnosis. Areas covered: The focus of this article is to portray the scenario of PID in LA covering different aspects from different countries. For this, a questionnaire was sent to countries that participate in the Latin American Society for Immunodeficiencies (LASID) registry, with questions related to PID challenges in LA. We realized that today the greatest challenge is the availability of laboratory tests to investigate newly described PIDs. Expert commentary: Despite being faced with many difficulties, the Latin America Society for Immunodeficiencies is supporting clinical immunologists throughout the continent, which has resulted in a greater awareness of these diseases and an increase in the number of diagnosis.

  14. Pulmonary Manifestations of Primary Immunodeficiency Disorders in Children

    PubMed Central

    Jesenak, Milos; Banovcin, Peter; Jesenakova, Barbora; Babusikova, Eva

    2014-01-01

    Primary immunodeficiencies (PIDs) are inherited disorders in which one or several components of immune system are decreased, missing, or of non-appropriate function. These diseases affect the development, function, or morphology of the immune system. The group of PID comprises more than 200 different disorders and syndromes and the number of newly recognized and revealed deficiencies is still increasing. Their clinical presentation and complications depend on the type of defects and there is a great variability in the relationship between genotypes and phenotypes. A variation of clinical presentation across various age categories is also presented and children could widely differ from adult patients with PID. Respiratory symptoms and complications present a significant cause of morbidity and also mortality among patients suffering from different forms of PIDs and they are observed both in children and adults. They can affect primarily either upper airways (e.g., sinusitis and otitis media) or lower respiratory tract [e.g., pneumonia, bronchitis, bronchiectasis, and interstitial lung diseases (ILDs)]. The complications from lower respiratory tract are usually considered to be more important and also more specific for PIDs and they determinate patients’ prognosis. The spectrum of the causal pathogens usually demonstrates typical pattern characteristic for each PID category. The respiratory signs of PIDs can be divided into infectious (upper and lower respiratory tract infections and complications) and non-infectious (ILDs, bronchial abnormalities – especially bronchiectasis, malignancies, and benign lymphoproliferation). Early diagnosis and appropriate therapy can prevent or at least slow down the development and course of respiratory complications of PIDs. PMID:25121077

  15. Chapter 27: Approach to primary immunodeficiency.

    PubMed

    Uzzaman, Ashraf; Fuleihan, Ramsay L

    2012-01-01

    Primary immunodeficiency diseases (PID) are inherited defects of the innate or adaptive arms of the immune system that lead to an increase in the incidence, frequency, or severity of infections. There may be defects in the adaptive arm of the immune system that include combined immunodeficiency and antibody deficiency syndromes or by abnormalities in innate immunity such as disorders of phagocytes, the complement pathway, or Toll-Like receptor (TLR) mediated signaling. Recurrent sinopulmonary infections with encapsulated bacteria such as Haemophilus influenza type B or Streptococcus pneumoniae may be characteristic of an IgG antibody deficiency or dysfunction. Frequent viral, fungal, or protozoal infections may suggest T lymphocyte dysfunction. Multiple staphylococcal skin infections and fungal infections may imply neutrophil dysfunction or the hyper-IgE syndrome, and recurrent neisserial infection is a characteristic manifestation of late complement component (C5-9, or the membrane attack complex) defects. Recurrent viral or pyogenic bacterial infections often without the presence of a significant inflammatory response suggest a defect in TLR signaling. Mycobacterial infections are characteristic of defects in interleukin (IL)-12, interferon (IFN) gamma, or their receptors. Screening of newborns for T-cell lymphopenia using a polymerase chain reaction to amplify T-cell receptor excision circles (TRECs), which are formed when a T cell rearranges the variable region of its receptor, serves as a surrogate for newly synthesized naïve T cells. Because of very low numbers of TRECs, severe combined immunodeficiency, DiGeorge syndrome, and other causes of T-cell lymphopenia have been identified in newborns.

  16. Gene therapy for primary immunodeficiencies.

    PubMed

    Thrasher, Adrian J

    2008-05-01

    Primary immunodeficiencies are a group of disorders that are highly amenable to gene therapy because of their defined pathophysiology and the accessibility of the hematopoietic system to molecular intervention. The development of this new therapeutic modality has been driven by the established morbidity and mortality associated with conventional allogeneic stem cell transplantation, particularly in the human leukocyte antigen-mismatched setting. Recently, several clinical studies have shown that gamma retroviral gene transfer technology can produce major beneficial therapeutic effects, but, as for all cellular and pharmacologic treatment approaches, with a finite potential for toxicity. Newer developments in vector design showing promise in overcoming these issues are likely to establish gene therapy as an efficacious strategy for many forms of primary immunodeficiencies.

  17. Immunodeficiencies

    PubMed Central

    Ballow, M; Notarangelo, L; Grimbacher, B; Cunningham-Rundles, C; Stein, M; Helbert, M; Gathmann, B; Kindle, G; Knight, A K; Ochs, H D; Sullivan, K; Franco, J L

    2009-01-01

    Primary immunodeficiencies (PIDs) are uncommon, chronic and severe disorders of the immune system in which patients cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The treatment of choice for PID patients with predominant antibody deficiency is intravenous immunoglobulin (Ig) replacement therapy. Despite major advances over the last 20 years in the molecular characterization of PIDs, many patients remain undiagnosed or are diagnosed too late, with severe consequences. Various strategies to ensure timely diagnosis of PIDs are in place, and novel approaches are being developed. In recent years, several patient registries have been established. Such registries shed light on the pathology and natural history of these varied disorders. Analyses of the registry data may also reveal which patients are likely to respond well to higher Ig infusion rates and may help to determine the optimal dosing of Ig products. Faster infusion rates may lead to improved convenience for patients and thus increase patient compliance, and may reduce nursing time and the need for hospital resources. Data from two recent studies suggest that Gamunex® and Privigen® are well tolerated at high infusion rates. Nevertheless, careful selection of patients for high infusion rates, based on co-morbid conditions and tolerance of the current infusion rate, is advisable. Based on the available data, intravenous Ig offers broad protection against encapsulated organisms. As vaccine trends change, careful monitoring of specific antibody levels in the general population, such as those against pneumococcal and meningococcal bacteria, should be implemented. PMID:19883420

  18. Increased Incidence of Fatigue in Patients with Primary Immunodeficiency Disorders: Prevalence and Associations Within the US Immunodeficiency Network Registry

    PubMed Central

    Guffey, Danielle; Minard, Charles G.; Orange, Jordan S.

    2017-01-01

    Introduction Patients with primary immunodeficiency (PID) often report fatigue, yet this symptom has not been studied in PID. Fatigue affects 6–7.5% of healthy adults. The goal of this study is to estimate the prevalence of fatigue in patients with PID and investigate its associated factors. Methods We analyzed 2537 PID patients registered in USIDNET to determine responses to the field “fatigue” in the core registry form. Demographics, immune phenotypes, and comorbid conditions were compared between fatigued and non-fatigued patients to identify relevant associations and potential drivers. A focused analysis was performed for patients with predominantly antibody deficiency disorders (PADs). Results Fatigue was reported in 25.9%(95% CI 23.7–28.3) of PAD patients, compared to 6.4% (95% CI 4.9–8.2) of non-PAD. Patients with common variable immunodeficiency (CVID) had the highest prevalence of fatigue (p < 0.001) among all PID diagnoses. Other factors that were associated with a higher rate of fatigue among PAD patients included female sex, higher BMI, depression, bronchiectasis, and autoimmunity. Additionally, fatigued PAD patients had lower absolute lymphocyte, CD3, CD4, and CD8 counts compared to non-fatigued patients. Conclusion Our findings suggest that fatigue is overrepresented in PAD patients. Prospective studies to estimate prevalence, risk factors, and fatigue etiology in PID are warranted, so therapeutic interventions can be considered. PMID:28124237

  19. Prediction of Candidate Primary Immunodeficiency Disease Genes Using a Support Vector Machine Learning Approach

    PubMed Central

    Keerthikumar, Shivakumar; Bhadra, Sahely; Kandasamy, Kumaran; Raju, Rajesh; Ramachandra, Y.L.; Bhattacharyya, Chiranjib; Imai, Kohsuke; Ohara, Osamu; Mohan, Sujatha; Pandey, Akhilesh

    2009-01-01

    Screening and early identification of primary immunodeficiency disease (PID) genes is a major challenge for physicians. Many resources have catalogued molecular alterations in known PID genes along with their associated clinical and immunological phenotypes. However, these resources do not assist in identifying candidate PID genes. We have recently developed a platform designated Resource of Asian PDIs, which hosts information pertaining to molecular alterations, protein–protein interaction networks, mouse studies and microarray gene expression profiling of all known PID genes. Using this resource as a discovery tool, we describe the development of an algorithm for prediction of candidate PID genes. Using a support vector machine learning approach, we have predicted 1442 candidate PID genes using 69 binary features of 148 known PID genes and 3162 non-PID genes as a training data set. The power of this approach is illustrated by the fact that six of the predicted genes have recently been experimentally confirmed to be PID genes. The remaining genes in this predicted data set represent attractive candidates for testing in patients where the etiology cannot be ascribed to any of the known PID genes. PMID:19801557

  20. Novel Primary Immunodeficiency Candidate Genes Predicted by the Human Gene Connectome

    PubMed Central

    Itan, Yuval; Casanova, Jean-Laurent

    2015-01-01

    Germline genetic mutations underlie various primary immunodeficiency (PID) diseases. Patients with rare PID diseases (like most non-PID patients and healthy individuals) carry, on average, 20,000 rare and common coding variants detected by high-throughput sequencing. It is thus a major challenge to select only a few candidate disease-causing variants for experimental testing. One of the tools commonly used in the pipeline for estimating a potential PID-candidate gene is to test whether the specific gene is included in the list of genes that were already experimentally validated as PID-causing in previous studies. However, this approach is limited because it cannot detect the PID-causing mutation(s) in the many PID patients carrying causal mutations of as yet unidentified PID-causing genes. In this study, we expanded in silico the list of potential PID-causing candidate genes from 229 to 3,110. We first identified the top 1% of human genes predicted by the human genes connectome to be biologically close to the 229 known PID genes. We then further narrowed down the list of genes by retaining only the most biologically relevant genes, with functionally enriched gene ontology biological categories similar to those for the known PID genes. We validated this prediction by showing that 17 of the 21 novel PID genes published since the last IUIS classification fall into this group of 3,110 genes (p < 10−7). The resulting new extended list of 3,110 predicted PID genes should be useful for the discovery of novel PID genes in patients. PMID:25883595

  1. Novel primary immunodeficiency candidate genes predicted by the human gene connectome.

    PubMed

    Itan, Yuval; Casanova, Jean-Laurent

    2015-01-01

    Germline genetic mutations underlie various primary immunodeficiency (PID) diseases. Patients with rare PID diseases (like most non-PID patients and healthy individuals) carry, on average, 20,000 rare and common coding variants detected by high-throughput sequencing. It is thus a major challenge to select only a few candidate disease-causing variants for experimental testing. One of the tools commonly used in the pipeline for estimating a potential PID-candidate gene is to test whether the specific gene is included in the list of genes that were already experimentally validated as PID-causing in previous studies. However, this approach is limited because it cannot detect the PID-causing mutation(s) in the many PID patients carrying causal mutations of as yet unidentified PID-causing genes. In this study, we expanded in silico the list of potential PID-causing candidate genes from 229 to 3,110. We first identified the top 1% of human genes predicted by the human genes connectome to be biologically close to the 229 known PID genes. We then further narrowed down the list of genes by retaining only the most biologically relevant genes, with functionally enriched gene ontology biological categories similar to those for the known PID genes. We validated this prediction by showing that 17 of the 21 novel PID genes published since the last IUIS classification fall into this group of 3,110 genes (p < 10(-7)). The resulting new extended list of 3,110 predicted PID genes should be useful for the discovery of novel PID genes in patients.

  2. Primary immunodeficiencies due to abnormalities of the actin cytoskeleton.

    PubMed

    Burns, Siobhan O; Zarafov, Anton; Thrasher, Adrian J

    2017-01-01

    Primary immunodeficiencies (PIDs) are inherited conditions where components of the immune system are missing or dysfunctional. Over 300 genes have been causally linked to monogenic forms of PID, including a number that regulate the actin cytoskeleton. The majority of cytoskeletal defects disrupt assembly and disassembly of filamentous actin in multiple immune cell lineages impacting functions such as cell migration and adhesion, pathogen uptake, intercellular communication, intracellular signalling, and cell division. In the past 24 months, new actin defects have been identified through next generation sequencing technologies. Substantial progress has also been made in understanding the pathogenic mechanisms that contribute to immunological dysfunction, and also how the cytoskeleton participates in normal physiological immune processes. This review summarises recent advances in the field, raising awareness of these conditions and our current understanding of their presentation. Description of further cases and new conditions will extend the clinical phenotype of actin-related disorders, and will promote the development of more effective and targeted therapies.

  3. Primary Immunodeficiencies and Inflammatory Disease: A Growing Genetic Intersection

    PubMed Central

    Fodil, Nassima; Langlais, David; Gros, Philippe

    2016-01-01

    Recent advances in genome analysis have provided important insights into the genetic architecture of infectious and inflammatory diseases. The combined analysis of loci detected by genome-wide association studies (GWAS) in 22 inflammatory diseases has revealed a shared genetic core and associated biochemical pathways that play a central role in pathological inflammation. Parallel whole exome sequencing studies have identified 265 genes mutated in primary immunodeficiencies (PID). Here we examine the overlap between these two datasets, and find that it consists of genes essential for protection against infections and in which persistent activation causes pathological inflammation. Based on this intersection, we propose that although strong or inactivating mutations (rare variants) in these genes may cause severe disease (PIDs), their more subtle modulation potentially by common regulatory/coding variants may contribute to chronic inflammation. PMID:26791050

  4. Laboratory diagnosis of primary immunodeficiencies.

    PubMed

    Locke, Bradley A; Dasu, Trivikram; Verbsky, James W

    2014-04-01

    Primary immune deficiency disorders represent a highly heterogeneous group of disorders with an increased propensity to infections and other immune complications. A careful history to delineate the pattern of infectious organisms and other complications is important to guide the workup of these patients, but a focused laboratory evaluation is essential to the diagnosis of an underlying primary immunodeficiency. Initial workup of suspected immune deficiencies should include complete blood counts and serologic tests of immunoglobulin levels, vaccine titers, and complement levels, but these tests are often insufficient to make a diagnosis. Recent advancements in the understanding of the immune system have led to the development of novel immunologic assays to aid in the diagnosis of these disorders. Classically utilized to enumerate lymphocyte subsets, flow cytometric-based assays are increasingly utilized to test immune cell function (e.g., neutrophil oxidative burst, NK cytotoxicity), intracellular cytokine production (e.g., TH17 production), cellular signaling pathways (e.g., phosphor-STAT analysis), and protein expression (e.g., BTK, Foxp3). Genetic testing has similarly expanded greatly as more primary immune deficiencies are defined, and the use of mass sequencing technologies is leading to the identification of novel disorders. In order to utilize these complex assays in clinical care, one must have a firm understanding of the immunologic assay, how the results are interpreted, pitfalls in the assays, and how the test affects treatment decisions. This article will provide a systematic approach of the evaluation of a suspected primary immunodeficiency, as well as provide a comprehensive list of testing options and their results in the context of various disease processes.

  5. Primary Immunodeficiency Diseases at Reference and High-Specialty Hospitals in the State of Guanajuato, Mexico

    PubMed Central

    Guaní-Guerra, Eduardo; García-Ramírez, Ulises Noel; Jiménez-Romero, Ana Isabel; Velázquez-Ávalos, José Manuel; Gallardo-Martínez, Gabriela; Mendoza-Espinoza, Francisco-Javier

    2013-01-01

    Background. In general, primary immunodeficiency diseases (PIDs) are underdiagnosed in most countries. The objective of this study was to describe the frequency and clinical spectrum of PID in the most important tertiary hospitals in our region. Methods. An observational, cross-sectional, with retrospective chart, review study was conducted. A total of 26 patients were included and grouped according to the updated classification of PIDs. Results. PIDs spectra were as follows: predominantly antibody deficiency diseases were the most common category (65.38%), followed by other well-defined immunodeficiency syndromes (11.55%), congenital defects of phagocyte number and/or function (7.69%), complement deficiencies (3.85%), combined T- and B-cell immunodeficiencies (3.85%), and defects in innate immunity (3.85%). The mean time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 4.65 ± 6.95 years. Conclusions. Predominant antibody deficiency disease was the most common group of PIDs, agreeing with international reports. Awareness of underdiagnosis by physicians is crucial for a prompt diagnosis and treatment, which in turn should improve the quality of life among patients with PIDs. PMID:24073395

  6. Primary immunodeficiencies in Chile evaluated through ICD-10 coded hospital admissions.

    PubMed

    Poli, C; Hoyos-Bachiloglu, R; Borzutzky, A

    The epidemiology and hospitalisation trends of primary immunodeficiency (PID) in Chile are unknown. We aimed to evaluate hospitalisation trends and demographic characteristics of PID admissions in Chile. PID admissions between 2001 and 2010 (ICD-10 codes D70.0, D70.4, D71, 72.0, D76.1, D80-D84, E70.3, G11.3) were reviewed using national hospital discharge databases. During the study period, 5486 admissions due to PID were registered (0.03% of total). 58.5% of patients were male and 66.3% were under 18 years. Median length of stay was one day (range 1-403 days). The most frequent diagnoses were hypogammaglobulinaemia (27.6%), unspecified immunodeficiency (21.9%), haemophagocytic lymphohystiocytosis (18.3%) and common variable immunodeficiency (11.2%). There was a significant increase in PID admission rate and in one-day hospitalisations during this period (β=0.2; P=0.001 and β=33; P≤0.001, respectively), however no significant variation was found for longer admissions (β=4.8; P=0.175). The increasing trend in PID admission rate was significant in patients with private, but not public insurance (β=0.53; P≤0.001 vs. β=0.08; P=0.079, respectively). We report an increasing trend in admissions due to PID in Chile over a 10-year period. Increase is mainly due to short hospitalisations, possibly accounting for improvements in IVIG access. Higher admission rates in patients with private vs. public insurance suggest socioeconomic disparities in access to PID treatment. ICD-10 coded hospitalisation databases may be useful to determine hospitalisation trends and demographic characteristics of PID admissions worldwide. Copyright © 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

  7. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015.

    PubMed

    Picard, Capucine; Al-Herz, Waleed; Bousfiha, Aziz; Casanova, Jean-Laurent; Chatila, Talal; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Holland, Steven M; Klein, Christoph; Nonoyama, Shigeaki; Ochs, Hans D; Oksenhendler, Eric; Puck, Jennifer M; Sullivan, Kathleen E; Tang, Mimi L K; Franco, Jose Luis; Gaspar, H Bobby

    2015-11-01

    We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.

  8. [Lymphocytes B and primary immunodeficiencies].

    PubMed

    López-Herrera, Gabriela

    2016-01-01

    Primary antibody deficiencies represent the most frequent genetic diseases of the immune system and the first to be recognized along immunology history. The antibodies were recognized as part of the humoral immune system long ago, and after immunoglobulin discovery, the first antibody immunodeficiency were recognized and named as "agammaglobulinemia", followed by the common variable immunoendeficiency and the hyper-IgM syndrome. The following discoveries in immunology history made possible the understanding of these pathologies, for example: the discoveries of B cells, pre-B cells, the signaling pathway directed by the antigen receptor and many other cellular and molecular mechanisms. Primary antibody deficiencies have been studied for a long time and the discoveries of new syndromes have been helpful in the understanding of immunological mechanisms that take place in our organism. Then, this manuscript pretends to review the relevant findings in the history of immunology, focused on the B cells and the connection with the description of representative clinical entities of primary antibody deficiencies. The aim of this manuscript is to show to the reader that the generation of scientific knowledge has a direct application in the understanding of the molecular mechanisms that are affected in these diseases.

  9. Flow Cytometry, a Versatile Tool for Diagnosis and Monitoring of Primary Immunodeficiencies

    PubMed Central

    Aubert, Geraldine

    2016-01-01

    Genetic defects of the immune system are referred to as primary immunodeficiencies (PIDs). These immunodeficiencies are clinically and immunologically heterogeneous and, therefore, pose a challenge not only for the clinician but also for the diagnostic immunologist. There are several methodological tools available for evaluation and monitoring of patients with PIDs, and of these tools, flow cytometry has gained prominence, both for phenotyping and functional assays. Flow cytometry allows real-time analysis of cellular composition, cell signaling, and other relevant immunological pathways, providing an accessible tool for rapid diagnostic and prognostic assessment. This minireview provides an overview of the use of flow cytometry in disease-specific diagnosis of PIDs, in addition to other broader applications, which include immune phenotyping and cellular functional measurements. PMID:26912782

  10. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

    PubMed Central

    2014-01-01

    Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches. PMID:25163701

  11. Clinical applications of gene therapy for primary immunodeficiencies.

    PubMed

    Cicalese, Maria Pia; Aiuti, Alessandro

    2015-04-01

    Primary immunodeficiencies (PIDs) have represented a paradigmatic model for successes and pitfalls of hematopoietic stem cells gene therapy. First clinical trials performed with gamma retroviral vectors (γ-RV) for adenosine deaminase severe combined immunodeficiency (ADA-SCID), X-linked SCID (SCID-X1), and Wiskott-Aldrich syndrome (WAS) showed that gene therapy is a valid therapeutic option in patients lacking an HLA-identical donor. No insertional mutagenesis events have been observed in more than 40 ADA-SCID patients treated so far in the context of different clinical trials worldwide, suggesting a favorable risk-benefit ratio for this disease. On the other hand, the occurrence of insertional oncogenesis in SCID-X1, WAS, and chronic granulomatous disease (CGD) RV clinical trials prompted the development of safer vector construct based on self-inactivating (SIN) retroviral or lentiviral vectors (LVs). Here we present the recent results of LV-mediated gene therapy for WAS showing stable multilineage engraftment leading to hematological and immunological improvement, and discuss the differences with respect to the WAS RV trial. We also describe recent clinical results of SCID-X1 gene therapy with SIN γ-RV and the perspectives of targeted genome editing techniques, following early preclinical studies showing promising results in terms of specificity of gene correction. Finally, we provide an overview of the gene therapy approaches for other PIDs and discuss its prospects in relation to the evolving arena of allogeneic transplant.

  12. Pharmacoeconomics of immunoglobulins in primary immunodeficiency.

    PubMed

    Simoens, Steven

    2009-08-01

    Primary immunodeficiency disorders are associated with increased patient susceptibility to recurrent infections. Since the 1950s, intramuscular, intravenous and subcutaneous immunoglobulin products have been used to replace functionally deficient or absent immunoglobulins, reduce the incidence of infections and prevent organ damage caused by infections. This article aims to review the use of immunoglobulin therapy in primary immunodeficiency by focusing on costs, effectiveness, cost-effectiveness, supply and off-label use. To date, the economic burden of primary immunodeficiency is unknown. Past studies have supported minimal differences in effectiveness between intravenous and subcutaneous immunoglobulins. Subcutaneous therapy may be considered for patients who prefer treatment at home. The small number of economic evaluations and their methodological limitations precludes the recommendation of a specific product for use in primary immunodeficiency on pharmacoeconomic grounds. Demand for immunoglobulins has increased over time, leading to periodic shortages and emphasizing the importance of its appropriate use.

  13. Patients with Primary Immunodeficiencies Are a Reservoir of Poliovirus and a Risk to Polio Eradication

    PubMed Central

    Aghamohammadi, Asghar; Abolhassani, Hassan; Kutukculer, Necil; Wassilak, Steve G.; Pallansch, Mark A.; Kluglein, Samantha; Quinn, Jessica; Sutter, Roland W.; Wang, Xiaochuan; Sanal, Ozden; Latysheva, Tatiana; Ikinciogullari, Aydan; Bernatowska, Ewa; Tuzankina, Irina A.; Costa-Carvalho, Beatriz T.; Franco, Jose Luis; Somech, Raz; Karakoc-Aydiner, Elif; Singh, Surjit; Bezrodnik, Liliana; Espinosa-Rosales, Francisco J.; Shcherbina, Anna; Lau, Yu-Lung; Nonoyama, Shigeaki; Modell, Fred; Modell, Vicki; Ozen, Ahmet; Barbouche, Mohamed-Ridha; McKinlay, Mark A.

    2017-01-01

    Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame. PMID:28952612

  14. Warts and All: HPV in Primary Immunodeficiencies

    PubMed Central

    Leiding, Jennifer W.; Holland, Steven M.

    2012-01-01

    Infection with human papilloma virus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and DOCK8 are typically associated with extensive HPV infections, whereas several other primary immune defects have severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them. PMID:23036745

  15. Severe Viral Infections and Primary Immunodeficiencies

    PubMed Central

    Cohen, Jeffrey I.

    2011-01-01

    Patients with severe viral infections are often not thoroughly evaluated for immunodeficiencies. In this review, we summarize primary immunodeficiencies that predispose individuals to severe viral infections. Some immunodeficiencies enhance susceptibility to disease with a specific virus or family of viruses, whereas others predispose to diseases with multiple viruses in addition to disease with other microbes. Although the role of cytotoxic T cells in controlling viral infections is well known, a number of immunodeficiencies that predispose to severe viral diseases have recently been ascribed to defects in the Toll-like receptor–interferon signaling pathway. These immunodeficiencies are rare, but it is important to identify them both for prognostic information and for genetic counseling. Undoubtedly, additional mutations in proteins in the innate and adaptive arms of the immune system will be identified in the future, which will reveal the importance of these proteins in controlling infections caused by viruses and other pathogens. PMID:21960712

  16. Diagnostic Delay of Primary Immunodeficiencies at a Tertiary Care Hospital in Peru- Brief Report.

    PubMed

    Veramendi-Espinoza, Liz E; Zafra-Tanaka, Jessica H; Pérez-Casquino, Gabriela A; Córdova-Calderón, Wilmer O

    2017-05-01

    The aim of the study was to assess the diagnostic delay in pediatric patients with primary immunodeficiencies (PID) at a tertiary care hospital in Peru. A descriptive study was carried out in which patients from a third-level referral center in Peru were included. Those without a specific diagnosis of PID were excluded. Data was collected by reviewing the medical records and interviewing patients' family members. A total of 45 patients with a mean of 7.4 years (SD = 4.3) were studied. The most frequent diagnosis was predominant antibody defects (35.5%), and the diagnostic delay had a median of 12.17 months (IQR 5.1-30.3). The most frequently diagnosed group of PID was predominant antibody deficiency. The overall median diagnostic delays for PID and predominant antibody deficiency were 12 and 14 months, respectively. Even though early detection of PIDs is crucial for effective treatment, current available laboratory tests required for PID diagnosis are both complex and expensive. Early detection and management of these pathologies cannot be achieved without training non-specialist health professionals in the diagnosis of PID, as well as integrating multidisciplinary and multi-center cooperation at both national and international levels.

  17. Improving current immunoglobulin therapy for patients with primary immunodeficiency: quality of life and views on treatment.

    PubMed

    Espanol, Teresa; Prevot, Johan; Drabwell, Jose; Sondhi, Seema; Olding, Laurence

    2014-01-01

    Subcutaneous or intravenous immunoglobulin replacement is the mainstay of treatment for most patients with primary immunodeficiency disease (PID). The purpose of this study was to gain an understanding of how existing PID therapies affect patient lives and to identify desired improvements to immunoglobulin treatments. An online questionnaire was made available through the International Patient Organisation for Primary Immunodeficiencies to patients with PID and their caregivers regarding current treatment satisfaction, living with PID, and patient preferences using a conjoint approach. Health-related quality of life was canvassed via questionnaires using the Short Form 12 Health Survey and EuroQoL 5 Dimensions. A total of 300 responded to the survey (72% patients with PID and 28% caregivers) from across 21 countries, mostly the UK, Sweden, Canada, France, Germany, and Spain. Fifty-three percent and 45% of patients received intravenous and subcutaneous therapy, respectively. Most respondents (76%) were satisfied with their current treatment, reflecting the benefits that immunoglobulin therapy provides for patient health and well-being. However, patients remained below the physical and mental well-being norms for health-related quality of life as determined by the questionnaire. All respondents expressed a desire for 4-weekly infusions, the ability to administer these at home, self-administration, shorter duration of administration, and fewer needle sticks. The results of this survey highlight the importance of providing access to different treatment options and modes of administration to ensure individual patient needs are best met.

  18. Improving current immunoglobulin therapy for patients with primary immunodeficiency: quality of life and views on treatment

    PubMed Central

    Espanol, Teresa; Prevot, Johan; Drabwell, Jose; Sondhi, Seema; Olding, Laurence

    2014-01-01

    Background Subcutaneous or intravenous immunoglobulin replacement is the mainstay of treatment for most patients with primary immunodeficiency disease (PID). The purpose of this study was to gain an understanding of how existing PID therapies affect patient lives and to identify desired improvements to immunoglobulin treatments. Methods An online questionnaire was made available through the International Patient Organisation for Primary Immunodeficiencies to patients with PID and their caregivers regarding current treatment satisfaction, living with PID, and patient preferences using a conjoint approach. Health-related quality of life was canvassed via questionnaires using the Short Form 12 Health Survey and EuroQoL 5 Dimensions. Results A total of 300 responded to the survey (72% patients with PID and 28% caregivers) from across 21 countries, mostly the UK, Sweden, Canada, France, Germany, and Spain. Fifty-three percent and 45% of patients received intravenous and subcutaneous therapy, respectively. Most respondents (76%) were satisfied with their current treatment, reflecting the benefits that immunoglobulin therapy provides for patient health and well-being. However, patients remained below the physical and mental well-being norms for health-related quality of life as determined by the questionnaire. All respondents expressed a desire for 4-weekly infusions, the ability to administer these at home, self-administration, shorter duration of administration, and fewer needle sticks. Conclusion The results of this survey highlight the importance of providing access to different treatment options and modes of administration to ensure individual patient needs are best met. PMID:24833896

  19. Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies.

    PubMed

    Rezaei, Nima; Hedayat, Mona; Aghamohammadi, Asghar; Nichols, Kim E

    2011-06-01

    Primary immunodeficiencies (PIDs) are commonly characterized by an increased susceptibility to specific infections and, in certain instances, a higher than usual incidence of malignancies. Although improved diagnosis and early treatment of PIDs have reduced early morbidity and mortality from infection, the development of cancer remains a significant cause of premature death. The emergence of cancer in patients with PIDs often results from impairments in the immune response that lead to weakened surveillance against oncogenic viruses, premalignant or malignant cells, or both. Here we review the clinical and biologic features of several PIDs associated with enhanced susceptibility to viral infections and cancer, including X-linked lymphoproliferative disease; IL-2-inducible T-cell kinase deficiency; epidermodysplasia verruciformis; warts, hypogammaglobulinemia, infections, and myelokathexis syndrome; autosomal recessive hyper-IgE syndrome; X-linked agammaglobulinemia; and common variable immunodeficiency. It is of importance that we gain in-depth insights into the fundamental molecular nature of these unique PIDs to better understand the pathogenesis of virus-associated malignancies and to develop innovative therapeutic strategies.

  20. Single-institution Experience of Unrelated Cord Blood Transplantation for Primary Immunodeficiency.

    PubMed

    Chang, Tsung-Yun; Jaing, Tang-Her; Lee, Wei-I; Chen, Shih-Hsiang; Yang, Chao-Ping; Hung, Iou-Jih

    2015-04-01

    Pediatric patients with primary immunodeficiencies (PID) constitute life-threatening medical emergencies. In the absence of an HLA-identical hematopoietic stem cell donor, unrelated donor cord blood transplantation (CBT) is another treatment option. There are little data regarding the outcome of unrelated CBT for PID in Taiwan. We report the results of CBT performed in 8 patients with PID between 2004 and 2013 at Chang Gung Memorial Hospital. The cases included severe combined immunodeficiency (n=4), chronic granulomatous disease (n=2), Wiskott-Aldrich syndrome (n=1), and T-cell immunodeficiency (n=1). Median follow-up time was 73 months. Most UCB recipients received a myeloablative conditioning regimen. There were 7 boys and 1 girl with a median age of 2.5 months at diagnosis (range, antenatal to 17 mo). Median age at transplant was 5.5 months (range, 2 to 74 mo). All but 1 patients engrafted at a median time of 14 days. One developed significant grade III graft-versus-host disease after transplant. Our data show that unrelated CBT in PID is possible. However, no definite conclusions can be drawn from this small number of patients, and more studies are needed to further investigate and confirm these findings.

  1. 2. Update on primary immunodeficiency diseases.

    PubMed

    Bonilla, Francisco A; Geha, Raif S

    2006-02-01

    The pace of discovery in primary immunodeficiency continues to accelerate. In particular, lymphocyte defects have been the source of the most impressive expansion in recent years. Novel forms of agammaglobulinemia, class-switch defects, and T-B(+) severe combined immunodeficiency have been described. Little by little, the genetic heterogeneity of the common variable immunodeficiency and IgA deficiency phenotypes continues to be unraveled as new molecular defects have been reported in these patients as well. The phenotypic spectrum of DiGeorge syndrome has been further developed, along with promising advances in therapy. Defects of nuclear factor kappaB regulation and Toll-like receptor signaling have been described, along with defects of chemokine receptors and cytoplasmic proteases. Clinically defined immunodeficiencies, such as hyper-IgE syndrome and idiopathic CD4 lymphocytopenia, are also discussed. Finally, significant adverse effects in some patients have tempered initial enthusiasm for gene therapy.

  2. [Revertant somatic mosaicism in primary immunodeficiency diseases].

    PubMed

    Wada, Taizo

    2014-01-01

    Revertant somatic mosaicism has been described in an increasing number of genetic disorders including primary immunodeficiency diseases. Both back mutations leading to restoration of wild-type sequences and second-site mutations resulting in compensatory changes have been demonstrated in mosaic individuals. Recent studies identifying revertant somatic mosaicism caused by multiple independent genetic changes further support its frequent occurrence in primary immunodeficiency diseases. Revertant mosaicism acquires a particular clinical relevance because it may lead to selective growth advantage of the corrected cells, resulting in improvement of disease symptoms or atypical clinical presentations. This phenomenon also provides us unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. Here we review the recent findings of revertant somatic mosaicism in primary immunodeficiency diseases and discuss its clinical implications.

  3. Immunoglobulin Replacement Therapy for Primary Immunodeficiency.

    PubMed

    Sriaroon, Panida; Ballow, Mark

    2015-11-01

    Immunoglobulin replacement therapy has been standard treatment in patients with primary immunodeficiency diseases for the past 3 decades. The goal of therapy is to reduce serious bacterial infections in individuals with antibody function defects. Approximately one-third of patients receiving intravenous immunoglobulin treatment experience adverse reactions. Recent advances in manufacturing processes have resulted in products that are safer and better tolerated. Self-infusion by the subcutaneous route has become popular and resulted in better quality of life. This review summarizes the use of immunoglobulin therapy in primary immunodeficiency diseases including its properties, dosing, adverse effects, and different routes of administration. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Primary immunodeficiency investigation in patients during and after hospitalization in a pediatric Intensive Care Unit

    PubMed Central

    Suavinho, Érica; de Nápolis, Ana Carolina R.; Segundo, Gesmar Rodrigues S.

    2014-01-01

    Objective: To analyze whether the patients with severe infections, admitted in the Pediatric Intensive Care Unit of the Hospital de Clínicas of the Universidade Federal de Uberlândia, underwent the active screening for primary immunodeficiencies (PID). Methods: Retrospective study that assessed the data records of patients with any severe infections admitted in the Pediatric Intensive Care Unit, covering a period from January 2011 to January 2012, in order to confirm if they performed an initial investigation for PID with blood count and immunoglobulin dosage. Results: In the studied period, 53 children were hospitalized with severe infections in the Pediatric Intensive Care Unit, and only in seven (13.2%) the initial investigation of PID was performed. Among these patients, 3/7 (42.8%) showed quantitative alterations in immunoglobulin G (IgG) levels, 1/7 (14.3%) had the diagnosis of cyclic neutropenia, and 1/7 (14.3%) presented thrombocytopenia and a final diagnosis of Wiskott-Aldrich syndrome. Therefore, the PID diagnosis was confirmed in 5/7 (71.4%) of the patients. Conclusions: The investigation of PID in patients with severe infections has not been routinely performed in the Pediatric Intensive Care Unit. Our findings suggest the necessity of performing PID investigation in this group of patients. PMID:24676187

  5. Current progress on gene therapy for primary immunodeficiencies.

    PubMed

    Zhang, L; Thrasher, A J; Gaspar, H B

    2013-10-01

    Primary immunodeficiencies have played a major role in the development of gene therapy for monogenic diseases of the bone marrow. The last decade has seen convincing evidence of long-term disease correction as a result of ex vivo viral vector-mediated gene transfer into autologous haematopoietic stem cells. The success of these early studies has been balanced by the development of vector-related insertional mutagenic events. More recently the use of alternative vector designs with self-inactivating designs, which have an improved safety profile has led to the initiation of a wave of new studies that are showing early signs of efficacy. The ongoing development of safer vector platforms and gene-correction technologies together with improvements in cell-transduction techniques and optimised conditioning regimes is likely to make gene therapy amenable for a greater number of PIDs. If long-term efficacy and safety are shown, gene therapy will become a standard treatment option for specific forms of PID.

  6. Advances of gene therapy for primary immunodeficiencies

    PubMed Central

    Candotti, Fabio

    2016-01-01

    In the recent past, the gene therapy field has witnessed a remarkable series of successes, many of which have involved primary immunodeficiency diseases, such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome. While such progress has widened the choice of therapeutic options in some specific cases of primary immunodeficiency, much remains to be done to extend the geographical availability of such an advanced approach and to increase the number of diseases that can be targeted. At the same time, emerging technologies are stimulating intensive investigations that may lead to the application of precise genetic editing as the next form of gene therapy for these and other human genetic diseases. PMID:27508076

  7. Targeted strategies directed at the molecular defect: Toward precision medicine for select primary immunodeficiency disorders.

    PubMed

    Notarangelo, Luigi D; Fleisher, Thomas A

    2017-03-01

    Primary immunodeficiency disorders (PIDs) represent a range of genetically determined diseases that typically have increased susceptibility to infections and in many cases also have evidence of immune dysregulation that often presents as autoimmunity. Most recently, the concept of gain-of-function mutations associated with PIDs has become well recognized and adds a new dimension to the understanding of this group of disorders, moving beyond the more commonly seen loss-of-function mutations. The rapidly expanding genetic defects that have been identified in patients with previously uncharacterized PIDs has opened up the potential for targeted therapy directed at the specific disease-causing abnormality. This has been driven by linking PID-specific genetic defects to the associated unique abnormalities in cellular signaling pathways amenable to directed therapies. These include agents that either block overactive or enhance underresponsive cellular pathways. Selected primary immunodeficiencies were chosen, the genetic defects of which have been recently characterized and are amenable to targeted therapy, as a reflection of the power of precision medicine. Published by Elsevier Inc.

  8. Comparison of American and European practices in the management of patients with primary immunodeficiencies

    PubMed Central

    Hernandez-Trujillo, H S; Chapel, H; Lo Re III, V; Notarangelo, L D; Gathmann, B; Grimbacher, B; Boyle, J M; Hernandez-Trujillo, V P; Scalchunes, C; Boyle, M L; Orange, J S

    2012-01-01

    Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of rare disorders. This study was devised in order to compare management of these diseases in the northern hemisphere, given the variability of practice among clinicians in North America. The members of two international societies for clinical immunologists were asked about their management protocols in relation to their PID practice. An anonymous internet questionnaire, used previously for a survey of the American Academy of Allergy, Asthma and Immunology (AAAAI), was offered to all full members of the European Society for Immunodeficiency (ESID). The replies were analysed in three groups, according to the proportion of PID patients in the practice of each respondent; this resulted in two groups from North America and one from Europe. The 123 responses from ESID members (23·7%) were, in the majority, very similar to those of AAAAI respondents, with > 10% of their practice devoted to primary immunodeficiency. There were major differences between the responses of these two groups and those of the general AAAAI respondents whose clinical practice was composed of < 10% of PID patients. These differences included the routine use of intravenous immunoglobulin therapy (IVIg) for particular types of PIDs, initial levels of IVIg doses, dosing intervals, routine use of prophylactic antibiotics, perceptions of the usefulness of subcutaneous immunoglobulin therapy (SCIg) and of the risk to patients' health of policies adopted by health-care funders. Differences in practice were identified and are discussed in terms of methods of health-care provision, which suggest future studies for ensuring continuation of appropriate levels of immunoglobulin replacement therapies. PMID:22670779

  9. Gene therapy of primary T cell immunodeficiencies.

    PubMed

    Fischer, Alain; Hacein-Bey-Abina, Salima; Cavazzana-Calvo, Marina

    2013-08-10

    Gene therapy of severe combined immunodeficiencies has been proven to be effective to provide sustained correction of the T cell immunodeficiencies. This has been achieved for 2 forms of SCID, i.e SCID-X1 (γc deficiency) and adenosine deaminase deficiency. Occurrence of gene toxicity generated by integration of first generation retroviral vectors, as observed in the SCID-X1 trials has led to replace these vectors by self inactivated (SIN) retro(or lenti) viruses that may provide equivalent efficacy with a better safety profile. Results of ongoing clinical studies in SCID as well as in other primary immunodeficiencies, such as the Wiskott Aldrich syndrome, will be thus very informative.

  10. Lentiviral vectors for the treatment of primary immunodeficiencies.

    PubMed

    Farinelli, Giada; Capo, Valentina; Scaramuzza, Samantha; Aiuti, Alessandro

    2014-07-01

    In the last years important progress has been made in the treatment of several primary immunodeficiency disorders (PIDs) with gene therapy. Hematopoietic stem cell (HSC) gene therapy indeed represents a valid alternative to conventional transplantation when a compatible donor is not available and recent success confirmed the great potential of this approach. First clinical trials performed with gamma retroviral vectors were promising and guaranteed clinical benefits to the patients. On the other hand, the outcome of severe adverse events as the development of hematological abnormalities highlighted the necessity to develop a safer platform to deliver the therapeutic gene. Self-inactivating (SIN) lentiviral vectors (LVVs) were studied to overcome this hurdle through their preferable integration pattern into the host genome. In this review, we describe the recent advancements achieved both in vitro and at preclinical level with LVVs for the treatment of Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD), ADA deficiency (ADA-SCID), Artemis deficiency, RAG1/2 deficiency, X-linked severe combined immunodeficiency (γchain deficiency, SCIDX1), X-linked lymphoproliferative disease (XLP) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.

  11. Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis

    PubMed Central

    Asgari, Samira; McLaren, Paul J.; Peake, Jane; Wong, Melanie; Wong, Richard; Bartha, Istvan; Francis, Joshua R.; Abarca, Katia; Gelderman, Kyra A.; Agyeman, Philipp; Aebi, Christoph; Berger, Christoph; Fellay, Jacques; Schlapbach, Luregn J.; Posfay-Barbe, Klara

    2016-01-01

    One out of three pediatric sepsis deaths in high income countries occur in previously healthy children. Primary immunodeficiencies (PIDs) have been postulated to underlie fulminant sepsis, but this concept remains to be confirmed in clinical practice. Pseudomonas aeruginosa (P. aeruginosa) is a common bacterium mostly associated with health care-related infections in immunocompromised individuals. However, in rare cases, it can cause sepsis in previously healthy children. We used exome sequencing and bioinformatic analysis to systematically search for genetic factors underpinning severe P. aeruginosa infection in the pediatric population. We collected blood samples from 11 previously healthy children, with no family history of immunodeficiency, who presented with severe sepsis due to community-acquired P. aeruginosa bacteremia. Genomic DNA was extracted from blood or tissue samples obtained intravitam or postmortem. We obtained high-coverage exome sequencing data and searched for rare loss-of-function variants. After rigorous filtrations, 12 potentially causal variants were identified. Two out of eight (25%) fatal cases were found to carry novel pathogenic variants in PID genes, including BTK and DNMT3B. This study demonstrates that exome sequencing allows to identify rare, deleterious human genetic variants responsible for fulminant sepsis in apparently healthy children. Diagnosing PIDs in such patients is of high relevance to survivors and affected families. We propose that unusually severe and fatal sepsis cases in previously healthy children should be considered for exome/genome sequencing to search for underlying PIDs. PMID:27703454

  12. Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis.

    PubMed

    Asgari, Samira; McLaren, Paul J; Peake, Jane; Wong, Melanie; Wong, Richard; Bartha, Istvan; Francis, Joshua R; Abarca, Katia; Gelderman, Kyra A; Agyeman, Philipp; Aebi, Christoph; Berger, Christoph; Fellay, Jacques; Schlapbach, Luregn J

    2016-01-01

    One out of three pediatric sepsis deaths in high income countries occur in previously healthy children. Primary immunodeficiencies (PIDs) have been postulated to underlie fulminant sepsis, but this concept remains to be confirmed in clinical practice. Pseudomonas aeruginosa (P. aeruginosa) is a common bacterium mostly associated with health care-related infections in immunocompromised individuals. However, in rare cases, it can cause sepsis in previously healthy children. We used exome sequencing and bioinformatic analysis to systematically search for genetic factors underpinning severe P. aeruginosa infection in the pediatric population. We collected blood samples from 11 previously healthy children, with no family history of immunodeficiency, who presented with severe sepsis due to community-acquired P. aeruginosa bacteremia. Genomic DNA was extracted from blood or tissue samples obtained intravitam or postmortem. We obtained high-coverage exome sequencing data and searched for rare loss-of-function variants. After rigorous filtrations, 12 potentially causal variants were identified. Two out of eight (25%) fatal cases were found to carry novel pathogenic variants in PID genes, including BTK and DNMT3B. This study demonstrates that exome sequencing allows to identify rare, deleterious human genetic variants responsible for fulminant sepsis in apparently healthy children. Diagnosing PIDs in such patients is of high relevance to survivors and affected families. We propose that unusually severe and fatal sepsis cases in previously healthy children should be considered for exome/genome sequencing to search for underlying PIDs.

  13. First report on the Moroccan registry of primary immunodeficiencies: 15 years of experience (1998-2012).

    PubMed

    Bousfiha, A A; Jeddane, L; El Hafidi, N; Benajiba, N; Rada, N; El Bakkouri, J; Kili, A; Benmiloud, S; Benhsaien, I; Faiz, I; Maataoui, O; Aadam, Z; Aglaguel, A; Baba, L Ait; Jouhadi, Z; Abilkassem, R; Bouskraoui, M; Hida, M; Najib, J; Alj, H Salih; Ailal, F

    2014-05-01

    Primary immunodeficiencies (PIDs) are a large group of diseases characterized by susceptibility to infections. We provide the first comprehensive report on PIDs in Morocco, the epidemiological, clinical, etiological and outcome features which have never before been described. A national registry was established in 2008, grouping together data for PID patients diagnosed since 1998. In total, 421 patients were diagnosed between 1998 and 2012. Parental consanguinity was common (recorded for 43.2 % of patients) and the median time to diagnosis was 2.0 years. Overall, 27.4 % of patients were considered to have well defined syndromes with immunodeficiency (48 cases of hyper-IgE syndrome and 40 of ataxia-telangiectasia); 22.7 % had predominantly antibody deficiencies (29 cases of agammaglobulinemia and 24 of CVID); 20.6 % had combined immunodeficiencies (37 cases of SCID and 26 of MHC II deficiencies) and 17.5 % had phagocyte disorders (14 cases of SCN and 10 of CGD). The principal clinical signs were lower respiratory tract infections (60.8 %), skin infections (33.5 %) and candidiasis (26.1 %). Mortality reached 28.8 %, and only ten patients underwent bone marrow transplantation. We analyzed the impact on mortality of residence, family history, parental consanguinity, date of diagnosis and time to diagnosis, but only date of diagnosis had a significant effect. The observed prevalence of PID was 0.81/100,000 inhabitants, suggesting considerable underdiagnosis and a need to increase awareness of these conditions in Morocco. The distribution of PIDs was different from that reported in Western countries, with a particularly high proportion of SCID, MHC II deficiencies, hyper-IgE syndrome and autosomal recessive agammaglobulinemia. However, we have now organized a national network, which should improve diagnosis rates in remote regions.

  14. Evaluation of primary immunodeficiency disease in children.

    PubMed

    Reust, Carin E

    2013-06-01

    One in 2,000 children younger than 18 years is thought to have a primary immunodeficiency disease. Antibody, combined B-cell and T-cell, phagocytic, and complement disorders are the most common types. Children with these diseases tend to have bacterial or fungal infections with unusual organisms, or unusually severe and recurrent infections with common organisms. A family history of primary immunodeficiency disease is the strongest predictor of a person having this type of disease. When an immunodeficiency disease is suspected, initial laboratory screening should include a complete blood count with differential and measurement of serum immunoglobulin and complement levels. The presence of lymphocytopenia on complete blood count suggests a T-cell disorder, whereas a finding of neutropenia suggests a phagocytic disorder. Abnormal serum immunoglobulin levels suggest a B-cell disorder. Abnormalities on assay of the classic or alternative complement pathways suggest a complement disorder. If laboratory results are abnormal, or if clinical suspicion continues despite normal laboratory results, children should be referred for further evaluation. Human immunodeficiency virus infection should also be considered, and testing should be performed, if appropriate; this infection often clinically resembles a T-cell disorder.

  15. Overview of Immunodeficiency Disorders

    PubMed Central

    Raje, Nikita; Dinakar, Chitra

    2015-01-01

    Synopsis The spectrum of primary immunodeficiency disorders (PID) is expanding. It includes typical disorders that primarily present with defective immunity as well as disorders that predominantly involve other systems and exhibit few features of impaired immunity. The rapidly growing list of new immunodeficiency disorders and treatment modalities makes it imperative for the provider to stay abreast of the latest and best management strategies. We present a brief overview of recent clinical advances in the field of PIDs. PMID:26454309

  16. Disease burden for patients with primary immunodeficiency diseases identified at reference hospitals in Guanajuato, Mexico.

    PubMed

    Guaní-Guerra, Eduardo; Jiménez-Romero, Ana Isabel; García-Ramírez, Ulises Noel; Velázquez-Ávalos, José Manuel; Martínez-Guzmán, Edgar; Sandoval-Ramírez, Eunice; Camacho-Meza, Ignacio

    2017-01-01

    In addition to the deleterious effect on health, there is considerable economic and psychosocial morbidity associated with primary immunodeficiency diseases (PID). Also, the cost of a late diagnosis frequently results in a heavy disease burden on the patient. The objective of this study was to collect and analyze data on patients with PID in the state of Guanajuato in Mexico, to indirectly estimate the burden of the disease. An observational, longitudinal, and comparative study was conducted. A total of 44 patients were included and grouped according to the updated classification of PID. The median time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 2.17 (IQR = 6.44) years. Before diagnosis, the number of hospitalizations/year per patient was 0.86 (IQR = 2.28), the number of visit to emergency room/year per patient was 0.92 (IQR = 1.77), the number of doctor's visits/year per patient was 15 (IQR = 11.25), whereas the school/work absence days per patient were reported in 52.72 (IQR = 56.35) days per year. After diagnosis, 20 patients (45.45%) received IVIG replacement therapy, and all of them presented a significant improvement (p <0.05) in all the mentioned variables. Characteristically, even when patients with PID received IVIG, there was still an important disease burden when comparing them against healthy controls. Complications secondary to PID were detected in 19 patients (43.18%). The reported overall mortality rate was 6.82% (n = 3). We were able to indirectly estimate an important disease burden in patients with PID; which is considered to be preventable, at least in part, with effective interventions like health planning, research, collaboration with primary care providers, and generation of policies and practices, in order to improve the quality of life and care of families with PID.

  17. Dendritic cell analysis in primary immunodeficiency

    PubMed Central

    Bigley, Venetia; Barge, Dawn; Collin, Matthew

    2016-01-01

    Purpose of review Dendritic cells are specialized antigen-presenting cells which link innate and adaptive immunity, through recognition and presentation of antigen to T cells. Although the importance of dendritic cells has been demonstrated in many animal models, their contribution to human immunity remains relatively unexplored in vivo. Given their central role in infection, autoimmunity, and malignancy, dendritic cell deficiency or dysfunction would be expected to have clinical consequences. Recent findings Human dendritic cell deficiency disorders, related to GATA binding protein 2 (GATA2) and interferon regulatory factor 8 (IRF8) mutations, have highlighted the importance of dendritic cells and monocytes in primary immunodeficiency diseases and begun to shed light on their nonredundant roles in host defense and immune regulation in vivo. The contribution of dendritic cell and monocyte dysfunction to the pathogenesis of primary immunodeficiency disease phenotypes is becoming increasingly apparent. However, dendritic cell analysis is not yet a routine part of primary immunodeficiency disease workup. Summary Widespread uptake of dendritic cell/monocyte screening in clinical practice will facilitate the discovery of novel dendritic cell and monocyte disorders as well as advancing our understanding of human dendritic cell biology in health and disease. PMID:27755182

  18. The altered landscape of the human skin microbiome in patients with primary immunodeficiencies.

    PubMed

    Oh, Julia; Freeman, Alexandra F; Park, Morgan; Sokolic, Robert; Candotti, Fabio; Holland, Steven M; Segre, Julia A; Kong, Heidi H

    2013-12-01

    While landmark studies have shown that microbiota activate and educate host immunity, how immune systems shape microbiomes and contribute to disease is incompletely characterized. Primary immunodeficiency (PID) patients suffer recurrent microbial infections, providing a unique opportunity to address this issue. To investigate the potential influence of host immunity on the skin microbiome, we examined skin microbiomes in patients with rare monogenic PIDs: hyper-IgE (STAT3-deficient), Wiskott-Aldrich, and dedicator of cytokinesis 8 syndromes. While specific immunologic defects differ, a shared hallmark is atopic dermatitis (AD)-like eczema. We compared bacterial and fungal skin microbiomes (41 PID, 13 AD, 49 healthy controls) at four clinically relevant sites representing the major skin microenvironments. PID skin displayed increased ecological permissiveness with altered population structures, decreased site specificity and temporal stability, and colonization with microbial species not observed in controls, including Clostridium species and Serratia marcescens. Elevated fungal diversity and increased representation of opportunistic fungi (Candida, Aspergillus) supported increased PID skin permissiveness, suggesting that skin may serve as a reservoir for the recurrent fungal infections observed in these patients. The overarching theme of increased ecological permissiveness in PID skin was counterbalanced by the maintenance of a phylum barrier in which colonization remained restricted to typical human-associated phyla. Clinical parameters, including markers of disease severity, were positively correlated with prevalence of Staphylococcus, Corynebacterium, and other less abundant taxa. This study examines differences in microbial colonization and community stability in PID skin and informs our understanding of host-microbiome interactions, suggesting a bidirectional dialogue between skin commensals and the host organism.

  19. The altered landscape of the human skin microbiome in patients with primary immunodeficiencies

    PubMed Central

    Oh, Julia; Freeman, Alexandra F.; Park, Morgan; Sokolic, Robert; Candotti, Fabio; Holland, Steven M.; Segre, Julia A.; Kong, Heidi H.

    2013-01-01

    While landmark studies have shown that microbiota activate and educate host immunity, how immune systems shape microbiomes and contribute to disease is incompletely characterized. Primary immunodeficiency (PID) patients suffer recurrent microbial infections, providing a unique opportunity to address this issue. To investigate the potential influence of host immunity on the skin microbiome, we examined skin microbiomes in patients with rare monogenic PIDs: hyper-IgE (STAT3-deficient), Wiskott-Aldrich, and dedicator of cytokinesis 8 syndromes. While specific immunologic defects differ, a shared hallmark is atopic dermatitis (AD)–like eczema. We compared bacterial and fungal skin microbiomes (41 PID, 13 AD, 49 healthy controls) at four clinically relevant sites representing the major skin microenvironments. PID skin displayed increased ecological permissiveness with altered population structures, decreased site specificity and temporal stability, and colonization with microbial species not observed in controls, including Clostridium species and Serratia marcescens. Elevated fungal diversity and increased representation of opportunistic fungi (Candida, Aspergillus) supported increased PID skin permissiveness, suggesting that skin may serve as a reservoir for the recurrent fungal infections observed in these patients. The overarching theme of increased ecological permissiveness in PID skin was counterbalanced by the maintenance of a phylum barrier in which colonization remained restricted to typical human-associated phyla. Clinical parameters, including markers of disease severity, were positively correlated with prevalence of Staphylococcus, Corynebacterium, and other less abundant taxa. This study examines differences in microbial colonization and community stability in PID skin and informs our understanding of host–microbiome interactions, suggesting a bidirectional dialogue between skin commensals and the host organism. PMID:24170601

  20. Unbalanced Immune System: Immunodeficiencies and Autoimmunity

    PubMed Central

    Giardino, Giuliana; Gallo, Vera; Prencipe, Rosaria; Gaudino, Giovanni; Romano, Roberta; De Cataldis, Marco; Lorello, Paola; Palamaro, Loredana; Di Giacomo, Chiara; Capalbo, Donatella; Cirillo, Emilia; D’Assante, Roberta; Pignata, Claudio

    2016-01-01

    Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PIDs). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms, including defects of tolerance to self-antigens and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained. PMID:27766253

  1. Autoimmunity in Immunodeficiency

    PubMed Central

    Todoric, Krista; Koontz, Jessica B.; Mattox, Daniel; Tarrant, Teresa K.

    2013-01-01

    Primary immunodeficiencies (PID) comprise a diverse group of clinical disorders with varied genetic defects. Paradoxically, a substantial proportion of PID patients develop autoimmune phenomena in addition to having increased susceptibility to infections from their impaired immunity. Although much of our understanding comes from data gathered through experimental models, there are several well-characterized PID that have improved our knowledge of the pathways that drive autoimmunity. The goals of this review will be to discuss these immunodeficiencies and to review the literature with respect to the proposed mechanisms for autoimmunity within each put forth to date. PMID:23591608

  2. Immune dysregulation in primary immunodeficiency disorders.

    PubMed

    Torgerson, Troy R

    2008-05-01

    The past several years have brought an increased awareness of the prevalence of autoimmunity and immune dysregulation among patients who have primary immunodeficiency disorders (PIDD). The recent clinical and molecular definition of PIDD, in which the primary defect is in the immunoregulatory compartment of the immune system, has offered insight into the basic mechanisms of immune tolerance, which has provided new targets and new techniques to study immune tolerance in PIDD. Many of these studies have focused on the presence and function of regulatory T (T(REG)) cells in PIDD, particularly since the discovery of murine and human syndromes associated with T(REG) deficiency. This article focuses on the current state of knowledge regarding the role of T(REG) in various PIDD that have clinical features indicative of dysregulated immunity.

  3. Acquired factor VIII deficiency associated with a novel primary immunodeficiency suggestive of autosomal recessive hyper IgE syndrome.

    PubMed

    Ozgur, Tuba Turul; Asal, Gulten Turkkan; Gurgey, Aytemiz; Tezcan, Ilhan; Ersoy, Fugen; Sanal, Ozden

    2007-05-01

    Primary immunodeficiency diseases (PID) are associated with various autoimmune complications and several manifestations of autoimmunity can be seen in the disorders of T cells, B cells, phagocytes, and complement components. Acquired hemophilia is a rare entity in childhood. Although autoantibodies may develop in various forms of PID, Factor VIII (FVIII) inhibitors have not been described before. Herein, we present a case of acquired hemophilia resulting from FVIII inhibitors who had underlying undefined PID features suggestive of autosomal recessive hyper IgE syndrome. Our patient responded to corticosteroid treatment rather well and quickly, with an increased FVIII level and decreased FVIII inhibitors. However, FVIII inhibitor reappeared 7 months later, and disappeared spontaneously 4 months ago. Long-term and close follow-up is needed to observe the long-term prognosis in this child.

  4. A family history of serious complications due to BCG vaccination is a tool for the early diagnosis of severe primary immunodeficiency.

    PubMed

    Roxo-Junior, Pérsio; Silva, Jorgete; Andrea, Mauro; Oliveira, Larissa; Ramalho, Fernando; Bezerra, Thiago; Nunes, Altacílio A

    2013-09-10

    Severe Combined Immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency (PID). Complications of BCG vaccination, especially disseminated infection and its most severe forms, are known to occur in immunodeficient patients, particularly in SCID. A carefully taken family history before BCG injection as well as delaying vaccination if PID is suspected could be a simple and effective method to avoid inappropriate vaccination of an immunodeficient child in some cases until the prospect of newborn screening for SCID has been fully developed. We describe a patient with a very early diagnosis of SCID, which was suspected on the basis of the previous death of two siblings younger than one year due to severe complications secondary to the BCG vaccine. We suggest that a family history of severe or fatal reactions to BCG should be included as a warning sign for an early diagnosis of SCID.

  5. Clinical-Epidemiological Pattern of Primary Immunodeficiencies in Malaysia 1987-2006: A 20 year experience in Four Malaysian Hospitals.

    PubMed

    Noh, L M; Nasuruddin, B A; Abdul Latiff, A H; Noah, R M; Kamarul Azahar, M R; Norzila, M Z; Zulkifli, I; Gill, H K; Nik Zainal, N I; Suhaimi, A W M; Nik Khairulddin, N Y; Maraina, H; Intan, H I; Mat, I; Shahnaz, M; B H O, Azizi

    2013-01-01

    To determine the clinical and epidemiological characteristics of patients seen with primary immunodeficiencies referred at four Malaysian Hospitals between 1987 to 2007. Patient data were retrospectively obtained from patient records and supplemented by information from a standardized questionnaires taken at the time of diagnosis from 4 participating hospitals. The completed data were transferred to document records kept by the first author. The diagnoses made were based on criteria set by WHO Scientific Committee 1986. Fifty one (51) patients with completed records satisfied the criteria of primary immunodeficiencies based on WHO Scientific Committee 1986. Predominant Antibody deficiency (40.4%) is the commonest of the class of primary immunodeficiency (based on modified IUIS classification) followed by phagocytic defect (17.3%), combined immunodeficiencies (15.4%) and other cellular immunodeficiencies (11.5%). The commonest clinical presentation is pneumonia (54%) . A positive Family history with a close family relative afflicted was a strong pointer to diagnosis for PID (52.6%) Primary immnodeficiencies are seen in all the major ethnic groups of Malaysia, predominantly among Malays. As observed in other patient registries, diagnostic delay remains the major cause of morbidity and mortality. Primary immunodeficiencies is relative rare but is an emerging disease in Malaysia. Creating awareness of the disease, may reveal more cases within the community. It is sufficient to be a health issue in Malaysia as in other developing countries in the future.

  6. Modern management of primary T-cell immunodeficiencies.

    PubMed

    Pachlopnik Schmid, Jana; Güngör, Tayfun; Seger, Reinhard

    2014-06-01

    The study of human T-cell PIDs with Mendelian inheritance has enabled the molecular characterization of important key functions and pathways in T-cell biology. In most cases, T-cell PIDs become apparent as combined T- and B-cell deficiencies. Severe combined immunodeficiencies (SCIDs) are characterized by a complete lack of T-cell development and, in some cases, a developmental block in other lymphoid lineages and manifest within the first year of life. Combined immunodeficiency syndromes (CIDs) result from hypomorphic mutations in typical SCID associated genes or from partial defects of T-cell development and manifest later in childhood by increased susceptibility to infection often combined with disturbances in immune homeostasis, e.g., autoimmunity and increased incidence in lymphoproliferation. The discovery of mutations and characterization of the cellular changes that underlie lymphocyte defects and immune dysregulation have led to novel, specific, successful therapies for severe diseases which are often fatal if left untreated. Over the last few years, impressive progress has been made in understanding the disease mechanisms of T-cell immunodeficiencies and in improving the long-term outcomes of potentially curative treatments, including gene therapy.

  7. Magnetic Resonance Imaging May Be a Valuable Radiation-Free Technique for Lung Pathologies in Patients with Primary Immunodeficiency.

    PubMed

    Arslan, Sevket; Poyraz, Necdet; Ucar, Ramazan; Yesildag, Mihrican; Yesildag, Ahmet; Caliskaner, Ahmet Zafer

    2016-01-01

    In some primary immunodeficiency (PID) patients, especially in the subgroup with common variable immunodeficiency (CVID), radiosensitivity is a concern and avoidance of repeated radiation exposure has been recommended. To investigate the use of lung Magnetic resonance imaging (MRI) instead of Computed Tomography (CT) for the diagnosis and follow-up of various lesions in the lung parenchyma and airways, especially in PID patients in whom x-ray exposure should be limited. The study enrolled 23 patients with PID who underwent thorax CT within the last 3 months and/or who will undergo initial radiological assessment. Lung MRI was performed in all patients to compare the pulmonary findings with CT images. MRI performance was weaker at detecting bronchiectasis extension, and a low concordance was found between MRI and CT in the assessment of the number of bronchial generations. CT better identified peripheral airway abnormalities, while CT and MRI gave similar results for detecting the presence and extension of consolidation, bullae, mucus plugging, bronchial wall thickening, bronchiectasis severity and nodules. Despite the low spatial resolution, higher cost, and low availability, we suggest MRI as a possible radiation-free alternative to CT in selected patients with PID.

  8. Low-dose serotherapy improves early immune reconstitution after cord blood transplantation for primary immunodeficiencies.

    PubMed

    Lane, Jonathan P; Evans, Philippa T G; Nademi, Zohreh; Barge, Dawn; Jackson, Anthony; Hambleton, Sophie; Flood, Terry J; Cant, Andrew J; Abinun, Mario; Slatter, Mary A; Gennery, Andrew R

    2014-02-01

    Cord blood transplantation (CBT) is curative for many primary immunodeficiencies (PIDs) but is associated with risks of viral infection and graft-versus-host disease (GvHD). Serotherapy reduces GvHD but potentially increases the risk of viral infection by delaying immune reconstitution. Because many PID patients have pre-existing viral infections, the optimal dose of serotherapy is unclear. We performed a retrospective analysis in 34 consecutive PID patients undergoing CBT and compared immune reconstitution, viral infection, GvHD, mortality, and long-term immune function between high-dose (n = 11) and low-dose (n = 9) serotherapy. Serotherapy dose had no effect on neutrophil engraftment. Median CD3(+) engraftment occurred at 92.5 and 97 days for high- and low-dose serotherapy, respectively. The low-dose serotherapy group had higher CD3(+), CD4(+), and early thymic emigrant counts at 4 months compared with the high-dose group. GvHD severity and number of viral infections did not differ between serotherapy doses. Survival from the transplantation process was 90.9% for high-dose and 100% for low-dose groups. In conclusion, low-dose serotherapy enhanced T cell reconstitution and thymopoiesis during the first year after CBT with no increase in GvHD. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  9. Primary immunodeficiencies and the control of Epstein-Barr virus infection.

    PubMed

    Palendira, Umaimainthan; Rickinson, Alan B

    2015-11-01

    Human primary immunodeficiency (PID) states, where mutations in single immune system genes predispose individuals to certain infectious agents and not others, are experiments of nature that hold important lessons for the immunologist. The number of genetically defined PIDs is rising rapidly, as is the opportunity to learn from them. Epstein-Barr virus (EBV), a human herpesvirus, has long been of interest because of its complex interaction with the immune system. Thus, it causes both infectious mononucleosis (IM), an immunopathologic disease associated with exaggerated host responses, and at least one malignancy, EBV-positive lymphoproliferative disease, when those responses are impaired. Here, we describe the full range of PIDs currently linked with an increased risk of EBV-associated disease. These provide examples where IM-like immunopathology is fatally exaggerated, and others where responses impaired at the stage of induction, expansion, or effector function predispose to malignancy. Current evidence from this rapidly moving field supports the view that lesions in both natural killer cell and T cell function can lead to EBV pathology.

  10. [Current status and future prospects of stem cell gene therapy for primary immunodeficiency].

    PubMed

    Uchiyama, Toru; Onodera, Masafumi

    2013-01-01

    Patients affected by primary immunodeficiency (PID) can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). In the absence of HLA-matched donors, however, incidence of HSCT-related complications is observed. Therefore, gene therapy has been developed as a highly desirable alternative treatment for patients lacking suitable donors. Retrovirus-based gene therapy was begun in 1990 for the patients of adenosine deaminase deficiency, followed by X-linked severe combined immunodeficiency, Wiskott-Aldrich syndrome and chronic granulomatous disease. Although treated patients have had excellent immune reconstitution and resolution of ongoing infections, complications such as a lymphoproliferative syndrome and a disappearance of gene-modified cells were observed in some clinical trials. To overcome these, ongoing and upcoming clinical trials use some new strategies. The use of preconditioning chemotherapy makes space in the bone marrow for the gene-treated stem cells and allows engraftment of multi lineage stem/progenitor cells. Self-inactivating vectors in which strong enhancers of long terminal repeat are eliminated may reduce the risk of insertional activation of proto-oncogene resulting in leukemia. These modifications will surely increase the safety and efficacy of stem cell gene therapy for PID.

  11. Strategies for B-Cell Receptor Repertoire Analysis in Primary Immunodeficiencies: From Severe Combined Immunodeficiency to Common Variable Immunodeficiency

    PubMed Central

    IJspeert, Hanna; Wentink, Marjolein; van Zessen, David; Driessen, Gertjan J.; Dalm, Virgil A. S. H.; van Hagen, Martin P.; Pico-Knijnenburg, Ingrid; Simons, Erik J.; van Dongen, Jacques J. M.; Stubbs, Andrew P.; van der Burg, Mirjam

    2015-01-01

    The antigen receptor repertoires of B- and T-cells form the basis of the adaptive immune response. The repertoires should be sufficiently diverse to recognize all possible pathogens. However, careful selection is needed to prevent responses to self or harmless antigens. Limited antigen receptor repertoire diversity leads to immunodeficiency, whereas unselected or misdirected repertoires can result in autoimmunity. The antigen receptor repertoire harbors information about abnormalities in many immunological disorders. Recent developments in next generation sequencing allow the analysis of the antigen receptor repertoire in much greater detail than ever before. Analyzing the antigen receptor repertoire in patients with mutations in genes responsible for the generation of the antigen receptor repertoire will give new insights into repertoire formation and selection. In this perspective, we describe strategies and considerations for analysis of the naive and antigen-selected B-cell repertoires in primary immunodeficiency patients with a focus on severe combined immunodeficiency and common variable immunodeficiency. PMID:25904919

  12. Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies

    PubMed Central

    Ott de Bruin, Lisa M.; Volpi, Stefano; Musunuru, Kiran

    2015-01-01

    Severe combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient’s own HSCs with gene therapy offers an attractive alternative. Gene therapies currently being used in clinical settings insert a functional copy of the entire gene by means of a viral vector. With this treatment, severe complications may result due to integration within oncogenes. A promising alternative is the use of endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 to introduce a double-stranded break in the DNA and thus induce homology-directed repair. With these genome-editing tools a correct copy can be inserted in a precisely targeted “safe harbor.” They can also be used to correct pathogenic mutations in situ and to develop cellular or animal models needed to study the pathogenic effects of specific genetic defects found in immunodeficient patients. This review discusses the advantages and disadvantages of these endonucleases in gene correction and modeling with an emphasis on CRISPR/Cas9, which offers the most promise due to its efficacy and versatility. PMID:26052330

  13. The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency.

    PubMed

    Turvey, Stuart E; Durandy, Anne; Fischer, Alain; Fung, Shan-Yu; Geha, Raif S; Gewies, Andreas; Giese, Thomas; Greil, Johann; Keller, Bärbel; McKinnon, Margaret L; Neven, Bénédicte; Rozmus, Jacob; Ruland, Jürgen; Snow, Andrew L; Stepensky, Polina; Warnatz, Klaus

    2014-08-01

    Next-generation DNA sequencing has accelerated the genetic characterization of many human primary immunodeficiency diseases (PIDs). These discoveries can be lifesaving for the affected patients and also provide a unique opportunity to study the effect of specific genes on human immune function. In the past 18 months, a number of independent groups have begun to define novel PIDs caused by defects in the caspase recruitment domain family, member 11 (CARD11)-B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1 [CBM]) signalosome complex. The CBM complex forms an essential molecular link between the triggering of cell-surface antigen receptors and nuclear factor κB activation. Germline mutations affecting the CBM complex are now recognized as the cause of novel combined immunodeficiency phenotypes, which all share abnormal nuclear factor κB activation and dysregulated B-cell development as defining features. For this "Current perspectives" article, we have engaged experts in both basic biology and clinical immunology to capture the worldwide experience in recognizing and managing patients with PIDs caused by CBM complex mutations.

  14. Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency.

    PubMed

    Bodemer, C; Sauvage, V; Mahlaoui, N; Cheval, J; Couderc, T; Leclerc-Mercier, S; Debré, M; Pellier, I; Gagnieur, L; Fraitag, S; Fischer, A; Blanche, S; Lecuit, M; Eloit, M

    2014-10-01

    Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T-lymphocytes. Primary immunodeficiency (PID) is associated with the development of extensive cutaneous granulomas, whose aetiology remains unknown. We performed high-throughput sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases, and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of rubella virus-the core component of a universally used paediatric vaccine-was present in the cutaneous granuloma of these three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals, and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the rubella vaccine virus was also demonstrated in granuloma lesions sampled 4-5 years earlier. The persistence of the rubella virus vaccine strain in all three consecutive cutaneous granuloma patients with PID strongly suggests a causal relationship between rubella virus and granuloma in this setting.

  15. Primary immunodeficiency association with systemic lupus erythematosus: review of literature and lessons learned by the Rheumatology Division of a tertiary university hospital at São Paulo, Brazil.

    PubMed

    Errante, Paolo Ruggero; Perazzio, Sandro Félix; Frazão, Josias Brito; da Silva, Neusa Pereira; Andrade, Luis Eduardo Coelho

    2016-01-01

    Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells; thus, turning individuals susceptible to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (AIDs), in special systemic lupus erythematosus (SLE) which arose associated to the course of PID, are described. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components, (2) defects in immunoglobulin synthesis, and (3) chronic granulomatous disease (CGD). Currently, other PID have been described with clinical manifestation of SLE, such as Wiskott-Aldrich syndrome (WAS), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS) and idiopathic CD4(+) lymphocytopenia. Also we present findings from an adult cohort from the outpatient clinic of the Rheumatology Division of Universidade Federal de São Paulo. The PID manifestations found by our study group were considered mild in terms of severity of infections and mortality in early life. Thus, it is possible that some immunodeficiency states are compatible with survival regarding infectious susceptibility; however these states might represent a strong predisposing factor for the development of immune disorders like those observed in SLE.

  16. Cancers Related to Immunodeficiencies: Update and Perspectives

    PubMed Central

    Mortaz, Esmaeil; Tabarsi, Payam; Mansouri, Davod; Khosravi, Adnan; Garssen, Johan; Velayati, Aliakbar; Adcock, Ian M.

    2016-01-01

    The life span of patients with primary and secondary immunodeficiency is increasing due to recent improvements in therapeutic strategies. While the incidence of primary immunodeficiencies (PIDs) is 1:10,000 births, that of secondary immunodeficiencies are more common and are associated with posttransplantation immune dysfunction, with immunosuppressive medication for human immunodeficiency virus or with human T-cell lymphotropic virus infection. After infection, malignancy is the most prevalent cause of death in both children and adults with (PIDs). PIDs more often associated with cancer include common variable immunodeficiency (CVID), Wiskott–Aldrich syndrome, ataxia-telangiectasia, and severe combined immunodeficiency. This suggests that a protective immune response against both infectious non-self-(pathogens) and malignant self-challenges (cancer) exists. The increased incidence of cancer has been attributed to defective elimination of altered or “transformed” cells and/or defective immunity towards cancer cells. The concept of aberrant immune surveillance occurring in PIDs is supported by evidence in mice and from patients undergoing immunosuppression after transplantation. Here, we discuss the importance of PID defects in the development of malignancies and the current limitations associated with molecular pathogenesis of these diseases and emphasize the need for further knowledge of how specific mutations can modulate the immune system to alter immunosurveillance and thereby play a key role in the etiology of malignancies in PID patients. PMID:27703456

  17. Human immunoglobulin 10 % with recombinant human hyaluronidase: replacement therapy in patients with primary immunodeficiency disorders.

    PubMed

    Sanford, Mark

    2014-08-01

    Human immunoglobulin is an established replacement therapy for patients with primary immunodeficiency disorders (PIDs). Recombinant human hyaluronidase (rHuPH20) is a spreading factor that temporarily digests hyaluronan in the skin interstitium enabling large volumes of fluid or drug solutions to be infused and absorbed subcutaneously. HyQvia® (IGHy) is a new combination product whereby rHuPH20 is injected subcutaneously, followed by human immunoglobulin 10 % infused through the same needle. Thus, IGHy can be administered at a reduced frequency compared with non-facilitated subcutaneous injection of human immunoglobulin, and with a lower frequency of infusion reactions than with intravenous administration. Home-based administration of IGHy is also feasible for adequately trained patients. IGHy was compared with intravenous human immunoglobulin 10 % in a non-randomized, open-label, phase 3 study in patients aged ≥2 years with PIDs who were receiving human immunoglobulin replacement therapy (n = 87). In this study, trough IgG concentrations, acute serious bacterial infection rates (primary endpoint) and occurrences of adverse events during the IGHy treatment period were generally similar to those observed during an intravenous treatment period. IGHy was associated with a numerically lower rate of systemic adverse events and a numerically higher rate of localized adverse events than those observed with intravenous treatment. Compared with intravenous administration, IGHy was administered at a significantly higher maximum flow rate and at a similar frequency. Most patients preferred IGHy over intravenous administration. IGHy offers a new method for subcutaneous delivery of human immunoglobulin replacement therapy in patients with PIDs.

  18. Recent advances in treatment of severe primary immunodeficiencies

    PubMed Central

    Gennery, Andrew

    2015-01-01

    Primary immunodeficiencies are rare, inborn errors that result in impaired, disordered or uncontrolled immune responses. Whilst symptomatic and prophylactic treatment is available, hematopoietic stem cell transplantation is an option for many diseases, leading to cure of the immunodeficiency and establishing normal physical and psychological health. Newborn screening for some diseases, whilst improving outcomes, is focusing research on safer and less toxic treatment strategies, which result in durable and sustainable immune function without adverse effects. New conditioning regimens have reduced the risk of hematopoietic stem cell transplantation, and new methods of manipulating stem cell sources should guarantee a donor for almost all patients. Whilst incremental enhancements in transplantation technique have gradually improved survival outcomes over time, some of these new applications are likely to radically alter our approach to treating primary immunodeficiencies. PMID:26918153

  19. Primary immunodeficiencies appearing as combined lymphopenia, neutropenia, and monocytopenia.

    PubMed

    Dotta, Laura; Badolato, Raffaele

    2014-10-01

    Recurrent or prolonged severe infections associated to panleukopenia strongly suggest primary immune disorders. In recent years, new immunodeficiency syndromes turned up: besides the importance of continuous clinical characterization throughout added reports, the phenotype can easily lead to diagnosis of known rare entities. Our purpose is to review main emerging genetic syndromes featuring lymphopenia combined to neutropenia and/or monocytopenia in order to facilitate diagnosis of rare primary immune deficiencies.

  20. T cell-B cell interactions in primary immunodeficiencies.

    PubMed

    Tangye, Stuart G; Deenick, Elissa K; Palendira, Umaimainthan; Ma, Cindy S

    2012-02-01

    Regulated interactions between cells of the immune system facilitate the generation of successful immune responses, thereby enabling efficient neutralization and clearance of pathogens and the establishment of both cell- and humoral-mediated immunological memory. The corollary of this is that impediments to efficient cell-cell interactions, normally necessary for differentiation and effector functions of immune cells, underly the clinical features and disease pathogenesis of primary immunodeficiencies. In affected individuals, these defects manifest as impaired long-term humoral immunity and susceptibility to infection by specific pathogens. In this review, we discuss the importance of, and requirements for, effective interactions between B cells and T cells during the formation of CD4(+) T follicular helper cells and the elicitation of cytotoxic function of virus-specific CD8(+) T cells, as well as how these processes are abrogated in primary immunodeficiencies due to loss-of-function mutations in defined genes. © 2012 New York Academy of Sciences.

  1. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus

    PubMed Central

    Li, Feng-Yen; Chaigne-Delalande, Benjamin; Su, Helen; Uzel, Gulbu; Matthews, Helen

    2014-01-01

    Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named “X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high-level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and has led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease. PMID:24550228

  2. 7th International Immunoglobulin Conference: Immunodeficiencies

    PubMed Central

    Schmidt, R E; Ochs, H D

    2014-01-01

    Awareness of the challenges involved in diagnosing and treating a heterogeneous group of immunodeficiency disorders is growing. The improvements in neonatal screening offer new methods to ensure that primary immunodeficiencies (PIDs) are diagnosed as early as possible, enabling accurate treatment and the prevention of life-threatening infections and other complications. Additionally, the need to individualize patient therapy in order to optimize both clinical outcomes and quality-of-life is obvious and is exemplified by the ability to switch between intravenous and subcutaneous immunoglobulin administration offering flexible treatment regimens. However, further research is crucial in order to determine the optimal treatment for secondary immunodeficiencies, and to gain greater understanding of the underlying causes of PIDs, including common variable immunodeficiency. The information relating to the growth of patient registries is encouraging, with approximately 25 000 patients with PIDs included in the two registries discussed. Registries such as this are vital for future research, as well as providing an educational resource. PMID:25546748

  3. Hyaluronidase facilitated subcutaneous immunoglobulin in primary immunodeficiency

    PubMed Central

    Jolles, Stephen

    2013-01-01

    Immunoglobulin (Ig)-replacement therapy represents the mainstay of treatment for patients with primary antibody deficiency and is administered either intravenously (IVIg) or subcutaneously (SCIg). While hyaluronidase has been used in clinical practice for over 50 years, the development of a high-purity recombinant form of this enzyme (recombinant human hyaluronidase PH20) has recently enabled the study of repeated and more prolonged use of hyaluronidase in facilitating the delivery of SC medicines. It has been used in a wide range of clinical settings to give antibiotics, local anesthetics, insulin, morphine, fluid replacement, and larger molecules, such as antibodies. Hyaluronidase has been used to help overcome the limitations on the maximum volume that can be delivered into the SC space by enabling dispersion of SCIg and its absorption into lymphatics. The rate of facilitated SCIg (fSCIg) infusion is equivalent to that of IVIg, and the volume administered at a single site can be greater than 700 mL, a huge increase over conventional SCIg, at 20–40 mL. The use of fSCIg avoids the higher incidence of systemic side effects of IVIg, and it has higher bioavailability than SCIg. Data on the long-term safety of this approach are currently lacking, as fSCIg has only recently become available. fSCIg may help several areas of patient management in primary antibody deficiency, and the extent to which it may be used in future will depend on long-term safety data and cost–benefit analysis. PMID:27471693

  4. Respiratory syncytial virus infections in infants affected by primary immunodeficiency.

    PubMed

    Lanari, Marcello; Vandini, Silvia; Capretti, Maria Grazia; Lazzarotto, Tiziana; Faldella, Giacomo

    2014-01-01

    Primary immunodeficiencies are rare inherited disorders that may lead to frequent and often severe acute respiratory infections. Respiratory syncytial virus (RSV) is one of the most frequent pathogens during early infancy and the infection is more severe in immunocompromised infants than in healthy infants, as a result of impaired T- and B-cell immune response unable to efficaciously neutralize viral replication, with subsequent increased viral shedding and potentially lethal lower respiratory tract infection. Several authors have reported a severe clinical course after RSV infections in infants and children with primary and acquired immunodeficiencies. Environmental prophylaxis is essential in order to reduce the infection during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F protein, is currently recommended in high-risk infants born prematurely, with chronic lung disease or congenital heart disease. Currently however the prophylaxis is not routinely recommended in infants with primary immunodeficiency, although some authors propose the extension of prophylaxis to this high risk population.

  5. What is the status of gene therapy for primary immunodeficiency?

    PubMed

    Blaese, R Michael

    2007-01-01

    The efforts to find satisfactory treatments for seriously ill patients with primary immunodeficiency have resulted in the development of important new therapeutic procedures with benefits reaching far beyond the relatively small number of patients affected with these rare disorders. Allogeneic bone marrow transplantation, immunoglobulin and enzyme replacement treatments and more recently gene therapy have all been introduced into clinical medicine as treatments for one or more of the primary immunodeficiency diseases. Beginning in 1990, gene-corrected T cells were first used to treat ADA deficiency SCID. With this demonstration that the gene-transfer procedure could be safely used to introduce functional transgenes into patient cells, clinical trials for a broad range of inherited disorders and cancer were started in the mid 90s. Of all these early clinical experiments, those addressing primary immunodeficiency have also been the most successful. Both ADA and X-SCID have now been cured using gene insertion into autologous bone marrow stem cells. In addition some patients with chronic granulomatous disease (CGD) have shown an unexpectedly high level of functionally corrected granulocytes in their blood following infusion of autologous gene-corrected bone marrow. There remain however a great many significant challenges to be overcome before gene therapy becomes the treatment of choice for these and other disorders. The use of genes as medicines is the most complex therapeutic system ever attempted and it may rake several more decades of work before its real potential as a treatment for both inherited and sporadic disorders if finally realized.

  6. Respiratory Syncytial Virus Infections in Infants Affected by Primary Immunodeficiency

    PubMed Central

    Capretti, Maria Grazia; Lazzarotto, Tiziana; Faldella, Giacomo

    2014-01-01

    Primary immunodeficiencies are rare inherited disorders that may lead to frequent and often severe acute respiratory infections. Respiratory syncytial virus (RSV) is one of the most frequent pathogens during early infancy and the infection is more severe in immunocompromised infants than in healthy infants, as a result of impaired T- and B-cell immune response unable to efficaciously neutralize viral replication, with subsequent increased viral shedding and potentially lethal lower respiratory tract infection. Several authors have reported a severe clinical course after RSV infections in infants and children with primary and acquired immunodeficiencies. Environmental prophylaxis is essential in order to reduce the infection during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F protein, is currently recommended in high-risk infants born prematurely, with chronic lung disease or congenital heart disease. Currently however the prophylaxis is not routinely recommended in infants with primary immunodeficiency, although some authors propose the extension of prophylaxis to this high risk population. PMID:25089282

  7. Monogenic mutations differentially impact the quantity and quality of T follicular helper cells in human primary immunodeficiencies

    PubMed Central

    Ma, Cindy S; Wong, Natalie; Rao, Geetha; Avery, Danielle T; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada, Satoshi; Stoddard, Jennifer L; Deenick, Elissa K; Pelham, Simon J; Payne, Katherine; Boisson-Dupuis, Stéphanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D; Kilic, Sara Sebnem; Baghdadi, Jamila El; Nonoyama, Shigeaki; Minegishi, Yoshiyuki; Mahdaviani, Seyed Alireza; Mansouri, Davood; Bousfiha, Aziz; Blincoe, Annaliesse K; French, Martyn A; Hsu, Peter; Campbell, Dianne E.; Stormon, Michael O; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M; Fulcher, David A; Cook, Matthew C; Phan, Tri G; Stepensky, Polina; Boztug, Kaan; Kansu, Aydan; Ikincioğullari, Aydan; Baumann, Ulrich; Beier, Rita; Roscioli, Tony; Ziegler, John B; Gray, Paul; Picard, Capucine; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M; Casanova, Jean-Laurent; Uzel, Gulbu; Tangye, Stuart G

    2016-01-01

    Background T follicular helper (Tfh) cells underpin T-cell dependent humoral immunity and the success of most vaccines. Tfh cells also contribute to human immune disorders such as autoimmunity, immunodeficiency and malignancy. Understanding the molecular requirements for the generation and function of Tfh cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunological abnormalities. Objective To determine the signaling pathways and cellular interactions required for the development and function of Tfh cells in humans. Methods Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating Tfh (cTfh) cell subsets, memory B cells and serum Ig levels were quantified and functionally assessed in healthy controls as well as patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS or BTK. Results Loss-of function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS or BTK reduced cTfh frequencies. STAT3, IL21/R LOF and STAT1 gain-of function mutations skewed cTfh differentiation towards a phenotype characterized by over-expression of IFNγ and programmed death -1 (PD-1). IFNγ inhibited cTfh function in vitro and in vivo, corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1 and IL12RB1 LOF mutations. Conclusion Specific mutations impact the quantity and quality of cTfh cells, highlighting the need to assess Tfh cells in patients by multiple criteria, including phenotype and function. Furthermore, IFNγ functions in vivo to restrain Tfh-induced B cell differentiation. These findings shed new light on Tfh biology and the integrated signaling pathways required for their generation, maintenance and effector function, and explain compromised humoral immunity in some PIDs. PMID:26162572

  8. Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

    PubMed Central

    Al-Herz, Waleed; Bousfiha, Aziz; Casanova, Jean-Laurent; Chapel, Helen; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Fischer, Alain; Franco, Jose Luis; Geha, Raif S.; Hammarström, Lennart; Nonoyama, Shigeaki; Notarangelo, Luigi Daniele; Ochs, Hans Dieter; Puck, Jennifer M.; Roifman, Chaim M.; Seger, Reinhard; Tang, Mimi L. K.

    2011-01-01

    We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases. PMID:22566844

  9. Immune globulin subcutaneous (human) 20%: in primary immunodeficiency disorders.

    PubMed

    McCormack, Paul L

    2012-05-28

    Immune globulin subcutaneous 20% is a new high-concentration (200 g/L) solution of highly purified human IgG (≥98%) indicated in the EU and the US for antibody replacement therapy in patients with primary immunodeficiency with antibody deficiency, and in the EU for replacement therapy in humoral immunodeficiency secondary to myeloma or chronic lymphocytic leukaemia. Immune globulin subcutaneous 20% is formulated with L-proline, which imparts long-term stability at room temperature and a relatively low viscosity. In two pivotal phase III trials in stably treated patients with primary immunodeficiency, immune globulin subcutaneous 20% at weekly subcutaneous dosages either equivalent to each patient's previous intravenous or subcutaneous replacement therapy, or providing equivalent systemic exposure to previous intravenous therapy, produced mean serum IgG trough levels equal to or greater than pre-study levels. In each trial, there were no serious bacterial infections during treatment throughout the 28-week or 12-month efficacy periods. The rates of infectious episodes, days missed from work/school, days hospitalized or days with antibiotics were low. Immune globulin subcutaneous 20% was generally well tolerated. A high proportion of patients experienced local infusion-site reactions, but infusion-related systemic adverse events were relatively infrequent. Most adverse events were of mild or moderate intensity and did not interfere with therapy.

  10. 7th International Immunoglobulin Conference: Immunodeficiencies

    PubMed Central

    Schmidt, R E; Ochs, H D

    2014-01-01

    Most primary immunodeficiency disorders (PID) are the result of single gene defects. Based on this fact, more than 240 different entities have been identified. Those PIDs with predominant antibody deficiency are treated with immunoglobulin (Ig) replacement therapy. This review focuses on the diagnosis, clinical characteristics and treatment of patients suffering from PID, or secondary immunodeficiency disorders (SID) caused, for instance, by irradiation, immunosuppressive drugs or thymectomy. Common variable immunodeficiency (CVID) is the most commonly diagnosed and least understood form of PID, with a heterogeneous range of symptoms and genotypes, requiring individualized treatment plans. This includes adjusting the dose and treatment interval, administrating Ig by intravenous or subcutaneous injection by either pump or push, and finally deciding which treatment options are best for a given patient. Ig therapy can also be used to treat immunodeficiencies resulting from lymphoproliferative and autoimmune diseases or immunosuppression following organ transplantation; however, there is an urgent need for research in this field. Accurate and early diagnosis of PID is important to ensure that optimal treatment is started early to maintain the patient's health. Detailed patient registries have been established to increase awareness of PID, as well as provide a valuable resource for further research. PMID:25546741

  11. Primary Care of the Human Immunodeficiency Virus Patient.

    PubMed

    Buckhold, Fred R

    2015-09-01

    Human immunodeficiency virus (HIV) is a disease that affects 1 million patients in the United States. Many excellent drug regimens exist that effectively suppress the viral load and improve immune function, but there are consequences of long-term antiviral therapy. In addition, patients with HIV tend to have much higher rates of chronic disease, substance abuse, and cancer. Thus, while expert care in the treatment of HIV remains critical, the skill set of a primary care provider in the prevention, detection, and management of acute and chronic illness is vital to the care of the HIV patient.

  12. Primary pulmonary hypertension associated with human immunodeficiency virus infection.

    PubMed Central

    Golpe, R.; Fernandez-Infante, B.; Fernandez-Rozas, S.

    1998-01-01

    Several cardiorespiratory diseases can complicate human immunodeficiency virus infection. Primary pulmonary hypertension is a rare clinical disorder which carries a bad prognosis. More than 90 cases of HIV-associated primary pulmonary hypertension have been reported to date. Although its pathogenesis remains unknown, some evidence suggests a possible role for the virus itself in its development. Genetic susceptibility may also be implicated. The clinical and histopathologic features of this entity do not differ from those of classic primary pulmonary hypertension. The diagnosis requires a high degree of clinical suspicion and a careful evaluation to rule out causes of secondary pulmonary hypertension. In addition to supportive measures, anticoagulation and vasodilators have been used to treat this disorder, although sufficient data regarding long-term results with these therapies are lacking. PMID:9799910

  13. Primary pulmonary hypertension associated with human immunodeficiency virus infection.

    PubMed

    Golpe, R; Fernandez-Infante, B; Fernandez-Rozas, S

    1998-07-01

    Several cardiorespiratory diseases can complicate human immunodeficiency virus infection. Primary pulmonary hypertension is a rare clinical disorder which carries a bad prognosis. More than 90 cases of HIV-associated primary pulmonary hypertension have been reported to date. Although its pathogenesis remains unknown, some evidence suggests a possible role for the virus itself in its development. Genetic susceptibility may also be implicated. The clinical and histopathologic features of this entity do not differ from those of classic primary pulmonary hypertension. The diagnosis requires a high degree of clinical suspicion and a careful evaluation to rule out causes of secondary pulmonary hypertension. In addition to supportive measures, anticoagulation and vasodilators have been used to treat this disorder, although sufficient data regarding long-term results with these therapies are lacking.

  14. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies

    PubMed Central

    Conley, Mary Ellen; Seligman, Stephen J.; Abel, Laurent; Notarangelo, Luigi D.

    2014-01-01

    Can genetic and clinical findings made in a single patient be considered sufficient to establish a causal relationship between genotype and phenotype? We report that up to 49 of the 232 monogenic etiologies (21%) of human primary immunodeficiencies (PIDs) were initially reported in single patients. The ability to incriminate single-gene inborn errors in immunodeficient patients results from the relative ease in validating the disease-causing role of the genotype by in-depth mechanistic studies demonstrating the structural and functional consequences of the mutations using blood samples. The candidate genotype can be causally connected to a clinical phenotype using cellular (leukocytes) or molecular (plasma) substrates. The recent advent of next generation sequencing (NGS), with whole exome and whole genome sequencing, induced pluripotent stem cell (iPSC) technology, and gene editing technologies—including in particular the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology—offer new and exciting possibilities for the genetic exploration of single patients not only in hematology and immunology but also in other fields. We propose three criteria for deciding if the clinical and experimental data suffice to establish a causal relationship based on only one case. The patient’s candidate genotype must not occur in individuals without the clinical phenotype. Experimental studies must indicate that the genetic variant impairs, destroys, or alters the expression or function of the gene product (or two genetic variants for compound heterozygosity). The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, or by default via a relevant animal phenotype. When supported by satisfaction of rigorous criteria, the report of single patient–based discovery of Mendelian disorders should be encouraged, as it can provide the first step in the understanding of a group of

  15. Fibromyalgia in 300 adult index patients with primary immunodeficiency.

    PubMed

    Barton, James C; Bertoli, Luigi F; Barton, Jackson C; Acton, Ronald T

    2017-01-01

    We sought to determine the prevalence and clinical and laboratory associations of fibromyalgia in adults with primary immunodeficiency (immunoglobulin (Ig) G subclass deficiency (IgGSD) and common variable immunodeficiency (CVID). We performed a retrospective analysis of these observations in 300 non-Hispanic white adult index patients with recurrent/severe respiratory tract infections and IgGSD or CVID: age; sex; IgGSD; fibromyalgia; chronic fatigue; autoimmune conditions (ACs); interstitial cystitis (IC); diabetes; body mass index; serum Ig isotypes; blood lymphocytes and subsets; and human leukocyte antigen (HLA)-A and -B types and haplotypes. We performed univariate comparisons, logistic multivariable regressions, and an analysis of covariance. Mean age was 49 ± 12 (standard deviation) y. There were 246 women (82.0%). IgGSD was diagnosed in 276 patients (92.0%). Fifty-six patients had fibromyalgia (18.7%; female:male 13:1). Other characteristics included: chronic fatigue, 63.0%; aggregate ACs, 35.3%; Sjögren's syndrome, 8.0%; IC, 3.0%; diabetes, 10.3%; and HLA-A*29, B*44 positivity, 9.7%. Prevalences of female sex; chronic fatigue; IC; and HLA-A*29, B*44 positivity were greater in patients with fibromyalgia. Logistic regression on fibromyalgia revealed three positive associations: chronic fatigue (p=0.0149; odds ratio 2.6 [95% confidence interval 1.2, 5.6]); Sjögren's syndrome (p=0.0004; 5.2 [2.1, 13.2]); and IC (p=0.0232; 5.7 [1.3, 25.7]). In an analysis of covariance, there were significant interactions of chronic fatigue, Sjögren's syndrome, and interstitial cystitis on fibromyalgia. Fibromyalgia is common in non-Hispanic white adult index patients with primary immunodeficiency, especially women. Chronic fatigue, Sjögren's syndrome, and IC are significantly associated with fibromyalgia after adjustment for other independent variables.

  16. Recurrent and Sustained Viral Infections in Primary Immunodeficiencies

    PubMed Central

    Ruffner, Melanie A.; Sullivan, Kathleen E.; Henrickson, Sarah E.

    2017-01-01

    Viral infections are commonplace and often innocuous. Nevertheless, within the population of patients with primary immunodeficiencies (PIDDs), viral infections can be the feature that drives a diagnostic evaluation or can be the most significant morbidity for the patient. This review is focused on the viral complications of PIDDs. It will focus on respiratory viruses, the most common type of viral infection in the general population. Children and adults with an increased frequency or severity of respiratory viral infections are often referred for an immunologic evaluation. The classic teaching is to investigate humoral function in people with recurrent sinopulmonary infections, but this is often interpreted to mean recurrent bacterial infections. Recurrent or very severe viral infections may also be a harbinger of a primary immunodeficiency as well. This review will also cover persistent cutaneous viral infections, systemic infections, central nervous system infections, and gastrointestinal infections. In each case, the specific viral infections may drive a diagnostic evaluation that is specific for that type of virus. This review also discusses the management of these infections, which can become problematic in patients with PIDDs. PMID:28674531

  17. Actin cytoskeletal defects in immunodeficiency

    PubMed Central

    Moulding, Dale A; Record, Julien; Malinova, Dessislava; Thrasher, Adrian J

    2013-01-01

    The importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin-related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott-Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency. PMID:24117828

  18. Practice parameter for the diagnosis and management of primary immunodeficiency.

    PubMed

    Bonilla, Francisco A; Khan, David A; Ballas, Zuhair K; Chinen, Javier; Frank, Michael M; Hsu, Joyce T; Keller, Michael; Kobrynski, Lisa J; Komarow, Hirsh D; Mazer, Bruce; Nelson, Robert P; Orange, Jordan S; Routes, John M; Shearer, William T; Sorensen, Ricardo U; Verbsky, James W; Bernstein, David I; Blessing-Moore, Joann; Lang, David; Nicklas, Richard A; Oppenheimer, John; Portnoy, Jay M; Randolph, Christopher R; Schuller, Diane; Spector, Sheldon L; Tilles, Stephen; Wallace, Dana

    2015-11-01

    The American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the "Practice parameter for the diagnosis and management of primary immunodeficiency." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. Published by Elsevier Inc.

  19. [Serratia infections, should we think about primary immunodeficiencies?

    PubMed

    Montaner Ramón, Alicia; Murillo Sanjuán, Laura; Martínez Faci, Cristina; Guerrero Laleona, Carmelo; Rodríguez-Vigil Iturrate, Carmen

    2017-04-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency with an incidence of 1/200,000-250,000 live births. CGD affects mainly male patients, most of the mutations being X-linked, and autosomal recessive forms occur more frequently in communities with greater numbers of consanguineous marriages. CGD is characterized by sensitivity to recurrent and severe bacterial and fungal infections, with formation of granulomas due to the inability of phagocytes to generate reactive oxygen compounds, necessary for the intracellular death of phagocytic microorganisms. We report three cases of CGD in which Serratia marcescens was isolated, and after detailed anamnesis and performance of neutrophil function tests, a molecular diagnosis of the disease was reached. CGD can be manifested in a wide variety of ways, so that high suspicion and a meticulous anamnesis are essential to reach a diagnosis.

  20. Gene therapy for primary immunodeficiencies: current status and future prospects.

    PubMed

    Qasim, Waseem; Gennery, Andrew R

    2014-06-01

    Gene therapy using autologous haematopoietic stem cells offers a valuable treatment option for patients with primary immunodeficiencies who do not have access to an HLA-matched donor, although such treatments have not been without their problems. This review details gene therapy trials for X-linked and adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). X-linked SCID was chosen for gene therapy because of previous 'natural' genetic correction through a reversion event in a single lymphoid precursor, demonstrating limited thymopoiesis and restricted T-lymphocyte receptor repertoire, showing selective advantage of progenitors possessing the wild-type gene. In early studies, patients were treated with long terminal repeats-intact gamma-retroviral vectors, without additional chemotherapy. Early results demonstrated gene-transduced cells, sustained thymopoiesis, and a diverse T-lymphocyte repertoire with normal function. Serious adverse effects were subsequently reported in 5 of 20 patients, with T-lymphocyte leukaemia developing, secondary to the viral vector integrating adjacent to a known oncogene. New trials using self-inactivating gamma-retroviral vectors are progressing. Trials for ADA-SCID using gamma-retroviral vectors have been successful, with no similar serious adverse effects reported; trials using lentiviral vectors are in progress. Patients with WAS and CGD treated with early gamma-retroviral vectors have developed similar lymphoproliferative adverse effects to those seen in X-SCID--current trials are using new-generation vectors. Targeted gene insertion using homologous recombination of corrected gene sequences by cellular DNA repair pathways following targeted DNA breakage will improve efficacy and safety of gene therapy. A number of new techniques are discussed.

  1. Primary immune deficiencies presenting in adults: seven years of experience from Iran.

    PubMed

    Mansouri, Davood; Adimi, Parisa; Mirsaedi, Mehdi; Mansouri, Nahal; Tabarsi, Payam; Amiri, Majid; Jamaati, Hamid R; Motavasseli, Masoud; Baghaii, Noushin; Cheraghvandi, Ali; Rouhi, Reza; Roozbahany, Navid A; Zahirifard, Soheila; Mohammadi, Forouzan; Masjedi, Mohammad R; Velayati, Ali A; Casanova, Jean L; Speert, David P; Elwood, R Kevin; Schellenberg, Robert; Turvey, Stuart E

    2005-07-01

    Primary immunodeficiencies (PIDs) are not solely diseases of childhood. We describe the clinical presentation and outcome for 55 adult patients with previously unrecognized PIDs. This series provides unique data regarding PIDs presenting in adulthood, and serves as a timely reminder that physicians must consider the diagnosis of PIDs in their adult patients. Using the experience gained from these patients, we outline key "warning signs" suggestive of an underlying PID. Only through increased physician awareness will patients with PIDs receive timely diagnosis and optimal management.

  2. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

    PubMed

    Ma, Cindy S; Wong, Natalie; Rao, Geetha; Avery, Danielle T; Torpy, James; Hambridge, Thomas; Bustamante, Jacinta; Okada, Satoshi; Stoddard, Jennifer L; Deenick, Elissa K; Pelham, Simon J; Payne, Kathryn; Boisson-Dupuis, Stéphanie; Puel, Anne; Kobayashi, Masao; Arkwright, Peter D; Kilic, Sara Sebnem; El Baghdadi, Jamila; Nonoyama, Shigeaki; Minegishi, Yoshiyuki; Mahdaviani, Seyed Alireza; Mansouri, Davood; Bousfiha, Aziz; Blincoe, Annaliesse K; French, Martyn A; Hsu, Peter; Campbell, Dianne E; Stormon, Michael O; Wong, Melanie; Adelstein, Stephen; Smart, Joanne M; Fulcher, David A; Cook, Matthew C; Phan, Tri Giang; Stepensky, Polina; Boztug, Kaan; Kansu, Aydan; İkincioğullari, Aydan; Baumann, Ulrich; Beier, Rita; Roscioli, Tony; Ziegler, John B; Gray, Paul; Picard, Capucine; Grimbacher, Bodo; Warnatz, Klaus; Holland, Steven M; Casanova, Jean-Laurent; Uzel, Gulbu; Tangye, Stuart G

    2015-10-01

    Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised

  3. Medical awareness concerning primary immunodeficiency diseases in the city of São Paulo, Brazil

    PubMed Central

    Dantas, Ellen de Oliveira; Aranda, Carolina Sanchez; Nobre, Fernanda Aimée; Fahl, Kristine; Mazzucchelli, Juliana Themudo Lessa; Felix, Erika; Nero, Dora Lisa Friedlander-Del; Nudelman, Victor; Sano, Flavio; Condino-Neto, Antonio; Damasceno, Elaine; Costa-Carvalho, Beatriz Tavares

    2013-01-01

    ABSTRACT Objective: To evaluate medical knowledge of primary immunodeficiency in the city of Sao Paulo (SP). Methods: A 14-item questionnaire about primary immunodeficiency was applied to physicians who worked at general hospitals. One of the questions presented 25 clinical situations that could be associated or not with primary immunodeficiency, and the percentage of appropriate answers generated a knowledge indicator. Results: Seven hundred and forty-six participated in the study, among them 215 pediatricians (28.8%), 244 surgeons (32.7%), and 287 clinicians (38.5%). About 70% of the physicians responded that they had learned about primary immunodeficiency in graduate school or in residency training. Treatment of patients that use antibiotics frequently was reported by 75% dos physicians, but only 34.1% had already investigated a patient and 77.8% said they did not know the ten warning signs for primary immunodeficiency. The knowledge indicator obtained showed a mean of 45.72% (±17.87). Only 26.6% if the pediatricians and 6.6% of clinicians and surgeons showed a knowledge indicator of at least 67% (equivalent to an appropriate answer in two thirds of the clinical situations). Conclusion: There is a deficit in medical knowledge of primary immunodeficiency in the city of Sao Paulo, even among pediatricians, despite having greater contact with the theme over the last few years. The improvement of information on primary immunodeficiency in the medical community is an important step towards the diagnosis and treatment process of these diseases. PMID:24488388

  4. Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies

    ClinicalTrials.gov

    2009-10-14

    Immunologic Deficiency Syndromes; Chediak-Higashi Syndrome; Common Variable Immunodeficiency; Graft Versus Host Disease; X-Linked Lymphoproliferative Syndrome; Familial Erythrophagocytic Lymphohistiocytosis; Hemophagocytic Lymphohistiocytosis; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Hyper IgM Syndrome; Severe Combined Immunodeficiency; Leukocyte Adhesion Deficiency Syndrome; Virus-Associated Hemophagocytic Syndrome

  5. Efficacy and Safety of a New 20% Immunoglobulin Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary Immunodeficiency

    PubMed Central

    Fasano, Mary B.; Spector, Sheldon; Wasserman, Richard L.; Melamed, Isaac; Rojavin, Mikhail A.; Zenker, Othmar; Orange, Jordan S.

    2010-01-01

    Subcutaneous human IgG (SCIG) therapy in primary immunodeficiency (PID) offers sustained IgG levels throughout the dosing cycle and fewer adverse events (AEs) compared to intravenous immunoglobulin (IVIG). A phase I study showed good local tolerability of IgPro20, a new 20% liquid SCIG stabilized with L-proline. A prospective, open-label, multicenter, single-arm, phase III study evaluated the efficacy and safety of IgPro20 in patients with PID over 15 months. Forty-nine patients (5–72 years) previously treated with IVIG received weekly subcutaneous infusions of IgPro20. The mean serum IgG level was 12.5 g/L. No serious bacterial infections were reported. There were 96 nonserious infections (rate 2.76/patient per year). The rate of days missed from work/school was 2.06/patient per year, and the rate of hospitalization was 0.2/patient per year. Ninety-nine percent of AEs were mild or moderate. No serious, IgPro20-related AEs were reported. IgPro20 effectively protected patients with PID against infections and maintained serum IgG levels without causing unexpected AEs. PMID:20454851

  6. Vaccine-Derived Polioviruses and Children with Primary Immunodeficiency, Iran, 1995–2014

    PubMed Central

    Shaghaghi, Mohammadreza; Shahmahmoodi, Shohreh; Abolhassani, Hassan; Soleyman-jahi, Saeed; Parvaneh, Leila; Mahmoudi, Sussan; Chavoshzadeh, Zahra; Yazdani, Reza; Zahraei, Seyed Mohsen; Ebrahimi, Mohsen; Eslamian, Mohammad H.; Tabatabaie, Hamideh; Yousefi, Maryam; Kandelousi, Yaghoob M.; Oujaghlou, Aliasghar; Rezaei, Nima

    2016-01-01

    Widespread use of oral poliovirus vaccine has led to an ≈99.9% decrease in global incidence of poliomyelitis (from ≈350,000 cases in 1988 to 74 cases in 2015) and eradication of wild-type poliovirus serotypes 2 and 3. However, patients with primary immunodeficiency might shed vaccine-derived polioviruses (VDPVs) for an extended period, which could pose a major threat to polio eradication programs. Since 1995, sixteen VDPV populations have been isolated from 14 patients with immunodeficiency in Iran. For these patients, vaccine-associated paralysis, mostly in >1 extremity, was the first manifestation of primary immunodeficiency. Seven patients with humoral immunodeficiency cleared VDPV infection more frequently than did 6 patients with combined immunodeficiencies. Our results raise questions about manifestations of VDPVs in immunodeficient patients and the role of cellular immunity against enterovirus infections. On the basis of an association between VDPVs and immunodeficiency, we advocate screening of patients with primary immunodeficiency for shedding of polioviruses. PMID:27648512

  7. II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies

    PubMed Central

    Goudouris, Ekaterini Simões; Silva, Almerinda Maria do Rego; Ouricuri, Aluce Loureiro; Grumach, Anete Sevciovic; Condino, Antonio; Costa-Carvalho, Beatriz Tavares; Prando, Carolina Cardoso de Mello; Kokron, Cristina Maria; Vasconcelos, Dewton de Moraes; Tavares, Fabíola Scancetti; Segundo, Gesmar Rodrigues Silva; Barreto, Irma Cecília Douglas Paes; Dorna, Mayra de Barros; Barros, Myrthes Anna Maragna Toledo; Forte, Wilma Carvalho Neves

    2017-01-01

    ABSTRACT In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil. PMID:28444082

  8. [Hematopoietic stem cell transplant in combined immunodeficiency syndromes of childhood: an optimal treatment for primary immunodeficiency].

    PubMed

    Olaya-Vargas, Alberto; Coronel-Moran, Rocío; Rivera-Luna, Roberto; Bravo-Lindoro, Amalia; Bejar-Ramírez, Yadira; Lormendez-Jacome, Doris

    2005-01-01

    The congenital immunodeficiency disorders in which the defect has been clearly traced to the stem cell can be cured with allogeneic stem-cell transplantation (SCT) from an unaffected donor. Widespread application of this treatment modality has been tempered by the fact that risk-benefit considerations do not always favor a procedure that carries a significant risk for morbidity and mortality. Some malignant disorders of childhood eventually have to be treated by an autologous or allogeneic SCT, however nonmalignant disorders can also be treated with this approach. This article reviews the current status of SCT for nonmalignant inherited immunodeficiency disorders.

  9. A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside

    PubMed Central

    Jeddane, Leïla; Ailal, Fatima; Al Herz, Waleed; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Fischer, Alain; Franco, Jose Luis; Geha, Raif S.; Hammarström, Lennart; Nonoyama, Shigeaki; Ochs, Hans D.; Roifman, Chaim M.; Seger, Reinhard; Tang, Mimi L. K.; Puck, Jennifer M.; Chapel, Helen; Notarangelo, Luigi D.; Casanova, Jean-Laurent

    2014-01-01

    The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician’s observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way.We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since. PMID:23657403

  10. Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency.

    PubMed

    Agarwal, Shradha; Mayer, Lloyd

    2013-09-01

    Gastrointestinal disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can indicate immune deficiency. The gastrointestinal tract is the largest lymphoid organ in the body, so it is not surprising that intestinal diseases are common among immunodeficient patients. Gastroenterologists therefore must be able to diagnose and treat patients with primary immunodeficiency. Immune-related gastrointestinal diseases can be classified as those that develop primarily via autoimmunity, infection, an inflammatory response, or malignancy. Immunodeficient and immunocompetent patients with gastrointestinal diseases present with similar symptoms. However, intestinal biopsy specimens from immunodeficient patients often have distinct histologic features, and these patients often fail to respond to conventional therapies. Therefore, early recognition of symptoms and referral to an immunologist for a basic immune evaluation is required to select appropriate treatments. Therapies for primary immunodeficiency comprise immunoglobulin replacement, antibiotics, and, in severe cases, bone marrow transplantation. Treatment of immunodeficient patients with concomitant gastrointestinal disease can be challenging, and therapy with immunomodulators often is required for severe disease. This review aims to guide gastroenterologists in the diagnosis and treatment of patients with primary immunodeficiency.

  11. New frontiers in the therapy of primary immunodeficiency: From gene addition to gene editing.

    PubMed

    Kohn, Donald B; Kuo, Caroline Y

    2017-03-01

    The most severe primary immune deficiency diseases (PIDs) have been successfully treated with allogeneic hematopoietic stem cell transplantation for more than 4 decades. However, such transplantations have the best outcomes when there is a well-matched donor available because immune complications, such as graft-versus-host disease, are greater without a matched sibling donor. Gene therapy has been developed as a method to perform autologous transplantations of a patient's own stem cells that are genetically corrected. Through an iterative bench-to-bedside-and-back process, methods to efficiently add new copies of the relevant gene to hematopoietic stem cells have led to safe and effective treatments for several PIDs, including forms of severe combined immune deficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. New methods for gene editing might allow additional PIDs to be treated by gene therapy because they will allow the endogenous gene to be repaired and expressed under its native regulatory elements, which are essential for genes involved in cell processes of signaling, activation, and proliferation. Gene therapy is providing exciting new treatment options for patients with PIDs, and advances are sure to continue.

  12. The plethora, clinical manifestations and treatment options of autoimmunity in patients with primary immunodeficiency

    PubMed Central

    Barış, Hatice Ezgi; Kıykım, Ayça; Nain, Ercan; Özen, Ahmet Oğuzhan; Karakoç-Aydıner, Elif; Barış, Safa

    2016-01-01

    Aim Although the association between primary immunodeficiency and autoimmunity is already well-known, it has once again become a topic of debate with the discovery of newly-defined immunodeficiencies. Thus, investigation of the mechanisms of development of autoimmunity in primary immunodefficiency and new target-specific therapeutic options has come to the fore. In this study, we aimed to examine the clinical findings of autoimmunity, autoimmunity varieties, and treatment responses in patients who were genetically diagnosed as having primary immunodeficiency. Material and Methods The files of patients with primary immunodeficiency who had clinical findings of autoimmunity, who were diagnosed genetically, and followed up in our clinic were investigated. The demographic and clinical features of the patients and their medical treatments were evaluated. Results Findings of autoimmunity were found in 30 patients whose genetic mutations were identified. The mean age at the time of the first symptoms was 8.96±14.64 months, and the mean age of receiving a genetic diagnosis was 82.55±84.71 months. The most common diseases showing findings of autoimmunity included immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (16.7%); autoimmune lymphoproliferative syndrome (10%); lipopolysaccharide-responsive beige-like anchor protein deficiency (10%); and DiGeorge syndrome (10%). Twelve (40%) patients showed findings of autoimmunity at the time of first presentation. The most common findings of autoimmunity included inflammatory bowel disease, inflammatory bowel disease-like findings (n=14, 46.7%), immune thrombocytopenic purpura (n=11, 36.7%), and autoimmune hemolytic anemia (n=9, 30.0%). A response to immunosupressive agents was observed in 15 (50%) patients. Ten patients underwent hematopoietic stem cell transplantation. Six patients were lost to follow-up due to a variety of complications. Conclusion Autoimmunity is frequently observed in patients with

  13. Primary immunodeficiency diseases in Latin America: the second report of the LAGID registry.

    PubMed

    Leiva, Lily E; Zelazco, Marta; Oleastro, Matías; Carneiro-Sampaio, Magda; Condino-Neto, Antonio; Costa-Carvalho, Beatriz Tavares; Grumach, Anete Sevciovic; Quezada, Arnoldo; Patiño, Pablo; Franco, José Luis; Porras, Oscar; Rodríguez, Francisco Javier; Espinosa-Rosales, Francisco Javier; Espinosa-Padilla, Sara Elva; Almillategui, Diva; Martínez, Celia; Tafur, Juan Rodríguez; Valentín, Marilyn; Benarroch, Lorena; Barroso, Rosy; Sorensen, Ricardo U

    2007-01-01

    This is the second report on the continuing efforts of LAGID to increase the recognition and registration of patients with primary immunodeficiency diseases in 12 Latin American countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Honduras, Mexico, Panama, Paraguay, Peru, Uruguay, and Venezuela. This report reveals that from a total of 3321 patients registered, the most common form of primary immunodeficiency disease was predominantly antibody deficiency (53.2%) with IgA deficiency reported as the most frequent phenotype. This category was followed by 22.6% other well-defined ID syndromes, 9.5% combined T- and B-cell inmunodeficiency, 8.6% phagocytic disorders, 3.3% diseases of immune dysregulation, and 2.8% complement deficiencies. All countries that participated in the first publication in 1998 reported an increase in registered primary immunodeficiency cases, ranging between 10 and 80%. A comparison of the estimated minimal incidence of X-linked agammaglobulinemia, chronic granulomatous disease, and severe combined immunodeficiency between the first report and the present one shows an increase in the reporting of these diseases in all countries. In this report, the estimated minimal incidence of chronic granulomatous disease was between 0.72 and 1.26 cases per 100,000 births in Argentina, Chile, Costa Rica, and Uruguay and the incidence of severe combined immunodeficiency was 1.28 and 3.79 per 100,000 births in Chile and Costa Rica, respectively. However, these diseases are underreported in other participating countries. In addition to a better diagnosis of primary immunodeficiency diseases, more work on improving the registration of patients by each participating country and by countries that have not yet joined LAGID is still needed.

  14. Modeling strategy to identify patients with primary immunodeficiency utilizing risk management and outcome measurement.

    PubMed

    Modell, Vicki; Quinn, Jessica; Ginsberg, Grant; Gladue, Ron; Orange, Jordan; Modell, Fred

    2017-02-21

    This study seeks to generate analytic insights into risk management and probability of an identifiable primary immunodeficiency defect. The Jeffrey Modell Centers Network database, Jeffrey Modell Foundation's 10 Warning Signs, the 4 Stages of Testing Algorithm, physician-reported clinical outcomes, programs of physician education and public awareness, the SPIRIT® Analyzer, and newborn screening, taken together, generates P values of less than 0.05%. This indicates that the data results do not occur by chance, and that there is a better than 95% probability that the data are valid. The objectives are to improve patients' quality of life, while generating significant reduction of costs. The advances of the world's experts aligned with these JMF programs can generate analytic insights as to risk management and probability of an identifiable primary immunodeficiency defect. This strategy reduces the uncertainties related to primary immunodeficiency risks, as we can screen, test, identify, and treat undiagnosed patients. We can also address regional differences and prevalence, age, gender, treatment modalities, and sites of care, as well as economic benefits. These tools support high net benefits, substantial financial savings, and significant reduction of costs. All stakeholders, including patients, clinicians, pharmaceutical companies, third party payers, and government healthcare agencies, must address the earliest possible precise diagnosis, appropriate intervention and treatment, as well as stringent control of healthcare costs through risk assessment and outcome measurement. An affected patient is entitled to nothing less, and stakeholders are responsible to utilize tools currently available. Implementation offers a significant challenge to the entire primary immunodeficiency community.

  15. Glycosylation of Simian Immunodeficiency Virus Influences Immune-Tissue Targeting during Primary Infection, Leading to Immunodeficiency or Viral Control

    PubMed Central

    Sugimoto, Chie; Nakamura, Shinichiro; Hagen, Shoko I.; Tsunetsugu-Yokota, Yasuko; Villinger, Francois; Ansari, Aftab A.; Suzuki, Yasuo; Nagai, Yoshiyuki; Picker, Louis J.

    2012-01-01

    Glycans of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) play pivotal roles in modulating virus-target cell interactions. We have previously reported that, whereas SIVmac239 is pathogenic, its deglycosylated essentially nonpathogenic mutant (Δ5G) serves as a live-attenuated vaccine, although both replicate similarly during primary infection. These findings prompted us to determine whether such a polarized clinical outcome was due to differences in the immune tissues targeted by these viruses, where functionally and phenotypically different memory CD4+ T cells reside. The results showed that Δ5G replicates in secondary lymphoid tissue (SLT) at 1- to 2-log-lower levels than SIVmac239, whereas SIVmac239-infected but not Δ5G-infected animals deplete CXCR3+ CCR5+ transitional memory (TrM) CD4+ T cells. An early robust Δ5G replication was localized to small intestinal tissue, especially the lamina propria (effector site) rather than isolated lymphoid follicles (inductive site) and was associated with the induction and depletion of CCR6+ CXCR3− CCR5+ effector memory CD4+ T cells. These results suggest that differential glycosylation of Env dictates the type of tissue-resident CD4+ T cells that are targeted, which leads to pathogenic infection of TrM-Th1 cells in SLT and nonpathogenic infection of Th17 cells in the small intestine, respectively. PMID:22718828

  16. Single-Center Experience of Unrelated and Haploidentical Stem Cell Transplantation with TCRαβ and CD19 Depletion in Children with Primary Immunodeficiency Syndromes.

    PubMed

    Balashov, Dmitry; Shcherbina, Anna; Maschan, Michael; Trakhtman, Pavel; Skvortsova, Yulia; Shelikhova, Larisa; Laberko, Alexandra; Livshits, Anna; Novichkova, Galina; Maschan, Alexei

    2015-11-01

    The transplantation of stem cells from a matched unrelated donor (MUD) or a haploidentical mismatched related donor (MMRD) is a widely used variant of curative treatment for patients with primary immunodeficiency (PID). Currently, different strategies are used to reduce the risk of post-transplant complications and enhance immune reconstitution. We report the preliminary results of MUD and MMRD transplantation with TCRαβ/CD19 depletion in patients with PID (trial registered at www.clinicaltrials.gov as NCT02327351). Thirty-seven PID patients (median age, 2.6 years; range, .2 to 17) were transplanted from MUDs (n = 27) or haploidentical MMRDs (n = 10) after TCRαβ(+)/CD19(+) graft depletion. The median numbers of CD34(+) and TCRαβ(+) cells in the graft were 11.7 × 10(6)/kg and 10.6 × 10(3)/kg, respectively. Acute graft-versus-host disease (GVHD) was observed in 8 patients (22%), without a statistically significant difference between MUDs and MMRDs; 7 of these patients had grade II acute GVHD and responded to first-line therapy, whereas 1 patient had grade IV acute GVHD with transformation to extensive chronic GVHD. Primary and secondary graft failure (nonengraftment or rejection) was observed in 10 patients (27%), 9 of whom were treated with 1 alkylating agent in the conditioning regimen. All these patients were successfully retransplanted with different rescue protocols. Preliminary data on immune reconstitution were very encouraging. Most patients had significant numbers of T lymphocytes detected on the first assessment (day +30) and more than 500 T cells/μL, on day +120. Based on our preliminary data, no significant difference was seen between MMRD and MUD hematopoietic stem cell transplantation (HSCT). With a median follow-up period of 15 months, the cumulative probabilities of overall patient survival and transplant-related mortality were 96.7% and 3.3%, respectively. Based on the results, the ability to control the main post

  17. Surface markers on human lymphocytes: studies of normal subjects and of patients with primary immunodeficiencies

    PubMed Central

    Aiuti, F.; Lacava, V.; Garofalo, J. A.; D'Amelio, R.; D'Asero, C.

    1973-01-01

    Peripheral blood lymphocytes of twenty normal controls and twelve patients with primary immunodeficiencies were examined for surface membrane Ig and receptors for C3 complement (B cell markers) and for spontaneous rosette formation with sheep erythrocytes (T cell markers). In patients with defects in T cell function no lymphocytes forming spontaneous rosettes were seen. In patients with B cell deficiency they were normal or increased. Lymphocytes with membrane immunoglobulins were normal in patients with T cell defect and absent in patients with severe agammaglobulinaemia. Lymphocytes with receptors for C3 complement were increased in patients with T defect and normal in patients with most other forms of immunodeficiency studied. PMID:4587827

  18. [Primary hepatic lymphoma in subjects with acquired immunodeficiency syndrome].

    PubMed

    Trinchieri, V; Causo, T; Fabietti, P; Bellagamba, R; Berardelli, G; Cirelli, A; Catania, S

    1992-02-01

    In this study the authors describe a non-Hodgkin's lymphoma histologically typed "large non-cleaved cell immunophenotype B cell", placed primitively into the liver. It affected a woman twenty seven years old, who contracted HIV infection due to heterosexual intercourse with at risk partner. At the time of diagnosis the woman was already considered AIDS patient on account of a previous Pneumocystis carinii pneumoniae and severe immunodeficiency (DC4 = 13 cells/mm3). The patient received cycles of chemotherapy (adriamycin 40 mg/iv, teniposide 50 mg/iv, cyclophosphamide 500 mg/iv, vincristine 2 mg/iv, bleomycin 15 mg/iv, betamethasone 4 mg/iv). At the 15th day of therapeutic cycle vincristine 2 mg/iv, bleomycin 15 mg/iv and betamethasone 4 mg/iv were given. After one cycle of therapy, hepatic echography showed signs that the lymphoma was reduced significantly. The authors stress the uncommon non-Hodgkin lymphoma localization, which is frequently underestimated in HIV-patients.

  19. Primary immunodeficiency diseases in Latin America: proceedings of the Second Latin American Society for Immunodeficiencies (LASID) Advisory Board.

    PubMed

    Leiva, L E; Bezrodnik, L; Oleastro, M; Condino-Neto, A; Costa-Carvalho, B T; Grumach, A Sevciovic; Espinosa-Rosales, F J; Franco, J Luis; King, A; Inostroza, J; Quezada, A; Porras, O; Sorensen, R U

    2011-01-01

    Early diagnosis and appropriate therapy are essential for the best prognosis and quality of life in patients with primary immunodeficiency diseases (PIDDs). Experts from several Latin American countries have been meeting on a regular basis as part of an ongoing effort to improve the diagnosis and treatment of PIDD in this region. Three programmes are in development that will expand education and training and improve access to testing facilities throughout Latin America. These programmes are: an educational outreach programme (The L-Project); an immunology fellowship programme; and the establishment of a laboratory network to expand access to testing facilities. This report provides the status of these programmes based on the most recent discussions and describes the next steps toward full implementation of these programmes. Copyright © 2010 SEICAP. Published by Elsevier Espana. All rights reserved.

  20. Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience.

    PubMed

    Fernandes, Juliana Folloni; Kerbauy, Fabio Rodrigues; Ribeiro, Andreza Alice Feitosa; Kutner, Jose Mauro; Camargo, Luis Fernando Aranha; Stape, Adalberto; Troster, Eduardo Juan; Zamperlini-Netto, Gabriele; Azambuja, Alessandra Milani Prandini de; Carvalho, Bruna; Dorna, Mayra de Barros; Vilela, Marluce Dos Santos; Jacob, Cristina Miuki Abe; Costa-Carvalho, Beatriz Tavares; Cunha, Jose Marcos; Carneiro-Sampaio, Magda Maria; Hamerschlak, Nelson

    2011-06-01

    To report the experience of a tertiary care hospital with allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies. Seven pediatric patients with primary immunodeficiencies (severe combined immunodeficiency: n = 2; combined immunodeficiency: n = 1; chronic granulomatous disease: n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1) who underwent eight hematopoietic stem cell transplants in a single center, from 2007 to 2010, were studied. Two patients received transplants from HLA-identical siblings; the other six transplants were done with unrelated donors (bone marrow: n = 1; cord blood: n = 5). All patients had pre-existing infections before hematopoietic stem cell transplants. One patient received only anti-thymocyte globulin prior to transplant, three transplants were done with reduced intensity conditioning regimens and four transplants were done after myeloablative therapy. Two patients were not evaluated for engraftment due to early death. Three patients engrafted, two had primary graft failure and one received a second transplant with posterior engraftment. Two patients died of regimen related toxicity (hepatic sinusoidal obstruction syndrome); one patient died of progressive respiratory failure due to Parainfluenza infection present prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Patients' status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

  1. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis

    PubMed Central

    Bode, Sebastian FN; Ammann, Sandra; Al-Herz, Waleed; Bataneant, Mihaela; Dvorak, Christopher C; Gehring, Stephan; Gennery, Andrew; Gilmour, Kimberly C; Gonzalez-Granado, Luis I; Groß-Wieltsch, Ute; Ifversen, Marianne; Lingman-Framme, Jenny; Matthes-Martin, Susanne; Mesters, Rolf; Meyts, Isabelle; van Montfrans, Joris M; Schmid, Jana Pachlopnik; Pai, Sung-Yun; Soler-Palacin, Pere; Schuermann, Uta; Schuster, Volker; Seidel, Markus G.; Speckmann, Carsten; Stepensky, Polina; Sykora, Karl-Walter; Tesi, Bianca; Vraetz, Thomas; Waruiru, Catherine; Bryceson, Yenan T.; Moshous, Despina; Lehmberg, Kai; Jordan, Michael B; Ehl, Stephan

    2015-01-01

    Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as “lympho”-histiocytosis in these patients; and (iii) current criteria for

  2. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis.

    PubMed

    Bode, Sebastian Fn; Ammann, Sandra; Al-Herz, Waleed; Bataneant, Mihaela; Dvorak, Christopher C; Gehring, Stephan; Gennery, Andrew; Gilmour, Kimberly C; Gonzalez-Granado, Luis I; Groß-Wieltsch, Ute; Ifversen, Marianne; Lingman-Framme, Jenny; Matthes-Martin, Susanne; Mesters, Rolf; Meyts, Isabelle; van Montfrans, Joris M; Pachlopnik Schmid, Jana; Pai, Sung-Yun; Soler-Palacin, Pere; Schuermann, Uta; Schuster, Volker; Seidel, Markus G; Speckmann, Carsten; Stepensky, Polina; Sykora, Karl-Walter; Tesi, Bianca; Vraetz, Thomas; Waruiru, Catherine; Bryceson, Yenan T; Moshous, Despina; Lehmberg, Kai; Jordan, Michael B; Ehl, Stephan

    2015-07-01

    Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as "lympho"-histiocytosis in these patients; and (iii) current criteria for hemophagocytoc

  3. [Phenotypic diagnosis of primary immunodeficiencies in Antioquia, Colombia, 1994-2002].

    PubMed

    Montoya, Carlos Julio; Henao, Julieta; Salgado, Helí; Olivares, María M; López, Juan A; Rugeles, Claudia; Franco, José Luis; Orrego, Julio; García, Diana M; Patiño, Pablo J

    2002-12-01

    Recurrent infections are a frequent cause of medical visits. They can be due to a heterogeneous group of dysfunctions that increase the susceptibility to pathogenic and opportunistic microorganisms, such as immunological deficiencies. To define an opportune rational treatment and to guide the molecular diagnosis of primary immunodeficiency diseases, we establish a program for the phenotypic diagnosis of these illnesses in Antioquia, Colombia, including clinical and laboratory evaluations of patients who present recurrent infections with abnormal evolution. Between August 1, 1994 and July 31, 2002, phenotypic diagnosis of primary immunodeficiency was made in 98 patients. Similar to data reported in the literature, antibody deficiencies were the most frequent (40.8%), followed by combined deficiencies (21.4%). This phenotypic characterization has allowed for appropriate treatments for each patient and, in some cases, functional and molecular studies that can lead to a definite molecular diagnosis.

  4. Gene hunting in the genomic era: Approaches to diagnostic dilemmas in patients with primary immunodeficiencies

    PubMed Central

    Platt, Craig; Geha, Raif S.; Chou, Janet

    2013-01-01

    There are more than 180 different genetic causes of primary immunodeficiencies identified to date. Approaches for identifying causative mutations can be broadly classified into 3 strategies: (1) educated guesses based on known signaling pathways essential for immune cell development and function, (2) similarity of clinical phenotypes to mouse models, and (3) unbiased genetic approaches. Next-generation DNA sequencing permits efficient sequencing of whole genomes or exomes but also requires strategies for filtering vast amounts of data. Recent studies have identified ways to solve difficult cases, such as diseases with autosomal dominant inheritance, incomplete penetrance, or mutations in noncoding regions. This review focuses on recently identified primary immunodeficiencies to illustrate the strategies, technologies, and potential pitfalls in finding novel causes of these diseases. PMID:24100122

  5. Human Immunodeficiency Virus Type 1 Coat Protein Neurotoxicity Mediated by Nitric Oxide in Primary Cortical Cultures

    NASA Astrophysics Data System (ADS)

    Dawson, Valina L.; Dawson, Ted M.; Uhl, George R.; Snyder, Solomon H.

    1993-04-01

    The human immunodeficiency virus type 1 coat protein, gp120, kills neurons in primary cortical cultures at low picomolar concentrations. The toxicity requires external glutamate and calcium and is blocked by glutamate receptor antagonists. Nitric oxide (NO) contributes to gp120 toxicity, since nitroarginine, an inhibitor of NO synthase, prevents toxicity as does deletion of arginine from the incubation medium and hemoglobin, which binds NO. Superoxide dismutase also attenuates toxicity, implying a role for superoxide anions.

  6. Efficacy and tolerability of an argentine intravenous immunoglobulin in pediatric patients with primary immunodeficiency diseases.

    PubMed

    Krasovec, S; Ornani, A; Oleastro, M; Rosenzweig, S; Roy, A; Perez, L; Campos, G; Marín, N; Martinez, A; Mahieu, C; Manfredi, M J; Sisti, A; Zelazko, M

    2007-03-01

    Inmunoglobulina G Endovenosa UNC is a 5% liquid Argentine intravenous immunoglobulin obtained from South American donors. This prospective trial was designed to evaluate if the product meets the minimal efficacy requirement of the US Food and Drug Administration of <1 serious infection/subject/year as well as its safety in pediatric patients with Primary Immunodeficiency Diseases. Thirty patients under the age of 18, with well-defined Primary Immunodeficiency Diseases received Inmunoglobulina G Endovenosa UNC (330-700 mg/kg every 3-4 weeks) for 6 months. Vital signs, laboratory abnormalities, adverse events and viral tests were assessed to evaluate safety. Two serious infections occurred (pneumonia and bacteriemia). The estimated infection rate was 0.114 serious infection/subject/year (95% CI, 0.003-0.2277). Minor adverse events occurred in 5.5% of infusions; fever and headache were the most common. Neither severe adverse events, nor abnormal laboratory values were observed. All viral assessments were negative. Inmunoglobulina G Endovenosa UNC meets the minimal efficacy requirement of the US Food and Drug Administration for pediatric Primary Immunodeficiency Diseases patients and showed efficacy and safety data comparable with other data published.

  7. EBV-positive primary central nervous system lymphomas in monozygote twins with common variable immunodeficiency and suspected multiple sclerosis.

    PubMed

    Jensen, M K; Koch-Henriksen, N; Johansen, P; Varming, K; Christiansen, C B; Knudsen, F

    1997-12-01

    Common variable immunodeficiency represents the most frequently occurring primary immunodeficiency disorder and is usually detected sporadically in patients with no family history of immunodeficiency. We present the case stories of two monozygote twins, who following a period of decreasing serum immunoglobulins developed primary central nervous system lymphomas. One twin had clinical and paraclinical features mimicking multiple sclerosis. Immunohistochemical investigations on biopsy tissue showed expression of the bcl-2 and p53 gene products, and Epstein-Barr virus (EBV) encoded small RNA's (EBER) indicating latent infection were detected in lymphoma cells using in situ hybridisation techniques. The pathogenetic role of EBV in oncogenesis is discussed.

  8. Severe Thrombocytopenia and Acute Cytomegalovirus Colitis during Primary Human Immunodeficiency Virus Infection

    PubMed Central

    Furuhata, Masanori; Yanagisawa, Naoki; Nishiki, Shingo; Sasaki, Shugo; Suganuma, Akihiko; Imamura, Akifumi; Ajisawa, Atsushi

    2016-01-01

    We herein report the case of a 25-year-old man who was referred to our hospital due to acute cytomegalovirus (CMV) colitis. The initial blood tests showed that the patient had concurrent primary human immunodeficiency virus (HIV) infection and severe thrombocytopenia. Raltegravir-based antiretroviral therapy (ART) was initiated without the use of ganciclovir or corticosteroids and resulted in a rapid clinical improvement. Platelet transfusions were only necessary for a short period, and subsequent colonoscopy revealed a completely healed ulcer. This case implies that ART alone could be effective for treating severe thrombocytopenia during primary HIV and CMV coinfection. PMID:27980271

  9. [Survival analysis of hematopoietic stem cell transplantation in children with primary immunodeficiency in Spain].

    PubMed

    Hladun, R; Badell, I; González, M; Martínez, A M; Sánchez de Toledo, J; Olivé, M T; González, M E; Elorza, I; Díaz de Heredia, C

    2015-02-01

    Children with primary immunodeficiency have severe life-threatening infections and a higher prevalence of autoimmune problems, allergy and lymphoproliferative disorders. Allogenic hematopoietic stem cell transplantation has been the only potentially curative option. Patients with primary immunodeficiency underwent allogenic stem cell transplantation in the period 1985-2011, and registered in the Spanish Working Party for Bone Marrow Transplantation in Children. One hundred and fifty nine patients underwent 173 allogenic stem cell transplantations, of whom 97 had severe combined immunodeficiency, 30 with immune dysregulation disorders, 25 Wiskott-Aldrich syndrome, and 21 phagocyte disorders. The median patient age at diagnosis was 6 months (range: 17 days - 168 months) and the median patient age at transplant was 12 months (range: 1 month - 189 months). The donors were 30 (19%) identical siblings, 40 (25%) alternative family donors, and 89 (56%) unrelated donors. The source of stem cells was bone marrow in 68 (43%), cord blood in 52 (33%), and peripheral blood in 39 (24%). Ninety eight (61.6%) are alive, 57 (35.9%) died. Event-free survival at 10 years was 63%, with 90% for children transplanted from identical siblings, 36% for those transplanted from alternative family donors, and 66% for those transplanted from unrelated donors. The best results have been obtained with identical siblings, but other options may be considered. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  10. Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases.

    PubMed

    Candotti, Fabio

    2014-04-01

    Gene transfer into the hematopoietic stem cell has shown curative potential for a variety of hematological disorders. Primary immunodeficiency diseases have led to the way in this field of gene therapy as an example and a model. Clinical results from the past 15 years have shown that significant improvement and even cure can be achieved for diseases such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease and Wiskott-Aldrich syndrome. Unfortunately, with the initial clear clinical benefits, the first serious complications of gene therapy have also occurred. In a significant number of patients treated using vectors based on murine gamma-retroviruses and carrying powerful viral enhancer elements, insertional oncogenesis events have resulted in acute leukemias that, in some cases, have had fatal outcomes. These serious adverse events have sparked a revision of the assessment of risks and benefits of integrating gene transfer for hematological diseases and prompted the development and application of new generations of viral vectors with recognized superior safety characteristics. This review summarizes the clinical experience of gene therapy for primary immunodeficiencies and discusses the likely avenues of progress in the future development of this expanding field of clinical investigations.

  11. Formalin-treated bacteria as selective B cell mitogens: results in primary and acquired immunodeficiencies.

    PubMed Central

    Sirianni, M C; Pucillo, L P; Fiorilli, M; Aiuti, F; Banck, G; Forsgren, A

    1981-01-01

    The mitogenic activity of the formalin-treated bacterial strains Branhamella catarrhalis, Haemophilus influenzae and the Cowan I strain of Staphylococcus aureus was assessed in peripheral blood lymphocytes (PBL) from patients with primary immunodeficiencies, acute lymphocytic leukaemia (ALL), chronic lymphocytic leukemia (CLL) and in umbilical cord blood lymphocytes. The bacteria selectively stimulated B cells, as demonstrated by the finding of a normal de novo DNA synthesis in children with a T cell defect and of an absent response in X-linked agammaglobulinaemia and severe combined immunodeficiency. A decreased mitogenic activity was exerted on PBL from four out of seven adults with common variable hypogammaglobulinemia (CVH). In B-CLL the mitogenic activity was normal while in T-ALL it was decreased. Umbilical cord blood lymphocytes responded better than PBL from adults. The selective stimulative ability of the bacteria for B lymphocytes is expressed when PBL are cultured together with the formalin-treated bacteria for 48 to 72 hr. PMID:6976247

  12. Inflammatory Duodenal Polyposis Associated with Primary Immunodeficiency Disease: A Novel Case Report

    PubMed Central

    Shera, Irfan Ali; Khurshid, Sheikh Mudassir

    2017-01-01

    Agammaglobulinemia is a rare form of B-cell primary immunodeficiency disease characterized by reduced levels of IgG, IgA, or IgM and recurrent bacterial infections. Agammaglobulinemia is most commonly associated with diffuse nodular lymphoid hyperplasia. Duodenal polyps are a rare entity; however, due to wide use of esophagogastroduodenoscopy, incidental diagnosis of duodenal polyps appears to be increasing. Although inflammatory duodenal polyposis has been reported in the literature, its association with common variable immunodeficiency has not been reported till date to the best of our knowledge. We report a case of a 59-year-old male with chronic symptoms of agammaglobulinemia associated with inflammatory duodenal polyposis. PMID:28163721

  13. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management.

    PubMed

    Griffith, Linda M; Cowan, Morton J; Notarangelo, Luigi D; Puck, Jennifer M; Buckley, Rebecca H; Candotti, Fabio; Conley, Mary Ellen; Fleisher, Thomas A; Gaspar, H Bobby; Kohn, Donald B; Ochs, Hans D; O'Reilly, Richard J; Rizzo, J Douglas; Roifman, Chaim M; Small, Trudy N; Shearer, William T

    2009-12-01

    More than 20 North American academic centers account for the majority of hematopoietic stem cell transplantation (HCT) procedures for primary immunodeficiency diseases (PIDs), with smaller numbers performed at additional sites. Given the importance of a timely diagnosis of these rare diseases and the diversity of practice sites, there is a need for guidance as to best practices in management of patients with PIDs before, during, and in follow-up for definitive treatment. In this conference report of immune deficiency experts and HCT physicians who care for patients with PIDs, we present expert guidance for (1) PID diagnoses that are indications for HCT, including severe combined immunodeficiency disease (SCID), combined immunodeficiency disease, and other non-SCID diseases; (2) the critical importance of a high degree of suspicion of the primary care physician and timeliness of diagnosis for PIDs; (3) the need for rapid referral to an immune deficiency expert, center with experience in HCT, or both for patients with PIDs; (4) medical management of a child with suspicion of SCID/combined immunodeficiency disease while confirming the diagnosis, including infectious disease management and workup; (5) the posttransplantation follow-up visit schedule; (6) antimicrobial prophylaxis after transplantation, including gamma globulin administration; and (7) important indications for return to the transplantation center after discharge. Finally, we discuss the role of high-quality databases in treatment of PIDs and HCT as an element of the infrastructure that will be needed for productive multicenter clinical trials in these rare diseases.

  14. Improving cellular therapy for primary immune deficiency diseases: Recognition, diagnosis, and management

    PubMed Central

    Griffith, Linda M.; Cowan, Morton J.; Notarangelo, Luigi D.; Puck, Jennifer M.; Buckley, Rebecca H.; Candotti, Fabio; Conley, Mary Ellen; Fleisher, Thomas A.; Gaspar, H. Bobby; Kohn, Donald B.; Ochs, Hans D.; O'Reilly, Richard J.; Rizzo, J. Douglas; Roifman, Chaim M.; Small, Trudy N.; Shearer, William T.

    2010-01-01

    More than 20 North American academic centers account for the majority of hematopoietic stem cell transplantation (HCT) procedures for primary immunodeficiency diseases (PIDs), with smaller numbers performed at additional sites. Given the importance of a timely diagnosis of these rare diseases and the diversity of practice sites, there is a need for guidance as to best practices in management of patients with PIDs before, during, and in follow-up for definitive treatment. In this conference report of immune deficiency experts and HCT physicians who care for patients with PIDs, we present expert guidance for (1) PID diagnoses that are indications for HCT, including severe combined immunodeficiency disease (SCID), combined immunodeficiency disease, and other non-SCID diseases; (2) the critical importance of a high degree of suspicion of the primary care physician and timeliness of diagnosis for PIDs; (3) the need for rapid referral to an immune deficiency expert, center with experience in HCT, or both for patients with PIDs; (4) medical management of a child with suspicion of SCID/combined immunodeficiency disease while confirming the diagnosis, including infectious disease management and workup; (5) the posttransplantation follow-up visit schedule; (6) antimicrobial prophylaxis after transplantation, including gamma globulin administration; and (7) important indications for return to the transplantation center after discharge. Finally, we discuss the role of high-quality databases in treatment of PIDs and HCTas an element of the infrastructure that will be needed for productive multicenter clinical trials in these rare diseases. PMID:20004776

  15. II Brazilian Consensus on the use of human immunoglobulin in patients with primary immunodeficiencies.

    PubMed

    Goudouris, Ekaterini Simões; Rego Silva, Almerinda Maria do; Ouricuri, Aluce Loureiro; Grumach, Anete Sevciovic; Condino-Neto, Antonio; Costa-Carvalho, Beatriz Tavares; Prando, Carolina Cardoso; Kokron, Cristina Maria; Vasconcelos, Dewton de Moraes; Tavares, Fabíola Scancetti; Silva Segundo, Gesmar Rodrigues; Barreto, Irma Cecília; Dorna, Mayra de Barros; Barros, Myrthes Anna; Forte, Wilma Carvalho Neves

    2017-01-01

    In the last few years, new primary immunodeficiencies and genetic defects have been described. Recently, immunoglobulin products with improved compositions and for subcutaneous use have become available in Brazil. In order to guide physicians on the use of human immunoglobulin to treat primary immunodeficiencies, based on a narrative literature review and their professional experience, the members of the Primary Immunodeficiency Group of the Brazilian Society of Allergy and Immunology prepared an updated document of the 1st Brazilian Consensus, published in 2010. The document presents new knowledge about the indications and efficacy of immunoglobulin therapy in primary immunodeficiencies, relevant production-related aspects, mode of use (routes of administration, pharmacokinetics, doses and intervals), adverse events (major, prevention, treatment and reporting), patient monitoring, presentations available and how to have access to this therapeutic resource in Brazil. RESUMO Nos últimos anos, novas imunodeficiências primárias e defeitos genéticos têm sido descritos. Recentemente, produtos de imunoglobulina, com aprimoramento em sua composição e para uso por via subcutânea, tornaram-se disponíveis em nosso meio. Com o objetivo de orientar o médico no uso da imunoglobulina humana para o tratamento das imunodeficiências primárias, os membros do Grupo de Assessoria em Imunodeficiências da Associação Brasileira de Alergia e Imunologia produziram um documento que teve por base uma revisão narrativa da literatura e sua experiência profissional, atualizando o I Consenso Brasileiro publicado em 2010. Apresentam-se novos conhecimentos sobre indicações e eficácia do tratamento com imunoglobulina nas imunodeficiências primárias, aspectos relevantes sobre a produção, forma de utilização (vias de administração, farmacocinética, doses e intervalos), efeitos adversos (principais efeitos, prevenção, tratamento e notificação), monitorização do

  16. Efficacy and safety of a new immunoglobulin G product, Gammaplex®, in primary immunodeficiency diseases

    PubMed Central

    Moy, J N; Scharenberg, A M; Stein, M R; Suez, D; Roberts, R L; Levy, R J; Ballow, M; Fasano, M B; Dash, C H; Leach, S J

    2010-01-01

    This open-label multi-centre study evaluated a new intravenous immunoglobulin, Gammaplex®, in the treatment of 50 patients with primary immunodeficiency and significant hypogammglobulinaemia. Patients treated previously with other intravenous immunoglobulins received Gammaplex® on their same infusion schedule for 1 year; 22 were on a 21-day and 28 on a 28-day regimen (300–800 mg/kg/infusion). There were no serious, acute bacterial infections, whereas six subjects (12·0%) had at least one such infection in the 6 months before enrolment. Forty subjects (80·0%) had at least one non-serious infection; the median number of infective episodes per subject per year was 3·07. Antibiotics were taken by 38 subjects therapeutically and prophylactically by 16 at some time. Fewer than half (46·0%) missed any time off work or school because of infection or other illness. Trough immunoglobulin (Ig)G levels were above 6·00 g/l in all subjects at all assessments after 15 weeks with two exceptions. Overall, 21·2% of infusions were associated with an adverse event up to 72 h after infusion. The frequency of adverse events increased with infusion rate. Headache was the most common product-related adverse event (7·5% of 703 infusions). In conclusion, Gammaplex® is effective in primary immunodeficiency and is well tolerated. PMID:21070209

  17. Does the proper intravenous immunoglobulin substitution in primary immunodeficiency protect against HBV infections?: a description of a case series.

    PubMed

    Joanna, Glück; Slawomir, Zeglen; Barbara, Rymarczyk; Barbara, Rogala

    2008-09-01

    There are no recommendations concerning preoperative management of primary immunodeficiency patients in cases of emergency or planned surgery in relation to risk of hepatitis type B virus infection. To assess if immunodeficient patients regularly supplemented with immunoglobulins are protected against hepatitis B. IgG, IgM and IgA total levels and anti-HBs level were estimated in adult patients with primary humoral immunodeficiency before and after immunoglobulins supplementation according to a standardized schedule. Serum IgG and anti-HBs level significantly increased after immunoglobulin supplementation. Anti-HBs titer increased in all cases over 100 IU/L regardless of initial total IgG serum value, reaching a highly protective level. There was no correlation between increase in concentration of IgG (DeltaIgG) versus Deltaanti-HBs in the studied patients. Patients with primary hypogammaglobulinemia supplemented with immunoglobulin are protected against hepatitis type B.

  18. Cytokine-Mediated Regulation of Human Lymphocyte Development and Function: Insights from Primary Immunodeficiencies.

    PubMed

    Tangye, Stuart G; Pelham, Simon J; Deenick, Elissa K; Ma, Cindy S

    2017-09-15

    Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of individuals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such individuals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation. Copyright © 2017 by The American Association of Immunologists, Inc.

  19. [Sepsis due to Pseudomona as a debut of a primary immunodeficiency in a child].

    PubMed

    Vera Sáez-Benito, M Cristina; López Úbeda, Marta; Madurga Revilla, Paula; de Arriba Muñoz, Antonio; Bustillo Alonso, Matilde; Rodríguez-Vigil Iturrate, Carmen

    2016-12-01

    X-linked agammaglobulinemia is a primary humoral immunodeficiency. It is a recessive X-linked disorder characterized by low or absent circulating mature B cells, hypo/agammaglobulinemia and no humoral response to immunizations due to mutations along chromosome X. It is characterized by severe, recurrent and difficult treatment infections. It is diagnosed in the first 6 months of life in children; the only sign of alarm is the absent or decreased size of tonsils and lymph nodes, but it is not always present. The main cornerstones of treatment are immunoglobulin replacement therapy to maintain serum levels above 500-700 mg/dl and infection control; this allows these patients to do their day-to-day activities. We report a 2 year old boy with X-linked agammaglobulinemia, with no history of interest, who presented with P. aeruginosa sepsis. He had an excellent clinical improvement without further important infections after intravenous immunoglobulin replacement therapy.

  20. Immune globulin (human) 10 % liquid: a review of its use in primary immunodeficiency disorders.

    PubMed

    McCormack, Paul L

    2013-08-01

    Human immune globulin (IG) 10 % liquid (Gammagard Liquid®) is a ready-to-use, highly purified, and concentrated immunoglobulin (Ig)G solution approved in the US for both intravenous and subcutaneous antibody replacement therapy in patients aged ≥ 2 years with primary humoral immunodeficiency. Intravenous IG 10 % liquid every 3-4 weeks for ≥ 12 months, at median serum IgG trough levels of 9.6-11.2 g/L, completely prevented acute serious bacterial infections (SBIs) in a phase III clinical trial. Weekly subcutaneous IG 10 % liquid at a dose equal to 137 % of the equivalent weekly intravenous dose, which was earlier determined to produce the same IgG exposure, produced higher serum trough IgG levels and lower peak IgG levels than intravenous administration, and also effectively reduced SBIs; the infection rate was 0.067 SBIs/subject/year, which met the US FDA efficacy criterion of < 1 SBI/subject/year. The rates for non-serious infections of any kind were low for both intravenous and subcutaneous therapy. Both intravenous and subcutaneous IG 10 % liquid were safe and generally well tolerated. Systemic adverse reactions were more frequent with intravenous therapy and local infusion-site reactions were more frequent with subcutaneous therapy, but the latter reduced over time. Most adverse reactions were of mild or moderate intensity. Thus, IG 10 % liquid is an effective and generally well-tolerated preparation for both intravenous and subcutaneous IgG replacement therapy in patients with primary immunodeficiency disorders involving antibody deficiency. It offers the benefits of a ready-to-use, liquid preparation and the convenience of home-based therapy in appropriate patients.

  1. Disseminated bronchiectasis in an adult with common variable immunodeficiency.

    PubMed

    Zea-Vera, Andrés Felipe; Agudelo-Rojas, Olga Lucia

    2015-01-01

    Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year-old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow-up. Common Variable Immunodeficiency (CVID) diagnosis was made.

  2. Disseminated bronchiectasis in an adult with common variable immunodeficiency

    PubMed Central

    Agudelo-Rojas, Olga Lucia

    2015-01-01

    Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year-old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow-up. Common Variable Immunodeficiency (CVID) diagnosis was made. PMID:26019385

  3. Single-Particle Tracking of Human Immunodeficiency Virus Type 1 Productive Entry into Human Primary Macrophages.

    PubMed

    Li, Qin; Li, Wei; Yin, Wen; Guo, Jia; Zhang, Zhi-Ping; Zeng, Dejun; Zhang, Xiaowei; Wu, Yuntao; Zhang, Xian-En; Cui, Zongqiang

    2017-04-25

    Macrophages are one of the major targets of human immunodeficiency virus (HIV-1), but the viral entry pathway remains poorly understood in these cells. Noninvasive virus labeling and single-virus tracking are effective tools for studying virus entry. Here, we constructed a quantum dot (QD)-encapsulated infectious HIV-1 particle to track viral entry at a single-particle level in live human primary macrophages. QDs were encapsulated in HIV-1 virions by incorporating viral accessory protein Vpr-conjugated QDs during virus assembly. With the HIV-1 particles encapsulating QDs, we monitored the early phase of viral infection in real time and observed that, during infection, HIV-1 was endocytosed in a clathrin-mediated manner; the particles were translocated into Rab5A-positive endosomes, and the core was released into the cytoplasm by viral envelope-mediated endosomal fusion. Drug inhibition assays verified that endosome fusion contributes to HIV-1 productive infection in primary macrophages. Additionally, we observed that a dynamic actin cytoskeleton is critical for HIV-1 entry and intracellular migration in primary macrophages. HIV-1 dynamics and infection could be blocked by multiple different actin inhibitors. Our study revealed a productive entry pathway in macrophages that requires both endosomal function and actin dynamics, which may assist in the development of inhibitors to block the HIV entry in macrophages.

  4. Immunodeficiency disorders in horses.

    PubMed

    Crisman, Mark V; Scarratt, W Kent

    2008-08-01

    Immunodeficiencies are characterized as primary (genetic) or secondary (acquired). Primary immunodeficiencies are relatively uncommon; however, clinically, they present a significant challenge to the practitioner, especially if the underlying disorder goes unrecognized. Secondary immunodeficiencies may present at any age, but failure of passive transfer in neonatal foals is most commonly encountered. This article provides a general overview of clinical signs and diagnosis of primary and secondary immunodeficiencies currently recognized in horses.

  5. Prospective evaluation of Streptococcus pneumoniae serum antibodies in patients with primary immunodeficiency on regular intravenous immunoglobulin treatment.

    PubMed

    Simão-Gurge, R M; Costa-Carvalho, B T; Nobre, F A; Gonzalez, I G S; de Moraes-Pinto, M I

    This is a prospective study that assessed pneumococcal antibody levels in PID patients under intravenous immunoglobulin (IVIG) treatment using different brands. Twenty-one patients receiving regular IVIG every 28 days were invited to participate: 12 with common variable immunodeficiency, six with X-linked agammaglobulinaemia and three with hyper-IgM syndrome. One blood sample was collected from each patient just prior to IVIG administration at a three-month time interval during one year. A questionnaire was filled in with patient's demographic data and history of infections during the study period. Streptococcus pneumoniae antibodies against six serotypes (1, 5, 6B, 9V, 14 and 19F) were assessed by ELISA both in patients' serum (trough levels) and in IVIG samples. Median total IgG trough serum levels were 7.91g/L (range, 4.59-12.20). All patients had antibody levels above 0.35μg/mL to the six serotypes on all four measurements. However, only 28.6% of patients had pneumococcal antibodies for the six analysed serotypes above 1.3μg/mL on all four evaluations during the one-year period. No correlation was found between IgG trough levels and pneumococcal specific antibodies. Eighteen of the 21 patients (85.7%) had infections at some point during the 12-month follow-up, 62/64 (96.9%) clinically classified in respiratory tract infections, four of which were pneumonia. Pneumococcal antibodies are present in a high range of concentrations in sera from PID patients and also in IVIG preparations. Even maintaining a recommended IgG trough level, these patients can be susceptible to these bacteria and that may contribute to recurrent respiratory infections. Copyright © 2016 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

  6. Replication of human immunodeficiency virus type 1 in primary dendritic cell cultures.

    PubMed Central

    Langhoff, E; Terwilliger, E F; Bos, H J; Kalland, K H; Poznansky, M C; Bacon, O M; Haseltine, W A

    1991-01-01

    The ability of the human immunodeficiency virus type 1 (HIV-1) to replicate in primary blood dendritic cells was investigated. Dendritic cells compose less than 1% of the circulating leukocytes and are nondividing cells. Highly purified preparations of dendritic cells were obtained using recent advances in cell fractionation. The results of these experiments show that dendritic cells, in contrast to monocytes and T cells, support the active replication of all strains of HIV-1 tested, including T-cell tropic and monocyte/macrophage tropic isolates. The dendritic cell cultures supported much more virus production than did cultures of primary unseparated T cells, CD4+ T cells, and adherent as well as nonadherent monocytes. Replication of HIV-1 in dendritic cells produces no noticeable cytopathic effect nor does it decrease total cell number. The ability of the nonreplicating dendritic cells to support high levels of replication of HIV-1 suggests that this antigen-presenting cell population, which is also capable of supporting clonal T-cell growth, may play a central role in HIV pathogenesis, serving as a source of continued infection of CD4+ T cells and as a reservoir of virus infection. Images PMID:1910172

  7. Efficacy, safety and pharmacokinetics of a novel subcutaneous immunoglobulin, Evogam®, in primary immunodeficiency.

    PubMed

    Empson, Marianne B; Tang, Mimi L K; Pearce, Lisa K C; Rozen, Leon; Gold, Michael S; Katelaris, Constance H; Langton, David; Smart, Joanne; Smith, William B; Steele, Richard H; Ziegler, John B; Maher, Darryl

    2012-10-01

    This phase III, open-label, multi-centre study investigated the efficacy, safety, pharmacokinetics and quality of life impact of Evogam(®), a new chromatographically fractionated 16% subcutaneous immunoglobulin, utilising a 1:1 dose transition ratio from previous immunoglobulin therapy. Thirty-five previously treated patients with primary immunodeficiency received weekly Evogam over 36 weeks. Primary endpoints were rate of serious bacterial infections (SBIs) and steady-state serum immunoglobulin G (IgG) trough concentrations. No SBIs were reported during the study. Evogam produced significantly higher mean trough IgG concentrations with 1:1 dose conversion compared to previous immunoglobulin treatment (8.94 versus 8.27 g/L, p = 0.0063). Evogam was efficacious in the prevention of infections and maintenance of trough levels using a 1:1 dose conversion. It was well tolerated with no withdrawals due to adverse events and was preferred to IVIg by the majority of patients.

  8. Indications to Epigenetic Dysfunction in the Pathogenesis of Common Variable Immunodeficiency.

    PubMed

    Rae, William

    2017-04-01

    Primary immunodeficiencies (PIDs) are a group of rare genetic diseases resulting in the impairment of one or more functions of the human immune system. Common variable immunodeficiency (CVID) is one of the most prevalent PIDs, yet despite extensive genetic analysis, most patients do not have a monogenetic diagnosis. This has led to the theory that CVID must be a polygenetic condition. An alternative theory to a monogenetic or polygenetic underlying cause of CVID is that it is epigenetic phenomena that are causal in the majority of CVID patients. I will briefly discuss epigenetic regulation in B-cell biology and development, current examples of epigenetic diseases causing CVID-like primary antibody deficiencies, and how these observations may guide future investigation into the role of epigenetics in CVID.

  9. A severe combined immunodeficient-hu in vivo mouse model of human primary mantle cell lymphoma.

    PubMed

    Wang, Michael; Zhang, Liang; Han, Xiaohong; Yang, Jing; Qian, Jianfei; Hong, Sungyoul; Lin, Pei; Shi, Yuankai; Romaguera, Jorge; Kwak, Larry W; Yi, Qing

    2008-04-01

    To establish a severe combined immunodeficient (SCID)-hu in vivo mouse model of human primary mantle cell lymphoma (MCL) for the study of the biology and novel therapy of human MCL. Primary MCL cells were isolated from spleen, lymph node, bone marrow aspirates, or peripheral blood of six different patients and injected respectively into human bone chips, which had been s.c. implanted in SCID-hu. Circulating human beta(2)-microglobulin in mouse serum was used to monitor the engraftment and growth of patient's MCL cells. H&E staining and immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies were used to confirm the tumor growth and migration. Increasing levels of circulating human beta(2)-microglobulin in mouse serum indicated that the patient's MCL cells were engrafted successfully into human bone chip of SCID-hu mice. The engraftment and growth of patient's MCL cells were dependent on human bone marrow microenvironment. Immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies confirmed that patient's MCL cells were able to not only survive and propagate in the bone marrow microenvironment of the human fetal bone chips, but also similar to the human disease, migrate to lymph nodes, spleen, bone marrow, and gastrointestinal tract of host mice. Treatment of MCL-bearing SCID-hu mice with atiprimod, a novel antitumor compound against the protection of bone marrow stromal cells, induced tumor regression. This is the first human primary MCL animal model that should be useful for the biological and therapeutic research on MCL.

  10. Gene therapy for PIDs: Progress, pitfalls and prospects

    PubMed Central

    Mukherjee, Sayandip; Thrasher, Adrian J.

    2013-01-01

    Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future. PMID:23566838

  11. Gene therapy for PIDs: progress, pitfalls and prospects.

    PubMed

    Mukherjee, Sayandip; Thrasher, Adrian J

    2013-08-10

    Substantial progress has been made in the past decade in treating several primary immunodeficiency disorders (PIDs) with gene therapy. Current approaches are based on ex-vivo transfer of therapeutic transgene via viral vectors to patient-derived autologous hematopoietic stem cells (HSCs) followed by transplantation back to the patient with or without conditioning. The overall outcome from all the clinical trials targeting different PIDs has been extremely encouraging but not without caveats. Malignant outcomes from insertional mutagenesis have featured prominently in the adverse events associated with these trials and have warranted intense pre-clinical investigation into defining the tendencies of different viral vectors for genomic integration. Coupled with issues pertaining to transgene expression, the therapeutic landscape has undergone a paradigm shift in determining safety, stability and efficacy of gene therapy approaches. In this review, we aim to summarize the progress made in the gene therapy trials targeting ADA-SCID, SCID-X1, CGD and WAS, review the pitfalls, and outline the recent advancements which are expected to further enhance favourable risk benefit ratios for gene therapeutic approaches in the future.

  12. Pelvic Inflammatory Disease (PID)

    MedlinePlus

    Pelvic Inflammatory Disease (PID) - CDC Fact Sheet Untreated sexually transmitted diseases (STDs) can cause pelvic inflammatory disease (PID), a ... tubal blockage; •• Ectopic pregnancy (pregnancy outside the womb); •• Infertility (inability to get pregnant); •• Long-term pelvic/abdominal ...

  13. TOXIRAE PRO PID

    EPA Science Inventory

    The ToxiRAE Pro PID measures total volatile organic compounds (VOCs) using a photoionization detector (PID). This sensor can be programmed to measure concentrations of a specified compound automatically and has a real time reading of VOC concentrations in parts per million (ppm) ...

  14. TOXIRAE PRO PID

    EPA Science Inventory

    The ToxiRAE Pro PID measures total volatile organic compounds (VOCs) using a photoionization detector (PID). This sensor can be programmed to measure concentrations of a specified compound automatically and has a real time reading of VOC concentrations in parts per million (ppm) ...

  15. PID controllers' fragility.

    PubMed

    Alfaro, Víctor M

    2007-10-01

    In this paper, an index for measuring fragility of proportional integral derivative (PID) controllers is proposed. This index relates the losses of robustness of the control loop when controller parameters change, to the nominal robustness of the control loop. Furthermore, it defines when a PID controller is fragile, nonfragile or resilient.

  16. Imbalances of T cell subpopulations in primary immunodeficiencies and systemic lupus erythematosus.

    PubMed

    Pandolfi, F; Quinti, I; Sirianni, M C; Fiorilli, M; Zolla, S; Aiuti, F

    1981-01-01

    In the present report we describe a recently proposed technique for the enumeration of T lymphocyte subpopulations. The study was performed on peripheral blood lymphocytes (PBL) of 21 patients with primary immunodeficiencies and 10 with systemic lupus erythematosus (SLE). With this methodology, sheep rosettes are evaluated before and after preincubation with theophylline. Previous reports have shown that cells rosetting after the preincubation (T-res) contain most of the percentages of the helper activity, whereas sensitive cells (T-sens) exert suppression. T-res and T-sens cells were compared to several clinical and immunological parameters, including the detection of lymphocytes with Fc IgM and IgG receptors. We demonstrated a significant positive correlation between T-res and and EAox IgM cells and between T-sens and EAox IgG cells. In addition, patients with Ig defects demonstrated heterogeneity regarding alterations in the proportions of T-res and T-sens cells. On the contrary, in 8 patients with SLE, there was a markedly reduced proportion of T-sens cells. Variations in the balance of subpopulations were observed after treatment with thymic hormones and levamisole. We may conclude that theophylline rosettes represent an easy technique that can be profitably used in the evaluation of T cell subpopulations in immunological diseases.

  17. Subcutaneous immunoglobulins: product characteristics and their role in primary immunodeficiency disease.

    PubMed

    Melamed, Isaac; Testori, Alessandro; Spirer, Zvi

    2012-12-01

    Research on the role of subcutaneous immunoglobulin in primary immunodeficiency disease (PIDD) is ongoing. We analyzed pivotal studies for four subcutaneous immunoglobulin products: IGSC 10% (Gammagard(®) Liquid), IGIV-C 10% (Gamunex(®)-C), IGSC 16% (Vivaglobin(®)) and IGSC 20% (Hizentra(®)). To identify similarities and differences between products, we examined infusion parameters, adverse event profiles and improvements in tolerability over time. Maximum volume infused was 30 mL/site for IGSC 10%, 34 mL/site for IGIV-C 10%, 15 mL/site for IGSC 16% and 25 mL/site for IGSC 20%. Maximum number of simultaneous infusion sites was 10 for IGSC 10%, 8 for IGIV-C 10%, 6 for IGSC 16% and 4 for IGSC 20%. Local adverse reaction rate per infusion was 0.02 for IGSC 10%, 0.59 for IGIV-C, 0.49 for IGSC 16% and 0.58 for IGSC 20%. IGSC products have similar efficacy profiles; however, their tolerability profiles vary. Reasons for these differences are unknown and warrant further research.

  18. Efficacy of subcutaneous immunoglobulins in primary immunodeficiency with Crohn's-like phenotype: report of a case.

    PubMed

    Sanges, M; Spadaro, G; Miniero, M; Mattera, D; Sollazzo, R; D'Armiento, F P; De Palma, G D; Pecoraro, A; Borrelli, F; Genovese, A; D'Arienzo, A

    2015-01-01

    Common variable immune deficiency (CVID) is the most frequent primary immunodeficiency in adults. In CVID, the prevalence of gastrointestinal manifestations ranges between 2 and 50% with a complication-related morbidity second only to that of the respiratory tract. In some cases, clinical and endoscopic features are undistinguishable from those of inflammatory bowel disease (IBD). We describe the case of a 28-year-old man in which a diagnosis of Crohn's disease was firstly suspected. Subsequently, a diagnosis of Crohn's-like disease in a patient with CVID was made and a replacement therapy with human normal immunoglobulin intravenously was started. Unfortunately, serum IgG levels remained below 2.0 g/l in pre-infusional controls with persistence of gastrointestinal symptoms and malnutrition despite anti-inflammatory therapy (mesalazine, corticosteroids). Then, the patient began treatment with human normal immunoglobulins administered subcutaneously. The follow-up visits showed a progressive increase in serum IgG. Moreover, the patient reported improvement of gastrointestinal symptoms with reduction of diarrhoea, and laboratory tests showed a progressive and significant improvement. We confirm that therapy with subcutaneously administered immunoglobulins is safe and effective. In addition, our observations indicate that, for patients with CVID and enteropathic complications, replacement therapy with subcutaneous IgG may be the treatment of choice.

  19. Genetic and Functional Diversity of Human Immunodeficiency Virus Type 1 Subtype B Nef Primary Isolates

    PubMed Central

    Foster, John L.; Molina, Rene P.; Luo, Tianci; Arora, Vivek K.; Huang, Yaoxing; Ho, David D.; Garcia, J. Victor

    2001-01-01

    We have characterized the functional integrity of seven primary Nef isolates: five from a long-term nonprogressing human immunodeficiency virus (HIV)-infected individual and one each from two patients with AIDS. One of the seven Nefs was defective for CD4 downregulation, two others were defective for PAK-2 activation, and one Nef was defective for PAK-2 activation and major histocompatibility complex (MHC) class I downregulation. Five of the Nefs were tested and found to be functional for the enhancement of virus particle infectivity. The structural basis for each of the functional defects has been analyzed by constructing a consensus nef, followed by mutational analysis of the variant amino acid residues. Mutations A29V and F193I were deleterious to CD4 downregulation and PAK-2 activation, respectively, while S189R rendered Nef defective for both MHC class I downregulation and PAK-2 activation. A search of the literature identified HIVs from five patients with Nefs predominantly mutated at F193 and from one patient with Nefs predominantly mutated at A29. A29 is highly conserved in all HIV subtypes except for subtype E. F193 is conserved in subtype B (and possibly in the closely related subtype D), but none of the other HIV group M subtypes. Our results suggest that functional distinctions may exist between HIV subtypes. PMID:11160665

  20. Critical issues and needs in management of primary immunodeficiency diseases in Latin America.

    PubMed

    Condino-Neto, A; Franco, J L; Trujillo-Vargas, C; Espinosa-Rosales, F J; Leiva, L E; Rodriguez-Quiroz, F; King, A; Lagos, M; Oleastro, M; Bezrodnik, L; Grumach, A S; Costa-Carvalho, B T; Sorensen, R U

    2011-01-01

    Experts from six Latin American countries met to discuss critical issues and needs in the diagnosis and management of primary immunodeficiency diseases (PIDD). The diagnosis of PIDD is generally made following referral to an immunology centre located in a major city, but many paediatricians and general practitioners are not sufficiently trained to suspect PIDD in the first place. Access to laboratory testing is generally limited, and only some screening tests are typically covered by government health programmes. Specialised diagnostic tests are generally not reimbursed. Access to treatment varies by country reflecting differences in healthcare systems and reimbursement policies. An online PIDD Registry Programme for Latin America has been available since 2009, which will provide information about PIDD epidemiology in the region. Additional collaboration across countries appears feasible in at least two areas: a laboratory network to facilitate the diagnosis of PIDD, and educational programmes to improve PIDD awareness. In total, these collaborations should make it possible to advance the diagnosis and management of PIDD in Latin America. Copyright © 2010 SEICAP. Published by Elsevier Espana. All rights reserved.

  1. Hematopoietic stem cell transplantation for pediatric patients with primary immunodeficiency diseases at All Children's Hospital/University of South Florida.

    PubMed

    Petrovic, A; Dorsey, M; Miotke, J; Shepherd, C; Day, N

    2009-01-01

    We retrospectively analyzed the transplantation outcomes of 31 patients with primary immunodeficiency diseases treated at our center (All Children's Hospital, University of South Florida) since its inception in 1986. The primary immune diseases included severe combined immunodeficiency, Wiscott-Aldrich syndrome, X-linked hyper-IgM syndrome, and chronic granulomatous disease. The age of the patient's at the time of transplant ranged from 1 month to 19 years, and conditioning regimens varied based on the patients underlying disease. In 23 patients, the graft source was bone marrow, 4 patients received umbilical cord blood grafts and 4 patients received peripheral blood stem cell grafts. Better survival rates were observed in those patients transplanted at a younger age and free of infections, demonstrating that transplantation at an early age before significant infections, autoimmune manifestation and malignant transformation have occurred is beneficial.

  2. Serotyping of primary human immunodeficiency virus type 1 isolates from diverse geographic locations by flow cytometry.

    PubMed Central

    Zolla-Pazner, S; O'Leary, J; Burda, S; Gorny, M K; Kim, M; Mascola, J; McCutchan, F

    1995-01-01

    The immunologic relatedness of the various human immunodeficiency virus type 1 (HIV-1) clades was determined with 13 human anti-HIV-1 monoclonal antibodies (MAbs) to six immunogenic regions of the HIV-1 structural proteins. The immunoreactivity of the native, oligomeric viral envelope glycoproteins expressed on the surfaces of human peripheral blood mononuclear cells infected in vitro with primary isolates from clades A through E was determined by flow cytometry. Some epitopes in the immunodominant region of gp41 and the C terminus of gp120 appear to be HIV-1 group specific in that they are expressed on the surfaces of cells in cultures infected with the majority of viruses tested from clades A to E. Epitopes within the V3 region appear to be clade restricted. Surprisingly, one MAb to an epitope in the C terminus of gp120 was entirely clade B specific. Staining with anti-V2 and anti-CD4 binding domain (CD4bd) reagents was infrequently detected. Anti-CD4bd MAbs stained only CD4-negative T cells because the CD4bd of gp120 appeared to be complexed with membrane CD4. When present, the epitopes of V2 and the CD4bd appeared to be expressed on cells infected with various clades. Thus, the results suggest that MAbs to gp41, the C terminus, and the V3 loop of gp120 are most useful in serotyping primary isolates of HIV-1, providing group-specific, clade-restricted, and clade-specific reagents. The use of the immunofluorescent method with the reagents described herein distinguishes infection with clade B from that with all other HIV-1 clades. With additional MAbs, this technique will allow a broadly applicable, reproducible, and practical method for serotyping HIV-1. PMID:7745728

  3. Primary immunodeficiency disease: a model for case management of chronic diseases.

    PubMed

    Burton, Janet; Murphy, Elyse; Riley, Patty

    2010-01-01

    Patient-centered chronic care management is a new model for the management of rare chronic diseases such as primary immunodeficiency disease (PIDD). This approach emphasizes helping patients become experts on the management of their disease as informed, involved, and interactive partners in healthcare decisions with providers. Because only a few patients are affected by rare illnesses, these patients are forced to become knowledgeable about their disease and therapies and to seek treatment from a healthcare team, which includes physicians and nurse specialists who are equipped to manage the complexity of the disease and its comorbidities. Importantly, therapy for PIDD can be self-administered at home, which has encouraged the transition toward a proactive stance that is at the heart of patient-centered chronic care management. We discuss the evolution of therapy, the issues with the disease, and challenges with its management within the framework of other chronic disease management programs. Suggestions and rationale to move case management of PIDD forward are presented with the intent that sharing our experiences will improve process and better manage outcomes in this patient population. The patient-centered model for the management of PIDD is applicable to the primary care settings, where nurse case managers assist patients through education, support them and their families, and facilitate access to community resources in an approach, which has been described as "guided care." The model also applies specifically to immunology centers where patients receive treatment or instruction on its self-administration at home. Patient-centered management of PIDD, with its emphasis on full involvement of patients in their treatment, has the potential to improve compliance with treatment, and thus patient outcomes, as well as patients' quality of life. The patient-centered model expands the traditional model of chronic disease management, which relies on evidence

  4. 'Pseudolymphoma'. A case associated with primary immunodeficiency disease and polyglandular failure syndrome.

    PubMed

    Snover, D C; Filipovich, A H; Dehner, L P; Krivit, W

    1981-01-01

    An atypical lymphoproliferative process occurred in the liver and spleen of a child with combined immunodeficiency disease and polyglandular failure syndrome. The initial pathologic interpretation was that of malignant lymphoma, although the child's subsequent clinical course was complicated by rheumatoid arthritis, thyroiditis, and chronic active hepatitis, with no clear evidence of lymphoid neoplasia. This case illustrates that unusual lymphoid proliferations in patients with immunodeficiencies may simulate malignant lymphoma.

  5. B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency.

    PubMed

    Low, Lawrence K; Song, Joo Y

    2016-03-01

    The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade.

  6. Immunodeficiency disorders.

    PubMed

    Cooper, Max D; Lanier, Lewis L; Conley, Mary Ellen; Puck, Jennifer M

    2003-01-01

    Hematological complications occur frequently in patients with both primary and secondary immunodeficiency disorders. Anemia, thrombocytopenia or leukopenias may bring these individuals to the attention of hematologists. Conversely, evidence suggesting a lymphoproliferative disorder may be the cause for referral. This session will provide an update on the diagnosis and treatment of immunodeficiency diseases ranging from isolated defects in antibody production to the severe combined immunodeficiencies (SCID). Immunodeficiency diseases have traditionally been defined as defects in the development and function of T and B cells, the primary effector cells of specific cellular and humoral immunity. However, it has become increasingly evident that innate immune mechanisms contribute greatly to host defense, either through acting alone or by enhancing specific T and B cell responses. In Section I, Dr. Lewis Lanier reviews the burgeoning information on the extensive families of activating and inhibitory immunoreceptors that are expressed on NK cells, dendritic cells, T and B cells, and phagocytic cells. He provides an overview on the biological functions of these receptors in host defense. In Section II, Dr. Mary Ellen Conley defines the spectrum of antibody deficiency disorders, the most frequently occurring types of primary immunodeficiencies. She covers the different defects in B-cell development and function that lead to antibody deficiencies, and includes diagnosis and therapy of these disorders. In Section III, Dr. Jennifer Puck discusses the diagnosis and treatment of the different types of SCID. She describes the genetic basis for SCID, and the benefits, pitfalls, and complications of gene therapy and bone marrow transplantation in SCID patients.

  7. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency.

    PubMed

    Wasserman, Richard L; Melamed, Isaac; Stein, Mark R; Gupta, Sudhir; Puck, Jennifer; Engl, Werner; Leibl, Heinz; McCoy, Barbara; Empson, Victoria G; Gelmont, David; Schiff, Richard I

    2012-10-01

    Subcutaneous immunoglobulin (IGSC) replacement therapy for primary immunodeficiency (PI) is equally efficacious to intravenous immunoglobulin (IGIV), induces fewer systemic reactions, and may be self-infused. Limited SC infusion volumes and reduced bioavailability, however, necessitate multiple infusion sites, more frequent treatment, and dose adjustment to achieve pharmacokinetic equivalence. Recombinant human hyaluronidase (rHuPH20) increases SC tissue permeability and facilitates dispersion and absorption, enabling administration of monthly doses in one site. This study investigated the efficacy and tolerability of rHuPH20-facilitated IGSC (IGHy) in patients with PI. In this open-label, multicenter phase III study, 87 patients with PI aged ≥2 years received 10% IGIV for 3 months, then IGHy (n = 83) for approximately 14 to 18 months at 108% of the IGIV dose. IGHy infusions began weekly, increasing to 3- or 4-week intervals. The majority (94.0%) of IGHy infusions were administered every 3 or 4 weeks, using one site (median, 1.09/month), with a mean volume of 292.2 mL. The bioavailability of IGHy measured by area under the concentration versus time curve was 93.3% of IGIV, which is pharmacokinetically equivalent. Systemic reactions were less frequent with IGHy than with IGIV (8.3% vs 25.0% of infusions). Local reactions to IGHy were generally mild to moderate, with a rate of 0.203 per infusion. The acute serious bacterial infection rate per subject-year for IGHy was low (0.025; upper 99% CI limit, 0.046). Overall infection rates per subject-year were 2.97 for IGHy and 4.51 for IGIV. IGHy was effective, safe, and pharmacokinetically equivalent to IGIV at the same administration intervals, but it caused fewer systemic reactions. Tolerability was good despite high infusion volumes and rates. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  8. Pelvic Inflammatory Disease (PID)

    MedlinePlus

    ... that are not sexually transmitted, such as bacterial vaginosis . What are the long-term effects of PID? ... Drugs that treat certain types of infections. Bacterial Vaginosis: A type of vaginal infection caused by the ...

  9. Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism.

    PubMed

    Okuno, Yusuke; Hoshino, Akihiro; Muramatsu, Hideki; Kawashima, Nozomu; Wang, Xinan; Yoshida, Kenichi; Wada, Taizo; Gunji, Masaharu; Toma, Tomoko; Kato, Tamaki; Shiraishi, Yuichi; Iwata, Atsuko; Hori, Toshinori; Kitoh, Toshiyuki; Chiba, Kenichi; Tanaka, Hiroko; Sanada, Masashi; Takahashi, Yoshiyuki; Nonoyama, Shigeaki; Ito, Masafumi; Miyano, Satoru; Ogawa, Seishi; Kojima, Seiji; Kanegane, Hirokazu

    2015-10-01

    Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8(+) and CD56(+) cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.

  10. Treatment of Pediatric Acute Graft-versus-Host Disease—Lessons from Primary Immunodeficiency?

    PubMed Central

    Flinn, Aisling M.; Gennery, Andrew R.

    2017-01-01

    Allogeneic hematopoietic stem cell transplant (HSCT) is used to treat increasing numbers of malignant and non-malignant disorders. Despite significant advances in improved human leukocyte antigens-typing techniques, less toxic conditioning regimens and better supportive care, resulting in improved clinical outcomes, acute graft-versus-host disease (aGvHD) continues to be a major obstacle and, although it principally involves the skin, gastrointestinal tract, and liver, the thymus is also a primary target. An important aim following HSCT is to achieve complete and durable immunoreconstitution with a diverse T-cell receptor (TCR) repertoire to recognize a broad range of pathogens providing adequate long-term adaptive T-lymphocyte immunity, essential to reduce the risk of infection, disease relapse, and secondary malignancies. Reconstitution of adaptive T-lymphocyte immunity is a lengthy and complex process which requires a functioning and structurally intact thymus responsible for the production of new naïve T-lymphocytes with a broad TCR repertoire. Damage to the thymic microenvironment, secondary to aGvHD and the effect of corticosteroid treatment, disturbs normal signaling required for thymocyte development, resulting in impaired T-lymphopoiesis and reduced thymic export. Primary immunodeficiencies, in which failure of central or peripheral tolerance is a major feature, because of intrinsic defects in hematopoietic stem cells leading to abnormal T-lymphocyte development, or defects in thymic stroma, can give insights into critical processes important for recovery from aGvHD. Extracorporeal photopheresis is a potential alternative therapy for aGvHD, which acts in an immunomodulatory fashion, through the generation of regulatory T-lymphocytes (Tregs), alteration of cytokine patterns and modulation of dendritic cells. Promoting normal central and peripheral immune tolerance, with selective downregulation of immune stimulation, could reduce aGvHD, and enable a

  11. Primary Neuritic Hansen's Disease presenting as Ulnar Nerve Abscess in a Human Immunodeficiency Virus Positive Patient.

    PubMed

    Karjigi, S; Herakal, K; Murthy, S C; Bathina, A; Kusuma, M R; Nikhil, K R Y

    2015-01-01

    Leprosy has been increasingly known to have an enigmatic relationship with human immunodeficiency virus infection. Co-infection may result in atypical manifestations of leprosy. A 45-year old human immunodeficiency virus-positive male; agricultural laborer presented with a swelling over right elbow, right hand deformity, generalized itching and recurrent vesicles overthe perinasal area. Clinical and investigational findings were consistent with mononeuritic type of Hansen's disease with right sided silent ulnar nerve abscess, partial claw hand. CD4+ count of the patientwas 430 cells/cmm. This patient also hadherpes simplex labialis, with HIV-associated pruritus. To the best of our knowledge such an atypical presentation has not been reported earlier.

  12. Current state and future perspectives of the Latin American Society for Immunodeficiencies (LASID).

    PubMed

    Condino-Neto, A; Sorensen, R U; Gómez Raccio, A C; King, A; Espinosa-Rosales, F J; Franco, J L

    2015-01-01

    Primary immunodeficiencies (PID) are genetic diseases that affect the immune system and for the last 20 years, the Latin American Society for Immunodeficiencies (LASID) has been promoting initiatives in awareness, research, diagnosis, and treatment for the affected patients in Latin America. These initiatives have resulted in the development of programmes such as the LASID Registry (with 4900 patients registered as of January 2014), fellowships in basic and clinical research, PID summer schools, biannual meetings, and scientific reports, amongst others. These achievements highlight the critical role that LASID plays as a scientific organisation in promoting science, research and education in this field in Latin America. However, challenges remain in some of these areas and the Society must envision additional strategies to tackle them for the benefit of the patients. In June 2013, a group of experts in the field met to discuss the contributions of LASID to the initiatives of PID in Latin America, and this article summarises the current state and future perspectives of this society and its role in the advance of PIDs in Latin America. Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.

  13. Zebrafish as a model for understanding the evolution of the vertebrate immune system and human primary immunodeficiency.

    PubMed

    Iwanami, Norimasa

    2014-08-01

    Zebrafish is an important vertebrate model that provides the opportunity for the combination of genetic interrogation with advanced live imaging in the analysis of complex developmental and physiologic processes. Among the many advances that have been achieved using the zebrafish model, it has had a great impact on immunology. Here, I discuss recent work focusing on the genetic underpinnings of the development and function of lymphocytes in fish. Lymphocytes play critical roles in vertebrate-specific acquired immune systems of jawless and jawed fish. The unique opportunities afforded by the ability to carry out forward genetic screens and the rapidly evolving armamentarium of reverse genetics in fish usher in a new immunologic research that complements the traditional models of chicken and mouse. Recent work has greatly increased our understanding of the molecular components of the zebrafish immune system, identifying evolutionarily conserved and fish-specific functions of immune-related genes. Interestingly, some of the genes whose mutations underlie the phenotypes in immunodeficient zebrafish were also identified in immunodeficient human patients. In addition, because of the generally conserved structure and function of immune facilities, the zebrafish also provides a versatile model to examine the functional consequences of genetic variants in immune-relevant genes in the human population. Thus, I propose that genetic approaches using the zebrafish hold great potential for a better understanding of molecular mechanisms of human primary immunodeficiencies and the evolution of vertebrate immune systems. Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  14. Prolonged Excretion of Poliovirus among Individuals with Primary Immunodeficiency Disorder: An Analysis of the World Health Organization Registry.

    PubMed

    Macklin, Grace; Liao, Yi; Takane, Marina; Dooling, Kathleen; Gilmour, Stuart; Mach, Ondrej; Kew, Olen M; Sutter, Roland W

    2017-01-01

    Individuals with primary immunodeficiency disorder may excrete poliovirus for extended periods and will constitute the only remaining reservoir of virus after eradication and withdrawal of oral poliovirus vaccine. Here, we analyzed the epidemiology of prolonged and chronic immunodeficiency-related vaccine-derived poliovirus cases in a registry maintained by the World Health Organization, to identify risk factors and determine the length of excretion. Between 1962 and 2016, there were 101 cases, with 94/101 (93%) prolonged excretors and 7/101 (7%) chronic excretors. We documented an increase in incidence in recent decades, with a shift toward middle-income countries, and a predominance of poliovirus type 2 in 73/101 (72%) cases. The median length of excretion was 1.3 years (95% confidence interval: 1.0, 1.4) and 90% of individuals stopped excreting after 3.7 years. Common variable immunodeficiency syndrome and residence in high-income countries were risk factors for long-term excretion. The changing epidemiology of cases, manifested by the greater incidence in recent decades and a shift to from high- to middle-income countries, highlights the expanding risk of poliovirus transmission after oral poliovirus vaccine cessation. To better quantify and reduce this risk, more sensitive surveillance and effective antiviral therapies are needed.

  15. Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies.

    PubMed

    Borte, M; Bernatowska, E; Ochs, H D; Roifman, C M

    2011-06-01

    Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2-<12 years) who participated in two prospective, open-label studies (one in Europe/Brazil, one in North America). All children had previously received intravenous immunoglobulins. They started weekly subcutaneous immunoglobulin infusions with an approximately 3-month wash-in/wash-out period, followed by a 6-month (Europe/Brazil) or 12-month (North America) efficacy evaluation period. In Europe/Brazil, subcutaneous doses generally equalled the previous weekly equivalent intravenous doses. In North America, subcutaneous doses during the efficacy evaluation period were 126% (median) of the previous weekly equivalent intravenous doses. Efficacy end-points in both studies included the occurrence of serious bacterial infections and any infections, and serum immunoglobulin G trough levels. Median serum immunoglobulin G trough levels exceeded those during previous intravenous therapy by 13% (North America) and 16% (Europe/Brazil). During the efficacy evaluation period of both studies, none of the children had a serious bacterial infection; the mean overall infection rate/patient year was 4·7 in Europe/Brazil and 5·6 in North America, concurring with previous reports in adults. The adverse event profile was comparable to previous reports in adults. Both studies confirmed the efficacy and safety of subcutaneous immunoglobulin therapy with Vivaglobin in children with primary immunodeficiencies. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

  16. Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies

    PubMed Central

    Borte, M; Bernatowska, E; Ochs, H D; Roifman, C M

    2011-01-01

    Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2–<12 years) who participated in two prospective, open-label studies (one in Europe/Brazil, one in North America). All children had previously received intravenous immunoglobulins. They started weekly subcutaneous immunoglobulin infusions with an approximately 3-month wash-in/wash-out period, followed by a 6-month (Europe/Brazil) or 12-month (North America) efficacy evaluation period. In Europe/Brazil, subcutaneous doses generally equalled the previous weekly equivalent intravenous doses. In North America, subcutaneous doses during the efficacy evaluation period were 126% (median) of the previous weekly equivalent intravenous doses. Efficacy end-points in both studies included the occurrence of serious bacterial infections and any infections, and serum immunoglobulin G trough levels. Median serum immunoglobulin G trough levels exceeded those during previous intravenous therapy by 13% (North America) and 16% (Europe/Brazil). During the efficacy evaluation period of both studies, none of the children had a serious bacterial infection; the mean overall infection rate/patient year was 4·7 in Europe/Brazil and 5·6 in North America, concurring with previous reports in adults. The adverse event profile was comparable to previous reports in adults. Both studies confirmed the efficacy and safety of subcutaneous immunoglobulin therapy with Vivaglobin in children with primary immunodeficiencies. PMID:21413943

  17. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency

    PubMed Central

    Maffucci, Patrick; Filion, Charles A.; Boisson, Bertrand; Itan, Yuval; Shang, Lei; Casanova, Jean-Laurent; Cunningham-Rundles, Charlotte

    2016-01-01

    Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes. PMID:27379089

  18. The ligurian human immunodeficiency virus clinical network: a web tool to manage patients with human immunodeficiency virus in primary care and multicenter clinical trials.

    PubMed

    Fraccaro, Paolo; Pupella, Valeria; Gazzarata, Roberta; Dentone, Chiara; Cenderello, Giovanni; De Leo, Pasqualina; Bozzano, Federica; Casalino Finocchio, Giorgetta; De Maria, Andrea; Fenoglio, Daniela; Filaci, Gilberto; Guerra, Michele; Di Biagio, Antonio; Mantia, Eugenio; Orofino, Giancarlo; Ferrea, Giuseppe; Viscoli, Claudio; Giacomini, Mauro

    2013-01-01

    In recent years, Highly-Active Anti-Retroviral Therapies (HAARTs) have modified the Human Immunodeficiency Virus (HIV) life-cycle and the disease is now considered chronic. Consequently, a longitudinal and complex follow-up is now required for HIV positive patients during their lifetime. Moreover, patients often encounter various complications due to comorbidities, related to the immunodeficiency state and HAARTs' side effects. Thus, HIV positive patients are involved in multicenter clinical trials (MCTs) to improve treatments and discover a preventive vaccine. Therefore, physicians require proper instruments to access comprehensive patient data for managing patients during follow-ups, and tools for data collection and analysis in MCTs. The Ligurian HIV Clinical Network aims to provide physicians with a Web-tool to administrate HIV positive patients' data within primary-care and to reuse the collected clinical information to perform MCTs in Northern Italy. The key aspect of the system is a relational database which allows the storage of various types of clinical information (eg, related to HIV, cardiovascular, or hepatic diseases) in multiple formats. The modular design of the database permits a rapid insertion of new parameters without requiring any changes in the database structure. Furthermore, codes from biomedical ontologies controlled vocabularies ("Logical Observation Identifier Names and Codes", and "International Classification of Diseases 9") and ontologies ("Systematized Nomenclature of Medicine Clinical Terms"), units and normality ranges used by all partners participating in the project were collected to achieve a complete semantic interoperability. Accordingly, data can be automatically normalized through the z score formula and physicians can extract and correctly compare information with external statistical tools. Moreover, to respect patients' privacy and legal issues, a local identifier, determined through an HASH cryptography algorithm, is

  19. An Unusual Case of Primary Human Immunodeficiency Virus Infection Presenting as Mononucleosis-like Syndrome and Acute Aseptic Meningoencephalitis. Report of a Case and Review of the Literature.

    PubMed

    Corti, Marcelo; Gilardi, Leonardo

    2014-07-01

    Clinical presentation of primary human immunodeficiency virus (HIV) infection includes a wide spectrum of manifestations from asymptomatic infection to a symptomatic and severe illness. Central nervous system involvement should be always considered as a severe clinical form of primary HIV infection. Physicians should be aware to the broad clinical spectrum of primary HIV infection. We report a case of a female with diagnosis of mononucleosis-like syndrome and acute aseptic meningoencephalitis during primary HIV infection.

  20. An Unusual Case of Primary Human Immunodeficiency Virus Infection Presenting as Mononucleosis-like Syndrome and Acute Aseptic Meningoencephalitis. Report of a Case and Review of the Literature

    PubMed Central

    Corti, Marcelo; Gilardi, Leonardo

    2014-01-01

    Clinical presentation of primary human immunodeficiency virus (HIV) infection includes a wide spectrum of manifestations from asymptomatic infection to a symptomatic and severe illness. Central nervous system involvement should be always considered as a severe clinical form of primary HIV infection. Physicians should be aware to the broad clinical spectrum of primary HIV infection. We report a case of a female with diagnosis of mononucleosis-like syndrome and acute aseptic meningoencephalitis during primary HIV infection. PMID:25374871

  1. Epidemiology and pathophysiology of malignancy in common variable immunodeficiency?

    PubMed

    Tak Manesh, A; Azizi, G; Heydari, A; Kiaee, F; Shaghaghi, M; Hossein-Khannazer, N; Yazdani, R; Abolhassani, H; Aghamohammadi, A

    2017-04-12

    Common variable immunodeficiency (CVID) is a diagnostic category of primary immunodeficiency (PID) which may present with heterogeneous disorders including recurrent infections, autoimmunity, granulomatous diseases, lymphoid and other types of malignancies. Generally, the incidence of malignancy in CVID patients is around 1.5-20.7% and usually occurs during the 4th-6th decade of life. Non-Hodgkin lymphoma is the most frequent malignancy, followed by epithelial tumours of stomach, breast, bladder and cervix. The exact pathological mechanisms for cancer development in CVID are not fully determined; however, several mechanisms including impaired genetic stability, genetic predisposition, immune dysregulation, impaired clearance of oncogenic viruses and bacterial infections, and iatrogenic causes have been proposed to contribute to the high susceptibility of these patients to malignancies. Copyright © 2017. Published by Elsevier España, S.L.U.

  2. Progress and prospects: gene therapy for inherited immunodeficiencies.

    PubMed

    Qasim, W; Gaspar, H B; Thrasher, A J

    2009-11-01

    Haematopoietic stem cell transplantation (HSCT) is now widely used to treat primary immunodeficiencies (PID). For patients with specific disorders (severe combined immunodeficiency (SCID)-X1, adenosine deaminase deficiency (ADA)-SCID, X-chronic granulomatous disease (CGD) and Wiskott-Aldrich Syndrome (WAS)) who lack a suitable human leukocyte antigen (HLA)-matched donor, gene therapy has offered an important alternative treatment option. The success of gene therapy can be attributed, in part, to the selective advantage offered to gene-corrected cells, the avoidance of graft-versus-host disease and to the use of pre-conditioning in patients with chemotherapy to facilitate engraftment of corrected cells. Adverse events have been encountered and this has led to detailed characterization of retroviral vector integration profiles. A new generation of self-inactivating retroviral and lentiviral vectors have been designed to address these safety concerns, and are at an advanced stage of preparation for the next phase of clinical testing.

  3. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.

    PubMed Central

    Koup, R A; Safrit, J T; Cao, Y; Andrews, C A; McLeod, G; Borkowsky, W; Farthing, C; Ho, D D

    1994-01-01

    Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo. PMID:8207839

  4. Shared usage of the chemokine receptor CXCR4 by primary and laboratory-adapted strains of feline immunodeficiency virus.

    PubMed

    Richardson, J; Pancino, G; Merat, R; Leste-Lasserre, T; Moraillon, A; Schneider-Mergener, J; Alizon, M; Sonigo, P; Heveker, N

    1999-05-01

    Strains of the feline immunodeficiency virus (FIV) presently under investigation exhibit distinct patterns of in vitro tropism. In particular, the adaptation of FIV for propagation in Crandell feline kidney (CrFK) cells results in the selection of strains capable of forming syncytia with cell lines of diverse species origin. The infection of CrFK cells by CrFK-adapted strains appears to require the chemokine receptor CXCR4 and is inhibited by its natural ligand, stromal cell-derived factor 1alpha (SDF-1alpha). Here we found that inhibitors of CXCR4-mediated infection by human immunodeficiency virus type I (HIV-1), such as the bicyclam AMD3100 and short peptides derived from the amino-terminal region of SDF-1alpha, also blocked infection of CrFK by FIV. Nevertheless, we observed differences in the ranking order of the peptides as inhibitors of FIV and HIV-1 and showed that such differences are related to the species origin of CXCR4 and not that of the viral envelope. These results suggest that, although the envelope glycoproteins of FIV and HIV-1 are substantially divergent, FIV and HIV-1 interact with CXCR4 in a highly similar manner. We have also addressed the role of CXCR4 in the life cycle of primary isolates of FIV. Various CXCR4 ligands inhibited infection of feline peripheral blood mononuclear cells (PBMC) by primary FIV isolates in a concentration-dependent manner. These ligands also blocked the viral transduction of feline PBMC by pseudotyped viral particles when infection was mediated by the envelope glycoprotein of a primary FIV isolate but not by the G protein of vesicular stomatitis virus, indicating that they act at an envelope-mediated step and presumably at viral entry. These findings strongly suggest that primary and CrFK-adapted strains of FIV, despite disparate in vitro tropisms, share usage of CXCR4.

  5. Is Graves' disease a primary immunodeficiency? New immunological perspectives on an endocrine disease.

    PubMed

    Struja, Tristan; Kutz, Alexander; Fischli, Stefan; Meier, Christian; Mueller, Beat; Recher, Mike; Schuetz, Philipp

    2017-09-25

    Uncertainty about factors influencing the susceptibility and triggers for Graves' disease persists, along with a wide variation in the response to anti-thyroid drugs, currently at approximately 50% of non-responders. The aim of this narrative review is to summarize immunological concepts, with a combined endocrine and immunological perspective, to highlight potential new areas of research. Relevant studies were identified through a systematic literature search using the PubMed and EMBASE databases in March 2016. No cut-offs regarding dates were imposed. We used the terms "Graves' Disease" or "Basedow" or "thyrotoxicosis" together with the terms "etiology", "pathophysiology", "immunodeficiency", "causality", and "autoimmunity". The terms "orbitopathy", "ophthalmopathy", and "amiodarone" were excluded. Articles in English, French, German, Croatian, Spanish, and Italian were eligible for inclusion. While concepts such as the impact of iodine, smoking, human leucocyte antigen, infections, and ethnicity are established, new ideas have emerged. Pertaining evidence suggests the involvement of autoimmunity and immunodeficiency in the pathophysiology of Graves' disease. Recent studies point to specific immunological mechanisms triggering the onset of disease, which may also serve as targets for more specific therapies.

  6. An Aggressive Plasmablastic Lymphoma of the Oral Cavity as Primary Manifestation of Acquired Immunodeficiency Syndrome: Case Report and Literature Review

    PubMed Central

    Corti, Marcelo; Minué, Gonzalo; Campitelli, Ana; Narbaitz, Marina; Gilardi, Leonardo

    2015-01-01

    Introduction Plasmablastic lymphoma is a rare entity that was first described in the jaws and the oral cavity of patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Plasmablastic lymphoma is considered as a diffuse, large, B-cell lymphoma with a unique phenotype and a predilection for the oral cavity. Objective The authors describe a case of an aggressive plasmablastic lymphoma of the oral cavity as the primary manifestation of AIDS. Resumed Report We report a case of plasmablastic lymphoma involving only the oral cavity as the first manifestation of AIDS. Diagnosis was confirmed by the oral lesion biopsy and the histopathologic examination that showed a dense infiltrate composed of atypical lymphocytes with numerous plasmocytes that expressed the plasma cell markers MUM-1 and CD138 and that were negative for the B-cell markers CD3, CD20, and CD45. Immunohistochemical and in situ hybridization revealed the Epstein-Barr virus genome in the atypical cells. Polymerase chain reaction was also positive for human herpesvirus-8 RNA. Conclusion The HIV serologic status should be evaluated in all patients with plasmablastic lymphoma of the oral cavity or extraoral sites. PMID:26491484

  7. An Aggressive Plasmablastic Lymphoma of the Oral Cavity as Primary Manifestation of Acquired Immunodeficiency Syndrome: Case Report and Literature Review.

    PubMed

    Corti, Marcelo; Minué, Gonzalo; Campitelli, Ana; Narbaitz, Marina; Gilardi, Leonardo

    2015-10-01

    Introduction Plasmablastic lymphoma is a rare entity that was first described in the jaws and the oral cavity of patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Plasmablastic lymphoma is considered as a diffuse, large, B-cell lymphoma with a unique phenotype and a predilection for the oral cavity. Objective The authors describe a case of an aggressive plasmablastic lymphoma of the oral cavity as the primary manifestation of AIDS. Resumed Report We report a case of plasmablastic lymphoma involving only the oral cavity as the first manifestation of AIDS. Diagnosis was confirmed by the oral lesion biopsy and the histopathologic examination that showed a dense infiltrate composed of atypical lymphocytes with numerous plasmocytes that expressed the plasma cell markers MUM-1 and CD138 and that were negative for the B-cell markers CD3, CD20, and CD45. Immunohistochemical and in situ hybridization revealed the Epstein-Barr virus genome in the atypical cells. Polymerase chain reaction was also positive for human herpesvirus-8 RNA. Conclusion The HIV serologic status should be evaluated in all patients with plasmablastic lymphoma of the oral cavity or extraoral sites.

  8. Long-term survival and late deaths after hematopoietic cell transplantation for primary immunodeficiency diseases and inborn errors of metabolism.

    PubMed

    Eapen, Mary; Ahn, Kwang Woo; Orchard, Paul J; Cowan, Morton J; Davies, Stella M; Fasth, Anders; Hassebroek, Anna; Ayas, Mouhab; Bonfim, Carmem; O'Brien, Tracey A; Gross, Thomas G; Horwitz, Mitchell; Horwitz, Edwin; Kapoor, Neena; Kurtzberg, Joanne; Majhail, Navneet; Ringden, Olle; Szabolcs, Paul; Veys, Paul; Baker, K Scott

    2012-09-01

    It is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD), and inborn errors of metabolism (IEM) return to rates observed in the general population, matched for age, sex, and nationality. We studied patients with SCID (n = 201), non-SCID PIDD (n = 405), and IEM (n = 348) who survived for at least 2 years after transplantation with normal T cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rate was significantly higher in these patients compared with the general population for several years after transplantation. The rate decreased toward the normal rate in patients with SCID and non-SCID PIDD beyond 6 years after transplantation, but not in patients with IEM. Active chronic graft-versus-host disease at 2 years was associated with increased risk of late mortality for all diseases (hazard ratio [HR], 1.87; P = .05). In addition, late mortality was higher in patients with non-SCID PIDD who received T cell-depleted grafts (HR 4.16; P = .007) and in patients with IEM who received unrelated donor grafts (HR, 2.72; P = .03) or mismatched related donor grafts (HR, 3.76; P = .01). The finding of higher mortality rates in these long-term survivors for many years after transplantation confirms the need for long-term surveillance.

  9. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology.

    PubMed

    Yong, Pierre L; Boyle, John; Ballow, Mark; Boyle, Marcia; Berger, Melvin; Bleesing, Jack; Bonilla, Franciso A; Chinen, Javier; Cunninghamm-Rundles, Charlotte; Fuleihan, Ramsay; Nelson, Lois; Wasserman, Richard L; Williams, Kathleen C; Orange, Jordan S

    2010-05-01

    There are an expanding number of primary immunodeficiency diseases (PIDDs), each associated with unique diagnostic and therapeutic complexities. Limited data, however, exist supporting specific therapeutic interventions. Thus, a survey of PIDD management was administered to allergists/immunologists in the United States to identify current perspectives and practices. Among 405 respondents, the majority of key management practices identified were consistent with existing data and guidelines, including the provision of immunoglobulin therapy, immunoglobulin dosing and selective avoidance of live viral vaccines. Practices for which there are little specific data or evidence-based guidance were also examined, including evaluation of IgG trough levels for patients receiving immunoglobulin, use of prophylactic antibiotics and recommendations for complementary/alternative medicine. Here, variability applied to PIDD patients was identified. Differences between practitioners clinically focused upon PIDD and general allergists/immunologists were also identified. Thus, a need for expanded clinical research in PIDD to optimize management and potentially improve outcomes was defined.

  10. Dynamic PID loop control

    SciTech Connect

    Pei, L.; Klebaner, A.; Theilacker, J.; Soyars, W.; Martinez, A.; Bossert, R.; DeGraff, B.; Darve, C.; /Fermilab

    2011-06-01

    The Horizontal Test Stand (HTS) SRF Cavity and Cryomodule 1 (CM1) of eight 9-cell, 1.3GHz SRF cavities are operating at Fermilab. For the cryogenic control system, how to hold liquid level constant in the cryostat by regulation of its Joule-Thompson JT-valve is very important after cryostat cool down to 2.0 K. The 72-cell cryostat liquid level response generally takes a long time delay after regulating its JT-valve; therefore, typical PID control loop should result in some cryostat parameter oscillations. This paper presents a type of PID parameter self-optimal and Time-Delay control method used to reduce cryogenic system parameters oscillation.

  11. Impact of antiretroviral pressure on selection of primary human immunodeficiency virus type 1 envelope sequences in vitro

    PubMed Central

    Harada, Shigeyoshi; Yamaguchi, Aki; Boonchawalit, Samatchaya; Yusa, Keisuke; Matsushita, Shuzo

    2013-01-01

    The initiation of drug therapy results in a reduction in the human immunodeficiency virus type 1 (HIV-1) population, which represents a potential genetic bottleneck. The effect of this drug-induced genetic bottleneck on the population dynamics of the envelope (Env) regions has been addressed in several in vivo studies. However, it is difficult to investigate the effect on the env gene of the genetic bottleneck induced not only by entry inhibitors but also by non-entry inhibitors, particularly in vivo. Therefore, this study used an in vitro selection system using unique bulk primary isolates established in the laboratory to observe the effects of the antiretroviral drug-induced bottleneck on the integrase and env genes. Env diversity was decreased significantly in one primary isolate [KP-1, harbouring both CXCR4 (X4)- and CCR5 (R5)-tropic variants] when passaged in the presence or absence of raltegravir (RAL) during in vitro selection. Furthermore, the RAL-selected KP-1 variant had a completely different Env sequence from that in the passage control (particularly evident in the gp120, V1/V2 and V4-loop regions), and a different number of potential N-glycosylation sites. A similar pattern was also observed in other primary isolates when using different classes of drugs. This is the first study to explore the influence of anti-HIV drugs on bottlenecks in bulk primary HIV isolates with highly diverse Env sequences using in vitro selection. PMID:23288425

  12. Herpes simplex virus type 2 infection increases human immunodeficiency virus type 1 entry into human primary macrophages.

    PubMed

    Sartori, Elena; Calistri, Arianna; Salata, Cristiano; Del Vecchio, Claudia; Palù, Giorgio; Parolin, Cristina

    2011-04-12

    Epidemiological and clinical data indicate that genital ulcer disease (GUD) pathogens are associated with an increased risk of human immunodeficiency virus type 1 (HIV-1) acquisition and/or transmission. Among them, genital herpes simplex virus type 2 (HSV-2) seems to play a relevant role. Indeed, the ability of HSV-2 to induce massive infiltration at the genital level of cells which are potential targets for HIV-1 infection may represent one of the mechanisms involved in this process. Here we show that infection of human primary macrophages (MDMs) by HSV-2 results in an increase of CCR5 expression levels on cell surface and allows higher efficiency of MDMs to support entry of R5 HIV-1 strains. This finding could strengthen, at the molecular level, the evidence linking HSV-2 infection to an increased susceptibility to HIV-1 acquisition.

  13. WS/PIDS: standard interoperable PIDS in web services environments.

    PubMed

    Vasilescu, E; Dorobanţu, M; Govoni, S; Padh, S; Mun, S K

    2008-01-01

    An electronic health record depends on the consistent handling of people's identities within and outside healthcare organizations. Currently, the Person Identification Service (PIDS), a CORBA specification, is the only well-researched standard that meets these needs. In this paper, we introduce WS/PIDS, a PIDS specification for Web Services (WS) that closely matches the original PIDS and improves on it by providing explicit support for medical multimedia attributes. WS/PIDS is currently supported by a test implementation, layered on top of a PIDS back-end, with Java- and NET-based, and Web clients. WS/PIDS is interoperable among platforms; it preserves PIDS semantics to a large extent, and it is intended to be fully compliant with established and emerging WS standards. The specification is open source and immediately usable in dynamic clinical systems participating in grid environments. WS/PIDS has been tested successfully with a comprehensive set of use cases, and it is being used in a clinical research setting.

  14. Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response

    PubMed Central

    Jones, Nicola A.; Wei, Xiping; Flower, Darren R.; Wong, MaiLee; Michor, Franziska; Saag, Michael S.; Hahn, Beatrice H.; Nowak, Martin A.; Shaw, George M.; Borrow, Persephone

    2004-01-01

    CD8+ cytotoxic T lymphocytes (CTLs) play an important role in containment of virus replication in primary human immunodeficiency virus (HIV) infection. HIV's ability to mutate to escape from CTL pressure is increasingly recognized; but comprehensive studies of escape from the CD8 T cell response in primary HIV infection are currently lacking. Here, we have fully characterized the primary CTL response to autologous virus Env, Gag, and Tat proteins in three patients, and investigated the extent, kinetics, and mechanisms of viral escape from epitope-specific components of the response. In all three individuals, we observed variation beginning within weeks of infection at epitope-containing sites in the viral quasispecies, which conferred escape by mechanisms including altered peptide presentation/recognition and altered antigen processing. The number of epitope-containing regions exhibiting evidence of early CTL escape ranged from 1 out of 21 in a subject who controlled viral replication effectively to 5 out of 7 in a subject who did not. Evaluation of the extent and kinetics of HIV-1 escape from >40 different epitope-specific CD8 T cell responses enabled analysis of factors determining escape and suggested that escape is restricted by costs to intrinsic viral fitness and by broad, codominant distribution of CTL-mediated pressure on viral replication. PMID:15545352

  15. Cerebral toxoplasmosis in a middle-aged man as first presentation of primary immunodeficiency due to a hypomorphic mutation in the CD40 ligand gene.

    PubMed

    Yong, P F K; Post, F A; Gilmour, K C; Grosse-Kreul, D; King, A; Easterbrook, P; Ibrahim, M A A

    2008-11-01

    Cerebral toxoplasmosis can occur outside the setting of advanced HIV immunodeficiency or drug-induced immunosuppression. A case of cerebral toxoplasmosis is reported in a previously healthy 41-year-old man who was found to have a genetic defect in CD40 ligand, resulting in the X linked hyper-IgM syndrome despite normal surface protein expression on flow cytometry. This highlights the fact that primary immunodeficiencies can first present late in life with a relatively mild phenotype and should be considered in the differential diagnosis of opportunistic infections in non-HIV infected patients; in addition, normal protein expression does not necessarily rule out hypomorphic mutations.

  16. Pattern recognitions receptors in immunodeficiency disorders.

    PubMed

    Mortaz, Esameil; Adcock, Ian M; Tabarsi, Payam; Darazam, Ilad Alavi; Movassaghi, Masoud; Garssen, Johan; Jamaati, Hamidreza; Velayati, Aliakbar

    2017-01-14

    Pattern recognition receptors (PRRs) recognize common microbial or host-derived macromolecules and have important roles in early activation and response of the immune system. Initiation of the innate immune response starts with the recognition of microbial structures called pathogen associated molecular patterns (PAMPs). Recognition of PAMPs is performed by germline-encoded receptors expressed mainly on immune cells termed pattern recognition receptors (PRRs). Several classes of pattern recognition receptors (PRRs) are involved in the pathogenesis of diseases, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and Nod-like receptors (NLRs). Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins in the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are associated with susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Altered TLR responses to TLR2 and 4 agonists are seen in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome (HIES), and for most TLRs in adenosine deaminase deficiency. In this review we provide the reader with an update on the role of TLRs and downstream signaling pathways in PID disorders.

  17. Primary antiretroviral drug resistance in newly human immunodeficiency virus-diagnosed individuals testing anonymously and confidentially.

    PubMed

    Markovitz, Amanda R; Thibault, Christina S; Brandauer, Peter W; Buskin, Susan E

    2011-06-01

    The purpose of this study was to determine if anonymous and confidential testers differ in recency of human immunodeficiency virus (HIV) infection at time of testing and prevalence of antiretroviral drug (ARV) resistance. We examined data from the Centers for Disease Control and Prevention-sponsored Antiretroviral Drug Resistance Testing project, which performed genotypic testing on leftover HIV diagnostic serum specimens of confidentially and anonymously tested ARV-naïve persons newly diagnosed with HIV in Colorado (n = 365 at 11 sites) and King County, Washington (n = 492 at 44 sites). The serologic testing algorithm for recent HIV seroconversion was used to classify people as likely to have been recently infected or not. Type of testing, anonymous or confidential, was not significantly associated with either timing of HIV testing by serologic testing algorithm for recent HIV seroconversion or resistance rates. Mutations conferring any level of ARV resistance were present in 17% of testers, and high-level resistance mutations were present in 10%. Anonymous testers were significantly more likely to have CD4+ counts >500 cells per mm(3) (45% vs. 28%; p = 0.018), indicative of an early infection. This study indicates that anonymous testers have demographic differences relative to confidential HIV testers but were not more likely to exhibit drug resistance. Findings related to when in the course of disease anonymous testers are tested are inconsistent, but anonymous testers had higher CD4 counts, which indicates early testing and is consistent with other studies.

  18. Natural killer cell biology illuminated by primary immunodeficiency syndromes in humans.

    PubMed

    Voss, Matthias; Bryceson, Yenan T

    2017-04-01

    Natural killer (NK) cells are innate immune cytotoxic effector cells well known for their role in antiviral immunity and tumor immunosurveillance. In parts, this knowledge stems from rare inherited immunodeficiency disorders in humans that abrogate NK cell function leading to immune impairments, most notably associated with a high susceptibility to viral infections. Phenotypically, these disorders range from deficiencies selectively affecting NK cells to complex general immune defects that affect NK cells but also other immune cell subsets. Moreover, deficiencies may be associated with reduced NK cell numbers or rather impair specific NK cell effector functions. In recent years, genetic defects underlying the various NK cell deficiencies have been uncovered and have triggered investigative efforts to decipher the molecular mechanisms underlying these disorders. Here we review the associations between inherited human diseases and NK cell development as well as function, with a particular focus on defects in NK cell exocytosis and cytotoxicity. Furthermore we outline how reports of diverse genetic defects have shaped our understanding of NK cell biology. Copyright © 2015. Published by Elsevier Inc.

  19. Primary Radiation Therapy for Head-and-Neck Cancer in the Setting of Human Immunodeficiency Virus

    SciTech Connect

    Klein, Emily A.; Guiou, Michael; Farwell, D. Gregory; Luu, Quang; Lau, Derick H.; Stuart, Kerri; Vaughan, Andrew; Vijayakumar, Srinivasan; Chen, Allen M.

    2011-01-01

    Purpose: To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). Methods and Materials: The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. Results: The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. Conclusions: Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.

  20. The feasibility of identifying children with primary immunodeficiency disorders: preparation for the polio post-eradication era in Bangladesh.

    PubMed

    Sazzad, Hossain M S; Rainey, Jeanette J; Mach, Ondrej; Sutter, Roland; Diordista, Serguei; Kawser, Choudhury A; Mobarak, Reaz; Alam, Didarul; Chowdhury, Mahmood A; Hossain, M Jahangir; Hasan, A S M Mainul; Luby, Stephen P

    2012-08-03

    Persons with primary immunodeficiency disorders (PIDD) who receive oral poliovirus vaccine (OPV) or are household contacts of OPV recipients are at risk of excreting immunodeficiency-associated vaccine-derived polioviruses (iVDPVs). iVDPVs can be transmitted and cause paralytic polio. The objective of this study was to determine the feasibility of identifying infants and young children with PIDD in Bangladesh, and among those identified, to estimate the proportion excreting iVDPVs. Patients admitted at 5 referral and teaching hospitals from the hospital catchment area were screened for PIDD using a standardized clinical case definition. PIDD was confirmed using results of testing for age-specific quantitative immunoglobulins (QIGs) levels. Stool specimens were collected according to WHO guidelines from children with confirmed PIDD. During February-July 2009, 13 patients were identified who met the clinical case definition for PIDD; their median age was 1.4 years (range: 2 months to 10 years). Six (46%) of the patients had age-specific QIG results that confirmed PIDD. Stool specimens from four patients tested negative for polio vaccine viruses. All four had received OPV between 50 and 264 days prior to study recruitment. Identifying children with PIDD at referral and teaching hospitals in Bangladesh is feasible, but a larger number of patients is needed to estimate the risk for iVDPV excretion. The national polio eradication program should expand surveillance for PIDD case-patients and regularly test persons with PIDD for poliovirus excretion. These efforts will be essential for developing effective prevention and control strategies following OPV cessation, especially for densely populated and tropical countries like Bangladesh where even a minimal iVDPV risk could have significant public health consequences. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment, and discovery.

    PubMed

    Modell, Vicki; Knaus, Megan; Modell, Fred; Roifman, Chaim; Orange, Jordan; Notarangelo, Luigi D

    2014-10-01

    Primary immunodeficiencies (PI) are defects of the immune system that cause severe infections if not diagnosed and treated appropriately. Many patients with PI are undiagnosed, under-diagnosed, or misdiagnosed. Over the last decade, the Jeffrey Modell Foundation has implemented a Physician Education and Public Awareness Campaign (PEPAC) to raise awareness, assure early diagnosis, appropriate treatment, and management, with the overall goal to reduce morbidities and mortalities related to PI. In order to evaluate the PEPAC program, data are requested annually from physician experts within the Jeffrey Modell Centers Network (JMCN). The JMCN, consisting of 556 expert physicians, at 234 academic institutions, in 196 cities, and 78 countries spanning six continents, provides the infrastructure for referral, diagnosis, and appropriate treatment for patients with PI. In addition, the JMCN has made a significant contribution to the field of immunology with the discovery of new genes at the centers. These advancements have led to an overall better understanding of the immune system and will continue to improve quality of life of those with PI.

  2. Evidence for Altered Glutamine Metabolism in Human Immunodeficiency Virus Type 1 Infected Primary Human CD4(+) T Cells.

    PubMed

    Hegedus, Andrea; Kavanagh Williamson, Maia; Khan, Mariam B; Dias Zeidler, Julianna; Da Poian, Andrea T; El-Bacha, Tatiana; Struys, Eduard A; Huthoff, Hendrik

    2017-10-04

    Glutamine is a conditionally essential amino acid that is an important metabolic resource for proliferating tissues by acting as a proteinogenic amino acid, a nitrogen donor for biosynthetic reactions and as a substrate for the citric acid or tricarboxylic acid cycle. The human immunodeficiency virus type 1 (HIV-1) productively infects activated CD4(+) T cells that are known to require glutamine for proliferation and for carrying out effector functions. As a virus, HIV-1 is furthermore entirely dependent on host metabolism to support its replication. In this study, we compared HIV-1 infected with uninfected activated primary human CD4(+) T cells with regard to glutamine metabolism. We report that glutamine concentrations are elevated in HIV-1-infected cells and that glutamine is important to support HIV-1 replication, although the latter is closely linked to the glutamine dependency of cell survival. Metabolic tracer experiments showed that entry of glutamine-derived carbon into the citric acid cycle is unaffected by HIV-1 infection, but that there is an increase in the secretion of glutamine-derived glutamic acid from HIV-1-infected cells. Western blotting of key enzymes that metabolize glutamine revealed marked differences in the expression of glutaminase isoforms, KGA and CAG, as well as the PPAT enzyme that targets glutamine-derived nitrogen toward nucleotide synthesis. Altogether, this demonstrates that infection of CD4(+) T cells with HIV-1 leads to considerable changes in the cellular glutamine metabolism.

  3. Human immunodeficiency virus (HIV)-specific effector CD8 T cell activity in patients with primary HIV infection.

    PubMed

    Alter, Galit; Merchant, Alefia; Tsoukas, Christos M; Rouleau, Danielle; LeBlanc, Roger P; Côté, Pierre; Baril, Jean-Guy; Thomas, Réjean; Nguyen, Vinh-Kim; Sékaly, Rafik-Pierre; Routy, Jean-Pierre; Bernard, Nicole F

    2002-03-15

    The interferon-gamma ELISPOT assay was used to assess and compare the magnitude and breadth of human immunodeficiency virus (HIV)-specific CD8 T cell responses in treatment-naive subjects during the first year of HIV primary infection and during the chronic phase of infection. Twenty-five subjects tested within a year of exposure to HIV resulting in seroconversion and 20 subjects with chronic infection were screened for HIV peptide-specific activity by stimulating peripheral blood mononuclear cells with a panel of 5-21 HLA class I-restricted HIV peptides (mean, 11.2 +/- 3.5 HIV peptides). There was a significant correlation between the magnitude and breadth of HIV-specific effector responses and time elapsed from exposure (r=0.63 for magnitude vs. time and r=0.64 for breadth vs. time; P<.02, paired t test). Maximal breadth of the HIV gene product reactivity was achieved within 2 months of exposure for Nef-specific responses and by 4 months of exposure for responses directed to Env, Gag, and reverse transcriptase.

  4. Dual tropism for macrophages and lymphocytes is a common feature of primary human immunodeficiency virus type 1 and 2 isolates.

    PubMed Central

    Valentin, A; Albert, J; Fenyö, E M; Asjö, B

    1994-01-01

    We have investigated the ability of human immunodeficiency virus type 1 (HIV-1) and HIV-2 isolates to infect and replicate in primary human macrophages. Monocytes from blood donors were allowed to differentiate into macrophages by culture in the presence of autologous lymphocytes and human serum for 5 days before infection. A panel of 70 HIV-1 and 12 HIV-2 isolates were recovered from seropositive individuals with different severities of HIV infection. A majority of isolates (55 HIV-1 and all HIV-2) were obtained from peripheral blood mononuclear cells, but isolates from cerebrospinal fluid, monocytes, brain tissue, plasma, and purified CD4+ lymphocytes were also included. All isolates were able to infect monocyte-derived macrophages, even though the replicative capacity of the isolates varied. Interestingly, isolates with a rapid/high, syncytium-inducing phenotype did not differ from slow/low, non-syncytium-inducing isolates in their ability to replicate in monocyte-derived macrophages. Others have reported that rapid/high, syncytium-inducing isolates have a reduced ability to infect and replicate in monocytes. However, different methods to isolate and culture the monocytes/macrophages were used in these studies and our study. Thus, the ability of HIV isolates to replicate in monocytes/macrophages appears to be strongly influenced by the isolation and culture procedures. It remains to be determined which culture procedure is more relevant for the in vivo situation. PMID:7521920

  5. [Indicator condition guided human immunodeficiency virus requesting in primary health care: results of a collaboration].

    PubMed

    Cayuelas-Redondo, Laia; Menacho-Pascual, Ignacio; Noguera-Sánchez, Pablo; Goicoa-Gago, Carmen; Pollio-Peña, Gernónimo; Blanco-Delgado, Rebeca; Barba-Ávila, Olga; Sequeira-Aymar, Ethel; Muns, Mercè; Clusa, Thais; García, Felipe; León, Agathe

    2015-12-01

    The search of HIV infected patients guided by indicator conditions (IC) is a strategy used to increase the early detection of HIV. The objective is to analyze whether a collaboration to raise awareness of the importance of early detection of HIV in 3 primary care centers influenced the proportion of HIV serology requested. Multicenter retrospective study was conducted comparing the baseline and a post-collaboration period. The collaboration consisted of training sessions and participation in the HIDES study (years 2009-2010). Patients between 18 and 64 years old with newly diagnosed herpes zoster, seborrheic eczema, mononucleosis syndrome, and leucopenia/thrombocytopenia in 3 primary care centers in 2008 (baseline period) and 2012 (post-collaboration period). The sociodemographic variables, HIV risk conditions, requests for HIV serology, and outcomes were evaluated. A total of 1,219 ICs were included (558 in 2008 and 661 in 2012). In 2008 the number of HIV tests in patients with an IC was 3.9%, and rose to 11.8% in 2012 (P<.0001). The HIV infection rate was 2.2% (95% CI: 0.4-7.3) (n=2). It was estimated that 25 new cases (12 in 2008 and 13 in 2012) would have been diagnosed if they had performed the test on all patients with IC. Predictors of HIV request were, having an IC in 2012, a younger age, having an mononucleosis syndrome, and not being Spanish. The HIV request demand tripled, after the collaboration with primary care centers, however in 88% the test was not requested, resulting in diagnostic losses. New strategies are needed to raise awareness of the importance of early detection of HIV. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  6. Long-lasting production of new T and B cells and T-cell repertoire diversity in patients with primary immunodeficiency who had undergone stem cell transplantation: a single-centre experience.

    PubMed

    Valotti, Monica; Sottini, Alessandra; Lanfranchi, Arnalda; Bolda, Federica; Serana, Federico; Bertoli, Diego; Giustini, Viviana; Tessitore, Marion Vaglio; Caimi, Luigi; Imberti, Luisa

    2014-01-01

    Levels of Kappa-deleting recombination excision circles (KRECs), T-cell receptor excision circles (TRECs), and T-cell repertoire diversity were evaluated in 1038 samples of 124 children with primary immunodeficiency, of whom 102 (54 with severe combined immunodeficiency and 48 with other types of immunodeficiency) underwent hematopoietic stem cell transplantation. Twenty-two not transplanted patients with primary immunodeficiency were used as controls. Only data of patients from whom at least five samples were sent to the clinical laboratory for routine monitoring of lymphocyte reconstitutions were included in the analysis. The mean time of the follow-up was 8 years. The long-lasting posttransplantation kinetics of KREC and TREC production occurred similarly in patients with severe combined immunodeficiency and with other types of immunodeficiency and, in both groups, the T-cell reconstitution was more efficient than in nontransplanted children. Although thymic output decreased in older transplanted patients, the degree of T-cell repertoire diversity, after an initial increase, remained stable during the observation period. However, the presence of graft-versus-host disease and ablative conditioning seemed to play a role in the time-related shaping of T-cell repertoire. Overall, our data suggest that long-term B- and T-cell reconstitution was equally achieved in children with severe combined immunodeficiency and with other types of primary immunodeficiency.

  7. Dynamic Modulation of Expression of Lentiviral Restriction Factors in Primary CD4(+) T Cells following Simian Immunodeficiency Virus Infection.

    PubMed

    Rahmberg, Andrew R; Rajakumar, Premeela A; Billingsley, James M; Johnson, R Paul

    2017-04-01

    Although multiple restriction factors have been shown to inhibit HIV/SIV replication, little is known about their expression in vivo Expression of 45 confirmed and putative HIV/SIV restriction factors was analyzed in CD4(+) T cells from peripheral blood and the jejunum in rhesus macaques, revealing distinct expression patterns in naive and memory subsets. In both peripheral blood and the jejunum, memory CD4(+) T cells expressed higher levels of multiple restriction factors compared to naive cells. However, relative to their expression in peripheral blood CD4(+) T cells, jejunal CCR5(+) CD4(+) T cells exhibited significantly lower expression of multiple restriction factors, including APOBEC3G, MX2, and TRIM25, which may contribute to the exquisite susceptibility of these cells to SIV infection. In vitro stimulation with anti-CD3/CD28 antibodies or type I interferon resulted in upregulation of distinct subsets of multiple restriction factors. After infection of rhesus macaques with SIVmac239, the expression of most confirmed and putative restriction factors substantially increased in all CD4(+) T cell memory subsets at the peak of acute infection. Jejunal CCR5(+) CD4(+) T cells exhibited the highest levels of SIV RNA, corresponding to the lower restriction factor expression in this subset relative to peripheral blood prior to infection. These results illustrate the dynamic modulation of confirmed and putative restriction factor expression by memory differentiation, stimulation, tissue microenvironment and SIV infection and suggest that differential expression of restriction factors may play a key role in modulating the susceptibility of different populations of CD4(+) T cells to lentiviral infection.IMPORTANCE Restriction factors are genes that have evolved to provide intrinsic defense against viruses. HIV and simian immunodeficiency virus (SIV) target CD4(+) T cells. The baseline level of expression in vivo and degree to which expression of restriction factors is

  8. PID Tuning Using Extremum Seeking

    SciTech Connect

    Killingsworth, N; Krstic, M

    2005-11-15

    Although proportional-integral-derivative (PID) controllers are widely used in the process industry, their effectiveness is often limited due to poor tuning. Manual tuning of PID controllers, which requires optimization of three parameters, is a time-consuming task. To remedy this difficulty, much effort has been invested in developing systematic tuning methods. Many of these methods rely on knowledge of the plant model or require special experiments to identify a suitable plant model. Reviews of these methods are given in [1] and the survey paper [2]. However, in many situations a plant model is not known, and it is not desirable to open the process loop for system identification. Thus a method for tuning PID parameters within a closed-loop setting is advantageous. In relay feedback tuning [3]-[5], the feedback controller is temporarily replaced by a relay. Relay feedback causes most systems to oscillate, thus determining one point on the Nyquist diagram. Based on the location of this point, PID parameters can be chosen to give the closed-loop system a desired phase and gain margin. An alternative tuning method, which does not require either a modification of the system or a system model, is unfalsified control [6], [7]. This method uses input-output data to determine whether a set of PID parameters meets performance specifications. An adaptive algorithm is used to update the PID controller based on whether or not the controller falsifies a given criterion. The method requires a finite set of candidate PID controllers that must be initially specified [6]. Unfalsified control for an infinite set of PID controllers has been developed in [7]; this approach requires a carefully chosen input signal [8]. Yet another model-free PID tuning method that does not require opening of the loop is iterative feedback tuning (IFT). IFT iteratively optimizes the controller parameters with respect to a cost function derived from the output signal of the closed-loop system, see [9

  9. The NF-kappa B binding site is necessary for efficient replication of simian immunodeficiency virus of macaques in primary macrophages but not in T cells in vitro.

    PubMed Central

    Bellas, R E; Hopkins, N; Li, Y

    1993-01-01

    We demonstrate here that the nuclear factor-kappa B (NF-kappa B) binding site in the simian immunodeficiency virus (SIVmac) long terminal repeat is essential for efficient virus replication in primary alveolar macrophages but dispensable for efficient replication in primary T cells. Mutation of the NF-kappa B site does not seriously impair replication of a T-cell-tropic SIVmac239 or a macrophagetropic SIVmacEm* in peripheral blood lymphocytes or established CD4+ cell lines; however, mutation of the NF-kappa B site prevents efficient SIVmacEm* replication in primary alveolar macrophages. These data suggest that efficient replication in primary macrophages requires both envelope and long terminal repeat determinants. Images PMID:8474179

  10. PID1 IS A NOVEL SENSITIZER OF BRAIN TUMOR CELLS TO CHEMOTHERAPY

    PubMed Central

    Erdreich-Epstein, Anat; Xu, Jingying; Ren, Xiuhai

    2014-01-01

    BACKGROUND: PID1 is a phosphotyrosine binding domain-containing protein of unknown function in cancer. We recently provided the first report of PID1 in brain tumors (and in cancer). PID1 inhibits growth and proliferation and induces cell death, apoptosis and mitochondrial depolarization in glioblastoma, medulloblastoma and ATRT cell lines. PID1 siRNA had the opposite effect on mitochondrial depolarization. PID1 mRNA level was directly correlated with survival of patients with medulloblastoma or glioma: PID1 mRNA was lowest in tumor subgroups with the poorest prognosis and highest in the more favorable prognosis groups within each diagnosis. The mechanism by which PID1 affects these tumors is currently unknown, and is the focus of studies in our laboratory. METHODS: Experiments were conducted in tissue culture in primary and established cell lines using established methods to assess mRNA, proliferation and signal transduction. RESULTS: Since lower PID1 mRNA was associated with poorer outcome in medulloblastoma and gliomas and higher PID1 was associated with improved outcome, we hypothesized that PID1 level may affect responsiveness of these brain tumors to therapy: higher responsiveness in tumors with high PID1 and resistance when it is low. Indeed, while both cisplatin (10 µg/ml) or transient PID1 overexpression increased apoptosis of glioma and medulloblastoma cell lines (indicated by increased AnnexinV, caspase-3 cleavage and mitochondrial depolarization), combining cisplatin with PID1 caused a markedly higher effect than each alone. Moreover, knockdown of PID1 by siRNA inhibited the cisplatin-induced mitochondrial membrane depolarization and apoptosis (AnnexinV and caspase-3 cleavage), suggesting that PID1 may be required for cisplatin-induced apoptosis. This supports our hypothesis that PID1 may sensitize brain tumor cells to chemotherapy. Intriguingly, PID1 mRNA increased in response to cisplatin (5 µg/ml) as well as to etoposide (5 µg/ml) and vincristine

  11. Activities of 3'-azido-3'-deoxythymidine nucleotide dimers in primary lymphocytes infected with human immunodeficiency virus type 1.

    PubMed Central

    Schinazi, R F; Sommadossi, J P; Saalmann, V; Cannon, D L; Xie, M Y; Hart, G C; Smith, G A; Hahn, E F

    1990-01-01

    The relative antiviral potencies of five nucleotide heterodimers of 3'-azido-3'-deoxythymidine (AZT), 3'-azido-3'-deoxythymidilyl-(5',5')-2'-3'-dideoxy-5'-adenylic acid (AZT-P-ddA), 3'-azido-3'-deoxythymidilyl-(5',5')-2',3'-dideoxy-5'-inosinic acid (AZT-P-ddI), and the corresponding 2-cyanoethyl congeners AZT-P(CyE)-ddA and AZT-P(CyE)-ddI, were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The homodimer 3'-azido-3'-deoxythymidilyl-(5',5')-3'-azido-3'-deoxythymidilic acid (AZT-P-AZT) was also included for comparison. The potencies of the compounds were AZT-P-ddA greater than or equal to AZT-P-ddI greater than AZT-P(CyE)-ddA greater than or equal to AZT-P(CyE)-ddI greater than or equal to AZT greater than AZT-P-AZT. Whereas AZT-P-ddA and AZT-P-ddI had in vitro therapeutic indices greater than that of AZT, the homodimer of AZT had a low therapeutic index. AZT-P-ddI exhibited the lowest toxicity in peripheral blood mononuclear, Vero, or CEM cells. Combination studies between AZT and 2',3'-dideoxyinosine (ddI) at nontoxic concentrations indicated a synergistic interaction at a drug ratio of 1:100. At higher ratios (1:500 and 1:1,000), the interactions were synergistic only at concentrations that produced up to 75% virus inhibition. At higher levels of antiviral effects, this combination was antagonistic, as determined by the multiple drug effect analysis method. AZT-P-ddI was about 10-fold less toxic than AZT to human granulocyte-macrophage progenitor cells. However, no significant difference was apparent when the compounds were evaluated against cells of the erythroid lineage. The greater antiviral activity and lower toxicity of this compound could not be attributed to the extracellular decomposition of the dimer in media at physiological temperature and pH. However, in acidic solutions, AZT-P-ddI decomposed in a pH-dependent manner. Advanced preclinical studies with this heterodimer of two clinically

  12. Multivariable PID control by decoupling

    NASA Astrophysics Data System (ADS)

    Garrido, Juan; Vázquez, Francisco; Morilla, Fernando

    2016-04-01

    This paper presents a new methodology to design multivariable proportional-integral-derivative (PID) controllers based on decoupling control. The method is presented for general n × n processes. In the design procedure, an ideal decoupling control with integral action is designed to minimise interactions. It depends on the desired open-loop processes that are specified according to realisability conditions and desired closed-loop performance specifications. These realisability conditions are stated and three common cases to define the open-loop processes are studied and proposed. Then, controller elements are approximated to PID structure. From a practical point of view, the wind-up problem is also considered and a new anti-wind-up scheme for multivariable PID controller is proposed. Comparisons with other works demonstrate the effectiveness of the methodology through the use of several simulation examples and an experimental lab process.

  13. Autoimmunity and Immunodeficiency.

    PubMed

    Dosanjh, Amrita

    2015-11-01

    The references provided include data from evidence A and B studies based on the relevant populations. Because many primary immunodeficiencies associated with autoimmune diseases are rare, illustrative cases (evidence D) also are referenced. On the basis of level A evidence, immunoglobulin A deficiency is the most common primary immunodeficiency and is associated with defective mucosal immunity and autoimmune disease. On the basis of strong evidence (level A), Wiskott Aldrich syndrome presents early in life and is associated with autoimmune arthritis and anemia. On the basis of strong evidence in the literature, a number of primary immunodeficiencies are associated with defects in T regulatory cell number and development, cytokine aberrancies, and, as a consequence, production of autoantibodies. On the basis of strong evidence (level A) and case reports (level D), complement deficiency can be associated with autoimmune disease, most notably systemic lupus erythematosus.

  14. Augmentation of virus secretion by the human immunodeficiency virus type 1 Vpu protein is cell type independent and occurs in cultured human primary macrophages and lymphocytes.

    PubMed Central

    Schubert, U; Clouse, K A; Strebel, K

    1995-01-01

    The human immunodeficiency virus type 1-specific Vpu protein is a small integral membrane phosphoprotein that induces degradation of the virus receptor CD4 in the endoplasmic reticulum and, independently, increases the release of progeny virions from infected cells. To address the importance of Vpu for virus replication in primary human cells such as peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM), we used three different sets of monocyte-tropic molecular clones of human immunodeficiency virus type 1: a primary isolate, AD8+, and two chimeric variants of the T-cell-tropic isolate NL4-3 carrying the env determinants of either AD8+ or SF162 monocyte-tropic primary isolates. Isogenic variants of these chimeric viruses were constructed to express either wild-type Vpu or various mutants of Vpu. The effects of these mutations in the vpu gene on virus particle secretion from infected MDM or PBMC were assessed by determination of the release of virion-associated reverse transcriptase into culture supernatants, Western blot (immunoblot) analysis of pelleted virions, and steady-state or pulse-chase metabolic labeling. Wild-type Vpu increased virus release four- to sixfold in MDM and two- to threefold in PBMC, while nonphosphorylated Vpu and a C-terminal truncation mutant of Vpu were partially active on virus release in primary cells. These results demonstrate that Vpu regulates virus release in primary lymphocyte and macrophage cultures in a similar manner and to a similar extent to those previously observed in HeLa cells or CD4+ T-cell lines. Thus, our findings provide evidence that Vpu functions in a variety of human cells, both primary cells and continuous cell lines, and mutations in Vpu affect its biological activity independent of the cell type and virus isolate used. PMID:7494279

  15. Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies.

    PubMed

    Serana, Federico; Chiarini, Marco; Zanotti, Cinzia; Sottini, Alessandra; Bertoli, Diego; Bosio, Andrea; Caimi, Luigi; Imberti, Luisa

    2013-05-09

    T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) are circular DNA segments generated in T and B cells during their maturation in the thymus and bone marrow. These circularized DNA elements persist in the cells, are unable to replicate, and are diluted as a result of cell division, thus are considered markers of new lymphocyte output. The quantification of TRECs and KRECs, which can be reliably performed using singleplex or duplex real-time quantitative PCR, provides novel information in the management of T- and B-cell immunity-related diseases. In primary immunodeficiencies, when combined with flow cytometric analysis of T- and B-cell subpopulations, the measure of TRECs and KRECs has contributed to an improved characterization of the diseases, to the identification of patients' subgroups, and to the monitoring of stem cell transplantation and enzyme replacement therapy. For the same diseases, the TREC and KREC assays, introduced in the newborn screening program, allow early disease identification and may lead to discovery of new genetic defects. TREC and KREC levels can also been used as a surrogate marker of lymphocyte output in acquired immunodeficiencies. The low number of TRECs, which has in fact been extensively documented in untreated HIV-infected subjects, has been shown to increase following antiretroviral therapy. Differently, KREC number, which is in the normal range in these patients, has been shown to decrease following long-lasting therapy. Whether changes of KREC levels have relevance in the biology and in the clinical aspects of primary and acquired immunodeficiencies remains to be firmly established.

  16. Immunomodulation and immunodeficiency.

    PubMed

    Foster, Aiden P

    2004-04-01

    This article briefly reviews the concepts of immunodeficiency and immunomodulation as they relate to selected skin diseases in the dog and cat. Immunodeficiency states are uncommon and may be associated with a subnormal or down-regulated immune system, including humoral deficiencies, such as IgA, and abnormal lymphocyte or neutrophil function. Establishing a causal relationship between a skin disease and presumed immunodeficient state has been difficult due to the rarity of such conditions, and the limited nature of the techniques used to characterise the immune system response. Severe combined immunodeficiency in dogs is a well characterised primary immunodeficiency state involving lymphocytes; retrovirus infection in cats may lead to an acquired immunodeficient state with some association with certain dermatological conditions although it remains unclear that infection is causally linked with disease. Immunomodulation usually implies stimulating the immune system along a beneficial pathway. Such a therapeutic approach may involve a wide variety of agents, for example intravenous immunoglobulin. There are few randomised controlled trials with veterinary patients that unequivocally demonstrate beneficial responses to immunomodulatory agents. Interferons are cytokines of major interest in human and veterinary medicine for their antiviral, anti-tumour and immunomodulatory effects. The advent of veterinary-licensed products containing recombinant interferon may enable demonstration of the efficacy of interferons for conditions such as canine papillomatosis and feline eosinophilic granuloma complex. Canine pyoderma has been treated with a number of presumed immunomodulatory agents with limited success. With more detailed knowledge of the pathogenesis of pyoderma it may be possible to develop efficacious immunomodulators.

  17. The Orphan Seven-Transmembrane Receptor Apj Supports the Entry of Primary T-Cell-Line-Tropic and Dualtropic Human Immunodeficiency Virus Type 1

    PubMed Central

    Choe, Hyeryun; Farzan, Michael; Konkel, Miriam; Martin, Kathleen; Sun, Ying; Marcon, Luisa; Cayabyab, Mark; Berman, Michael; Dorf, Martin E.; Gerard, Norma; Gerard, Craig; Sodroski, Joseph

    1998-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters target cells by sequential binding to CD4 and specific seven-transmembrane-segment (7TMS) coreceptors. Viruses use the chemokine receptor CCR5 as a coreceptor in the early, asymptomatic stages of HIV-1 infection but can adapt to the use of other receptors such as CXCR4 and CCR3 as the infection proceeds. Here we identify one such coreceptor, Apj, which supported the efficient entry of several primary T-cell-line tropic (T-tropic) and dualtropic HIV-1 isolates and the simian immunodeficiency virus SIVmac316. Another 7TMS protein, CCR9, supported the less efficient entry of one primary T-tropic isolate. mRNAs for both receptors were present in phytohemagglutinin- and interleukin-2-activated peripheral blood mononuclear cells. Apj and CCR9 share with other coreceptors for HIV-1 and SIV an N-terminal region rich in aromatic and acidic residues. These results highlight properties common to 7TMS proteins that can function as HIV-1 coreceptors, and they may contribute to an understanding of viral evolution in infected individuals. PMID:9621075

  18. Cascade control of superheated steam temperature with neuro-PID controller.

    PubMed

    Zhang, Jianhua; Zhang, Fenfang; Ren, Mifeng; Hou, Guolian; Fang, Fang

    2012-11-01

    In this paper, an improved cascade control methodology for superheated processes is developed, in which the primary PID controller is implemented by neural networks trained by minimizing error entropy criterion. The entropy of the tracking error can be estimated recursively by utilizing receding horizon window technique. The measurable disturbances in superheated processes are input to the neuro-PID controller besides the sequences of tracking error in outer loop control system, hence, feedback control is combined with feedforward control in the proposed neuro-PID controller. The convergent condition of the neural networks is analyzed. The implementation procedures of the proposed cascade control approach are summarized. Compared with the neuro-PID controller using minimizing squared error criterion, the proposed neuro-PID controller using minimizing error entropy criterion may decrease fluctuations of the superheated steam temperature. A simulation example shows the advantages of the proposed method. Copyright © 2012 ISA. Published by Elsevier Ltd. All rights reserved.

  19. The case for a national service for primary immune deficiency disorders in New Zealand.

    PubMed

    Ameratunga, Rohan; Steele, Richard; Jordan, Anthony; Preece, Kahn; Barker, Russell; Brewerton, Maia; Lindsay, Karen; Sinclair, Jan; Storey, Peter; Woon, See-Tarn

    2016-06-10

    Primary immune deficiency disorders (PIDs) are rare conditions for which effective treatment is available. It is critical these patients are identified at an early stage to prevent unnecessary morbidity and mortality. Treatment of these disorders is expensive and expert evaluation and ongoing management by a clinical immunologist is essential. Until recently there has been a major shortage of clinical immunologists in New Zealand. While the numbers of trained immunologists have increased in recent years, most are located in Auckland. The majority of symptomatic PID patients require life-long immunoglobulin replacement. Currently there is a shortage of subcutaneous and intravenous immunoglobulin (SCIG/IVIG) in New Zealand. A recent audit by the New Zealand Blood Service (NZBS) showed that compliance with indications for SCIG/IVIG treatment was poor in District Health Boards (DHBs) without an immunology service. The NZBS audit has shown that approximately 20% of annual prescriptions for SCIG/IVIG, costing $6M, do not comply with UK or Australian guidelines. Inappropriate use may have contributed to the present shortage of SCIG/IVIG necessitating importation of the product. This is likely to have resulted in a major unnecessary financial burden to each DHB. Here we present the case for a national service responsible for the tertiary care of PID patients and oversight for immunoglobulin use for primary and non-haematological secondary immunodeficiencies. We propose that other PIDs, including hereditary angioedema, are integrated into a national PID service. Ancillary services, including the customised genetic testing service, and research are also an essential component of an integrated national PID service and are described in this review. As we show here, a hub-and-spoke model for a national service for PIDs would result in major cost savings, as well as improved patient care. It would also allow seamless transition from paediatric to adult services.

  20. Characterization and Enhanced Processing of Soluble, Oligomeric gp140 Envelope Glycoproteins Derived from Human Immunodeficiency Virus Type-1 Primary Isolates

    DTIC Science & Technology

    2001-05-01

    impact on HIV-1 antibody detection J Clin Microbiol. 38:773-80. 80. Dragic, T., V. Litwin , G. P. Allaway, S. R. Martin, Y. Huang, K. A. Nagashima, C...immunodeficiency virus strain Proc Natl Acad Sci U S A. 94:14742-7. 94. Embretson, J., M. Zupancic, J. L. Ribas, A. Burke , P. Racz, K. Tenner-Racz...HIV neuropathogenesis and therapeutic strategies Acta Paediatr Jpn. 40:107-11. 98. Evans, D. J., J. McKeating, J. M. Meredith, K. L. Burke , K

  1. Common variable immunodeficiency: 20-yr experience at a single centre.

    PubMed

    Llobet, M Pilar; Soler-Palacin, Pere; Detkova, Drahomira; Hernández, Manuel; Caragol, Isabel; Espanol, Teresa

    2009-03-01

    Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency. It can present at any age in patients with a history of recurrent bacterial infections, with or without a family history of other primary immunodeficiencies (PID), and shows a wide range of clinical manifestations and immunological data. Diagnosis is based on low IgG, IgM and/or IgA levels. Delayed diagnosis and therapy can lead to bronchiectasis and malabsorption. The aim of this study was to describe a paediatric population diagnosed of CVID and its evolution in the population. Memory B-cell (MB) classification carried out in these patients was correlated with clinical manifestations and outcome. Clinical and immunological data of 22 CVID children under 18 yr treated at our centre between 1985 and 2005 are presented. Immunological studies included those for diagnosis and MB quantification. Differences in form of presentation, familial incidence and MB classification were reviewed. A statistical descriptive analysis was made. Infections were the commonest manifestation, affecting mainly respiratory (19/22) and gastrointestinal (10/22) tracts. Bronchiectasis was present in seven cases, and detected prior to CVID diagnosis in five. Replacement therapy led to a significant reduction in the number of infections. Severe complications appeared mostly in patients without MB. Patients of the same family share the same MB group. Family members had also been diagnosed of CVID in seven cases. Early diagnosis and therapy are essential to improve outcome in these patients. MB studies are useful in children to orient prognosis and further genetic studies.

  2. PID control of gas pipelines

    SciTech Connect

    Coltharp, B.; Bergmann, J.

    1996-09-01

    The use of low cost digital controllers for pipeline control is increasing as the reliability and cost improves. In pipeline applications, the proportional, integral, and derivative (PID) controller algorithm is often used. However, the unique problems associated with pipeline operation have caused manufacturers to modify the basic control algorithms. Features such as set point ramping, built in pressure control, freeze on input error, and high and low output limits help assure safe and predictable pipeline operation.

  3. Mental health in primary human immunodeficiency virus care in South Africa: a study of provider knowledge, attitudes, and practice.

    PubMed

    Mall, Sumaya; Sorsdahl, Katherine; Struthers, Helen; Joska, John A

    2013-03-01

    The role of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome care providers in detecting mental disorders in their patients is important to strengthen retention in antiretroviral care programs as well as adherence to treatment. A convenience sample of 66 HIV service providers were asked to participate in the study before attending a workshop. Two vignettes portraying HIV patients with depression and substance use (specifically problematic alcohol use) were presented to respondents to investigate their mental health literacy and attitudes toward mental disorders. Results indicated that 50% of respondents recognized depression (57% of professionals and 39% of nonprofessionals) and 37% recognized mental illness (28% of professionals and 31% of nonprofessionals). Psychosocial stress was reported more frequently than medical etiologies as a possible cause of mental disorders. Seeking help from a health professional in the form of psychotherapy was often endorsed as an effective treatment option. Further effort is required to educate HIV service providers about the psychobiological underpinnings of psychiatric disorders and effective treatments.

  4. Convergence performance comparisons of PID, MRAC, and PID + MRAC hybrid controller

    NASA Astrophysics Data System (ADS)

    Zhang, Dan; Wei, Bin

    2016-06-01

    This study proposes a hybrid controller by combining a proportional-integral-derivative (PID) control and a model reference adaptive control (MRAC), which named as PID + MRAC controller. The convergence performances of the PID control, MRAC, and hybrid PID + MRAC are also compared. Through the simulation in Matlab, the results show that the convergence speed and performance of the MRAC and the PID + MRAC controller are better than those of the PID controller. In addition, the convergence performance of the hybrid control is better than that of the MRAC control.

  5. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs.

    PubMed

    Griffith, Linda M; Cowan, Morton J; Kohn, Donald B; Notarangelo, Luigi D; Puck, Jennifer M; Schultz, Kirk R; Buckley, Rebecca H; Eapen, Mary; Kamani, Naynesh R; O'Reilly, Richard J; Parkman, Robertson; Roifman, Chaim M; Sullivan, Kathleen E; Filipovich, Alexandra H; Fleisher, Thomas A; Shearer, William T

    2008-12-01

    Allogeneic hematopoietic cell transplantation (HCT) has been used for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immunodeficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases to identify best practices and plan future investigative clinical trials. Our survey of incidence and prevalence of PID in North American practice sites indicates that such studies are feasible. A conference of experts in HCT treatment of PID has recommended (1) a comprehensive cross-sectional and retrospective analysis of HCT survivors with SCID; (2) a prospective study of patients with SCID receiving HCT, with comparable baseline and follow-up testing across participating centers; (3) a pilot study of newborn screening for SCID to identify affected infants before compromise by infection; and (4) studies of the natural history of disease in patients who do or do not receive HCT for the non-SCID diseases of Wiskott-Aldrich syndrome and chronic granulomatous disease. To accomplish these goals, collaboration by a consortium of institutions in North America is proposed. Participation of immunologists and HCT physicians having interest in PID and experts in laboratory methods, clinical outcomes assessment, databases, and analysis will be required for the success of these studies.

  6. Immunodeficiency disorders

    MedlinePlus

    ... that affect T cells may cause repeated Candida (yeast) infections. Inherited combined immunodeficiency affects both T cells ... infections (including some forms of pneumonia or repeated yeast infections) Symptoms depend on the disorder. For example, ...

  7. Unusual Case of Metastatic Gastrointestinal Adenocarcinoma to the Cervical Spine without a Detectable Primary Source in a Patient with Acquired Immunodeficiency Syndrome: A Case Report.

    PubMed

    Kaloostian, Paul E; Barry, Marc; Harrington, James Fred

    2012-01-01

    The authors report a case of metastatic gastrointestinal adenocarcinoma to the cervical spine in a patient with acquired immunodeficiency syndrome (AIDS) being treated with antiretroviral therapy. The source of this tumor could not be identified despite a thorough evaluation. A 49-year-old male being treated for AIDS presents with worsening neck pain and left distal arm weakness. MRI demonstrated an erosive mass within the cervical four vertebral body extending through the pedicle on the left side. Patient underwent needle biopsy followed by combined anterior and posterior fusion procedures. Pathology demonstrated metastatic gastrointestinal adenocarcinoma without known primary origin. He is currently undergoing palliative radiotherapy. This is an unusual case of metastatic gastrointestinal adenocarcinoma to the cervical spine. This should be included on the differential diagnosis of spinal lesions in this patient population and may represent a unique tumor in patients with HIV/AIDS who are on immunosuppressive therapy.

  8. Primary immunodeficiency in combination with transverse upper limb defect and anal atresia in a 34-year-old patient with Jacobsen syndrome.

    PubMed

    von Bubnoff, Dagmar; Kreiss-Nachtsheim, Martina; Novak, Natalija; Engels, Eva; Engels, Hartmut; Behrend, Claudia; Propping, Peter; de la Salle, Henri; Bieber, Thomas

    2004-04-30

    We describe a 34-year-old male patient with Jacobsen syndrome associated with a broad spectrum of anomalies and an increased susceptibility to infections. Features commonly seen in Jacobsen syndrome were short stature, mental retardation, congenital heart disease, cryptorchidism, strabismus, distal hypospadia glandis, and mild thrombocytopenia. Chromosome analysis disclosed a mosaic 46,XY,del(11)(q24.1)/46,XY karyotype with a very low percentage of normal cells. In addition, transverse upper limb defect, imperforate anus, and hearing impairment were noted. Cellular anomalies include functional impairment and deficiency of T-helper cells, and a low serum immunoglobulin M (IgM)-level. The presence of a transverse limb defect and primary immunodeficiency has not been reported previously in Jacobsen syndrome.

  9. A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients with Primary Immunodeficiency Diseases: A Systematic Review and Meta-Analysis.

    PubMed

    Shabaninejad, Hosein; Asgharzadeh, Asra; Rezaei, Nima; Rezapoor, Aziz

    2016-01-01

    Subcutaneous immunoglobulin (SCIG) is a new therapeutic procedure for patients with primary immunodeficiency (PI). This research is a systematic review of studies on the efficacy and safety of intravenous immunoglobulin (IVIG) and SCIG in adult patients with PI. This study includes a systematic review of cohorts and randomized clinical trials (24 articles) from 5 databases with no time limits. Random effects meta-analysis was performed for outcomes such as efficacy and safety. Standard mean difference (SMD) of serum immunoglobulin level was equal to 0.336 (P <0.01; 0.205-0.467) and the odds ratio (OR) of side effects was 0.497 (P=0.1; 0.180-1.371). The results indicate that SCIG leads to a higher level of immunoglobulin and a reduction in side effects but shows the same infection rate as IVIG. Our analysis shows that shifting from IVIG to SCIG therapy can have clinical benefits for PI patients.

  10. Envelope Glycoprotein Incorporation, Not Shedding of Surface Envelope Glycoprotein (gp120/SU), Is the Primary Determinant of SU Content of Purified Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus

    PubMed Central

    Chertova, Elena; Bess, Jr., Julian W.; Crise, Bruce J.; Sowder II, Raymond C.; Schaden, Terra M.; Hilburn, Joanne M.; Hoxie, James A.; Benveniste, Raoul E.; Lifson, Jeffrey D.; Henderson, Louis E.; Arthur, Larry O.

    2002-01-01

    Human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) particles typically contain small amounts of the surface envelope protein (SU), and this is widely believed to be due to shedding of SU from mature virions. We purified proteins from HIV-1 and SIV isolates using procedures which allow quantitative measurements of viral protein content and determination of the ratios of gag- and env-encoded proteins in virions. All of the HIV-1 and most of the SIV isolates examined contained low levels of envelope proteins, with Gag:Env ratios of approximately 60:1. Based on an estimate of 1,200 to 2,500 Gag molecules per virion, this corresponds to an average of between 21 and 42 SU molecules, or between 7 and 14 trimers, per particle. In contrast, some SIV isolates contained levels of SU at least 10-fold greater than SU from HIV-1 isolates. Quantification of relative amounts of SU and transmembrane envelope protein (TM) provides a means to assess the impact of SU shedding on virion SU content, since such shedding would be expected to result in a molar excess of TM over SU on virions that had shed SU. With one exception, viruses with sufficient SU and TM to allow quantification were found to have approximately equivalent molar amounts of SU and TM. The quantity of SU associated with virions and the SU:TM ratios were not significantly changed during multiple freeze-thaw cycles or purification through sucrose gradients. Exposure of purified HIV-1 and SIV to temperatures of 55°C or greater for 1 h resulted in loss of most of the SU from the virus but retention of TM. Incubation of purified virus with soluble CD4 at 37°C resulted in no appreciable loss of SU from either SIV or HIV-1. These results indicate that the association of SU and TM on the purified virions studied is quite stable. These findings suggest that incorporation of SU-TM complexes into the viral membrane may be the primary factor determining the quantity of SU associated with SIV and

  11. Isolation of CD4-independent primary human immunodeficiency virus type 1 isolates that are syncytium inducing and acutely cytopathic for CD8+ lymphocytes.

    PubMed

    Zerhouni, Bouchra; Nelson, Julie A E; Saha, Kunal

    2004-02-01

    Previous studies have established the existence of CD4-independent simian immunodeficiency virus, human immunodeficiency virus type 2 (HIV-2), and laboratory strains of HIV-1. However, whether CD4-independent viruses may also exist in HIV-1-infected patients has remained unclear. We have recently reported the isolation of viruses from an AIDS patient that were able to infect CD8(+) cells independent of CD4, using CD8 as a receptor. Using a similar approach, here we examined viruses from 12 randomly selected patients (obtained from the AIDS Research and Reference Program, National Institutes of Health) for the presence of CD4-independent HIV-1. CD4-independent variants were isolated from infected CD8(+) cells from the viral quasispecies of 7 of 12 patients. The CD4-independent isolates were able to infect primary CD8(+) cells as well as a CD4(-) CD8(+) T-cell line. Soluble CD4 and blocking anti-CD4 or -CD8 antibody had no effect on infection of CD8(+) cells. Remarkably, two of the seven CD4-independent isolates, but not their parental bulk viruses, induced syncytia and caused acute death of infected CD8(+) cells. Some of the CD4-independent variants were also able to infect U87 cells that were negative for CD4, CD8, and common HIV coreceptors, suggesting a novel entry mechanism for these isolates. The CD4-independent isolates were derived from adults and children infected with subtypes A, B, and D. Although no common motif for CD4 independence was found, novel sequence changes were observed in critical areas of the envelopes of the CD4-independent viruses. These results demonstrate that HIV-1-infected patients can frequently harbor viruses that are able to mediate CD4-independent infection of CD8(+) cells. In addition, this study also provides evidence of primary HIV-1 variants that are syncytium inducing and acutely cytopathic for CD8(+) lymphocytes.

  12. Primary Immune Deficiency Treatment Consortium (PIDTC) Report

    PubMed Central

    Griffith, Linda M.; Cowan, Morton J.; Notarangelo, Luigi D.; Kohn, Donald B.; Puck, Jennifer M.; Pai, Sung-Yun; Ballard, Barbara; Bauer, Sarah C.; Bleesing, Jack J. H.; Boyle, Marcia; Brower, Amy; Buckley, Rebecca H.; van der Burg, Mirjam; Burroughs, Lauri M.; Candotti, Fabio; Cant, Andrew J.; Chatila, Talal; Cunningham-Rundles, Charlotte; Dinauer, Mary C.; Dvorak, Christopher C.; Filipovich, Alexandra H.; Fleisher, Thomas A.; Gaspar, Hubert Bobby; Gungor, Tayfun; Haddad, Elie; Hovermale, Emily; Huang, Faith; Hurley, Alan; Hurley, Mary; Iyengar, Sumathi; Kang, Elizabeth M.; Logan, Brent R.; Long-Boyle, Janel R.; Malech, Harry L.; McGhee, Sean A.; Modell, Fred; Modell, Vicki; Ochs, Hans D.; O'Reilly, Richard J.; Parkman, Robertson; Rawlings, David J.; Routes, John M.; Shearer, William T.; Small, Trudy N.; Smith, Heather; Sullivan, Kathleen E.; Szabolcs, Paul; Thrasher, Adrian; Torgerson, Troy R.; Veys, Paul; Weinberg, Kenneth; Zuniga-Pflucker, Juan Carlos

    2013-01-01

    The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases (PID). Current protocols address the natural history of patients treated for Severe Combined Immunodeficiency (SCID), Wiskott-Aldrich Syndrome and Chronic Granulomatous Disease through retrospective, prospective and cross-sectional studies. The PIDTC additionally seeks to: encourage training of junior investigators; establish partnerships with European and other International colleagues; work with patient advocacy groups to promote community awareness; and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for PID. To date, the PIDTC has funded two pilot projects: newborn screening for SCID in Navajo Native Americans; and B cell reconstitution in SCID patients following hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first two PIDTC workshops, and consideration of future consortium objectives. PMID:24139498

  13. Update on gene therapy for immunodeficiencies.

    PubMed

    Kohn, Donald B

    2010-05-01

    Primary immune deficiencies (PID) are due to blood cell defects and can be treated with transplantation of normal hematopoietic stem cells (HSC) from another person (allogeneic). Gene therapy in which a patient's autologous HSC are genetically corrected represents an alternative treatment for patients with PID, which could avoid the immunologic risks of allogeneic HSCT and confer similar benefits. Recent clinical trials using gene therapy have led to immune restoration in patients with X-linked severe combined immune deficiency (XSCID), adenosine deaminase (ADA)-deficient SCID and chronic granulomatous disease (CGD). However, severe complications arose in several of the patients in whom the integrated retroviral vectors led to leukoproliferative disorders. New approaches using safer integrating vectors or direct correction of the defective gene underlying the PID are being developed and may lead to safer and effective gene therapy for PID.

  14. Human Immunodeficiency Virus Type 1 gp120 Induces Apoptosis in Human Primary Neurons through Redox-Regulated Activation of Neutral Sphingomyelinase

    PubMed Central

    Jana, Arundhati; Pahan, Kalipada

    2007-01-01

    Human immunodeficiency virus type 1 (HIV-1) infection is known to cause disorders of the CNS, including HIV-associated dementia (HAD). HIV-1 coat protein gp120 (glycoprotein 120) induces neuronal apoptosis and has been implicated in the pathogenesis of HAD. However, the mechanism by which gp120 causes neuronal apoptosis is poorly understood. The present study underlines the importance of gp120 in inducing the production of ceramide, an important inducer of apoptosis, in human primary neurons. gp120 induced the activation of sphingomyelinases (primarily the neutral one) and the production of ceramide in primary neurons. Antisense knockdown of neutral (NSMase) but not acidic (ASMase) sphingomyelinase markedly inhibited gp120-mediated apoptosis and cell death of primary neurons, suggesting that the activation of NSMase but not ASMase plays an important role in gp120-mediated neuronal apoptosis. Similarly, the HIV-1 regulatory protein Tat also induced neuronal cell death via NSMase. Furthermore, gp120-induced production of ceramide was redox sensitive, because reactive oxygen species were involved in the activation of NSMase but not ASMase. gp120 coupled CXCR4 (CXC chemokine receptor 4) to induce NADPH oxidase-mediated production of superoxide radicals in neurons, which was involved in the activation of NSMase but not ASMase. These studies suggest that gp120 may induce neuronal apoptosis in the CNS of HAD patients through the CXCR4–NADPH oxidase–superoxide–NSMase–ceramide pathway. PMID:15509740

  15. Poliovirus excretion among persons with primary immune deficiency disorders: summary of a seven-country study series.

    PubMed

    Li, Li; Ivanova, Olga; Driss, Nadia; Tiongco-Recto, Marysia; da Silva, Rajiva; Shahmahmoodi, Shohreh; Sazzad, Hossain M S; Mach, Ondrej; Kahn, Anna-Lea; Sutter, Roland W

    2014-11-01

    Persons with primary immune deficiency disorders (PID), especially those disorders affecting the B-cell system, are at substantially increased risk of paralytic poliomyelitis and can excrete poliovirus chronically. However, the risk of prolonged or chronic excretion is not well characterized in developing countries. We present a summary of a country study series on poliovirus excretion among PID cases. Cases with PID from participating institutions were enrolled during the first year and after obtaining informed consent were tested for polioviruses in stool samples. Those cases excreting poliovirus were followed on a monthly basis during the second year until 2 negative stool samples were obtained. A total of 562 cases were enrolled in Bangladesh, China, Iran, Philippines, Russia, Sri Lanka, and Tunisia during 2008-2013. Of these, 17 (3%) shed poliovirus, including 2 cases with immunodeficient vaccine-derived poliovirus. Poliovirus was detected in a single sample from 5/17 (29%) cases. One case excreted for more than 6 months. None of the cases developed paralysis during the study period. Chronic polioviruses excretion remains a rare event even among individuals with PID. Nevertheless, because these individuals were not paralyzed they would have been missed by current surveillance; therefore, surveillance for polioviruses among PID should be established. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Efficient Transduction of Human and Rhesus Macaque Primary T Cells by a Modified Human Immunodeficiency Virus Type 1-Based Lentiviral Vector.

    PubMed

    He, Huan; Xue, Jing; Wang, Weiming; Liu, Lihong; Ye, Chaobaihui; Cong, Zhe; Kimata, Jason T; Qin, Chuan; Zhou, Paul

    2017-03-01

    Human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors efficiently transduce genes to human, but not rhesus, primary T cells and hematopoietic stem cells (HSCs). The poor transduction of HIV-1 vectors to rhesus cells is mainly due to species-specific restriction factors such as rhesus TRIM5α. Previously, several strategies to modify HIV-1 vectors were developed to overcome rhesus TRIM5α restriction. While the modified HIV-1 vectors efficiently transduce rhesus HSCs, they remain suboptimal for rhesus primary T cells. Recently, HIV-1 variants that encode combinations of LNEIE mutations in capsid (CA) protein and SIVmac239 Vif were found to replicate efficiently in rhesus primary T cells. Thus, the present study tested whether HIV-1 vectors packaged by a packaging construct containing these CA substitutions could efficiently transduce both human and rhesus primary CD4 T cells. To accomplish this, LNEIE mutations were made in the packaging construct CEMΔ8.9, and recombinant HIV-1 vectors packaged by Δ8.9 WT or Δ8.9 LNEIE were generated. Transduction rates, CA stability, and vector integration in CEMss-CCR5 and CEMss-CCR5-rhTRIM5α/green fluorescent protein cells, as well as transduction rates in human and rhesus primary CD4 T cells by Δ8.9 WT or Δ8.9 LNEIE-packaged HIV-1 vectors, were compared. Finally, the influence of rhesus TRIM5α variations in transduction rates to primary CD4 T cells from a cohort of 37 Chinese rhesus macaques was studied. While it maintains efficient transduction for human T-cell line and primary CD4 T cells, Δ8.9 LNEIE-packaged HIV-1 vector overcomes rhesus TRIM5α-mediated CA degradation, resulting in significantly higher transduction efficiency of rhesus primary CD4 T cells than Δ8.9 WT-packaged HIV-1 vector. Rhesus TRIM5α variations strongly influence transduction efficiency of rhesus primary CD4 T cells by both Δ8.9 WT or Δ8.9 LNEIE-packaged HIV-1 vectors. Thus, it is concluded that Δ8.9 LNEIE-packaged HIV-1

  17. Nef from primary isolates of human immunodeficiency virus type 1 suppresses surface CD4 expression in human and mouse T cells.

    PubMed Central

    Anderson, S; Shugars, D C; Swanstrom, R; Garcia, J V

    1993-01-01

    The human immunodeficiency virus type 1 (HIV-1) nef gene was originally described as a negative regulator of transcription from the viral long terminal repeat promoter. This observation has been disputed, and the function of Nef remains unclear. In vivo experiments have indicated that an intact nef gene is required for disease progression in macaques infected with simian immunodeficiency virus, suggesting a role for Nef in the pathogenesis of AIDS. We and others have previously shown that expression of Nef in cells bearing surface CD4 results in a sustained decrease in surface CD4 expression. This was demonstrated for Nef from two laboratory strains of HIV-1, Bru and SF2. Because both of these isolates were passaged in vitro prior to molecular cloning and in vitro passage can result in mutations which might alter nef gene function, we have analyzed two primary isolates of Nef for their ability to suppress cell surface CD4 expression. The nef genes of HIV-1 isolates from two patients with fewer than 200 CD4+ T cells per mm3 of blood were introduced into human and mouse T-cell lines by retrovirus-mediated gene transfer. Expression of Nef from both isolates correlated with a decrease in surface expression of both human and mouse CD4. To determine whether the ability to suppress surface CD4 expression is a general function of Nef, we also tested an artificially generated consensus nef gene derived from analysis of 54 patient isolates of HIV-1. Expression of the consensus Nef protein also correlated with decreased cell surface CD4 expression in both mouse and human T-cell lines. These results suggest that the ability to suppress cell surface CD4 expression is an intrinsic feature of HIV-1 Nef. Images PMID:8331733

  18. [A first pilot study on the neonatal screening of primary immunodeficiencies in Spain: TRECS and KRECS identify severe T- and B-cell lymphopenia].

    PubMed

    Olbrich, P; de Felipe, B; Delgado-Pecellin, C; Rodero, R; Rojas, P; Aguayo, J; Marquez, J; Casanovas, J; Sánchez, B; Lucena, J M; Ybot-Gonzalez, P; Borte, S; Neth, O

    2014-11-01

    Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected infants/children. The measurement of T-cell receptor excision circles (TRECS) and kappa-deleting recombination excision circles (KRECS) can identify neonates with severe T or B-cell lymphopenia. To determine TRECS and KRECS levels from prospectively collected dried blood spot samples (DBS) and to correctly identify severe T and B-cell lymphopenia. Determination of TRECS and KRECS by multiplex PCR from neonates born in two tertiary hospitals in Seville between February 2014 and May 2014. PCR cut-off levels: TRECS<15 copies/μl, KRECS<10 copies/μl, ACTB (β-actin)>1000 copies/μl. Internal (XLA, ataxia telangiectasia) and external (SCID) controls were included. A total of 1068 out of 1088 neonates (mean GA 39 weeks (38-40) and BW 3238g (2930-3520) were enrolled in the study. Mean (median, min/max) copies/μl, were as follows: TRECS 145 (132, 8/503), KRECS 82 (71, 7/381), and ACTB 2838 (2763, 284/7710). Twenty samples (1.87%) were insufficient. Resampling was needed in one neonate (0.09%), subsequently giving a normal result. When using lower cut-offs (TRECS<8 and KRECS<4 copies/μl), all the samples tested were normal and the internal and external controls were correctly identified. This is the first prospective pilot study in Spain using TRECS/KRECS/ACTB-assay, describing the experience and applicability of this method to identify severe lymphopenias. The ideal cut-off remains to be established in our population. Quality of sampling, storage and preparation need to be further improved. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  19. New tuning method for PID controller.

    PubMed

    Shen, Jing-Chung

    2002-10-01

    In this paper, a tuning method for proportional-integral-derivative (PID) controller and the performance assessment formulas for this method are proposed. This tuning method is based on a genetic algorithm based PID controller design method. For deriving the tuning formula, the genetic algorithm based design method is applied to design PID controllers for a variety of processes. The relationship between the controller parameters and the parameters that characterize the process dynamics are determined and the tuning formula is then derived. Using simulation studies, the rules for assessing the performance of a PID controller tuned by the proposed method are also given. This makes it possible to incorporate the capability to determine if the PID controller is well tuned or not into an autotuner. An autotuner based on this new tuning method and the corresponding performance assessment rules is also established. Simulations and real-time experimental results are given to demonstrate the effectiveness and usefulness of these formulas.

  20. Human plasma enhances the infectivity of primary human immunodeficiency virus type 1 isolates in peripheral blood mononuclear cells and monocyte-derived macrophages.

    PubMed Central

    Wu, S C; Spouge, J L; Conley, S R; Tsai, W P; Merges, M J; Nara, P L

    1995-01-01

    Physiological microenvironments such as blood, seminal plasma, mucosal secretions, or lymphatic fluids may influence the biology of the virus-host cell and immune interactions for human immunodeficiency virus type 1 (HIV-1). Relative to media, physiological levels of human plasma were found to enhance the infectivity of HIV-1 primary isolates in both phytohemagglutinin-stimulated peripheral blood mononuclear cells and monocyte-derived macrophages. Enhancement was observed only when plasma was present during the virus-cell incubation and resulted in a 3- to 30-fold increase in virus titers in all of the four primary isolates tested. Both infectivity and virion binding experiments demonstrated a slow, time-dependent process generally requiring between 1 and 10 h. Human plasma collected in anticoagulants CPDA-1 and heparin, but not EDTA, exhibited this effect at concentrations from 90 to 40%. Furthermore, heat-inactivated plasma resulted in a loss of enhancement in peripheral blood mononuclear cells but not in monocyte-derived macrophages. Physiological concentrations of human plasma appear to recruit additional infectivity, thus increasing the infectious potential of the virus inoculum. PMID:7666510

  1. Resistance of primary isolates of human immunodeficiency virus type 1 to soluble CD4 is independent of CD4-rgp120 binding affinity.

    PubMed Central

    Ashkenazi, A; Smith, D H; Marsters, S A; Riddle, L; Gregory, T J; Ho, D D; Capon, D J

    1991-01-01

    The infection of human cells by laboratory strains of human immunodeficiency virus type 1 (HIV-1) can be blocked readily in vitro by recombinant soluble CD4 and CD4-immunoglobulin hybrid molecules. In contrast, infection by primary isolates of HIV-1 is much less sensitive to blocking in vitro by soluble CD4-based molecules. To investigate the molecular basis for this difference between HIV-1 strains, we isolated the gp120-encoding genes from several CD4-resistant and CD4-sensitive HIV-1 strains and characterized the CD4-binding properties of their recombinant gp120 (rgp120) products. Extensive amino acid sequence variation was found between the gp120 genes of CD4-resistant and CD4-sensitive HIV-1 isolates. However, the CD4-binding affinities of rgp120 from strains with markedly different CD4 sensitivities were essentially the same, and only small differences were observed in the kinetics of CD4 binding. These results suggest that the lower sensitivity of primary HIV-1 isolates to neutralization by CD4-based molecules is not due to lower binding affinity between soluble CD4 and free gp120. PMID:1871120

  2. Inhibition of clinical human immunodeficiency virus (HIV) type 1 isolates in primary CD4+ T lymphocytes by retroviral vectors expressing anti-HIV genes.

    PubMed Central

    Vandendriessche, T; Chuah, M K; Chiang, L; Chang, H K; Ensoli, B; Morgan, R A

    1995-01-01

    Gene therapy may be of benefit in human immunodeficiency virus type 1 (HIV-1)-infected individuals by virtue of its ability to inhibit virus replication and prevent viral gene expression. It is not known whether anti-HIV-1 gene therapy strategies based on antisense or transdominant HIV-1 mutant proteins can inhibit the replication and expression of clinical HIV-1 isolates in primary CD4+ T lymphocytes. We therefore transduced CD4+ T lymphocytes from uninfected individuals with retroviral vectors expressing either HIV-1-specific antisense-TAR or antisense-Tat/Rev RNA, transdominant HIV-1 Rev protein, and a combination of antisense-TAR and transdominant Rev. The engineered CD4+ T lymphocytes were then infected with four different clinical HIV-1 isolates. We found that replication of all HIV-1 isolates was inhibited by all the anti-HIV vectors tested. Greater inhibition of HIV-1 was observed with transdominant Rev than with antisense RNA. We hereby demonstrated effective protection by antisense RNA or transdominant mutant proteins against HIV-1 infection in primary CD4+ T lymphocytes using clinical HIV-1 isolates, and this represents an essential step toward clinical anti-HIV-1 gene therapy. PMID:7769662

  3. Detection of Antibody-Dependent Complement-Mediated Inactivation of both Autologous and Heterologous Virus in Primary Human Immunodeficiency Virus Type 1 Infection†

    PubMed Central

    Aasa-Chapman, Marlén M. I.; Holuigue, Sophie; Aubin, Keith; Wong, MaiLee; Jones, Nicola A.; Cornforth, David; Pellegrino, Pierre; Newton, Philippa; Williams, Ian; Borrow, Persephone; McKnight, Áine

    2005-01-01

    Specific CD8 T-cell responses to human immunodeficiency virus type 1 (HIV-1) are induced in primary infection and make an important contribution to the control of early viral replication. The importance of neutralizing antibodies in containing primary viremia is questioned because they usually arise much later. Nevertheless antienvelope antibodies develop simultaneously with, or even before, peak viremia. We determined whether such antibodies might control viremia by complement-mediated inactivation (CMI). In each of seven patients studied, antibodies capable of CMI appeared at or shortly after the peak in viremia, concomitantly with detection of virus-specific T-cell responses. The CMI was effective on both autologous and heterologous HIV-1 isolates. Activation of the classical pathway and direct viral lysis were at least partly responsible. Since immunoglobulin G (IgG)-antibodies triggered the CMI, specific memory B cells could also be induced by vaccination. Thus, consideration should be given to vaccination strategies that induce IgG antibodies capable of CMI. PMID:15709001

  4. Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome: A Paradigm of Immunodeficiency with Autoimmunity

    PubMed Central

    Barzaghi, Federica; Passerini, Laura; Bacchetta, Rosa

    2012-01-01

    Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type-1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is hematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed. PMID:23060872

  5. [Increasing participation of primary care in the management of people with human immunodeficiency virus: hospital care professionals express their views].

    PubMed

    Ortega López, Angela; Morales Asencio, José Miguel; Rengel Díaz, Cristóbal; Peñas Cárdenas, Eloísa María; González Rodríguez, María José; Prado de la Sierra, Rut

    2014-04-01

    To determine the opinions of infectious diseases professionals on the possibilities of monitoring patients with HIV in Primary Care. Qualitative study using in-depth interviews. Infectious Diseases Unit in the University Hospital "Virgen de la Victoria" in Málaga. Health professionals with more than one year experience working in infectious diseases. A total of 25 respondents: 5 doctors, 15 nurses and 5 nursing assistants. Convenience sample. Semi-structured interviews were used that were later transcribed verbatim. Content analysis was performed according to the Taylor and Bogdan approach with computer support. Validation of information was made through additional analysis, expert participation, and feedback of part of the results to the participants. Hospital care professionals considered the disease-related complexity of HIV, treatment and social aspects that may have an effect on the organizational level of care. Professionals highlighted the benefits of specialized care, although opinions differed between doctors and nurses as regards follow up in Primary Care. Some concerns emerged about the level of training, confidentiality and workload in Primary Care, although they mentioned potential advantages related to accessibility of patients. Physicians perceive difficulties in following up HIV patients in Primary Care, even for those patients with a good control of their disease. Nurses and nursing assistants are more open to this possibility due to the proximity to home and health promotion in Primary Care. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  6. Outcomes of hematopoietic stem cell transplantation in primary immunodeficiency: a report from the Australian and New Zealand Children's Haematology Oncology Group and the Australasian Bone Marrow Transplant Recipient Registry.

    PubMed

    Mitchell, Richard; Nivison-Smith, Ian; Anazodo, Antoinette; Tiedemann, Karin; Shaw, Peter; Teague, Lochie; Fraser, Chris; Carter, Tina; Tapp, Heather; Alvaro, Frank; O'Brien, Tracey A

    2013-03-01

    We performed a retrospective analysis on the outcomes of 135 hematopoietic stem cell transplantations (HSCTs) for primary immunodeficiency disorders in Australian and New Zealand Children's Haematology Oncology Group transplantation centers between 1992 and 2008. The most common indications for HSCT were severe combined immunodeficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Five-year overall survival (OS) was 72% for the entire cohort. Disease-specific 5-year OS was 70% for severe combined immunodeficiency, 81% for Wiskott-Aldrich syndrome, and 69% for chronic granulomatous disease. Transplantation-related mortality (TRM) was 10% at day +100. TRM and OS were equivalent in recipients of related and unrelated donor transplants. Source of stem cells had no impact on TRM or OS with outcomes following unrelated umbilical cord blood similar to unrelated bone marrow. The presence of interstitial pneumonitis, active cytomegalovirus infection, or veno-occlusive disease were all independent variables that significantly decreased OS. This large series supports the use of HSCT as curative therapy for a range of primary immunodeficiency disorders, demonstrating excellent survival after both related and unrelated donor transplantation.

  7. Usage of the coreceptors CCR-5, CCR-3, and CXCR-4 by primary and cell line-adapted human immunodeficiency virus type 2.

    PubMed Central

    Sol, N; Ferchal, F; Braun, J; Pleskoff, O; Tréboute, C; Ansart, I; Alizon, M

    1997-01-01

    The chemokine receptors CCR-5 and CXCR-4, and possibly CCR-3, are the principal human immunodeficiency virus type 1 (HIV-1) coreceptors, apparently interacting with HIV-1 envelope, in association with CD4. Cell lines coexpressing CD4 and these chemokine receptors were infected with a panel of seven primary HIV-2 isolates passaged in peripheral blood mononuclear cells (PBMC) and three laboratory HIV-2 strains passaged in T-cell lines. The CCR-5, CCR-3, and CXCR-4 coreceptors could all be used by HIV-2. The ability to use CXCR-4 represents a major difference between HIV-2 and the closely related simian immunodeficiency viruses. Most HIV-2 strains using CCR-5 could also use CCR-3, sometimes with similar efficiencies. As observed for HIV-1, the usage of CCR-5 or CCR-3 was observed principally for HIV-2 strains derived from asymptomatic individuals, while HIV-2 strains derived from AIDS patients used CXCR-4. However, there were several exceptions, and the patterns of coreceptor usage seemed more complex for HIV-2 than for HIV-1. The two T-tropic HIV-2 strains tested used CXCR-4 and not CCR-5, while T-tropic HIV-1 can generally use both. Moreover, among five primary HIV-2 strains all unable to use CXCR-4, three could replicate in CCR-5-negative PBMC, which has not been reported for HIV-1. These observations suggest that the CCR-5 coreceptor is less important for HIV-2 than for HIV-1 and indicate that HIV-2 can use other cell entry pathways and probably other coreceptors. One HIV-2 isolate replicating in normal or CCR-5-negative PBMC failed to infect CXCR-4+ cells or the U87MG-CD4 and sMAGI cell lines, which are permissive to infection by HIV-2 but not by HIV-1. This suggests the existence of several HIV-2-specific coreceptors, which are differentially expressed in cell lines and PBMC. PMID:9343175

  8. Altered distribution of natural killer cell subsets identified by CD56, CD27 and CD70 in primary and chronic human immunodeficiency virus-1 infection

    PubMed Central

    Titanji, Kehmia; Sammicheli, Stefano; De Milito, Angelo; Mantegani, Paola; Fortis, Claudio; Berg, Louise; Kärre, Klas; Travi, Giovanna; Tassandin, Chiara; Lopalco, Lucia; Rethi, Bence; Tambussi, Giuseppe; Chiodi, Francesca

    2008-01-01

    Human natural killer (NK) (CD3− CD56+) cells can be divided into two functionally distinct subsets, CD3− CD56dim and CD3− CD56bright. We analysed the distribution of NK cell subsets in primary and chronic human immunodeficiency virus-1 (HIV-1) infection, to determine if HIV infection stage may influence the subset distribution. In primary infection, contrary to chronic infection, the CD3− CD56dim subset was expanded compared to healthy controls. We also studied the effect of antiretroviral therapy administered early in infection and found that NK cell subset distribution was partially restored after 6 months of antiretroviral therapy in primary infection, but not normalized. Recently, NK cells have been divided into CD27− and CD27+ subsets with different migratory and functional capacity and CD27-mediated NK cell activation has been described in mice. We therefore investigated whether CD27 and/or CD70 (CD27 ligand) expression on NK cells, and thus the distribution of these novel NK subsets, was altered in HIV-1-infected patients. We found up-regulated expression of both CD27 and CD70 on NK cells of patients, resulting in higher proportions of CD27high and CD70high NK cells, and this phenomenon was more pronounced in chronic infection. Experiments conducted in vitro suggest that the high interleukin-7 levels found during HIV-1 infection may participate in up-regulation of CD70 on NK cell subsets. Imbalance of NK cell subsets and up-regulated expression of CD27 and CD70 initiated early in HIV-1 infection may indicate NK cell activation and intrinsic defects initiated by HIV-1 to disarm the innate immune response to the virus. PMID:17627773

  9. Quantitative model of antibody- and soluble CD4-mediated neutralization of primary isolates and T-cell line-adapted strains of human immunodeficiency virus type 1.

    PubMed Central

    Klasse, P J; Moore, J P

    1996-01-01

    Primary isolates (PI) of human immunodeficiency virus type 1 (HIV-1) are considerably less sensitive than T-cell line-adapted strains to neutralization by soluble CD4 and by most cross-reactive monoclonal antibodies to the viral envelope (Env) glycoprotein, as well as by postinfection and postvaccination sera (J. P. Moore and D. D. Ho, AIDS 9 [suppl. A]:5117-5136, 1995). We developed a quantitative model to explain the neutralization resistance of PI. The factors incorporated into the model are the dissociation constants for the binding of the neutralizing agent to native Env oligomers, the number of outer Env molecules on the viral surface (which decreases by shedding), and the minimum number of Env molecules required for attachment and fusion. We conclude that modest differences in all these factors can, when combined, explain a relative neutralization resistance of PI versus T-cell line-adapted strains that sometimes amounts to several orders of magnitude. The hypothesis that neutralization of HIV is due to the reduction below a minimum number of the Env molecules on a virion available for attachment and fusion is at odds with single- and few-hit neutralization theories. Our analysis of these ideas favors the hypothesis that neutralization of HIV is instead a competitive blocking of interactions with cellular factors, including adsorption receptors. PMID:8648701

  10. Screening for long-term poliovirus excretion among children with primary immunodeficiency disorders: preparation for the polio posteradication era in Bangladesh.

    PubMed

    Sazzad, Hossain M S; Rainey, Jeanette J; Kahn, Anna-Lea; Mach, Ondrej; Liyanage, Jayantha B L; Alam, Ahmed Nawsher; Kawser, Choudhury A; Hossain, Asgar; Sutter, Roland; Luby, Stephen P

    2014-11-01

    Persons with primary immune deficiency disorders (PIDD) who receive oral poliovirus vaccine (OPV) may transmit immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) and cause paralytic polio. The objective of this study was to identify children with PIDD in Bangladesh, and estimate the proportion with chronic poliovirus excretion. Patients admitted at 5 teaching hospitals were screened for PIDD according to standardized clinical case definitions. PIDD was confirmed by age-specific quantitative immunoglobulin levels. Stool specimens were collected from patients with confirmed PIDD. From February 2011 through January 2013, approximately 96 000 children were screened, and 53 patients were identified who met the clinical case definition for PIDD. Thirteen patients (24%) had age-specific quantitative immunoglobulins results that confirmed PIDD. Of these, 9 (69%) received OPV 3-106 months before stool specimen collection. Among 11 patients, stool specimens from 1 patient tested positive for polioviruses 34 months after OPV ingestion. However, the poliovirus isolate was not available for genetic sequencing, and a subsequent stool specimen 45 days later was negative. The risk of chronic poliovirus excretion among children with PIDD in Bangladesh seems to be low. The national polio eradication program should incorporate strategies for screening for poliovirus excretion among patients with PIDD. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Calculating the Dose of Subcutaneous Immunoglobulin for Primary Immunodeficiency Disease in Patients Switched From Intravenous to Subcutaneous Immunoglobulin Without the Use of a Dose-Adjustment Coefficient

    PubMed Central

    Fadeyi, Michael; Tran, Tin

    2013-01-01

    Primary immunodeficiency disease (PIDD) is an inherited disorder characterized by an inadequate immune system. The most common type of PIDD is antibody deficiency. Patients with this disorder lack the ability to make functional immunoglobulin G (IgG) and require lifelong IgG replacement therapy to prevent serious bacterial infections. The current standard therapy for PIDD is intravenous immunoglobulin (IVIG) infusions, but IVIG might not be appropriate for all patients. For this reason, subcutaneous immunoglobulin (SCIG) has emerged as an alternative to IVIG. A concern for physicians is the precise SCIG dose that should be prescribed, because there are pharmacokinetic differences between IVIG and SCIG. Manufacturers of SCIG 10% and 20% liquid (immune globulin subcutaneous [human]) recommend a dose-adjustment coefficient (DAC). Both strengths are currently approved by the FDA. This DAC is to be used when patients are switched from IVIG to SCIG. In this article, we propose another dosing method that uses a higher ratio of IVIG to SCIG and an incremental adjustment based on clinical status, body weight, and the presence of concurrent diseases. PMID:24391400

  12. The Natural History of Children with Severe Combined Immunodeficiency: Baseline Features of the First Fifty Patients of the Primary Immune Deficiency Treatment Consortium Prospective Study 6901

    PubMed Central

    Dvorak, Christopher C.; Cowan, Morton J.; Logan, Brent R.; Notarangelo, Luigi D.; Griffith, Linda M.; Puck, Jennifer M.; Kohn, Donald B.; Shearer, William T.; O'Reilly, Richard J.; Fleisher, Thomas A.; Pai, Sung-Yun; Hanson, I. Celine; Pulsipher, Michael A.; Fuleihan, Ramsay; Filipovich, Alexandra; Goldman, Frederick; Kapoor, Neena; Small, Trudy; Smith, Angela; Chan, Ka-Wah; Cuvelier, Geoff; Heimall, Jennifer; Knutsen, Alan; Loechelt, Brett; Moore, Theodore; Buckley, Rebecca H.

    2013-01-01

    The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID. From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research. Most patients (92%) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92%) were treated with HCT within 1–2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement. The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes. PMID:23818196

  13. Kinetics of human immunodeficiency virus type 1 (HIV-1) DNA and RNA synthesis during primary HIV-1 infection.

    PubMed Central

    Graziosi, C; Pantaleo, G; Butini, L; Demarest, J F; Saag, M S; Shaw, G M; Fauci, A S

    1993-01-01

    HIV-1 replication and viral burden in peripheral blood mononuclear cells (PBMC) have been reported to be high in primary infection but generally very low during the prolonged period of clinical latency. It is uncertain precisely when this transition occurs during the HIV-1 infection and what the relationship is between the changes in HIV-1 replication versus the clearance of infected cells in the overall control of viral replication. In the present study, the kinetics of viral burden (i.e., frequency of HIV-1-infected cells) and replication during primary and early-chronic infection were analyzed in PBMC of four acutely infected individuals. High frequencies of HIV-1-infected cells and high levels of virus replication were observed in PBMC after primary HIV-1 infection. Down-regulation of virus replication in PBMC was observed in all four patients coincident with the emergence of HIV-1-specific immune responses. Other parameters of virus replication, such as circulating plasma p24 antigen and plasma viremia showed similar kinetics. In contrast, a significant decline in viral burden in PBMC was observed in only one of four patients. These results indicate that the down-regulation in the levels of virus replication associated with the clinical transition from acute to chronic infection does not necessarily reflect a reduction in viral burden, thus suggesting the involvement of additional factors. Identification of these factors will be important in elucidating the host mechanisms involved in the early control of HIV-1 infection and disease. Images Fig. 1 Fig. 2 Fig. 3 PMID:8341646

  14. The human immunodeficiency virus-1 nef gene product: a positive factor for viral infection and replication in primary lymphocytes and macrophages

    PubMed Central

    1994-01-01

    Considerable controversy and uncertainty have surrounded the biological function of the Human Immunodeficiency Virus (HIV)-1 nef gene product. Initial studies suggested that this early, nonstructural viral protein functioned as a negative regulatory factor; thus, it was proposed to play a role in establishing or maintaining viral latency. In contrast, studies in Simian Immunodeficiency Virus (SIV)mac-infected rhesus monkeys have suggested that Nef is not a negative factor but rather plays a central role in promoting high-level viral replication and is required for viral pathogenesis in vivo. We sought to define a tissue culture system that would approximate the in vivo setting for virus infection in order to assess the role of HIV-1 Nef in viral replication. We show that infection of mitogen-activated peripheral blood mononuclear cells (PBMC) with Nef+ HIV results in enhanced replication as evidenced by earlier gag p24 expression when compared with infections performed with nef mutant viruses. Moreover, when unstimulated freshly isolated PBMC are infected with Nef+ and Nef- viruses and then subsequently activated with mitogen, the Nef-induced difference in viral replication kinetics is even more pronounced, with the Nef- viruses requiring much more time in culture for appreciable growth. A positive effect of Nef on viral replication was also observed in primary macrophages infected with a recombinant of YU-2, a patient- derived molecular clone with macrophage tropism. These positive effects of Nef on viral replication are dependent on the initial multiplicity of infection (MOI), in that infections of unstimulated PBMC at low MOI are most dependent upon intact nef for subsequent viral growth. We now provide evidence that the Nef+ HIV is more infectious than Nef- HIV from both a tissue culture infectious dose analysis, and a single-cell HIV infection assay. In the latter case, we demonstrate that infection with equivalent doses of HIV based on virion-associated gag p

  15. Recent advances in transplantation for primary immune deficiency diseases: a comprehensive review.

    PubMed

    de la Morena, M Teresa; Nelson, Robert P

    2014-04-01

    Hematopoietic cell transplantation (HCT) is a curative therapeutic option for severe combined immunodeficiency (SCID), a group of diseases which otherwise carry life expectancies that are of limited duration and quality. Survival following HCT for SCID has improved from approximately 23 to 91 % over the last 40 years. Success with SCID prompted efforts to apply HCT to the therapeutic challenge of well over 20 molecularly defined primary immune deficiency diseases (PID). Such success is due to both early recognition of PIDs and advances in the field of transplantation. Such advances include high-resolution HLA DNA donor-recipient matching, expansion of donor sources, better tolerated conditioning, new antibiotics, and wider availability. International collaborative efforts have provided patients and caregivers information that permit better treatment decisions now, and direct clinicians and investigators to ensure progress in the future. Pioneers in screening for SCID have taken steps to correct the fundamental challenge to successful treatment, which is the rapid discovery and characterization of cases and offering the transplant option to an affected child early in life; blood spot testing for T and B cell receptor quantification is now available to a growing fraction of newborns. Organizations including the Primary Immune Deficiency Treatment Consortium in the USA, The European Society for Primary Immunodeficiency, the European Group for Blood and Marrow Transplantation, the Pediatric Blood and Marrow Transplant Consortium, the United States Immunodeficiency Network, the Immune Deficiency Foundation, and the Jeffrey Modell Foundation are contributing mightily to increase awareness and standardize optimal utilization to the benefit of patients. This review will update the allergist-immunologist concerning disease presentations, indications for transplantation, methodologies, conditioning regimens, and clinical outcomes for patients with PID for which timely HCT is

  16. Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

    PubMed Central

    Madani, Navid; Princiotto, Amy M.; Easterhoff, David; Bradley, Todd; Luo, Kan; Williams, Wilton B.; Liao, Hua-Xin; Moody, M. Anthony; Phad, Ganesh E.; Vázquez Bernat, Néstor; Melillo, Bruno; Santra, Sampa; Smith, Amos B.; Karlsson Hedestam, Gunilla B.; Haynes, Barton

    2016-01-01

    ABSTRACT The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCE Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in

  17. [Acceptability of the opportunistic search for human immunodeficiency virus infection by serology in patients recruited in Primary Care Centres in Spain].

    PubMed

    Puentes Torres, Rafael Carlos; Aguado Taberné, Cristina; Pérula de Torres, Luis Angel; Espejo Espejo, José; Castro Fernández, Cristina; Fransi Galiana, Luís

    2016-01-01

    To assess the acceptability of opportunistic search for human immunodeficiency virus (HIV). Cross-sectional, observational study. Primary Care Centres (PCC) of the Spanish National Health Care System. patients aged 18 to 65 years who had never been tested for HIV, and were having a blood test for other reasons. RECORDED VARIABLES: age, gender, stable partner, educational level, tobacco/alcohol use, reason for blood testing, acceptability of taking the HIV test, reasons for refusing to take the HIV test, and reasons for not having taken an HIV test previously. A descriptive, bivariate, multivariate (logistic regression) statistical analysis was performed. A total of 208 general practitioners (GPs) from 150 health care centres recruited 3,314 patients. Most (93.1%) of patients agreed to take the HIV test (95%CI: 92.2-93.9). Of these patients, 56.9% reported never having had an HIV test before because they considered not to be at risk of infection, whereas 34.8% reported never having been tested for HIV because their doctor had never offered it to them. Of the 6.9% who refused to take the HIV test, 73.9% considered that they were not at risk. According to the logistic regression analysis, acceptability was positively associated to age (higher among between 26 and 35 year olds, OR=1.79; 95%CI: 1.10-2.91) and non-smokers (OR=1.39; 95%CI: 1.01-1.93). Those living in towns with between 10,000 and 50,000 inhabitants showed less acceptance to the test (OR=0.57; 95%CI: 0.40-0.80). The HIV prevalence detected was 0.24% Acceptability of HIV testing is very high among patients having a blood test in primary care settings in Spain. Opportunistic search is cost-effective. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  18. Evaluation of Performance of the Gen-Probe Human Immunodeficiency Virus Type 1 Viral Load Assay Using Primary Subtype A, C, and D Isolates from Kenya

    PubMed Central

    Emery, Sandra; Bodrug, Sharon; Richardson, Barbra A.; Giachetti, Cristina; Bott, Martha A.; Panteleeff, Dana; Jagodzinski, Linda L.; Michael, Nelson L.; Nduati, Ruth; Bwayo, Job; Kreiss, Joan K.; Overbaugh, Julie

    2000-01-01

    Accurate and sensitive quantification of human immunodeficiency virus type 1 (HIV-1) RNA has been invaluable as a marker for disease prognosis and for clinical monitoring of HIV-1 disease. The first generation of commercially available HIV-1 RNA tests were optimized to detect the predominant HIV-1 subtype found in North America and Europe, subtype B. However, these tests are frequently suboptimal in detecting HIV-1 genetic forms or subtypes found in other parts of the world. The goal of the present study was to evaluate the performance of a new viral load assay with non-subtype B viruses. A transcription-mediated amplification method for detection and quantitation of diverse HIV-1 subtypes, called the Gen-Probe HIV-1 viral load assay, is under development. In this study we examined the performance of the Gen-Probe HIV-1 viral load assay relative to that of the commonly used commercial HIV-1 RNA assays using a panel of primary isolates from Kenya. For comparison, we included several subtype B cloned viruses, and we quantified each virus using an in-house quantitative-competitive reverse transcriptase PCR (QC-RT-PCR) method and gagp24 antigen capture. The Gen-Probe HIV-1 viral load assay and a version of the Roche AMPLICOR HIV-1 MONITOR test (version 1.5) that was designed to detect a broader range of subtypes were both sensitive for the quantification of Kenyan primary isolates, which represented subtype A, C, and D viruses. The Gen-Probe HIV-1 viral load assay was more sensitive for the majority of viruses than the Roche AMPLICOR HIV-1 MONITOR test version 1.0, the Bayer Quantiplex HIV RNA 3.0 assay, or a QC-RT-PCR method in use in our laboratory, suggesting that it provides a useful method for quantifying HIV-1 RNAs from diverse parts of the world, including Africa. PMID:10878065

  19. Comprehensive Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon-Secreting CD8+ T Cells in Primary HIV-1 Infection

    PubMed Central

    Cao, Jianhong; McNevin, John; Holte, Sarah; Fink, Lisa; Corey, Lawrence; McElrath, M. Juliana

    2003-01-01

    Human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells provide an important defense in controlling HIV-1 replication, particularly following acquisition of infection. To delineate the breadth and potency of these responses in patients upon initial presentation and before treatment, we determined the fine specificities and frequencies of gamma interferon (IFN-γ)-secreting CD8+ T cells recognizing all HIV-1 proteins in patients with primary infection. In these subjects, the earliest detected responses were directed predominantly against Nef, Tat, Vpr, and Env. Tat- and Vpr-specific CD8+ T cells accounted for the greatest frequencies of mean IFN-γ spot-forming cells (SFC). Nef-specific responses (10 of 21) were more commonly detected. A mean of 2.3 epitopes were recognized with various avidities per subject, and the number increased with the duration of infection (R = 0.47, P = 0.031). The mean frequency of CD8+ T cells (985 SFC/106 peripheral blood mononuclear cells) correlated with the number of epitopes recognized (R = 0.84, P < 0.0001) and the number of HLA-restricting alleles (R = 0.79, P < 0.0001). Neither the total SFC frequencies nor the number of epitopes recognized correlated with the concurrent plasma viral load. Seventeen novel epitopes were identified, four of which were restricted to HLA alleles (A23 and B72) that are common among African descendents. Thus, primary HIV-1 infection induces strong CD8+-T-cell immunity whose specificities broaden over time, but their frequencies and breadth do not correlate with HIV-1 containment when examined concurrently. Many novel epitopes, particularly directed to Nef, Tat, and Env, and frequently with unique HLA restrictions, merit further consideration in vaccine design. PMID:12768006

  20. Pelvic Inflammatory Disease (PID) Treatment and Care

    MedlinePlus

    ... Treatment and Care Archive STDs Home Page Bacterial Vaginosis (BV) Chlamydia Genital Herpes Gonorrhea Hepatitis HIV/AIDS & ... PID) (June 4, 2015) STDs Home Page Bacterial Vaginosis (BV) Chlamydia Genital Herpes Gonorrhea Hepatitis HIV/AIDS & ...

  1. Multivariable PID Controller For Robotic Manipulator

    NASA Technical Reports Server (NTRS)

    Seraji, Homayoun; Tarokh, Mahmoud

    1990-01-01

    Gains updated during operation to cope with changes in characteristics and loads. Conceptual multivariable controller for robotic manipulator includes proportional/derivative (PD) controller in inner feedback loop, and proportional/integral/derivative (PID) controller in outer feedback loop. PD controller places poles of transfer function (in Laplace-transform space) of control system for linearized mathematical model of dynamics of robot. PID controller tracks trajectory and decouples input and output.

  2. Multivariable PID Controller For Robotic Manipulator

    NASA Technical Reports Server (NTRS)

    Seraji, Homayoun; Tarokh, Mahmoud

    1990-01-01

    Gains updated during operation to cope with changes in characteristics and loads. Conceptual multivariable controller for robotic manipulator includes proportional/derivative (PD) controller in inner feedback loop, and proportional/integral/derivative (PID) controller in outer feedback loop. PD controller places poles of transfer function (in Laplace-transform space) of control system for linearized mathematical model of dynamics of robot. PID controller tracks trajectory and decouples input and output.

  3. Gene Therapy for the Treatment of Primary Immune Deficiencies.

    PubMed

    Kuo, Caroline Y; Kohn, Donald B

    2016-05-01

    The use of gene therapy in the treatment of primary immune deficiencies (PID) has advanced significantly in the last decade. Clinical trials for X-linked severe combined immunodeficiency, adenosine deaminase deficiency (ADA), chronic granulomatous disease, and Wiskott-Aldrich syndrome have demonstrated that gene transfer into hematopoietic stem cells and autologous transplant can result in clinical improvement and is curative for many patients. Unfortunately, early clinical trials were complicated by vector-related insertional mutagenic events for several diseases with the exception of ADA-deficiency SCID. These results prompted the current wave of clinical trials for primary immunodeficiency using alternative retro- or lenti-viral vector constructs that are self-inactivating, and they have shown clinical efficacy without leukemic events thus far. The field of gene therapy continues to progress, with improvements in viral vector profiles, stem cell culturing techniques, and site-specific genome editing platforms. The future of gene therapy is promising, and we are quickly moving towards a time when it will be a standard cellular therapy for many forms of PID.

  4. Structural analysis of the principal immunodominant domain of the feline immunodeficiency virus transmembrane glycoprotein.

    PubMed Central

    Pancino, G; Camoin, L; Sonigo, P

    1995-01-01

    In the transmembrane envelope glycoprotein (TM) of lentiviruses, including human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV), two cysteine residues, conserved in most retroviruses, are thought to form a loop containing five to seven amino acids. These elements make up a B-cell epitope recognized by nearly 100% of sera from infected patients or animals, designated the principal immunodominant domain (PID). The PID amino acid sequences are highly conserved between isolates of the same lentivirus but are unrelated, except for the two cysteines, when divergent lentiviruses are compared. The aim of this study was to analyze the relationship between amino acid sequence in the PID and envelope function. We introduced two kinds of mutations in the PID of FIV: mutations which impeded the formation of a loop and mutations which substituted the sequence of FIV with the corresponding sequences from other lentiviruses, HIV-1, visna virus, and equine infectious anemia virus. We analyzed antibody recognition, processing, and fusogenic properties of the modified envelopes, using two methods of Env expression: a cell-free expression system and transfection of a feline fibroblast cell line with gag-pol-deleted FIV proviruses. Most mutations in the PID of FIV severely affected envelope processing and abolished syncytium formation. Only the chimeric envelope containing the HIV-1 PID sequence was correctly processed and maintained the capacity to induce syncytium formation, although less efficiently than the wild-type envelope. We computed three-dimensional structural models of the PID, which were consistent with mutagenesis data and confirmed the similarity of FIV and HIV-1 PID structures, despite their divergence in amino acid sequence. Considering these results, we discussed the respective importance of selection exerted by functional requirements or host antibodies to explain the observed variations of the PIDs in lentiviruses. PMID:7884857

  5. Antibody levels to tetanus, diphtheria, measles and varicella in patients with primary immunodeficiency undergoing intravenous immunoglobulin therapy: a prospective study

    PubMed Central

    2014-01-01

    Background Patients with antibody deficiencies depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG) to ensure continued protection against pathogens. Few studies have examined levels of antibodies to specific pathogens in IVIG preparations and little is known about the specific antibody levels in patients under regular IVIG treatment. The current study determined the range of antibodies to tetanus, diphtheria, measles and varicella in IVIG products and the levels of these antibodies in patients undergoing IVIG treatment. Methods We selected 21 patients with primary antibody deficiencies who were receiving regular therapy with IVIG. Over a period of one year, we collected four blood samples from each patient (every 3 months), immediately before immunoglobulin infusion. We also collected samples from the IVIG preparation the patients received the month prior to blood collection. Antibody levels to tetanus, diphtheria, measles and varicella virus were measured in plasma and IVIG samples. Total IgG levels were determined in plasma samples. Results Antibody levels to tetanus, diphtheria, varicella virus and measles showed considerable variation in different IVIG lots, but they were similar when compared between commercial preparations. All patients presented with protective levels of antibodies specific for tetanus, measles and varicella. Some patients had suboptimal diphtheria antibody levels. There was a significant correlation between serum and IVIG antibodies to all pathogens, except tetanus. There was a significant correlation between diphtheria and varicella antibodies with total IgG levels, but there was no significant correlation with antibodies to tetanus or measles. Conclusions The study confirmed the variation in specific antibody levels between batches of the same brand of IVIG. Apart from the most common infections to which these patients are susceptible, health care providers must be aware of other vaccine

  6. Antibody levels to tetanus, diphtheria, measles and varicella in patients with primary immunodeficiency undergoing intravenous immunoglobulin therapy: a prospective study.

    PubMed

    Nobre, Fernanda Aimée; Gonzalez, Isabela Garrido da Silva; Simão, Raquel Maria; de Moraes Pinto, Maria Isabel; Costa-Carvalho, Beatriz Tavares

    2014-06-21

    Patients with antibody deficiencies depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG) to ensure continued protection against pathogens. Few studies have examined levels of antibodies to specific pathogens in IVIG preparations and little is known about the specific antibody levels in patients under regular IVIG treatment. The current study determined the range of antibodies to tetanus, diphtheria, measles and varicella in IVIG products and the levels of these antibodies in patients undergoing IVIG treatment. We selected 21 patients with primary antibody deficiencies who were receiving regular therapy with IVIG. Over a period of one year, we collected four blood samples from each patient (every 3 months), immediately before immunoglobulin infusion. We also collected samples from the IVIG preparation the patients received the month prior to blood collection. Antibody levels to tetanus, diphtheria, measles and varicella virus were measured in plasma and IVIG samples. Total IgG levels were determined in plasma samples. Antibody levels to tetanus, diphtheria, varicella virus and measles showed considerable variation in different IVIG lots, but they were similar when compared between commercial preparations. All patients presented with protective levels of antibodies specific for tetanus, measles and varicella. Some patients had suboptimal diphtheria antibody levels. There was a significant correlation between serum and IVIG antibodies to all pathogens, except tetanus. There was a significant correlation between diphtheria and varicella antibodies with total IgG levels, but there was no significant correlation with antibodies to tetanus or measles. The study confirmed the variation in specific antibody levels between batches of the same brand of IVIG. Apart from the most common infections to which these patients are susceptible, health care providers must be aware of other vaccine preventable diseases, which still exist

  7. Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies.

    PubMed

    Borte, M; Kriván, G; Derfalvi, B; Maródi, L; Harrer, T; Jolles, S; Bourgeois, C; Engl, W; Leibl, H; McCoy, B; Gelmont, D; Yel, L

    2017-01-01

    A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2-67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient-year, P < 0·0001); the rate of all infections was 4·38/patient-year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non-serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13-year-old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3-4·1) h using mainly one to two administration sites [median = 2 sites (range = 1-5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well-tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment.

  8. Identification of gene products suppressed by human immunodeficiency virus type 1 infection or gp120 exposure of primary human astrocytes by rapid subtraction hybridization.

    PubMed

    Su, Zao-Zhong; Kang, Dong-Chul; Chen, Yinming; Pekarskaya, Olga; Chao, Wei; Volsky, David J; Fisher, Paul B

    2003-06-01

    Neurodegeneration and human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) are the major disease manifestations of HIV-1 colonization of the central nervous system (CNS). In the brain, HIV-1 replicates in microglial cells and infiltrating macrophages and it persists in a low-productive, noncytolytic state in astrocytes. Astrocytes play critical roles in the maintenance of the brain microenvironment, responses to injury, and in neuronal signal transmission, and disruption of these functions by HIV-1 could contribute to HAD. To better understand the potential effects of HIV-1 on astrocyte biology, the authors investigated changes in gene expression using an efficient and sensitive rapid subtraction hybridization approach, RaSH. Primary human astrocytes were isolated from abortus brain tissue, low-passage cells were infected with HIV-1 or mock infected, and total cellular RNAs were isolated at multiple time points over a period of 1 week. This approach is designed to identify gene products modulated early and late after HIV-1 infection and limits the cloning of genes displaying normal cell-cycle fluctuations in astrocytes. By subtracting temporal cDNAs derived from HIV-1-infected astrocytes from temporal cDNAs made from uninfected cells, 10 genes displaying reduced expression in infected cells, termed astrocyte suppressed genes (ASGs), were identified and their suppression was confirmed by Northern blot hybridization. Both known and novel ASGs, not reported in current DNA databases, that are down-regulated by HIV-1 infection are described. Northern blotting confirms suppression of the same panel of ASGs by treatment of astrocytes with recombinant HIV-1 envelope glycoprotein, gp120. These results extend our previous analysis of astrocyte genes induced or enhanced by HIV-1 infection and together they suggest that HIV-1 and viral proteins have profound effects on astrocyte physiology, which may influence their function in the CNS.

  9. Concurrent measures of fusion and transduction efficiency of primary CD34+ cells with human immunodeficiency virus 1-based lentiviral vectors reveal different effects of transduction enhancers.

    PubMed

    Ingrao, Dina; Majdoul, Saliha; Seye, Ababacar K; Galy, Anne; Fenard, David

    2014-02-01

    Lentiviral vectors (LVs) are used for various gene transfer applications, notably for hematopoietic gene therapy, but methods are lacking for precisely evaluating parameters that control the efficiency of transduction in relation to the entry of vectors into target cells. We adapted a fluorescence resonance energy transfer-based human immunodeficiency virus-1 fusion assay to measure the entry of nonreplicative recombinant LVs in various cell types, including primary human hematopoietic stem progenitor cells (HSPCs), and to quantify the level of transduction of the same initially infected cells. The assay utilizes recombinant LVs containing β-lactamase (BLAM)-Vpr chimeric proteins (BLAM-LVs) and encoding a truncated form of the low-affinity nerve growth factor receptor (ΔNGFR). After infection of target cells with BLAM-LVs, the vector entry rapidly leads to BLAM-Vpr release into the cytoplasm, which is measured by cleavage of a fluorescent substrate using flow cytometry. Parallel cultures of the same infected cells show transduction efficiency resulting from ΔNGFR expression. This LV-based fusion/transduction assay is a dynamic and versatile tool, revealing, for instance, the postentry restrictions of LVs known to occur in cells of hematopoietic origin, especially human HSPCs. Furthermore, this BLAM-LV assay allowed us to evaluate the effect of cytokine prestimulation of HSPCs on the entry step of LVs. The assay also shows that transduction enhancers such as Vectofusin-1 or Retronectin can partially relieve the postentry block, but their effects differ in how they promote LV entry. In conclusion, one such assay should be useful to study hematopoietic postentry restrictions directed against LVs and therefore should allow improvements in various LV-based gene therapy protocols.

  10. Diminished Human Immunodeficiency Virus Type 1 Reverse Transcription and Nuclear Transport in Primary Macrophages Arrested in Early G1 Phase of the Cell Cycle

    PubMed Central

    Kootstra, Neeltje A.; Zwart, Bianca M.; Schuitemaker, Hanneke

    2000-01-01

    Previously, we and others have demonstrated that the process of reverse transcription of human immunodeficiency virus type 1 (HIV-1) is disturbed in nondividing macrophages and quiescent T lymphocytes. Here we analyzed which phase of the cell cycle in macrophages is crucial for early steps in the HIV-1 replication cycle. HIV-1 Ba-L-inoculated macrophages arrested early in the G1 phase by n-butyrate contained incomplete products of reverse transcription. In gamma-irradiated macrophages, reverse transcription was successfully completed but proviral integration could not be detected. In these cells, nuclear import was disturbed as reflected by the absence of two-long-terminal-repeat circles. In macrophages arrested late in G1 phase by aphidicolin or 5,6-dichloro-1-β-d-ribofuranosyl-benzimidazole (DRB), reverse transcription was unaffected. Proviral integration occurred efficiently in DRB-treated macrophages, whereas integrated proviral DNA could not be detected after aphidicolin treatment. Arrest at G2 phase of the cell cycle by nocodazole did not affect reverse transcription or proviral integration. Treatment of macrophages with hydroxyurea (HU), which reduces the intracellular deoxynucleoside triphosphate (dNTP) pool by blocking the de novo synthesis of dNTP, resulted in a dose-dependent inhibition of HIV-1 reverse transcription. This could partially be restored by the addition of nucleoside precursors. Addition of nucleoside precursors enhanced both reverse transcription and cell proliferation. However, the disturbed reverse transcription observed in the nonproliferating and n-butyrate-treated macrophages could not be restored by addition of nucleoside precursors. Similar to observations in quiescent T lymphocytes, incomplete proviral DNA species were arrested in the cytoplasm of the macrophages. Our results indicate that also in primary macrophages the intracellular nucleotide pools and other cellular factors that coincide with late G1 phase of the cell cycle may

  11. Detection of Candida dubliniensis in Oropharyngeal Samples from Human Immunodeficiency Virus-Infected Patients in North America by Primary CHROMagar Candida Screening and Susceptibility Testing of Isolates

    PubMed Central

    Kirkpatrick, William R.; Revankar, Sanjay G.; Mcatee, Robert K.; Lopez-Ribot, Jose L.; Fothergill, Annette W.; McCarthy, Dora I.; Sanche, Stephen E.; Cantu, Rebecca A.; Rinaldi, Michael G.; Patterson, Thomas F.

    1998-01-01

    Candida dubliniensis has been associated with oropharyngeal candidiasis in patients infected with human immunodeficiency virus (HIV). C. dubliniensis isolates may have been improperly characterized as atypical Candida albicans due to the phenotypic similarity between the two species. Prospective screening of oral rinses from 63 HIV-infected patients detected atypical dark green isolates on CHROMagar Candida compared to typical C. albicans isolates, which are light green. Forty-eight atypical isolates and three control strains were characterized by germ tube formation, differential growth at 37, 42, and 45°C, identification by API 20C, fluorescence, chlamydoconidium production, and fingerprinting by Ca3 probe DNA hybridization patterns. All isolates were germ tube positive. Very poor or no growth occurred at 42°C with 22 of 51 isolates. All 22 poorly growing isolates at 42°C and one isolate with growth at 42°C showed weak hybridization of the Ca3 probe with genomic DNA, consistent with C. dubliniensis identification. No C. dubliniensis isolate but only 18 of 28 C. albicans isolates grew at 45°C. Other phenotypic or morphologic tests were less reliable in differentiating C. dubliniensis from C. albicans. Antifungal susceptibility testing showed fluconazole MICs ranging from ≤0.125 to 64 μg/ml. Two isolates were resistant to fluconazole (MIC, 64 μg/ml) and one strain was dose dependent susceptible (MIC, 16 μg/ml). MICs of other azoles, including voriconazole, itraconazole, and SCH 56592, for these isolates were lower. C. dubliniensis was identified in 11 of 63 (17%) serially evaluated patients. Variability in phenotypic characteristics dictates the use of molecular and biochemical techniques to identify C. dubliniensis. This study identifies C. dubliniensis in HIV-infected patients from San Antonio, Tex., and shows that C. dubliniensis is frequently detected in those patients by using a primary CHROMagar screen. PMID:9738058

  12. Subcutaneous immunoglobulin (16 or 20%) therapy in obese patients with primary immunodeficiency: a retrospective analysis of administration by infusion pump or subcutaneous rapid push.

    PubMed

    Shapiro, R

    2013-08-01

    A retrospective chart review was conducted at a single centre, capturing data on 173 primary immunodeficiency disease (PIDD) patients, including 40 obese patients, using subcutaneous administration of immunoglobulin (Ig) (SCIG) (16 or 20%) delivered by infusion pump or subcutaneous (s.c.) rapid push. Patients previously using Ig administered as intravenous (i.v.) infusions (IVIG) were converted to SCIG dosing on a 1:1 basis. In both obese and non-obese patients, mean serum Ig levels were higher during SCIG administration (steady state) compared with IVIG administration (trough values). Similar SCIG dose : serum IgG level relationships were observed between obese and non-obese patients, suggesting the consistent bioavailability of SCIG regardless of body mass index (BMI). The mean SCIG volume per dosing site and the mean number of dosing days per week were greater with s.c. rapid push compared with infusion pump in this cohort, but the mean number of sites per infusion session was lower with s.c. rapid push. Both methods were well tolerated. The use of 20 versus 16% SCIG in obese patients improved dosing efficiency, resulting in smaller weekly volumes (54·7 versus 74·5 ml/week) and dosing on fewer days per week (2·3 versus 3·4 days). These data do not suggest a need for SCIG dosing adjustments in obese individuals relative to non-obese patients. The administration of SCIG using either infusion pump or s.c. rapid push is a practical and well-tolerated alternative to IVIG in obese patients. Offering various administration techniques provides a greater opportunity for treatment satisfaction and patient empowerment, which may support high levels of patient compliance.

  13. The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901.

    PubMed

    Dvorak, Christopher C; Cowan, Morton J; Logan, Brent R; Notarangelo, Luigi D; Griffith, Linda M; Puck, Jennifer M; Kohn, Donald B; Shearer, William T; O'Reilly, Richard J; Fleisher, Thomas A; Pai, Sung-Yun; Hanson, I Celine; Pulsipher, Michael A; Fuleihan, Ramsay; Filipovich, Alexandra; Goldman, Frederick; Kapoor, Neena; Small, Trudy; Smith, Angela; Chan, Ka-Wah; Cuvelier, Geoff; Heimall, Jennifer; Knutsen, Alan; Loechelt, Brett; Moore, Theodore; Buckley, Rebecca H

    2013-10-01

    The Primary Immune Deficiency Treatment Consortium (PIDTC) consists of 33 centers in North America. We hypothesized that the analysis of uniform data on patients with severe combined immunodeficiency (SCID) enrolled in a prospective protocol will identify variables that contribute to optimal outcomes following treatment. We report baseline clinical, immunologic, and genetic features of the first 50 patients enrolled, and the initial therapies administered, reflecting current practice in the diagnosis and treatment of both typical (n = 37) and atypical forms (n = 13) of SCID. From August 2010 to May 2012, patients with suspected SCID underwent evaluation and therapy per local center practices. Diagnostic information was reviewed by the PIDTC eligibility review panel, and hematopoietic cell transplantation (HCT) details were obtained from the Center for International Blood and Marrow Transplant Research. Most patients (92 %) had mutations in a known SCID gene. Half of the patients were diagnosed by newborn screening or family history, were younger than those diagnosed by clinical signs (median 15 vs. 181 days; P = <0.0001), and went to HCT at a median of 67 days vs. 214 days of life (P = <0.0001). Most patients (92 %) were treated with HCT within 1-2 months of diagnosis. Three patients were treated with gene therapy and 1 with enzyme replacement. The PIDTC plans to enroll over 250 such patients and analyze short and long-term outcomes for factors beneficial or deleterious to survival, clinical outcome, and T- and B-cell reconstitution, and which biomarkers are predictive of these outcomes.

  14. Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a Phase 2/3 study in Europe in patients with primary immunodeficiencies

    PubMed Central

    Borte, M.; Kriván, G.; Derfalvi, B.; Maródi, L.; Harrer, T.; Jolles, S.; Bourgeois, C.; Engl, W.; Leibl, H.; McCoy, B.; Gelmont, D.

    2016-01-01

    Summary A highly concentrated (20%) immunoglobulin (Ig)G preparation for subcutaneous administration (IGSC 20%), would offer a new option for antibody replacement therapy in patients with primary immunodeficiency diseases (PIDD). The efficacy, safety, tolerability and pharmacokinetics of IGSC 20% were evaluated in a prospective trial in Europe in 49 patients with PIDD aged 2–67 years. Over a median of 358 days, patients received 2349 IGSC 20% infusions at monthly doses equivalent to those administered for previous intravenous or subcutaneous IgG treatment. The rate of validated acute bacterial infections (VASBIs) was significantly lower than 1 per year (0·022/patient‐year, P < 0·0001); the rate of all infections was 4·38/patient‐year. Median trough IgG concentrations were ≥ 8 g/l. There was no serious adverse event (AE) deemed related to IGSC 20% treatment; related non‐serious AEs occurred at a rate of 0·101 event/infusion. The incidence of local related AEs was 0·069 event/infusion (0·036 event/infusion, when excluding a 13‐year‐old patient who reported 79 of 162 total related local AEs). The incidence of related systemic AEs was 0·032 event/infusion. Most related AEs were mild, none were severe. For 64·6% of patients and in 94·8% of IGSC 20% infusions, no local related AE occurred. The median infusion duration was 0·95 (range = 0·3‐4·1) h using mainly one to two administration sites [median = 2 sites (range = 1–5)]. Almost all infusions (99·8%) were administered without interruption/stopping or rate reduction. These results demonstrate that IGSC 20% provides an effective and well‐tolerated therapy for patients previously on intravenous or subcutaneous treatment, without the need for dose adjustment. PMID:27613250

  15. Common variable immunodeficiency complicated with hemolytic uremic syndrome

    PubMed Central

    2012-01-01

    Common variable immunodeficiency is a primary immunodeficiency disease characterized by reduced serum immunoglobulins and heterogeneous clinical features. Recurrent pyogenic infections of upper and lower respiratory tracts are the main clinical manifestations of common variable immunodeficiency. Hemolytic uremic syndrome is a multisystemic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia due to platelet aggregation in the arterial microvasculature. This is one of the rare cases of patients diagnosed with common variable immunodeficiency, which was complicated by hemolytic uremic syndrome. PMID:22059898

  16. PIDs, Types and the Semantic Web

    NASA Astrophysics Data System (ADS)

    Schwardmann, Ulrich

    2017-04-01

    PID Information Types are becoming a crucial role in scientific data management because they can provide state (what) and binding (where) information about digital objects as attributes of the PID. This is a similar but much more flexible approach than the well known mime type characterization, because both of these types concepts allow to decide about preconditions for processes in advance and before touching the data. One aspect of this is the need for standards and correctness of the used types to ensure reliability for the processes operating on the digital objects. This requires registries and schemas for PID InfoTypes and suggests an automated schema generation process. Such a process in combination with data type registries will be described in more detail in the intended talk. Another aspect of PID InfoTypes is its intrinsic grammar as subject-predicate-object triple, with the PID as subject, the type as predicate and its value (often again a PID) as object in this relation. Given the registration of types and the proposed syntactical rigidness of the value, guaranteed by the schema, together with the use of PIDs in subject and predicate, the type concept has the ability to overcome the fuzziness and lack of reliability of semantic web categories with its URL references and possibly changing locations and content. The intended talk will also describe this approach in more detail, discusses the differences to linked data and describes some necessary technological developments for the type concept to keep up with the possibilities currently provided by the semantic web.

  17. Severe combined immunodeficiency (SCID): from molecular basis to clinical management.

    PubMed

    Sponzilli, Ivonne; Notarangelo, Luigi D

    2011-04-01

    Primary immune deficiency diseases (PID) comprise a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, as well as T and B lymphocytes. Severe combined immunodeficiency (SCID) is a group of disorders characterized by increased susceptibility to severe infections and early death. The diagnosis of SCID is supported by the demonstration of low absolute lymphocyte count and T cell lymphopenia (variably associated with numerical defects of B and NK cells). In the last two decades, advances in the characterization of the molecular pathophysiology of SCID, have permitted the development of novel diagnostic assays based on analysis of the expression of the disease-associated proteins and mutation analysis. More recently, pilot newborn screening programs for the identification of infants with SCID have been initiated in the United States. Prompt and aggressive treatment of infections, antimicrobial prophylaxis (in particular against Pneumocystis jiroveci) and regular administration of immunoglobulins are essential to reduce the risk of early death. However, survival ultimately depends on reconstitution of immune function, that is usually achieved by means of hematopoietic cell transplantation (HCT). Gene therapy and enzyme replacement therapy have also been used successfully is selected forms of SCID. Here we review the molecular and cellular pathophysiology and the mainstay of treatment of SCID.

  18. Kinetics of Lymphocyte Proliferation during Primary Immune Response in Macaques Infected with Pathogenic Simian Immunodeficiency Virus SIVmac251: Preliminary Report of the Effect of Early Antiviral Therapy

    PubMed Central

    Benlhassan-Chahour, Kadija; Penit, Claude; Dioszeghy, Vincent; Vasseur, Florence; Janvier, Geneviève; Rivière, Yves; Dereuddre-Bosquet, Nathalie; Dormont, Dominique; Le Grand, Roger; Vaslin, Bruno

    2003-01-01

    The aim of this study was to evaluate the kinetics of lymphocyte proliferation during primary infection of macaques with pathogenic simian immunodeficiency virus (SIV) and to study the impact of short-term postexposure highly active antiretroviral therapy (HAART) prophylaxis. Twelve macaques were infected by intravenous route with SIVmac251 and given treatment for 28 days starting 4 h postexposure. Group 1 received a placebo, and groups 2 and 3 received combinations of zidovudine (AZT), lamivudine (3TC), and indinavir. Macaques in group 2 received AZT (4.5 mg/kg of body weight), 3TC (2.5 mg/kg), and indinavir (20 mg/kg) twice per day by the oral route whereas macaques in group 3 were given AZT (4.5 mg/kg) and 3TC (2.5 mg/kg) subcutaneously twice per day, to improve the pharmacokinetic action of these drugs, and a higher dose of indinavir (60 mg/kg). The kinetics of lymphocyte proliferation were analyzed by monitoring 5-bromo-2′-deoxyuridine (BrdU) uptake ex vivo and by fluorescence-activated cell sorting analysis. HAART did not protect against SIV infection but did strongly impact on virus loads: viremia was delayed and lowered during antiviral therapy in group 2, with better control after treatment was stopped, and in group 3, viremia was maintained at lower levels during treatment, with virus even undetectable in the blood of some macaques, but there was no evidence of improved control of the virus after treatment. We provide direct evidence that dividing NK cells are detected earlier than dividing T cells in the blood (mostly in CD45RA− T cells), mirroring plasma viremia. Dividing CD8+ T cells were detected earlier than dividing CD4+ T cells, and the highest percentages of proliferating T cells coincided with the first evidence of partial control of peak viremia and with an increase in the percentage of circulating gamma interferon-positive CD8+ T cells. The level of cell proliferation in the blood during SIV primary infection was clearly associated with

  19. PID position domain control for contour tracking

    NASA Astrophysics Data System (ADS)

    Ouyang, P. R.; Pano, V.; Dam, T.

    2015-01-01

    Contour error reduction for modern machining processes is an important concern in multi-axis contour tracking applications in order to ensure the quality of final products. Many control methods were developed in time domain to deal with contour tracking problems, and a proportional-derivative (PD) position domain control (PDC) was also proposed by the authors. It is well known that proportional-integral-differential (PID) control is the most popular control in applications of control theory. In this paper, a PID PDC is proposed for reducing contour tracking errors and improving contour tracking performances. To determine proper control gains, system stability analysis is conducted for the proposed PDC. Several experiments are conducted to evaluate the performance of the developed approach and are compared with the PID time domain control (TDC) and the cross-coupled control. Different control gains are used in the simulations to explore the robustness of PID PDC. Comparison results demonstrate the effectiveness and good contour performances of PID PDC for contour tracking applications.

  20. Genetics Home Reference: X-linked severe combined immunodeficiency

    MedlinePlus

    ... Genome Research Institute: Learning About Severe Combined Immunodeficiency National Institute of Allergy and Infectious Diseases: Primary Immune ... Manual Consumer Version Orphanet: T-B+ severe ...

  1. Quantum Efficiency Loss after PID Stress: Wavelength Dependence on Cell Surface and Cell Edge

    SciTech Connect

    Oh, Jaewon; Bowden, Stuart; TamizhMani, GovindaSamy; Hacke, Peter

    2015-06-14

    It is known that the potential induced degradation (PID) stress of conventional p-base solar cells affects power, shunt resistance, junction recombination, and quantum efficiency (QE). One of the primary solutions to address the PID issue is a modification of chemical and physical properties of antireflection coating (ARC) on the cell surface. Depending on the edge isolation method used during cell processing, the ARC layer near the edges may be uniformly or non-uniformly damaged. Therefore, the pathway for sodium migration from glass to the cell junction could be either through all of the ARC surface if surface and edge ARC have low quality or through the cell edge if surface ARC has high quality but edge ARC is defective due to certain edge isolation process. In this study, two PID susceptible cells from two different manufacturers have been investigated. The QE measurements of these cells before and after PID stress were performed at both surface and edge. We observed the wavelength dependent QE loss only in the first manufacturer's cell but not in the second manufacturer's cell. The first manufacturer's cell appeared to have low quality ARC whereas the second manufacturer's cell appeared to have high quality ARC with defective edge. To rapidly screen a large number of cells for PID stress testing, a new but simple test setup that does not require laminated cell coupon has been developed and is used in this investigation.

  2. Neurodevelopmental Impairment among Infants Born to Mothers Infected with Human Immunodeficiency Virus and Uninfected Mothers from Three Peri-Urban Primary Care Clinics in Harare, Zimbabwe

    ERIC Educational Resources Information Center

    Kandawasvika, Gwendoline Q.; Ogundipe, Enitan; Gumbo, Felicity Z.; Kurewa, Edith N.; Mapingure, Munyaradzi P.; Stray-Pedersen, Babill

    2011-01-01

    Aim: The aim of this article is to document the risk of neurodevelopmental impairment (NDI) among infants enrolled in a programme for the prevention of mother-to-child transmission of HIV (human immunodeficiency virus) in Zimbabwe using the Bayley Infant Neurodevelopmental Screener (BINS). Method: We prospectively followed up infants at three…

  3. Neurodevelopmental Impairment among Infants Born to Mothers Infected with Human Immunodeficiency Virus and Uninfected Mothers from Three Peri-Urban Primary Care Clinics in Harare, Zimbabwe

    ERIC Educational Resources Information Center

    Kandawasvika, Gwendoline Q.; Ogundipe, Enitan; Gumbo, Felicity Z.; Kurewa, Edith N.; Mapingure, Munyaradzi P.; Stray-Pedersen, Babill

    2011-01-01

    Aim: The aim of this article is to document the risk of neurodevelopmental impairment (NDI) among infants enrolled in a programme for the prevention of mother-to-child transmission of HIV (human immunodeficiency virus) in Zimbabwe using the Bayley Infant Neurodevelopmental Screener (BINS). Method: We prospectively followed up infants at three…

  4. Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies - novel tool for diagnostics and patient follow-up.

    PubMed

    Osnes, Liv T; Nakken, Britt; Bodolay, Edit; Szodoray, Peter

    2013-08-01

    Serum and intracytoplasmic cytokines are mandatory in host defense against microbes, but also play a pivotal role in the pathogenesis of autoimmune diseases by initiating and perpetuating various cellular and humoral autoimmune processes. The intricate interplay and fine balance of pro- and anti-inflammatory processes drive, whether inflammation and eventually organ damage will occur, or the inflammatory cascade quenches. In the early and late, as well as inactive and active stages of autoimmune diseases, different cellular and molecular patterns can dominate in these patients. However, the simultaneous assessment of pro- and anti-inflammatory biomarkers aids to define the immunological state of a patient. A group of the most useful inflammatory biomarkers are cytokines, and with increasing knowledge during the last decade their role have been well-defined in patients with autoimmune diseases and immunodeficiencies. Multiple pathological processes drive the development of autoimmunity and immunodeficiencies, most of which involve quantitative and qualitative disturbances in regulatory cells, cytokine synthesis and signaling pathways. The assessment of these biomarkers does not aid only in the mechanistic description of autoimmune diseases and immunodeficiencies, but further helps to subcategorize diseases and to evaluate therapy responses. Here, we provide an overview, how monitoring of cytokines and regulatory cells aid in the diagnosis and follow-up of patients with autoimmune diseases and immunodeficiencies furthermore, we pinpoint novel cellular and molecular diagnostic possibilities in these diseases.

  5. British Lung Foundation/United Kingdom Primary Immunodeficiency Network Consensus Statement on the Definition, Diagnosis, and Management of Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders.

    PubMed

    Hurst, John R; Verma, Nisha; Lowe, David; Baxendale, Helen E; Jolles, Stephen; Kelleher, Peter; Longhurst, Hilary J; Patel, Smita Y; Renzoni, Elisabetta A; Sander, Clare R; Avery, Gerard R; Babar, Judith L; Buckland, Matthew S; Burns, Siobhan; Egner, William; Gompels, Mark M; Gordins, Pavels; Haddock, Jamanda A; Hart, Simon P; Hayman, Grant R; Herriot, Richard; Hoyles, Rachel K; Huissoon, Aarnoud P; Jacob, Joseph; Nicholson, Andrew G; Rassl, Doris M; Sargur, Ravishankar B; Savic, Sinisa; Seneviratne, Suranjith L; Sheaff, Michael; Vaitla, Prashantha M; Walters, Gareth I; Whitehouse, Joanna L; Wright, Penny A; Condliffe, Alison M

    2017-03-25

    A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).

  6. Rates of ectopic pregnancy, sterility follow PID rise.

    PubMed

    1980-05-01

    500,000 cases of PID (pelvic inflammatory disease) are reported annually in the US, with 34,000 to 92,000 women becoming sterile as a consequence of the disease. In addition, the contraceptive methods women use during their exposure to PID-causing agents may directly affect their relative risk of developing PID, at an annual cost of $2.7 billion in health-care expenses. Another sequelae of PID is ectopic pregnancy. The STD epidemic years from 1965 to 1975 are projected to increase the rate of ectopic pregnancies to 50,000 a year, or one for every 60 live births before leveling off. By 1990, 1 out of 32 women will have had an ectopic pregnancy. Tubal occlusion can result in involuntary infertility. The National Survey of Family Growth estimates that the prevalence of infertile women aged 15 to 44 who are married and use no contraceptive method has increased in the past 2-1/2 years from 2.7% to 6.1%. These women number 142,000 annually and resort to nonsurgical sterilization, with PID as a major reason. Gonococcal PID accounts for 34,000 to 92,000 women becoming involuntarily sterile each year. However, over 80% of PID is nongonococcal PID, which is a worst disease. Chronic PID and infertility are found "more often in women who have had nongonococcal PID than in women who have had gonococcal PID." Etiologic organisms of PID include gonorrhea; E. coli, anaerobes and Chlamydia trachomatis.

  7. NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation.

    PubMed

    Boztug, Heidrun; Hirschmugl, Tatjana; Holter, Wolfgang; Lakatos, Karoly; Kager, Leo; Trapin, Doris; Pickl, Winfried; Förster-Waldl, Elisabeth; Boztug, Kaan

    2016-08-01

    NF-κB signaling is critically important for regulation of both innate and adaptive immune responses. While activation of NF-κB has been implicated in malignancies such as leukemia and lymphoma, loss-of-function mutations affecting different NF-κB pathway components have been shown to cause primary immunodeficiency disorders. Recently, haploinsufficiency of NF-κB1 has been described in three families with common variable immunodeficiency (CVID). We studied a patient with recurrent respiratory infections and bacterial parapharyngeal abscess. Immunological investigations revealed normal total B- cell numbers, but hypogammaglobulinemia, decreased frequencies of class-switched B cells and impaired T-cell proliferation. Targeted next-generation sequencing using a custom-designed panel comprising all known PID genes (IUIS 2014 classification) and novel candidate genes identified a novel heterozygous frameshift mutation in the NFKB1 gene leading to a premature stop codon (c.491delG; p.G165A*31). We could show that the mutation leads to reduced phosphorylation of p105 upon stimulation, resulting in decreased protein levels of p50. The further disease course was mainly characterized by two episodes of severe EBV-associated lymphoproliferative disease responsive to rituximab treatment. Due to disease severity, the patient is considered for allogeneic hematopoietic stem cell transplantation. Interestingly, the father carries the same heterozygous NFKB1 mutation and also shows decreased frequencies of memory B cells but has a much milder clinical phenotype, in line with a considerable phenotypic disease heterogeneity. Deficiency of NF-κB1 leads to immunodeficiency with a wider phenotypic spectrum of disease manifestation than previously appreciated, including EBV lymphoproliferative diseases as a hitherto unrecognized feature of the disease.

  8. Common Variable Immunodeficiency.

    PubMed

    Saikia, Biman; Gupta, Sudhir

    2016-04-01

    Common variable immunodeficiency (CVID) is the most common primary immunodeficiency of young adolescents and adults which also affects the children. The disease remains largely under-diagnosed in India and Southeast Asian countries. Although in majority of cases it is sporadic, disease may be inherited in a autosomal recessive pattern and rarely, in autosomal dominant pattern. Patients, in addition to frequent sino-pulmonary infections, are also susceptible to various autoimmune diseases and malignancy, predominantly lymphoma and leukemia. Other characteristic lesions include lymphocytic and granulomatous interstitial lung disease, and nodular lymphoid hyperplasia of gut. Diagnosis requires reduced levels of at least two immunoglobulin isotypes: IgG with IgA and/or IgM and impaired specific antibody response to vaccines. A number of gene mutations have been described in CVID; however, these genetic alterations account for less than 20% of cases of CVID. Flow cytometry aptly demonstrates a disturbed B cell homeostasis with reduced or absent memory B cells and increased CD21(low) B cells and transitional B cell populations. Approximately one-third of patients with CVID also display T cell functional defects. Immunoglobulin therapy remains the mainstay of treatment. Immunologists and other clinicians in India and other South East Asian countries need to be aware of CVID so that early diagnosis can be made, as currently, majority of these patients still go undiagnosed.

  9. [Classification and diagnosis of immunodeficiency syndromes].

    PubMed

    Warnatz, K; Peter, H-H

    2004-08-01

    Primary immunodeficiency diseases of the adult are rare disorders, but often lead to serious consequences. Therefore an early diagnosis is critical. The variety in the clinical presentation, the complexity of the immune system and the ongoing discovery of new defects render it a difficult area for the involved physician. Due to the often imprecise complaint of a weak immune system the primary task is the identification of patients with true immunodeficiency. Subsequently, the immune defect needs to be identified in collaboration with a center for immunodeficiency disorders. The diagnostic procedure is dependent on the pattern of infections and follows a defined series of steps. This procedure should prevent costly diagnostic evaluation when not indicated, and also prevent the delayed diagnosis of patients with manifest immunodeficiency disease.

  10. Insertion of primary syncytium-inducing (SI) and non-SI envelope V3 loops in human immunodeficiency virus type 1 (HIV-1) LAI reduces neutralization sensitivity to autologous, but not heterologous, HIV-1 antibodies.

    PubMed Central

    Hogervorst, E; de Jong, J; van Wijk, A; Bakker, M; Valk, M; Nara, P; Goudsmit, J

    1995-01-01

    The aim of the study was to investigate the influence of V3 loops from naturally occurring viruses on the neutralization sensitivity of a molecularly cloned virus. A selection of well-defined syncytium-inducing (SI) and non-SI V3 loops of a single human immunodeficiency virus type 1-infected individual (H594) and the V3 regions of two SI laboratory strains were inserted in an infectious molecular clone of human immunodeficiency type 1 LAI. Neutralization was performed with a heterologous serum pool and autologous patient serum, using the virus reduction neutralization assay and peripheral blood lymphocytes as target cells. High sensitivity of the chimeric viruses containing the laboratory strain V3 regions to neutralization by H594 sequential sera as well as the heterologous serum pool was found. A statistically significant correlation between the sensitivities of these viruses was seen. In contrast, insertion of the primary isolate NSI and SI envelope V3 loops significantly reduced the neutralization by autologous serum but not by the heterologous serum pool. No correlation was found between the neutralization of the viruses with laboratory strain-derived V3 regions and the viruses with primary isolate V3 domains. We conclude that heterologous antibodies are able to neutralize infectious molecular clones with V3 loops of both SI and NSI viruses, regardless of whether they originated from laboratory strains or primary isolates. However, serum of patient H594 discriminated between the two types of viruses and showed reduced neutralization of the viruses with the autologous NSI and SI primary isolate V3 loops. These results indicated that the neutralization sensitivity of the viruses depended on the capacity of the V3 region to influence the conformation of the virus envelope. These V3-dependent conformational changes partially explain the neutralization sensitivity of laboratory strains and the relative neutralization resistance of primary isolates. PMID:7666535

  11. Genetic defects in common variable immunodeficiency

    PubMed Central

    Kopecký, O; Lukešová, Š

    2007-01-01

    Common variable immunodeficiency (CVID) is the most frequent clinically manifested primary immunodeficiency. According to clinical and laboratory findings, CVID is a heterogeneous group of diseases. Recently, the defects of molecules regulating activation and terminal differentiation of B lymphocytes have been described in some patients with CVID. In this study, we show the overview of deficiencies of inducible costimulator, transmembrane activator and calcium-modulator and cytophilin ligand interactor, CD19 molecules, their genetic basis, pathogenesis and clinical manifestations. PMID:17627754

  12. [Cancer as secondary immunodeficiency. Review].

    PubMed

    Vargas-Camaño, María Eugenia; Guido-Bayardo, Ricardo Leopoldo; Martínez-Aguilar, Nora Ernestina; Castrejón-Vázquez, María Isabel

    2016-01-01

    Secondary immunodeficiencys, previously presented in immunocompetent individuals. The lack of primary or secondary response to the presence of a foreign antigen, in the case of infections is a sentinel data in the diagnosis of immunodeficiency (can be primary or secondary), in the case of a self antigen may generate the presence of Cancer. Cancer has shown an increase in the prevalence and incidence globally. Most current medical treatments in cancer are focused primarily on immunomodulatory actions (immunosuppression / immune stimulation or both). Knowledge of key concepts from the perspective of innate and acquired immunity lead to cancer development, engaging immune surveillance and escape mechanisms of this that contribute to better understand the origin, behavior and treatment of neoplasm's. These treatments can cause immunological disorders such as allergy, anaphylaxis, lack of response immunogenicity care fields specialist in allergy and clinical immunology.

  13. PID Control Effectiveness for Surface Reactor Concepts

    SciTech Connect

    Dixon, David D.; Marsh, Christopher L.; Poston, David I.

    2007-01-30

    Control of space and surface fission reactors should be kept as simple as possible, because of the need for high reliability and the difficulty to diagnose and adapt to control system failures. Fortunately, compact, fast-spectrum, externally controlled reactors are very simple in operation. In fact, for some applications it may be possible to design low-power surface reactors without the need for any reactor control after startup; however, a simple proportional, integral, derivative (PID) controller can allow a higher performance concept and add more flexibility to system operation. This paper investigates the effectiveness of a PID control scheme for several anticipated transients that a surface reactor might experience. To perform these analyses, the surface reactor transient code FRINK was modified to simulate control drum movements based on bulk coolant temperature.

  14. Variable-order fuzzy fractional PID controller.

    PubMed

    Liu, Lu; Pan, Feng; Xue, Dingyu

    2015-03-01

    In this paper, a new tuning method of variable-order fractional fuzzy PID controller (VOFFLC) is proposed for a class of fractional-order and integer-order control plants. Fuzzy logic control (FLC) could easily deal with parameter variations of control system, but the fractional-order parameters are unable to change through this way and it has confined the effectiveness of FLC. Therefore, an attempt is made in this paper to allow all the five parameters of fractional-order PID controller vary along with the transformation of system structure as the outputs of FLC, and the influence of fractional orders λ and μ on control systems has been investigated to make the fuzzy rules for VOFFLC. Four simulation results of different plants are shown to verify the availability of the proposed control strategy.

  15. An adaptive pattern based nonlinear PID controller.

    PubMed

    Segovia, Juan Pablo; Sbarbaro, Daniel; Ceballos, Eric

    2004-04-01

    This paper presents a nonlinear proportional-integral-derivative (PID) controller, combining a pattern based adaptive algorithm to cope with the problem of tuning the controller, and an associative memory to store the parameters, according to different operating conditions. The simplicity of the algorithm enables its implementation in current programmable logic controller technology. Several real-time experiments, carried out in a pressurized tank, illustrate the performance of the proposed controller.

  16. Reduced Inflammation and Lymphoid Tissue Immunopathology in Rhesus Macaques Receiving Anti–Tumor Necrosis Factor Treatment During Primary Simian Immunodeficiency Virus Infection

    PubMed Central

    Tabb, Brian; Morcock, David R.; Trubey, Charles M.; Quiñones, Octavio A.; Hao, Xing Pei; Smedley, Jeremy; Macallister, Rhonda; Piatak, Michael; Harris, Levelle D.; Paiardini, Mirko; Silvestri, Guido; Brenchley, Jason M.; Alvord, W. Gregory; Lifson, Jeffrey D.; Estes, Jacob D.

    2013-01-01

    Background. Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections induce robust, generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation, fibrotic damage of lymphoid tissues, and CD4+ T-cell loss, pathogenic processes that contribute to disease progression. Methods. To better understand the contribution of tumor necrosis factor (TNF), a key regulator of acute inflammation, to lentiviral pathogenesis, rhesus macaques newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab (Humira), a human anti-TNF monoclonal antibody. Results. Adalimumab did not affect plasma SIV RNA levels or measures of T-cell immune activation (CD38 or Ki67) in peripheral blood or lymph node T cells. However, compared with untreated rhesus macaques, adalimumab-treated rhesus macaques showed attenuated expression of proinflammatory genes, decreased infiltration of polymorphonuclear cells into the T-cell zone of lymphoid tissues, and weaker antiinflammatory regulatory responses to SIV infection (ie, fewer presumed alternatively activated [ie, CD163+] macrophages, interleukin 10–producing cells, and transforming growth factor β–producing cells), along with reduced lymphoid tissue fibrosis and better preservation of CD4+ T cells. Conclusions. While HIV/SIV replication drives pathogenesis, these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis, and they suggest that early modulation of the inflammatory response may help attenuate disease progression. PMID:23087435

  17. Vaccine Associated Paralytic Poliomyelitis Unmasking Common Variable Immunodeficiency.

    PubMed

    Gomber, Sunil; Arora, Vanny; Dewan, Pooja

    2017-03-15

    Oral polio vaccine can rarely lead to Vaccine-associated paralytic poliomyelitis (VAPP). A 2-year-old child with asymmetric paralysis of lower limbs following first booster of oral polio vaccine; type 2 Vaccine-derived poliovirus (VDPV) isolated. Subsequently, the child was diagnosed to have common variable immunodeficiency. Paralysis gradually improved on follow-up; monthly intravenous immunoglobulin therapy started for primary immunodeficiency. We need to evaluate children with VAPP for underlying immunodeficiency.

  18. Soft Real-Time PID Control on a VME Computer

    NASA Technical Reports Server (NTRS)

    Karayan, Vahag; Sander, Stanley; Cageao, Richard

    2007-01-01

    microPID (uPID) is a computer program for real-time proportional + integral + derivative (PID) control of a translation stage in a Fourier-transform ultraviolet spectrometer. microPID implements a PID control loop over a position profile at sampling rate of 8 kHz (sampling period 125microseconds). The software runs in a strippeddown Linux operating system on a VersaModule Eurocard (VME) computer operating in real-time priority queue using an embedded controller, a 16-bit digital-to-analog converter (D/A) board, and a laser-positioning board (LPB). microPID consists of three main parts: (1) VME device-driver routines, (2) software that administers a custom protocol for serial communication with a control computer, and (3) a loop section that obtains the current position from an LPB-driver routine, calculates the ideal position from the profile, and calculates a new voltage command by use of an embedded PID routine all within each sampling period. The voltage command is sent to the D/A board to control the stage. microPID uses special kernel headers to obtain microsecond timing resolution. Inasmuch as microPID implements a single-threaded process and all other processes are disabled, the Linux operating system acts as a soft real-time system.

  19. Activation of the PAK-Related Kinase by Human Immunodeficiency Virus Type 1 Nef in Primary Human Peripheral Blood Lymphocytes and Macrophages Leads to Phosphorylation of a PIX-p95 Complex

    PubMed Central

    Brown, Amanda; Wang, Xia; Sawai, Earl; Cheng-Mayer, Cecilia

    1999-01-01

    Human immunodeficiency virus type 1 (HIV-1) Nef enhances virus replication in both primary T lymphocytes and monocyte-derived macrophages. This enhancement phenotype has been linked to the ability of Nef to modulate the activity of cellular kinases. We find that despite the reported high-affinity interaction between Nef and the Src kinase Hck in vitro, a Nef-Hck interaction in the context of HIV-1-infected primary macrophages is not detectable. However, Nef binding and activation of the PAK-related kinase and phosphorylation of its substrate could be readily detected in both infected primary T lymphocytes and macrophages. Furthermore, we show that this substrate is a complex composed of the recently characterized PAK interacting partner PIX (PAK-interacting guanine nucleotide exchange factor) and its tightly associated p95 protein. PAK and PIX-p95 appear to be differentially activated and phosphorylated depending on the intracellular environment in which nef is expressed. These results identify the PIX-p95 complex as a novel effector of Nef in primary cells and suggest that the regulation of the PAK signaling pathway may differ in T cells and macrophages. PMID:10559302

  20. Use and interpretation of diagnostic vaccination in primary immunodeficiency: a working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology.

    PubMed

    Orange, Jordan S; Ballow, Mark; Stiehm, E Richard; Ballas, Zuhair K; Chinen, Javier; De La Morena, Maite; Kumararatne, Dinakantha; Harville, Terry O; Hesterberg, Paul; Koleilat, Majed; McGhee, Sean; Perez, Elena E; Raasch, Jason; Scherzer, Rebecca; Schroeder, Harry; Seroogy, Christine; Huissoon, Aarnoud; Sorensen, Ricardo U; Katial, Rohit

    2012-09-01

    A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.

  1. Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes.

    PubMed Central

    Conant, K; Ma, M; Nath, A; Major, E O

    1996-01-01

    Human immunodeficiency virus type 1 (HIV-1) infection has been associated with an increase in the binding of the transcription factor NF-kappa B to its consensus sequence in the viral promoter. Using cultures of primary human fetal astrocytes, we show that exogenous HIV-1 Tat protein, which has been demonstrated to be released from infected cells, is associated with an increase in the binding of this transcription factor to an HIV-1 long terminal repeat kappa B sequence. This effect occurs rapidly and is independent of new protein synthesis. We also demonstrate that extracellular Tat protein is associated with an increase in protein kinase C activity. If Tat functions similarly in other cell types, such findings could relate to some of this protein's previously described physiological effects. These effects include Tat's ability to upregulate the synthesis of specific cytokines and to act as a growth factor. PMID:8627654

  2. Testing for Human Immunodeficiency Virus

    MedlinePlus

    ... education Fact Sheet PFS005: Testing for Human Immunodeficiency Virus AUGUST 2015 • Reasons for Getting Tested • Who Should ... For More Information • Glossary Testing for Human Immunodeficiency Virus Human immunodeficiency virus (HIV) is the virus that ...

  3. Exploiting Fractional Order PID Controller Methods in Improving the Performance of Integer Order PID Controllers: A GA Based Approach

    NASA Astrophysics Data System (ADS)

    Mukherjee, Bijoy K.; Metia, Santanu

    2009-10-01

    The paper is divided into three parts. The first part gives a brief introduction to the overall paper, to fractional order PID (PIλDμ) controllers and to Genetic Algorithm (GA). In the second part, first it has been studied how the performance of an integer order PID controller deteriorates when implemented with lossy capacitors in its analog realization. Thereafter it has been shown that the lossy capacitors can be effectively modeled by fractional order terms. Then, a novel GA based method has been proposed to tune the controller parameters such that the original performance is retained even though realized with the same lossy capacitors. Simulation results have been presented to validate the usefulness of the method. Some Ziegler-Nichols type tuning rules for design of fractional order PID controllers have been proposed in the literature [11]. In the third part, a novel GA based method has been proposed which shows how equivalent integer order PID controllers can be obtained which will give performance level similar to those of the fractional order PID controllers thereby removing the complexity involved in the implementation of the latter. It has been shown with extensive simulation results that the equivalent integer order PID controllers more or less retain the robustness and iso-damping properties of the original fractional order PID controllers. Simulation results also show that the equivalent integer order PID controllers are more robust than the normal Ziegler-Nichols tuned PID controllers.

  4. Variable Constraints on the Principal Immunodominant Domain of the Transmembrane Glycoprotein of Human Immunodeficiency Virus Type 1

    PubMed Central

    Merat, Rastine; Raoul, Herve; Leste-Lasserre, Thierry; Sonigo, Pierre; Pancino, Gianfranco

    1999-01-01

    Lentiviruses have in their transmembrane glycoprotein (TM) a highly immunogenic structure referred to as the principal immunodominant domain (PID). The PID forms a loop of 5 to 7 amino acids between two conserved cysteines. Previous studies showed that envelope (Env) glycoprotein functions of feline immunodeficiency virus (FIV) could be retained after extensive mutation of the PID loop sequence, in spite of its high conservation. In order to compare Env function in different lentiviruses, either random mutations were introduced in the PID loop sequence of human immunodeficiency virus type 1 (HIV-1) or the entire HIV-1 PID loop was replaced by the corresponding PID loop of FIV or simian immunodeficiency virus (SIV). In the macrophage-tropic HIV-1 ADA Env, mutations impaired the processing of the gp160 Env precursor, thereby abolishing viral infectivity. However, 6 of the 108 random Env mutants that were screened retained the capacity to induce cell membrane fusion. The SIV and FIV sequences and five random mutations were then introduced in the context of T-cell-line-adapted HIV-1 LAI which, although phenotypically distant from HIV-1 ADA, has an identical PID loop sequence. In contrast to the situation for HIV-1 ADA mutants, the cleavage of the Env precursor was unaffected in most HIV-1 LAI mutants. Such mutations, however, resulted in increased shedding of the gp120 surface glycoprotein (SU) from the gp41 TM. The HIV-1 LAI Env mutants showed high fusogenic efficiency. Three Env mutants retained the capacity to mediate virus entry in target cells, although less efficiently than the wild-type Env, and allowed the reconstitution of infectious molecular clones. These results indicated that in HIV-1, like FIV, the conserved PID sequence can be changed without impairing Env function. However, functional constraints on the PID of HIV-1 vary depending on the structural context of Env, presumably in relation to the role of the PID in the interaction of the SU and TM subunits

  5. Randomized Crossover Comparison of Personalized MPC and PID Control Algorithms for the Artificial Pancreas

    PubMed Central

    Pinsker, Jordan E.; Lee, Joon Bok; Dassau, Eyal; Seborg, Dale E.; Bradley, Paige K.; Gondhalekar, Ravi; Bevier, Wendy C.; Huyett, Lauren; Zisser, Howard C.

    2016-01-01

    OBJECTIVE To evaluate two widely used control algorithms for an artificial pancreas (AP) under nonideal but comparable clinical conditions. RESEARCH DESIGN AND METHODS After a pilot safety and feasibility study (n = 10), closed-loop control (CLC) was evaluated in a randomized, crossover trial of 20 additional adults with type 1 diabetes. Personalized model predictive control (MPC) and proportional integral derivative (PID) algorithms were compared in supervised 27.5-h CLC sessions. Challenges included overnight control after a 65-g dinner, response to a 50-g breakfast, and response to an unannounced 65-g lunch. Boluses of announced dinner and breakfast meals were given at mealtime. The primary outcome was time in glucose range 70–180 mg/dL. RESULTS Mean time in range 70–180 mg/dL was greater for MPC than for PID (74.4 vs. 63.7%, P = 0.020). Mean glucose was also lower for MPC than PID during the entire trial duration (138 vs. 160 mg/dL, P = 0.012) and 5 h after the unannounced 65-g meal (181 vs. 220 mg/dL, P = 0.019). There was no significant difference in time with glucose <70 mg/dL throughout the trial period. CONCLUSIONS This first comprehensive study to compare MPC and PID control for the AP indicates that MPC performed particularly well, achieving nearly 75% time in the target range, including the unannounced meal. Although both forms of CLC provided safe and effective glucose management, MPC performed as well or better than PID in all metrics. PMID:27289127

  6. Virions of primary human immunodeficiency virus type 1 isolates resistant to soluble CD4 (sCD4) neutralization differ in sCD4 binding and glycoprotein gp120 retention from sCD4-sensitive isolates.

    PubMed Central

    Moore, J P; McKeating, J A; Huang, Y X; Ashkenazi, A; Ho, D D

    1992-01-01

    Primary isolates of human immunodeficiency virus type 1 (HIV-1) are much less sensitive to neutralization by soluble CD4 (sCD4) and sCD4-immunoglobulin (Ig) chimeras (CD4-IgG) than are HIV-1 strains adapted to growth in cell culture. We demonstrated that there are significant reductions (10- to 30-fold) in the binding of sCD4 and CD4-IgG to intact virions of five primary isolates compared with sCD4-sensitive, cell culture-adapted isolates RF and IIIB. However, soluble envelope glycoproteins (gp120) derived from the primary isolate virions, directly by detergent solubilization or indirectly by recombinant DNA technology, differed in affinity from RF and IIIB gp120 by only one- to threefold. The reduced binding of sCD4 to these primary isolate virions must therefore be a consequence of the tertiary or quaternary structure of the envelope glycoproteins in their native, oligomeric form on the viral surface. In addition, the rate and extent of sCD4-induced gp120 shedding from these primary isolates was lower than that from RF. We suggest that reduced sCD4 binding and increased gp120 retention together account for the relative resistance of these primary isolates to neutralization by sCD4 and CD4-IgG and that virions of different HIV-1 isolates vary both in the mechanism of sCD4 binding and in subsequent conformational changes in their envelope glycoproteins. PMID:1727487

  7. Recognition of a Defined Region within p24 Gag by CD8+ T Cells during Primary Human Immunodeficiency Virus Type 1 Infection in Individuals Expressing Protective HLA Class I Alleles▿

    PubMed Central

    Streeck, Hendrik; Lichterfeld, Mathias; Alter, Galit; Meier, Angela; Teigen, Nickolas; Yassine-Diab, Bader; Sidhu, Harlyn K.; Little, Susan; Kelleher, Anthony; Routy, Jean-Pierre; Rosenberg, Eric S.; Sekaly, Rafick-Pierre; Walker, Bruce D.; Altfeld, Marcus

    2007-01-01

    Human immunodeficiency virus type 1 (HIV-1)-specific immune responses during primary HIV-1 infection appear to play a critical role in determining the ultimate speed of disease progression, but little is known about the specificity of the initial HIV-1-specific CD8+ T-cell responses in individuals expressing protective HLA class I alleles. Here we compared HIV-1-specific T-cell responses between subjects expressing the protective allele HLA-B27 or -B57 and subjects expressing nonprotective HLA alleles using a cohort of over 290 subjects identified during primary HIV-1 infection. CD8+ T cells of individuals expressing HLA-B27 or -B57 targeted a defined region within HIV-1 p24 Gag (amino acids 240 to 272) early in infection, and responses against this region contributed over 35% to the total HIV-1-specific T-cell responses in these individuals. In contrast, this region was rarely recognized in individuals expressing HLA-B35, an HLA allele associated with rapid disease progression, or in subjects expressing neither HLA-B57/B27 nor HLA-B35 (P < 0.0001). The identification of this highly conserved region in p24 Gag targeted in primary infection specifically in individuals expressing HLA class I alleles associated with slower HIV-1 disease progression provides a rationale for vaccine design aimed at inducing responses to this region restricted by other, more common HLA class I alleles. PMID:17494064

  8. A tuning method of two degrees of freedom PID controller

    SciTech Connect

    Kasahara, Masato; Kimbara, Akiomi; Kurosu, Shigeru; Matsuba, Tadahiko; Kamimura, Kazuyuki; Murasawa, Itaru; Hashimoto, Yukihiro

    1997-12-31

    This paper proposes a new tuning method when using a two degrees of freedom proportional-integral-derivative (PID) controller. Its control performance for a first-order lag plus deadtime system is shown as an example of the commonly approximated controlled plants in the heating, ventilating, and air-conditioning (HVAC) field. Reference and disturbance input changes to a conventional PID controller do not necessarily give a satisfactory response. To overcome this problem, several two degrees of freedom PID (2 DOF PID) algorithms have been developed to replace the conventional PID controllers. However, when these techniques are applied to real plants, it is not usually easy to obtain a set of optimum tuning parameters. To evaluate the control performance, a comparison is carried out between the two tuning methods--the optimization technique and the partial model matching method--using simulation. Graphs by which the controller parameters can be related to dynamics of a popular plant are developed. The 2 DOF PID control is studied taking into account modeling error due to a change in plant characteristics. It is found that the 2 DOF PID controller designed based on the partial model matching method is robust and useful in simulations where a traditional PID controller would be used.

  9. Flexible complexity reduced PID-like fuzzy controllers.

    PubMed

    Tao, C W; Taur, J S

    2000-01-01

    In this paper, a flexible complexity reduced design approach for PID-like fuzzy controllers is proposed. With the linear combination of input variables as a new input variable, the complexity of the fuzzy mechanism of PID-like fuzzy controllers is significantly reduced. However, the performance of the complexity reduced fuzzy PID controller may be degraded since the degree of freedom is decreased by the combination of input variables. To alleviate the drawback and improve the performance of the complexity reduced PID-like fuzzy controller, a flexible complexity reduced design approach is introduced in which the functional scaling factors are heuristically generated. Since the functional scaling factors are heuristically created, they can be easily adjusted for the flexible complexity reduced PID-like fuzzy controller without a priori knowledge of the exact mathematical model of the plant. Moreover, heuristic scaling factors are implemented as functionals. Therefore, the complexity of the flexible PID-like fuzzy controller will not be increased. Further, the stability of the fuzzy control system with a flexible complexity reduced PID-like fuzzy controller is discussed. Finally, the simulation results are also included to show the effectiveness of the PID-like fuzzy controller designed with the flexible complexity reduced approach.

  10. Primary Extranodal Non-Hodgkin Lymphoma of the Head and Neck in Patients with Acquired Immunodeficiency Syndrome: A Clinicopathologic Study of 24 Patients in a Single Hospital of Infectious Diseases in Argentina

    PubMed Central

    Corti, Marcelo; Villafañe, María; Bistmans, Alicia; Narbaitz, Marina; Gilardi, Leonardo

    2014-01-01

    Introduction Extranodal non-Hodgkin lymphomas (NHLs) are commonly described in patients with acquired immunodeficiency syndrome (AIDS) and are related with an atypical morphology and aggressive clinical course. AIDS-associated lymphomas are characterized by their rapid progression, frequent extranodal manifestations, and poor outcome. Objective The aim of this article is to remake the clinical features of head and neck (HN) NHL in patients with AIDS to facilitate early diagnosis and treatment. Methods We evaluated the epidemiologic, clinical, immunologic, virologic, and histopathologic characteristics of 24 patients with human immunodeficiency virus (HIV)/AIDS with primary HN NHL treated at a single institution between 2002 and 2012. Histopathologic diagnosis was made according to the criteria of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Additional immunohistochemical stains were applied in all cases. Results Eighteen patients (75%) were men and the median of age was 39 years. The gingiva and the hard palate were the most common sites of the lesions (15 patients, 62.5%). Lactate dehydrogenase levels were elevated in 16 cases (84%). Bone marrow infiltration was detected only in 4 cases (16.6%). The median CD4 T-cell count was 100 cells/µL. According to the histopathologic evaluation, the most common subtype was diffuse large B-cell lymphoma (12 cases, 50%), followed by plasmablastic lymphoma (9 cases, 37.5%) and Burkitt lymphoma (3 cases, 12.5%). Conclusion HN NHL is a severe complication of advanced HIV/AIDS disease. Early diagnosis followed by chemotherapy plus highly active antiretroviral treatment is necessary to improve the prognosis and the survival of these patients. PMID:25992103

  11. Primary extranodal non-hodgkin lymphoma of the head and neck in patients with acquired immunodeficiency syndrome: a clinicopathologic study of 24 patients in a single hospital of infectious diseases in Argentina.

    PubMed

    Corti, Marcelo; Villafañe, María; Bistmans, Alicia; Narbaitz, Marina; Gilardi, Leonardo

    2014-07-01

    Introduction Extranodal non-Hodgkin lymphomas (NHLs) are commonly described in patients with acquired immunodeficiency syndrome (AIDS) and are related with an atypical morphology and aggressive clinical course. AIDS-associated lymphomas are characterized by their rapid progression, frequent extranodal manifestations, and poor outcome. Objective The aim of this article is to remake the clinical features of head and neck (HN) NHL in patients with AIDS to facilitate early diagnosis and treatment. Methods We evaluated the epidemiologic, clinical, immunologic, virologic, and histopathologic characteristics of 24 patients with human immunodeficiency virus (HIV)/AIDS with primary HN NHL treated at a single institution between 2002 and 2012. Histopathologic diagnosis was made according to the criteria of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Additional immunohistochemical stains were applied in all cases. Results Eighteen patients (75%) were men and the median of age was 39 years. The gingiva and the hard palate were the most common sites of the lesions (15 patients, 62.5%). Lactate dehydrogenase levels were elevated in 16 cases (84%). Bone marrow infiltration was detected only in 4 cases (16.6%). The median CD4 T-cell count was 100 cells/µL. According to the histopathologic evaluation, the most common subtype was diffuse large B-cell lymphoma (12 cases, 50%), followed by plasmablastic lymphoma (9 cases, 37.5%) and Burkitt lymphoma (3 cases, 12.5%). Conclusion HN NHL is a severe complication of advanced HIV/AIDS disease. Early diagnosis followed by chemotherapy plus highly active antiretroviral treatment is necessary to improve the prognosis and the survival of these patients.

  12. A comparison of fuzzy logic-PID control strategies for PWR pressurizer control

    SciTech Connect

    Kavaklioglu, K.; Ikonomopoulos, A. )

    1993-01-01

    This paper describes the results obtained from a comparison performed between classical proportional-integral-derivative (PID) and fuzzy logic (FL) controlling the pressure in a pressurized water reactor (PWR). The two methodologies have been tested under various transient scenarios, and their performances are evaluated with respect to robustness and on-time response to external stimuli. One of the main concerns in the safe operation of PWR is the pressure control in the primary side of the system. In order to maintain the pressure in a PWR at the desired level, the pressurizer component equipped with sprayers, heaters, and safety relief valves is used. The control strategy in a Westinghouse PWR is implemented with a PID controller that initiates either the electric heaters or the sprayers, depending on the direction of the coolant pressure deviation from the setpoint.

  13. Toll-like receptor signaling in primary immune deficiencies

    PubMed Central

    Maglione, Paul J.; Simchoni, Noa; Cunningham-Rundles, Charlotte

    2015-01-01

    Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are specific for susceptibility to herpes simplex virus type 1 (HSV-1) encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell (pDC) defects enhance defective responses of B cells to shared TLR agonists. Dampening of TLR responses is seen for TLRs 2 and 4 in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome, and for most TLRs in adenosine deaminase deficiency. PMID:25930993

  14. Human Immunodeficiency Virus Type 1 Neutralization Measured by Flow Cytometric Quantitation of Single-Round Infection of Primary Human T Cells

    PubMed Central

    Mascola, John R.; Louder, Mark K.; Winter, Christine; Prabhakara, Ranjani; De Rosa, Stephen C.; Douek, Daniel C.; Hill, Brenna J.; Gabuzda, Dana; Roederer, Mario

    2002-01-01

    There is currently intensive research on the design of novel human immunodeficiency virus type 1 (HIV-1) vaccine immunogens that can elicit potent neutralizing antibodies. A prerequisite for comparing and optimizing these strategies is the ability to precisely measure neutralizing antibody responses. To this end, we sought to develop an assay that directly quantifies single-round HIV-1 infection of peripheral blood mononuclear cells (PBMC). Initial experiments demonstrated that essentially all productively infected PBMC could be identified by flow cytometric detection of intracellular p24 antigen (p24-Ag). After infection of PBMC with HIV-1, p24+ lymphocytes could be distinguished beginning 1 day postinfection, and the majority of CD8− T cells were p24-Ag positive by 3 to 4 days postinfection. To directly quantify first-round infection, we included a protease inhibitor in PBMC cultures. The resulting 2-day assay was highly sensitive and specific for the detection of HIV-1-infected PBMC. Serial dilutions of virus stocks demonstrated that the number of target cells infected was directly related to the amount of infectious virus input into the assay. In neutralization assays, the flow cytometric enumeration of first-round infection of PBMC provided quantitative data on the number of target cells infected and on the inactivation of infectious virus due to reaction with antibody. We also used this single-round assay to compare the percentage of cells expressing p24-Ag to the number of copies of HIV-1 gag per 100 PBMC. The precision and reproducibility of this assay will facilitate the measurement of HIV-1 neutralization, particularly incrementally improved neutralizing antibody responses generated by new candidate vaccines. PMID:11967298

  15. Infection of macrophages and dendritic cells with primary R5-tropic human immunodeficiency virus type 1 inhibited by natural polyreactive anti-CCR5 antibodies purified from cervicovaginal secretions.

    PubMed

    Eslahpazir, Jobin; Jenabian, Mohammad-Ali; Bouhlal, Hicham; Hocini, Hakim; Carbonneil, Cédric; Grésenguet, Gérard; Mbopi Kéou, François-Xavier; LeGoff, Jérôme; Saïdi, Héla; Requena, Mary; Nasreddine, Nadine; de Dieu Longo, Jean; Kaveri, Srinivas V; Bélec, Laurent

    2008-05-01

    Heterosexual contact is the primary mode of human immunodeficiency virus (HIV) type 1 (HIV-1) transmission worldwide. The chemokine receptor CCR5 is the major coreceptor that is associated with the mucosal transmission of R5-tropic HIV-1 during sexual intercourse. The CCR5 molecule is thus a target for antibody-based therapeutic strategies aimed at blocking HIV-1 entry into cells. We have previously demonstrated that polyreactive natural antibodies (NAbs) from therapeutic preparations of immunoglobulin G and from human breast milk contain NAbs directed against CCR5. Such antibodies inhibit the infection of human macrophages and T lymphocytes by R5-tropic isolates of HIV in vitro. In the present study, we demonstrate that human immunoglobulins from the cervicovaginal secretions of HIV-seronegative or HIV-seropositive women contain NAbs directed against the HIV-1 coreceptor CCR5. Natural affinity-purified anti-CCR5 antibodies bound to CCR5 expressed on macrophages and dendritic cells and further inhibited the infection of macrophages and dendritic cells with primary and laboratory-adapted R5-tropic HIV but not with X4-tropic HIV. Natural anti-CCR5 antibodies moderately inhibited R5-tropic HIV transfer from monocyte-derived dendritic cells to autologous T cells. Our results suggest that mucosal anti-CCR5 antibodies from healthy immunocompetent donors may hamper the penetration of HIV and may be suitable for use in the development of novel passive immunotherapy regimens in specific clinical settings of HIV infection.

  16. Infection of Macrophages and Dendritic Cells with Primary R5-Tropic Human Immunodeficiency Virus Type 1 Inhibited by Natural Polyreactive Anti-CCR5 Antibodies Purified from Cervicovaginal Secretions▿

    PubMed Central

    Eslahpazir, Jobin; Jenabian, Mohammad-Ali; Bouhlal, Hicham; Hocini, Hakim; Carbonneil, Cédric; Grésenguet, Gérard; Kéou, François-Xavier Mbopi; LeGoff, Jérôme; Saïdi, Héla; Requena, Mary; Nasreddine, Nadine; de Dieu Longo, Jean; Kaveri, Srinivas V.; Bélec, Laurent

    2008-01-01

    Heterosexual contact is the primary mode of human immunodeficiency virus (HIV) type 1 (HIV-1) transmission worldwide. The chemokine receptor CCR5 is the major coreceptor that is associated with the mucosal transmission of R5-tropic HIV-1 during sexual intercourse. The CCR5 molecule is thus a target for antibody-based therapeutic strategies aimed at blocking HIV-1 entry into cells. We have previously demonstrated that polyreactive natural antibodies (NAbs) from therapeutic preparations of immunoglobulin G and from human breast milk contain NAbs directed against CCR5. Such antibodies inhibit the infection of human macrophages and T lymphocytes by R5-tropic isolates of HIV in vitro. In the present study, we demonstrate that human immunoglobulins from the cervicovaginal secretions of HIV-seronegative or HIV-seropositive women contain NAbs directed against the HIV-1 coreceptor CCR5. Natural affinity-purified anti-CCR5 antibodies bound to CCR5 expressed on macrophages and dendritic cells and further inhibited the infection of macrophages and dendritic cells with primary and laboratory-adapted R5-tropic HIV but not with X4-tropic HIV. Natural anti-CCR5 antibodies moderately inhibited R5-tropic HIV transfer from monocyte-derived dendritic cells to autologous T cells. Our results suggest that mucosal anti-CCR5 antibodies from healthy immunocompetent donors may hamper the penetration of HIV and may be suitable for use in the development of novel passive immunotherapy regimens in specific clinical settings of HIV infection. PMID:18353923

  17. PID techniques: Alternatives to RICH Methods

    SciTech Connect

    Vavra, J.; /SLAC

    2011-03-01

    In this review article we discuss the recent progress in PID techniques other than the RICH methods. In particular we mention the recent progress in the Transition Radiation Detector (TRD), dE/dx cluster counting, and Time Of Flight (TOF) techniques. The TRD technique is mature and has been tried in many hadron colliders. It needs space though, about 20cm of detector radial space for every factor of 10 in the {pi}/e rejection power, and this tends to make such detectors large. Although the cluster counting technique is an old idea, it was never tried in a real physics experiment. Recently, there are efforts to revive it for the SuperB experiment using He-based gases and waveform digitizing electronics. A factor of almost 2 improvement, compared to the classical dE/dx performance, is possible in principle. However, the complexity of the data analysis will be substantial. The TOF technique is well established, but introduction of new fast MCP-PMT and G-APD detectors creates new possibilities. It seems that resolutions below 20-30ps may be possible at some point in the future with relatively small systems, and perhaps this could be pushed down to 10-15ps with very small systems, assuming that one can solve many systematic issues. However, the cost, rate limitation, aging and cross-talk in multi-anode devices at high BW are problems. There are several groups working on these issues, so progress is likely. Table 6 summarizes the author's opinion of pros and cons of various detectors presented in this paper based on their operational capabilities. We refer the reader to Ref.40 for discussion of other more general limits from the PID point of view.

  18. Analysis of direct action fuzzy PID controller structures.

    PubMed

    Mann, G I; Hu, B G; Gosine, R G

    1999-01-01

    The majority of the research work on fuzzy PID controllers focuses on the conventional two-input PI or PD type controller proposed by Mamdani (1974). However, fuzzy PID controller design is still a complex task due to the involvement of a large number of parameters in defining the fuzzy rule base. This paper investigates different fuzzy PID controller structures, including the Mamdani-type controller. By expressing the fuzzy rules in different forms, each PLD structure is distinctly identified. For purpose of analysis, a linear-like fuzzy controller is defined. A simple analytical procedure is developed to deduce the closed form solution for a three-input fuzzy inference. This solution is used to identify the fuzzy PID action of each structure type in the dissociated form. The solution for single-input-single-output nonlinear fuzzy inferences illustrates the effect of nonlinearity tuning. The design of a fuzzy PID controller is then treated as a two-level tuning problem. The first level tunes the nonlinear PID gains and the second level tunes the linear gains, including scale factors of fuzzy variables. By assigning a minimum number of rules to each type, the linear and nonlinear gains are deduced and explicitly presented. The tuning characteristics of different fuzzy PID structures are evaluated with respect to their functional behaviors. The rule decoupled and one-input rule structures proposed in this paper provide greater flexibility and better functional properties than the conventional fuzzy PHD structures.

  19. A new adaptive configuration of PID type fuzzy logic controller.

    PubMed

    Fereidouni, Alireza; Masoum, Mohammad A S; Moghbel, Moayed

    2015-05-01

    In this paper, an adaptive configuration for PID type fuzzy logic controller (FLC) is proposed to improve the performances of both conventional PID (C-PID) controller and conventional PID type FLC (C-PID-FLC). The proposed configuration is called adaptive because its output scaling factors (SFs) are dynamically tuned while the controller is functioning. The initial values of SFs are calculated based on its well-tuned counterpart while the proceeding values are generated using a proposed stochastic hybrid bacterial foraging particle swarm optimization (h-BF-PSO) algorithm. The performance of the proposed configuration is evaluated through extensive simulations for different operating conditions (changes in reference, load disturbance and noise signals). The results reveal that the proposed scheme performs significantly better over the C-PID controller and the C-PID-FLC in terms of several performance indices (integral absolute error (IAE), integral-of-time-multiplied absolute error (ITAE) and integral-of-time-multiplied squared error (ITSE)), overshoot and settling time for plants with and without dead time. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

  20. Glycosylation Disorders with Immunodeficiency

    MedlinePlus

    ... affected by these disorders and build upon our knowledge of harmful pathogens. Glycosylation disorders with immunodeficiency are ... Helps Researchers Explore Microbial Genomic Data Biological Materials Biological ... Clinical Sciences Support Center Vaccine and Treatment Evaluation Units Topical ...

  1. Novel intelligent PID control of traveling wave ultrasonic motor.

    PubMed

    Jingzhuo, Shi; Yu, Liu; Jingtao, Huang; Meiyu, Xu; Juwei, Zhang; Lei, Zhang

    2014-09-01

    A simple control strategy with acceptable control performance can be a good choice for the mass production of ultrasonic motor control system. In this paper, through the theoretic and experimental analyses of typical control process, a simpler intelligent PID speed control strategy of TWUM is proposed, involving only two expert rules to adjust the PID control parameters based on the current status. Compared with the traditional PID controller, this design requires less calculation and more cheap chips which can be easily involved in online performance. Experiments with different load torques and voltage amplitudes show that the proposed controller can deal with the nonlinearity and load disturbance to maintain good control performance of TWUM.

  2. Turbine speed control system based on a fuzzy-PID

    NASA Astrophysics Data System (ADS)

    Sun, Jian-Hua; Wang, Wei; Yu, Hai-Yan

    2008-12-01

    The flexibility demand of marine nuclear power plant is very high, the multiple parameters of the marine nuclear power plant with the once-through steam generator are strongly coupled, and the normal PID control of the turbine speed can’t meet the control demand. This paper introduces a turbine speed Fuzzy-PID controller to coordinately control the steam pressure and thus realize the demand for quick tracking and steady state control over the turbine speed by using the Fuzzy control’s quick dynamic response and PID control’s steady state performance. The simulation shows the improvement of the response time and steady state performance of the control system.

  3. Common Variable Immunodeficiency and Liver Involvement.

    PubMed

    Song, Junmin; Lleo, Ana; Yang, Guo Xiang; Zhang, Weici; Bowlus, Christopher L; Eric Gershwin, M; Leung, Patrick S C

    2017-08-07

    Common variable immunodeficiency (CVID) is a primary B-cell immunodeficiency disorder, characterized by remarkable hypogammaglobulinemia. The disease can develop at any age without gender predominance. The prevalence of CVID varies widely worldwide. The underlying causes of CVID remain largely unknown; primary B-cell dysfunctions, defects in T cells and antigen-presenting cells are involved. Although some monogenetic defects have been identified in some CVID patients, it is likely that CVID is polygenic. Patients with CVID develop recurrent and chronic infections (e.g., bacterial infections of the respiratory or gastrointestinal tract), autoimmune diseases, lymphoproliferation, malignancies, and granulomatous lesions. Interestingly, autoimmunity can be the only clinical manifestation of CVID at the time of diagnosis and may even develop prior to hypogammaglobulinemia. The diagnosis of CVID is largely based on the criteria established by European Society for Immunodeficiencies and Pan-American Group for Immunodeficiency (ESID/PAGID) and with some recent modifications. The disease can affect multiple organs, including the liver. Clinical features of CVID patients with liver involvement include abnormal liver biochemistries, primarily elevation of alkaline phosphatase (ALP), nodular regenerative hyperplasia (NRH), or liver cirrhosis and its complications. Replacement therapy with immunoglobulin (Ig) and anti-infection therapy are the primary treatment regimen for CVID patients. No specific therapy for liver involvement of CVID is currently available, and liver transplantation is an option only in select cases. The prognosis of CVID varies widely. Further understanding in the etiology and pathophysiology will facilitate early diagnosis and treatments to improve prognosis.

  4. Use of aspirin and statins for the primary prevention of myocardial infarction and stroke in patients with human immunodeficiency virus infection.

    PubMed

    Park, Tae Eun; Yusuff, Jameela; Sharma, Roopali

    2016-05-01

    This retrospective, cross-sectional study evaluated whether HIV-infected patients received aspirin and statins for the primary prevention of myocardial infarction and stroke. Among the 258 patients included, 50.4% (n = 130/258) of the patients had a high risk of myocardial infarction and 14% (n = 36/258) of stroke. Overall, 43.1% (n = 56/130) and 50% (n = 18/36) of the patients were prescribed aspirin for the primary prevention of myocardial infarction and stroke, respectively. Among the patients who required statin therapy, 42.5% (n = 34/80) and 37.1% (n = 13/35) of patients received it for the primary prevention of myocardial infarction and stroke, respectively. The patients who had hypertension (odds ratio 3.8, 95% confidence interval 1.5-10.9) and diabetes mellitus (odds ratio 5.6, 95% confidence interval 2.6-12.4) were more likely to receive aspirin. Interventions are needed to improve provider awareness of the use of aspirin and statins in the primary prevention of myocardial infarction and stroke in HIV-infected patients.

  5. Severe combined immunodeficiency in Serbia and Montenegro between years 1986 and 2010: a single-center experience.

    PubMed

    Pasic, Srdjan; Vujic, Dragana; Veljković, Dobrila; Slavkovic, Bojana; Mostarica-Stojkovic, Marija; Minic, Predrag; Minic, Aleksandra; Ristic, Goran; Giliani, Silvia; Villa, Anna; Sobacchi, Cristina; Lilić, Desa; Abinun, Mario

    2014-04-01

    Severe combined immunodeficiency (SCID), including the 'variant' Omenn syndrome (OS), represent a heterogeneous group of monogenic disorders characterized by defect in differentiation of T- and/or B lymphocytes and susceptibility to infections since birth. In the period of 25 years, between January 1986 and December 2010, a total of 21 patients (15 SCID, 6 OS) were diagnosed in Mother & Child Health Institute of Serbia, a tertiary-care teaching University hospital and a national referral center for patients affected with primary immunodeficiency (PID). The diagnoses were based on anamnestic data, clinical findings, and immunological and genetic analysis. The median age at the onset of the first infection was the 2nd month of life. Seven (33 %) patients had positive family history for SCID. Out of five male infants with T-B+NK- SCID phenotype, mutation analysis revealed interleukin-2 (common) gamma-chain receptor (IL2RG) mutations in 3 with positive X-linked family history, and Janus-kinase (JAK)-3 gene defects in the other two. Six patients had T-B-NK+ SCID phenotype and further 6 features of OS, 11 of which had recombinase-activating gene (RAG1or RAG2) and 1 Artemis gene mutations. One child with T+B+NK+ SCID phenotype as well had proven RAG mutation. One child each with T-B+NK+ SCID phenotype, CD8 lymphopenia and unknown phenotype remained without known underlying genetic defect. Of the eight patients who underwent hematopoetic stem cell transplant (HSCT) 5 survived, the other 13 died between 2 days and 12 months after diagnosis was made. Early diagnosis of SCID, before onset of severe infections, offers possibility for HSCT and cure. Education of primary-care pediatricians, in particular including awareness of the risk of using live vaccines and non-irradiated blood products, should improve prognosis of SCID in our setting.

  6. Fuzzy PID controller combines with closed-loop optimal fuzzy reasoning for pitch control system

    NASA Astrophysics Data System (ADS)

    Li, Yezi; Xiao, Cheng; Sun, Jinhao

    2013-03-01

    PID and fuzzy PID controller are applied into the pitch control system. PID control has simple principle and its parameters setting are rather easy. Fuzzy control need not to establish the mathematical of the control system and has strong robustness. The advantages of fuzzy PID control are simple, easy in setting parameters and strong robustness. Fuzzy PID controller combines with closed-loop optimal fuzzy reasoning (COFR), which can effectively improve the robustness, when the robustness is special requirement. MATLAB software is used for simulations, results display that fuzzy PID controller which combines with COFR has better performances than PID controller when errors exist.

  7. Computation of robustly stabilizing PID controllers for interval systems.

    PubMed

    Matušů, Radek; Prokop, Roman

    2016-01-01

    The paper is focused on the computation of all possible robustly stabilizing Proportional-Integral-Derivative (PID) controllers for plants with interval uncertainty. The main idea of the proposed method is based on Tan's (et al.) technique for calculation of (nominally) stabilizing PI and PID controllers or robustly stabilizing PI controllers by means of plotting the stability boundary locus in either P-I plane or P-I-D space. Refinement of the existing method by consideration of 16 segment plants instead of 16 Kharitonov plants provides an elegant and efficient tool for finding all robustly stabilizing PID controllers for an interval system. The validity and relatively effortless application of presented theoretical concepts are demonstrated through a computation and simulation example in which the uncertain mathematical model of an experimental oblique wing aircraft is robustly stabilized.

  8. Design of PID-type controllers using multiobjective genetic algorithms.

    PubMed

    Herreros, Alberto; Baeyens, Enrique; Perán, José R

    2002-10-01

    The design of a PID controller is a multiobjective problem. A plant and a set of specifications to be satisfied are given. The designer has to adjust the parameters of the PID controller such that the feedback interconnection of the plant and the controller satisfies the specifications. These specifications are usually competitive and any acceptable solution requires a tradeoff among them. An approach for adjusting the parameters of a PID controller based on multiobjective optimization and genetic algorithms is presented in this paper. The MRCD (multiobjective robust control design) genetic algorithm has been employed. The approach can be easily generalized to design multivariable coupled and decentralized PID loops and has been successfully validated for a large number of experimental cases.

  9. Autoimmunity in Common Variable Immunodeficiency

    PubMed Central

    Agarwal, Shradha; Cunningham-Rundles, Charlotte

    2010-01-01

    Common variable immunodeficiency (CVID) is the most common clinically significant primary immune defect. Although the hallmark of CVID is hypogammaglobulinemia, the intrinsic dysregulation of the immune system leads to defective T-cell activation and proliferation, as well as dendritic cell and cytokine defects. Although 70% to 80% of patients have had recurrent sinopulmonary infections, auto-immunity and inflammatory complications are also common. The most common autoimmune conditions are immune thrombocytopenic purpura and hemolytic anemia, but other autoimmune complications arise, including rheumatoid arthritis, pernicious anemia, primary biliary cirrhosis, thyroiditis, sicca syndrome, systemic lupus, and inflammatory bowel disease. Treatment of autoimmunity includes high-dose immunoglobulins, corticosteroids, selected immunosuppressants, and other immune modulators. This review focuses on autoimmune conditions associated with CVID, potential mechanisms of immune dysregulation, and therapeutic strategies. PMID:19671377

  10. Variable Structure PID Control to Prevent Integrator Windup

    NASA Technical Reports Server (NTRS)

    Hall, C. E.; Hodel, A. S.; Hung, J. Y.

    1999-01-01

    PID controllers are frequently used to control systems requiring zero steady-state error while maintaining requirements for settling time and robustness (gain/phase margins). PID controllers suffer significant loss of performance due to short-term integrator wind-up when used in systems with actuator saturation. We examine several existing and proposed methods for the prevention of integrator wind-up in both continuous and discrete time implementations.

  11. Differential role of long terminal repeat control elements for the regulation of basal and Tat-mediated transcription of the human immunodeficiency virus in stimulated and unstimulated primary human macrophages.

    PubMed

    Moses, A V; Ibanez, C; Gaynor, R; Ghazal, P; Nelson, J A

    1994-01-01

    Primary human macrophages induced to differentiate through contact with autologous activated nonadherent cells were used to investigate the transcriptional mechanisms involved in reactivation of human immunodeficiency virus (HIV) replication. Through transient transfection experiments with an HIV long terminal repeat (LTR)-chloramphenicol acetyltransferase reporter construct, we show that macrophage differentiation results in a 20-fold upregulation of basal LTR activity. To identify sequence elements responsive to the differentiation process, point mutations introduced into the LTR were tested in differentiated and undifferentiated macrophages. Several elements were identified as positive regulators of basal transcription. TATA, Sp1, and NF-kappa B binding sites were the most influential. The low-affinity site for LBP-1 (UBP-1) functioned as a negative regulator of LTR activity in undifferentiated macrophages, but this influence was lost upon differentiation. When tat was cotransfected into the expression system, the requirement for LTR elements identified as important for positive regulation of basal transcription remained in undifferentiated macrophages. Interestingly, however, the mutations in positive control elements which debilitated activity in undifferentiated macrophages had no effect on LTR activity in differentiated macrophages. Thus, it appears that while HIV-LTR activity is highly dependent on cellular transcription factors in undifferentiated cells, in differentiated macrophages the viral protein Tat confers pliability on the LTR and facilitates autonomy from absolute cellular control mechanisms. In vivo, release from either positive or negative regulation via cellular proteins may facilitate reactivation of HIV in macrophages.

  12. Design and tuning of robust PID controller for HVAC systems

    SciTech Connect

    Kasahara, Masato; Matsuba, Tadahiko; Kuzuu, Yoshiaki; Yamazaki, Takanori; Hashimoto, Yukihiro; Kamimura, Kazuyuki; Kurosu, Shigeru

    1999-07-01

    This paper concerns the development of a new design and tuning method for use with robust proportional-plus-integral-plus-derivative (PID) controllers that are commonly used in the heating, ventilating, and air-conditioning (HVAC) fields. The robust PID controller is designed for temperature control of a single-zone environmental space. Although the dynamics of environmental space are described by higher-order transfer functions, most HVAC plants are approximated by first-order lag plus deadtime systems. Its control performance is examined for this commonly approximated controlled plant. Since most HVAC plants are complex with nonlinearity, distributed parameters, and multivariables, a single set of PID gains does not necessarily yield a satisfactory control performance. For this reason, the PID controller must be designed as a robust control system considering model uncertainty caused by changes in characteristics of the plant. The PID gains obtained by solving a two-disk type of mixed sensitivity problem can be modified by contrast to those tuned by the traditional Ziegler-Nichols rule. The results, which are surprisingly simple, are given as linear functions of ratio of deadtime to time constant for robustness. The numerical simulation and the experiments on a commercial-size test plant for air conditioning suggest that the robust PID controller proposed in this paper is effective enough for practical applications.

  13. The focusing DIRC: An innovative PID detector

    NASA Astrophysics Data System (ADS)

    Borsato, M.; Arnaud, N.; Dey, B.; Nishimura, K.; Leith, D. W. G. S.; Roberts, D.; Ratcliff, B.; Va'vra, J.; Varner, G. S.

    2013-12-01

    The FDIRC (Focusing Detector of Internally Reflected Cherenkov light) is a new concept of PID (Particle IDentification) detector aimed at separating kaons from pions up to a few GeV/c. It is the successor of the BABAR DIRC and benefits from the knowledge accumulated with a first FDIRC prototype built and operated at SLAC. The FDIRC is intended to be used in an environment with a luminosity 100 times higher than for BABAR and Belle. Backgrounds will be higher as well; yet, the FDIRC has been designed to perform at least as well as the BABAR DIRC. The main improvement is a complete redesign of the photon camera, moving from a huge tank of ultra-pure water to much smaller focusing cameras with solid fused-silica optics. Furthermore, the detection chain will be 10 times faster than in BABAR to reject more background and to measure more accurately Cherenkov angles. This is achieved using H-8500 MaPMTs and a new front-end electronics (FEE) with significantly improved timing precision, higher hit rate capability, and small dead time. A full-scale FDIRC prototype covering 1/12th of the barrel azimuth is installed at SLAC and has just started recording cosmic-ray data. In this paper, we summarize the FDIRC design, present the status of the prototype test at SLAC and review the ongoing work to analyse the data.

  14. PID feedback control of monochromator thermal stabilization

    NASA Astrophysics Data System (ADS)

    Yoder, Derek W.; Makarov, Oleg; Corcoran, Stephen; Fischetti, Robert F.

    2011-09-01

    The desire for increasingly smaller X-ray beams for macromolecular crystallography experiments also stimulates the need for improvements in beam stability. There are numerous sources of instability, which influence beam quality on the micron-size scale. Typically, the most problematic source is thermal drift within the double crystal monochromators. In addition to using liquid nitrogen to indirectly cool both the first and second crystals, GM/CA-CAT previously used a combination of flowing water at constant temperature and copper braiding to stabilize the mechanics, mounts, and the Compton scatter shielding. However, the copper braids inefficiently stabilized the temperature of components that were distant from the water lines. Additionally, vibrations in the water lines propagated throughout the vibrationally dampened monochromator, thereby introducing both positional and intensity instabilities in the transmitted X-ray beam. To address these problems, heating pads were placed directly onto the temperature-sensitive components, with output controlled by a PID-feedback loop. As a result, there is negligible temperature change in the first crystal radiation shielding over the entire range of operational heat loads. Additionally, the angular drift in the second crystal induced by temperature changes in other components is dramatically decreased.

  15. The impact of human immunodeficiency virus (HIV) service scale-up on mechanisms of accountability in Zambian primary health centres: a case-based health systems analysis.

    PubMed

    Topp, Stephanie M; Black, Jim; Morrow, Martha; Chipukuma, Julien M; Van Damme, Wim

    2015-02-18

    Questions about the impact of large donor-funded HIV interventions on low- and middle-income countries' health systems have been the subject of a number of expert commentaries, but comparatively few empirical research studies. Aimed at addressing a particular evidence gap vis-à-vis the influence of HIV service scale-up on micro-level health systems, this article examines the impact of HIV scale-up on mechanisms of accountability in Zambian primary health facilities. Guided by the Mechanisms of Effect framework and Brinkerhoff's work on accountability, we conducted an in-depth multi-case study to examine how HIV services influenced mechanisms of administrative and social accountability in four Zambian primary health centres. Sites were selected for established (over 3 yrs) antiretroviral therapy (ART) services and urban, peri-urban and rural characteristics. Case data included provider interviews (60); patient interviews (180); direct observation of facility operations (2 wks/centre) and key informant interviews (14). Resource-intensive investment in HIV services contributed to some early gains in administrative answerability within the four ART departments, helping to establish the material capabilities necessary to deliver and monitor service delivery. Simultaneous investment in external supervision and professional development helped to promote transparency around individual and team performance and also strengthened positive work norms in the ART departments. In the wider health centres, however, mechanisms of administrative accountability remained weak, hindered by poor data collection and under capacitated leadership. Substantive gains in social accountability were also elusive as HIV scale-up did little to address deeply rooted information and power asymmetries in the wider facilities. Short terms gains in primary-level service accountability may arise from investment in health system hardware. However, sustained improvements in service quality and

  16. Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12.

    PubMed Central

    Mascola, J R; Louder, M K; VanCott, T C; Sapan, C V; Lambert, J S; Muenz, L R; Bunow, B; Birx, D L; Robb, M L

    1997-01-01

    Three antibody reagents that neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates were tested for magnitude and breadth of neutralization when used alone or in double or triple combinations. Hyperimmune anti-HIV immunoglobulin (HIVIG) is derived from the plasma of HIV-1-infected donors, and monoclonal antibodies (MAbs) 2F5 and 2G12 bind to distinct regions of the HIV-1 envelope glycoprotein. The antibodies were initially tested against a panel of 15 clade B HIV-1 isolates, using a single concentration that is achievable in vivo (HIVIG, 2,500 microg/ml; MAbs, 25 microg/ml). Individual antibody reagents neutralized many of the viruses tested, but antibody potency varied substantially among the viruses. The virus neutralization produced by double combinations of HIVIG plus 2F5 or 2G12, the two MAbs together, or the triple combination of HIVIG, 2F5, and 2G12 was generally equal to or greater than that predicted by the effect of individual antibodies. Overall, the triple combination displayed the greatest magnitude and breadth of neutralization. Synergistic neutralization was evaluated by analyzing data from dose-response curves of each individual antibody reagent compared to the triple combination and was demonstrated against each of four viruses tested. Therefore, combinations of polyclonal and monoclonal anti-HIV antibodies can produce additive or synergistic neutralization of primary HIV-1 isolates. Passive immunotherapy for treatment or prophylaxis of HIV-1 should consider mixtures of potent neutralizing antibody reagents to expand the magnitude and breadth of virus neutralization. PMID:9311792

  17. Potent and synergistic neutralization of human immunodeficiency virus (HIV) type 1 primary isolates by hyperimmune anti-HIV immunoglobulin combined with monoclonal antibodies 2F5 and 2G12.

    PubMed

    Mascola, J R; Louder, M K; VanCott, T C; Sapan, C V; Lambert, J S; Muenz, L R; Bunow, B; Birx, D L; Robb, M L

    1997-10-01

    Three antibody reagents that neutralize primary human immunodeficiency virus type 1 (HIV-1) isolates were tested for magnitude and breadth of neutralization when used alone or in double or triple combinations. Hyperimmune anti-HIV immunoglobulin (HIVIG) is derived from the plasma of HIV-1-infected donors, and monoclonal antibodies (MAbs) 2F5 and 2G12 bind to distinct regions of the HIV-1 envelope glycoprotein. The antibodies were initially tested against a panel of 15 clade B HIV-1 isolates, using a single concentration that is achievable in vivo (HIVIG, 2,500 microg/ml; MAbs, 25 microg/ml). Individual antibody reagents neutralized many of the viruses tested, but antibody potency varied substantially among the viruses. The virus neutralization produced by double combinations of HIVIG plus 2F5 or 2G12, the two MAbs together, or the triple combination of HIVIG, 2F5, and 2G12 was generally equal to or greater than that predicted by the effect of individual antibodies. Overall, the triple combination displayed the greatest magnitude and breadth of neutralization. Synergistic neutralization was evaluated by analyzing data from dose-response curves of each individual antibody reagent compared to the triple combination and was demonstrated against each of four viruses tested. Therefore, combinations of polyclonal and monoclonal anti-HIV antibodies can produce additive or synergistic neutralization of primary HIV-1 isolates. Passive immunotherapy for treatment or prophylaxis of HIV-1 should consider mixtures of potent neutralizing antibody reagents to expand the magnitude and breadth of virus neutralization.

  18. A conserved two-component regulatory system, PidS/PidR, globally regulates pigmentation and virulence-related phenotypes of Burkholderia glumae.

    PubMed

    Karki, Hari Sharan; Barphagha, Inderjit Kaur; Ham, Jong Hyun

    2012-09-01

    Burkholderia glumae is a rice pathogenic bacterium that causes bacterial panicle blight. Some strains of this pathogen produce dark brown pigments when grown on casamino-acid peptone glucose (CPG) agar medium. A pigment-positive and highly virulent strain of B. glumae, 411gr-6, was randomly mutagenized with mini-Tn5gus, and the resulting mini-Tn5gus derivatives showing altered pigmentation phenotypes were screened on CPG agar plates to identify the genetic elements governing the pigmentation of B. glumae. In this study, a novel two-component regulatory system (TCRS) composed of the PidS sensor histidine kinase and the PidR response regulator was identified as an essential regulatory factor for pigmentation. Notably, the PidS/PidR TCRS was also required for the elicitation of the hypersensitive response on tobacco leaves, indicating the dependence of the hypersensitive response and pathogenicity (Hrp) type III secretion system of B. glumae on this regulatory factor. In addition, B. glumae mutants defective in the PidS/PidR TCRS showed less production of the phytotoxin, toxoflavin, and less virulence on rice panicles and onion bulbs relative to the parental strain, 411gr-6. The presence of highly homologous PidS and PidR orthologues in other Burkholderia species suggests that PidS/PidR-family TCRSs may exert the same or similar functions in different Burkholderia species, including both plant and animal pathogens.

  19. Identification of new splice sites used for generation of rev transcripts in human immunodeficiency virus type 1 subtype C primary isolates.

    PubMed

    Delgado, Elena; Carrera, Cristina; Nebreda, Paloma; Fernández-García, Aurora; Pinilla, Milagros; García, Valentina; Pérez-Álvarez, Lucía; Thomson, Michael M

    2012-01-01

    The HIV-1 primary transcript undergoes a complex splicing process by which more than 40 different spliced RNAs are generated. One of the factors contributing to HIV-1 splicing complexity is the multiplicity of 3' splice sites (3'ss) used for generation of rev RNAs, with two 3'ss, A4a and A4b, being most commonly used, a third site, A4c, used less frequently, and two additional sites, A4d and A4e, reported in only two and one isolates, respectively. HIV-1 splicing has been analyzed mostly in subtype B isolates, and data on other group M clades are lacking. Here we examine splice site usage in three primary isolates of subtype C, the most prevalent clade in the HIV-1 pandemic, by using an in vitro infection assay of peripheral blood mononuclear cells. Viral spliced RNAs were identified by RT-PCR amplification using a fluorescently-labeled primer and software analyses and by cloning and sequencing the amplified products. The results revealed that splice site usage for generation of rev transcripts in subtype C differs from that reported for subtype B, with most rev RNAs using two previously unreported 3'ss, one located 7 nucleotides upstream of 3'ss A4a, designated A4f, preferentially used by two isolates, and another located 14 nucleotides upstream of 3'ss A4c, designated A4g, preferentially used by the third isolate. A new 5' splice site, designated D2a, was also identified in one virus. Usage of the newly identified splice sites is consistent with sequence features commonly found in subtype C viruses. These results show that splice site usage may differ between HIV-1 subtypes.

  20. Testing for Human Immunodeficiency Virus

    MedlinePlus

    ... incisions made in the mother’s abdomen and uterus. Human Immunodeficiency Virus (HIV): A virus that attacks certain cells of the body’s immune system and causes acquired immunodeficiency syndrome (AIDS). Immune System: ...

  1. Common variable immunodeficiency - an update

    PubMed Central

    2012-01-01

    Common variable immunodeficiency (CVID) describes a heterogeneous subset of hypogammaglobulinemias of unknown etiology. Typically, patients present with recurrent bacterial infections of the respiratory and gastrointestinal tract. A significant proportion of CVID patients develops additional autoimmune, inflammatory or lymphoproliferative complications. CVID is the most frequent symptomatic primary immunodeficiency encountered in adults. Informative monogenetic defects have been found in single patients and families but in most cases the pathogenesis is still elusive. Numerous immunological studies have demonstrated phenotypic and functional abnormalities of T cells, B cells and antigen-presenting cells. A hallmark is the impaired memory B-cell formation that has been taken advantage of for classifying CVID patients. Clinical multi-center studies have demonstrated a correlation between immunological markers and clinical presentation. Long-term outcome is significantly influenced by delay of diagnosis and treatment and the presence of chronic inflammatory complications. While immunoglobulin replacement therapy plus antibiotics can control infections in most cases, patients with non-infectious inflammatory complications such as granulomatous inflammation, interstitial lung disease, inflammatory bowel disease, lymphoproliferation and developing malignancies still represent a therapeutic challenge. In this review we provide a systematic overview of the immunological, clinical, diagnostic and therapeutic aspects of CVID and highlight recent developments in these fields. PMID:23043756

  2. Severe Combined Immunodeficiency Disorders.

    PubMed

    Chinn, Ivan K; Shearer, William T

    2015-11-01

    Severe combined immunodeficiency disorders represent pediatric emergencies due to absence of adaptive immune responses to infections. The conditions result from either intrinsic defects in T-cell development (ie, severe combined immunodeficiency disease [SCID]) or congenital athymia (eg, complete DiGeorge anomaly). Hematopoietic stem cell transplant provides the only clinically approved cure for SCID, although gene therapy research trials are showing significant promise. For greatest survival, patients should undergo transplant before 3.5 months of age and before the onset of infections. Newborn screening programs have yielded successful early identification and treatment of infants with SCID and congenital athymia in the United States.

  3. [Food protective property of new liquid food container PID (Pouch in Dispenser) for microbes].

    PubMed

    Tominari, Keita; Tanaka, Asato; Shinoda, Yuma; Futase, Katsunori; Nei, Daisuke; Isshiki, Kenji

    2011-01-01

    We examined the content protection characteristics of the PID (Pouch in Dispenser) when it was used in the usual manner and when it was polluted artificially. When the PID was used in the usual manner, the nozzle was opened, and experiments were carried out with and without air-blowing. The invasion of bacteria into the PID was not detected. Also, no bacteria were detected in the material poured from the nozzle of the PID. When 3 strains of bacteria suspensions were intentionally smeared on the nozzle of the PID, invasion of bacteria was observed. When the PID was wiped with a dirty cloth, no invasion of bacteria into the PID was detected. It may be necessary to label the PID with the instruction that the nozzle should not be touched. The effected of changes in the water activity and pH, and the preservatives used, may also need to be considered, depending on the contents in the PID.

  4. Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency.

    PubMed

    Azizi, G; Abolhassani, H; Kiaee, F; Tavakolinia, N; Rafiemanesh, H; Yazdani, R; Mahdaviani, S A; Mohammadikhajehdehi, S; Tavakol, M; Ziaee, V; Negahdari, B; Mohammadi, J; Mirshafiey, A; Aghamohammadi, A

    2017-07-20

    Common variable immunodeficiency (CVID) is one of the most prevalent symptomatic primary immunodeficiencies (PIDs), which manifests a wide clinical variability such as autoimmunity, as well as T cell and B cell abnormalities. A total of 72 patients with CVID were enrolled in this study. Patients were evaluated for clinical manifestations and classified according to the presence or absence of autoimmune disease. We measured regulatory T cells (Tregs) and B-cell subsets using flow cytometry, as well as specific antibody response (SAR) to pneumococcal vaccine, autoantibodies and anti-IgA in patients. Twenty-nine patients (40.3%) have shown at least one autoimmune manifestation. Autoimmune cytopenias and autoimmune gastrointestinal diseases were the most common. A significant association was detected between autoimmunity and presence of hepatomegaly and splenomegaly. Among CVID patients, 38.5% and 79.3% presented a defect in Tregs and switched memory B-cells, respectively, whereas 69.0% presented CD21(low) B cell expansion. Among patients with a defect in Treg, switched memory and CD21(low) B cell, the frequency of autoimmunity was 80.0%, 52.2% and 55.0%, respectively. A negative correlation was observed between the frequency of Tregs and CD21(low) B cell population. 82.2% of patients had a defective SAR which was associated with the lack of autoantibodies. Autoimmunity may be the first clinical manifestation of CVID, thus routine screening of immunoglobulins is suggested for patients with autoimmunity. Lack of SAR in CVID is associated with the lack of specific autoantibodies in patients with autoimmunity. It is suggested that physicians use alternative diagnostic procedures. Copyright © 2017. Published by Elsevier España, S.L.U.

  5. Clinical characteristics and genetic profiles of 44 patients with severe combined immunodeficiency (SCID): report from Shanghai, China (2004-2011).

    PubMed

    Yao, Chun-Mei; Han, Xiao-Hua; Zhang, Yi-Dan; Zhang, Hui; Jin, Ying-Ying; Cao, Rui-Ming; Wang, Xi; Liu, Quan-Hua; Zhao, Wei; Chen, Tong-Xin

    2013-04-01

    Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.

  6. Sporadic case of warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome.

    PubMed

    Tarzi, Michael D; Jenner, Michael; Hattotuwa, Keith; Faruqi, Asma Z; Diaz, George A; Longhurst, Hilary J

    2005-11-01

    The term WHIM syndrome (WHIMS) is an acronym describing a rare primary immunodeficiency disorder characterized by warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis, the unusual association of neutropenia with bone marrow myeloid hypercellularity. WHIMS was recently associated with mutations in the gene encoding the chemokine receptor CXCR4 and as such is the first disease ascribed to abnormalities of chemokine signaling. We report a sporadic case of WHIMS in a woman presenting with recurrent infections and human papilloma virus-related genital dysplasia.

  7. IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces nonobese diabetic/severe combined immunodeficient engraftment of some acute lymphoblastic leukemia cell lines and primary leukemic samples.

    PubMed

    Piloto, Obdulio; Nguyen, Bao; Huso, David; Kim, Kyu-Tae; Li, Yiwen; Witte, Larry; Hicklin, Daniel J; Brown, Patrick; Small, Donald

    2006-05-01

    The class III receptor tyrosine kinase FLT3 is expressed on the blasts of >90% of patients with B-lineage acute lymphoblastic leukemias (ALL). In addition, it is expressed at extremely high levels in ALL patients with mixed lineage leukemia rearrangements or hyperdiploidy and is sometimes mutated in these same patients. In this report, we investigate the effects of treating ALL cell lines and primary samples with human anti-FLT3 monoclonal antibodies (mAb) capable of preventing binding of FLT3 ligand. In vitro studies, examining the ability of two anti-FLT3 mAbs (IMC-EB10 and IMC-NC7) to affect FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. FLT3 phosphorylation was consistently inhibited by IMC-NC7 treatment, but in some cell lines, IMC-EB10 actually stimulated FLT3 activation, possibly as a result of antibody-mediated receptor dimerization. Through antibody-dependent, cell-mediated cytotoxicity, such an antibody could still prove efficacious against leukemia cells in vivo. In fact, IMC-EB10 treatment significantly prolonged survival and/or reduced engraftment of several ALL cell lines and primary ALL samples in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This occurred even when IMC-EB10 treatment resulted in FLT3 activation in vitro. Moreover, fluorescence-activated cell sorting and PCR analysis of IMC-EB10-treated NOD/SCID mice surviving 150 days post-leukemic cell injection revealed that FLT3 immunotherapy reduced leukemic engraftment below the level of detection in these assays (<0.001%). Furthermore, in vivo IMC-EB10 treatment did not select for resistant cells, because cells surviving IMC-EB10 treatment remain sensitive to IMC-EB10 cytotoxicity upon retransplantation. In vivo studies involving either partial depletion or activation of natural killer (NK) cells show that most of the cytotoxic effect of IMC-EB10 is mediated through NK cells. Therefore, such an antibody, either

  8. Human immunodeficiency virus.

    PubMed

    Skinner, Anita

    2016-11-23

    What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article discussed the importance of human immunodeficiency virus (HIV) testing and diagnosing the condition as early as possible, so that antiretroviral treatment can be initiated and patient outcomes improved.

  9. NeuroPID: a classifier of neuropeptide precursors

    PubMed Central

    Karsenty, Solange; Rappoport, Nadav; Ofer, Dan; Zair, Adva; Linial, Michal

    2014-01-01

    Neuropeptides (NPs) are short secreted peptides produced in neurons. NPs act by activating signaling cascades governing broad functions such as metabolism, sensation and behavior throughout the animal kingdom. NPs are the products of multistep processing of longer proteins, the NP precursors (NPPs). We present NeuroPID (Neuropeptide Precursor Identifier), an online machine-learning tool that identifies metazoan NPPs. NeuroPID was trained on 1418 NPPs annotated as such by UniProtKB. A large number of sequence-based features were extracted for each sequence with the goal of capturing the biophysical and informational-statistical properties that distinguish NPPs from other proteins. Training several machine-learning models, including support vector machines and ensemble decision trees, led to high accuracy (89–94%) and precision (90–93%) in cross-validation tests. For inputs of thousands of unseen sequences, the tool provides a ranked list of high quality predictions based on the results of four machine-learning classifiers. The output reveals many uncharacterized NPPs and secreted cell modulators that are rich in potential cleavage sites. NeuroPID is a discovery and a prediction tool that can be used to identify NPPs from unannotated transcriptomes and mass spectrometry experiments. NeuroPID predicted sequences are attractive targets for investigating behavior, physiology and cell modulation. The NeuroPID web tool is available at http:// neuropid.cs.huji.ac.il. PMID:24792159

  10. Parameters-tuning of PID controller for automatic voltage regulators using the African buffalo optimization

    PubMed Central

    Mohmad Kahar, Mohd Nizam; Noraziah, A.

    2017-01-01

    In this paper, an attempt is made to apply the African Buffalo Optimization (ABO) to tune the parameters of a PID controller for an effective Automatic Voltage Regulator (AVR). Existing metaheuristic tuning methods have been proven to be quite successful but there were observable areas that need improvements especially in terms of the system’s gain overshoot and steady steady state errors. Using the ABO algorithm where each buffalo location in the herd is a candidate solution to the Proportional-Integral-Derivative parameters was very helpful in addressing these two areas of concern. The encouraging results obtained from the simulation of the PID Controller parameters-tuning using the ABO when compared with the performance of Genetic Algorithm PID (GA-PID), Particle-Swarm Optimization PID (PSO-PID), Ant Colony Optimization PID (ACO-PID), PID, Bacteria-Foraging Optimization PID (BFO-PID) etc makes ABO-PID a good addition to solving PID Controller tuning problems using metaheuristics. PMID:28441390

  11. Pattern recognition and PID procedure with the ALICE-HMPID

    NASA Astrophysics Data System (ADS)

    Volpe, Giacomo

    2014-12-01

    The ALICE apparatus is dedicated to the study of pp, p-Pb and Pb-Pb collisions provided by LHC. ALICE has unique particle identification (PID) capabilities among the LHC experiments exploiting different PID techniques, i.e., energy loss, time-of-flight measurements, Cherenkov and transition radiation detection, calorimetry and topological ID. The ALICE-HMPID is devoted to the identification of charged hadrons. It consists of seven identical RICH counters, with liquid C6F14 as Cherenkov radiator (n≈1.299 at λph=175 nm). Photons and charged particles detection is performed by a proportional chamber, coupled with a pad segmented CsI coated photo-cathode. In pp and p-Pb events HMPID provides 3 sigmas separation for pions and kaons up to pT = 3 GeV / c and for protons up to pT = 5 GeV / c. PID is performed by means of photon emission angle measurement, a challenging task in the high multiplicity environment of the most central Pb-Pb collisions. A dedicated algorithm has been implemented to evaluate the Cherenkov angle starting from the bi-dimensional ring pattern on the photons detector, it is based on the Hough Transform Method (HTM) to separate signal from background. In this way HMPID is able to contribute to inclusive hadrons spectra measurement as well as to measurements where high purity PID is required, by means of statistical or track-by-track PID. The pattern recognition, the results from angular resolution studies and the PID strategy with HMPID are presented.

  12. Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency.

    PubMed

    Lee, Wen-I; Huang, Jing-Long; Chen, Chien-Chang; Lin, Ju-Li; Wu, Ren-Chin; Jaing, Tang-Her; Ou, Liang-Shiou

    2016-03-01

    Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs). Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study. Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs*2; heterozygous Y1169Ter and InsA1143, Fs*3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot-spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis. Patients of all ethnicities with SD/THE with the characteristic

  13. AIDS: acquired immunodeficiency syndrome.

    PubMed Central

    Gilmore, N. J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1983-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of utmost importance. PMID:6342737

  14. AIDS: acquired immunodeficiency syndrome *

    PubMed Central

    Gilmore, N.J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1992-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of the utmost importance. PMID:1544049

  15. Chronic inflammatory demyelinating polyneuropathy in common variable immunodeficiency.

    PubMed

    Özdemir, Özlem; Okan, Mehmet S; Kilic, Sara S

    2012-04-01

    Common variable immunodeficiency comprises a heterogeneous group of primary antibody deficiencies with complex clinical and immunologic phenotypes. Immune dysregulation leads to the generation of multiple autoantibodies against various antigenic targets in patients with common variable immunodeficiency. Chronic inflammatory demyelinating polyneuropathy is a heterogeneous disorder that indicates an autoimmune response against peripheral nerve myelin. We describe a 7-year-old girl with common variable immunodeficiency who developed chronic inflammatory polyneuropathy. A 5-day course of intravenous immunoglobulin (500 mg/kg/day) improved her neurologic disorder. Chronic inflammatory demyelinating polyneuropathy should be added to the broadening spectrum of neurologic complications in common variable immunodeficiency. Early detection and consequent treatment may reverse the neurologic sequelae.

  16. Recent advances in primary and acquired immunodeficiencies

    SciTech Connect

    Aiuti F.; Rosen, F.; Cooper, M.D.

    1986-01-01

    This book contains 38 selections. Some of the titles are: A new, X-chromosomal gene family (XLR) expressed in mature lymphoid cells; Molecular genetic analysis of T-cell antigen and Interleukin-32 receptors on normal and leukemic lymphocytes; Cogenital agammaglobulinaemia associated with malabsorption: no expression of MHC-class-II-antigens due to a regulatory gene defect; and DNA-mediated gene transfer into Ataxia-Telangiectasia cells.

  17. Gene therapy for primary immunodeficiencies: Part 1.

    PubMed

    Cavazzana-Calvo, Marina; Fischer, Alain; Hacein-Bey-Abina, Salima; Aiuti, Alessandro

    2012-10-01

    Over 60 patients affected by SCID due to IL2RG deficiency (SCID-X1) or adenosine deaminase (ADA)-SCID have received hematopoietic stem cell gene therapy in the past 15 years using gammaretroviral vectors, resulting in immune reconstitution and clinical benefit in the majority of them. However, the occurrence of insertional oncogenesis in the SCID-X1 trials has led to the development of new clinical trials based on integrating vectors with improved safety design as well as investigation on new technologies for highly efficient gene targeting and site-specific gene editing. Here we will present the experience and perspectives of gene therapy for SCID-X1 and ADA-SCID and discuss the pros and cons of gene therapy in comparison to allogeneic transplantation.

  18. [Radiographic changes in children with primary immunodeficiency].

    PubMed

    González-Uribe, Víctor; Pietropaolo-Cienfuegos, Dino Roberto; Del Río-Navarro, Blanca Estela; Del Río-Chivardi, Jaime Mariano; Sienra-Monge, Juan José Luis

    2015-01-01

    Antecedentes: si bien se cuenta con información epidemiológica de las inmunodeficiencias primarias, la información disponible en México es escasa. Objetivos: dar información epidemiológica del retraso del diagnóstico de las inmunodeficiencias primarias y de su correlación con daño pulmonar crónico. Material y método: estudio retrospectivo, analítico, efectuado en pacientes de 0 a 18 años de edad con diagnóstico de inmunodeficiencias primarias durante 11 años en el Hospital Infantil de México Federico Gómez; las variables estudiadas fueron: edad al inicio de los síntomas, edad al diagnóstico, tiempo desde el inicio de los síntomas al diagnóstico, número de neumonías previas y estudios radiográficos con datos de daño pulmonar crónico. Resultados: se incluyeron 48 pacientes que cumplieron los criterios de inclusión; 33 tenían daño pulmonar al diagnóstico, el déficit de anticuerpos fue el grupo con mayor afectación. Al correlacionar la edad de inicio de los síntomas y la diferencia de tiempo del inicio de los síntomas al diagnóstico se obtuvo una fuerte correlación (p <0.001, Rho > 0.80). Se observó una correlación moderada entre la diferencia en tiempo vs número de neumonías (p=0.005, Rho=0.495) y la correlación entre número de neumonías y daño pulmonar mostró significación alta (p <0.001, Rho=0.704). Conclusión: se encontró una relación estrecha entre el tiempo transcurrido desde el inicio de los síntomas y el número de neumonías con el daño pulmonar, por lo que las neumonías de repetición (más de dos) deben hacer sospechar el diagnóstico de inmunodeficiencia primaria, como se recomienda en la bibliografía mundial.

  19. Noninfectious Granulomas: A Sign of an Underlying Immunodeficiency?

    PubMed

    Shoimer, Ilya; Wright, Nicola; Haber, Richard M

    2016-05-01

    Primary immunodeficiency disorders, such as ataxia-telangiectasia (A-T), may rarely be associated with cutaneous granulomas without an identifiable infection. The authors report a case of a 3-year-old boy with A-T who presented with two persistent ulcerated erythematous nodules. Histopathology was consistent with a granulomatous process secondary to A-T, without an infectious origin. Partial improvement was noted with clobetasol propionate 0.05% cream applied twice daily under occlusion. Of note, the presence of multiple noninfectious granulomas in a child may be the initial sign of an immune deficiency and should alert the astute clinician to investigate for an underlying primary immunodeficiency. Herein, the authors discuss the associations of noninfectious granulomas and primary immunodeficiency disorders and present management options for these difficult-to-treat lesions.

  20. Advanced PID type fuzzy logic power system stabilizer

    SciTech Connect

    Hiyama, Takashi; Kugimiya, Masahiko; Satoh, Hironori . Dept. of Electrical Engineering and Computer Science)

    1994-09-01

    An advanced fuzzy logic control scheme has been proposed for a micro-computer based power system stabilizer to enhance the overall stability of power systems. The proposed control scheme utilizes the PID information of the generator speed. The input signal to the stabilizer is the real power output of a study unit. Simulations show the effectiveness of the advanced fuzzy logic control scheme.

  1. Design of a PID Controller for a PCR Micro Reactor

    ERIC Educational Resources Information Center

    Dinca, M. P.; Gheorghe, M.; Galvin, P.

    2009-01-01

    Proportional-integral-derivative (PID) controllers are widely used in process control, and consequently they are described in most of the textbooks on automatic control. However, rather than presenting the overall design process, the examples given in such textbooks are intended to illuminate specific focused aspects of selection, tuning and…

  2. Bidimensional MRI-based navigation system using a PID controller.

    PubMed

    Tamaz, Samer; Gourdeau, Richard; Martel, Sylvain

    2006-01-01

    The feasibility of using 2D real-time control to navigate ferromagnetic entities in an MRI bore for novel medical interventions is assessed. Preliminary experimental results confirm that a simple PID controller can be suitable for several applications where targeting out-of-reach locations within the cardiovascular system is essential.

  3. Design of a PID Controller for a PCR Micro Reactor

    ERIC Educational Resources Information Center

    Dinca, M. P.; Gheorghe, M.; Galvin, P.

    2009-01-01

    Proportional-integral-derivative (PID) controllers are widely used in process control, and consequently they are described in most of the textbooks on automatic control. However, rather than presenting the overall design process, the examples given in such textbooks are intended to illuminate specific focused aspects of selection, tuning and…

  4. All About PID - Testing and Avoidance in the Field

    SciTech Connect

    Hacke, Peter; Johnston, Steve

    2016-09-01

    Potential-induced degradation can cause significant power loss in modules if the appropriate precautions are not taken. In the first part of a new series in PV Tech Power on module failure, Peter Hacke and Steve Johnston assess the current state-of-the-art in detecting, avoiding and mitigating the worst effects of PID.

  5. Comparative analysis of PSO algorithms for PID controller tuning

    NASA Astrophysics Data System (ADS)

    Štimac, Goranka; Braut, Sanjin; Žigulić, Roberto

    2014-09-01

    The active magnetic bearing(AMB) suspends the rotating shaft and maintains it in levitated position by applying controlled electromagnetic forces on the rotor in radial and axial directions. Although the development of various control methods is rapid, PID control strategy is still the most widely used control strategy in many applications, including AMBs. In order to tune PID controller, a particle swarm optimization(PSO) method is applied. Therefore, a comparative analysis of particle swarm optimization(PSO) algorithms is carried out, where two PSO algorithms, namely (1) PSO with linearly decreasing inertia weight(LDW-PSO), and (2) PSO algorithm with constriction factor approach(CFA-PSO), are independently tested for different PID structures. The computer simulations are carried out with the aim of minimizing the objective function defined as the integral of time multiplied by the absolute value of error(ITAE). In order to validate the performance of the analyzed PSO algorithms, one-axis and two-axis radial rotor/active magnetic bearing systems are examined. The results show that PSO algorithms are effective and easily implemented methods, providing stable convergence and good computational efficiency of different PID structures for the rotor/AMB systems. Moreover, the PSO algorithms prove to be easily used for controller tuning in case of both SISO and MIMO system, which consider the system delay and the interference among the horizontal and vertical rotor axes.

  6. Organising pneumonia in common variable immunodeficiency

    PubMed Central

    Boujaoude, Ziad; Arya, Rohan; Rafferty, William; Dammert, Pedro

    2013-01-01

    Common variable immunodeficiency (CVID) is the most common of the primary immunodeficiency disorders. Pulmonary manifestations are characterised by recurrent rhinosinusitis, respiratory tract infections and bronchiectasis. Less commonly the lung may be affected by lymphoid disorders and sarcoid-like granulomas. Organising pneumonia (OP) is a rare pulmonary manifestation. We report the case of a 32-year-old woman with CVID who presented with fever, dyspnoea and persistent lung infiltrates despite antibiotic therapy. CT of the chest showed bilateral patchy alveolar infiltrates. Pulmonary function tests revealed moderate restriction and reduction in diffusion capacity. Initial bronchoscopy with transbronchial biopsies did not yield a diagnosis but surgical lung biopsies identified OP. Significant clinical, radiographic and physiological improvement was achieved after institution of corticosteroid therapy. PMID:23749855

  7. Organising pneumonia in common variable immunodeficiency.

    PubMed

    Boujaoude, Ziad; Arya, Rohan; Rafferty, William; Dammert, Pedro

    2013-06-07

    Common variable immunodeficiency (CVID) is the most common of the primary immunodeficiency disorders. Pulmonary manifestations are characterised by recurrent rhinosinusitis, respiratory tract infections and bronchiectasis. Less commonly the lung may be affected by lymphoid disorders and sarcoid-like granulomas. Organising pneumonia (OP) is a rare pulmonary manifestation. We report the case of a 32-year-old woman with CVID who presented with fever, dyspnoea and persistent lung infiltrates despite antibiotic therapy. CT of the chest showed bilateral patchy alveolar infiltrates. Pulmonary function tests revealed moderate restriction and reduction in diffusion capacity. Initial bronchoscopy with transbronchial biopsies did not yield a diagnosis but surgical lung biopsies identified OP. Significant clinical, radiographic and physiological improvement was achieved after institution of corticosteroid therapy.

  8. Increased Sensitivity to CD4 Binding Site-Directed Neutralization following In Vitro Propagation on Primary Lymphocytes of a Neutralization-Resistant Human Immunodeficiency Virus IIIB Strain Isolated from an Accidentally Infected Laboratory Worker

    PubMed Central

    Beaumont, Tim; Quakkelaar, Esther; van Nuenen, Ad; Pantophlet, Ralph; Schuitemaker, Hanneke

    2004-01-01

    We previously described the adaptation of the neutralization-sensitive human immunodeficiency virus type 1 (HIV-1) strain IIIB to a neutralization-resistant phenotype in an accidentally infected laboratory worker. During long-term propagation of this resistant isolate, designated FF3346, on primary peripheral blood leukocytes in vitro, an HIV-1 variant appeared that had regained sensitivity to neutralization by soluble CD4 (sCD4) and the broadly neutralizing monoclonal antibody b12. When an early passage of FF3346 was subjected to limiting-dilution culture in peripheral blood mononuclear cells, eight virus variants with various degrees of neutralization resistance were isolated. Two of them, the sCD4 neutralization-resistant variant LW_H8res and the sCD4 neutralization-sensitive variant LW_G9sens, were selected for further study. Interestingly, these two viruses were equally resistant to neutralization by agents that recognize domains other than the CD4 binding site. Site-directed mutagenesis revealed that the increased neutralization sensitivity of variant LW_G9sens resulted from only two changes, an Asn-to-Ser substitution at position 164 in the V2 loop and an Ala-to-Glu substitution at position 370 in the C3 domain of gp120. In agreement with this notion, the affinity of b12 for monomeric gp120 containing the N164S and A370E substitutions in the background of the molecular clone LW_H8res was higher than its affinity for the parental gp120. Surprisingly, no correlation was observed between CD4 binding affinity for monomeric gp120 and the level of neutralization resistance, suggesting that differences in sCD4 neutralization sensitivity between these viruses are only manifested in the context of the tertiary or quaternary structure of gp120 on the viral surface. The results obtained here indicate that the neutralization-sensitive strain IIIB can become neutralization resistant in vivo under selective pressure by neutralizing antibodies but that this resistance may

  9. Design and implementation of a 2-DOF PID compensation for magnetic levitation systems.

    PubMed

    Ghosh, Arun; Rakesh Krishnan, T; Tejaswy, Pailla; Mandal, Abhisek; Pradhan, Jatin K; Ranasingh, Subhakant

    2014-07-01

    This paper employs a 2-DOF (degree of freedom) PID controller for compensating a physical magnetic levitation system. It is shown that because of having a feedforward gain in the proposed 2-DOF PID control, the transient performance of the compensated system can be changed in a desired manner unlike the conventional 1-DOF PID control. It is also shown that for a choice of PID parameters, although the theoretical loop robustness is the same for both the compensated systems, in real-time, 2-DOF PID control may provide superior robustness if a suitable choice of the feedforward parameter is made. The results are verified through simulations and experiments.

  10. A Novel Technique for Performing PID Susceptibility Screening during the Solar Cell Fabrication Process

    SciTech Connect

    Oh, Jaewon; Dahal, Som; Dauksher, Bill; Bowden, Stuart; Tamizhmani, Govindasamy; Hacke, Peter

    2016-11-21

    Various characterization techniques have historically been developed in order to screen potential induced degradation (PID)-susceptible cells, but those techniques require final solar cells. We present a new characterization technique for screening PID-susceptible cells during the cell fabrication process. Illuminated Lock-In Thermography (ILIT) was used to image PID shunting of the cell without metallization and clearly showed PID-affected areas. PID-susceptible cells can be screened by ILIT, and the sample structure can advantageously be simplified as long as the sample has the silicon nitride antireflection coating and an aluminum back surface field.

  11. Hybrid PID and PSO-based control for electric power assist steering system for electric vehicle

    NASA Astrophysics Data System (ADS)

    Hanifah, R. A.; Toha, S. F.; Ahmad, S.

    2013-12-01

    Electric power assist steering (EPAS) system provides an important significance in enhancing the driving performance of a vehicle with its energy-conserving features. This paper presents a hybrid PID (Proportional-Integral-Derivative) and particle swarm optimization (PSO) based control scheme to minimize energy consumption for EPAS. This single objective optimization scheme is realized using the PSO technique in searching for best gain parameters of the PID controller. The fast tuning feature of this optimum PID controller produced high-quality solutions. Simulation results show the performance and effectiveness of the hybrid PSO-PID based controller as opposed to the conventional PID controller.

  12. Thermostatic system of sensor in NIR spectrometer based on PID control

    NASA Astrophysics Data System (ADS)

    Wang, Zhihong; Qiao, Liwei; Ji, Xufei

    2016-11-01

    Aiming at the shortcomings of the primary sensor thermostatic control system in the near infrared (NIR) spectrometer, a novel thermostatic control system based on proportional-integral-derivative (PID) control technology was developed to improve the detection precision of the NIR spectrometer. There were five parts including bridge amplifier circuit, analog-digital conversion (ADC) circuit, microcontroller, digital-analog conversion (DAC) circuit and drive circuit in the system. The five parts formed a closed-loop control system based on PID algorithm that was used to control the error between the temperature calculated by the sampling data of ADC and the designed temperature to ensure the stability of the spectrometer's sensor. The experimental results show that, when the operating temperature of sensor is -11°, compared with the original system, the temperature control precision of the new control system is improved from ±0.64° to ±0.04° and the spectrum signal to noise ratio (SNR) is improved from 4891 to 5967.

  13. Neural PID Control of Robot Manipulators With Application to an Upper Limb Exoskeleton.

    PubMed

    Yu, Wen; Rosen, Jacob

    2013-04-01

    In order to minimize steady-state error with respect to uncertainties in robot control, proportional-integral-derivative (PID) control needs a big integral gain, or a neural compensator is added to the classical proportional-derivative (PD) control with a large derivative gain. Both of them deteriorate transient performances of the robot control. In this paper, we extend the popular neural PD control into neural PID control. This novel control is a natural combination of industrial linear PID control and neural compensation. The main contributions of this paper are semiglobal asymptotic stability of the neural PID control and local asymptotic stability of the neural PID control with a velocity observer which are proved with standard weight training algorithms. These conditions give explicit selection methods for the gains of the linear PID control. An experimental study on an upper limb exoskeleton with this neural PID control is addressed.

  14. PID: from material properties to outdoor performance and quality control counter measures

    NASA Astrophysics Data System (ADS)

    Berghold, J.; Koch, S.; Pingel, S.; Janke, S.; Ukar, A.; Grunow, P.; Shioda, T.

    2015-09-01

    Although the main root causes and referring counter measures for PID are known, a significant part of the industrial modules are still found to be PID sensitive in testing and PID is increasingly evident in field. This paper discusses field occurrence of PID with respect to environmental conditions and material properties. Different PID pattern in field and in test are analyzed in terms of the potential distribution and surface conductivity. Examples are given for the correlation of PID lab tests of a (commercial) BOM with real outdoor degradation. PID progress is predicted for different locations and compared with measurement data. Suitable quality control measures are discussed for the modules as well as for the encapsulation material

  15. Two degree of freedom PID based inferential control of continuous bioreactor for ethanol production.

    PubMed

    Pachauri, Nikhil; Singh, Vijander; Rani, Asha

    2017-05-01

    This article presents the development of inferential control scheme based on Adaptive linear neural network (ADALINE) soft sensor for the control of fermentation process. The ethanol concentration of bioreactor is estimated from temperature profile of the process using soft sensor. The prediction accuracy of ADALINE is enhanced by retraining it with immediate past measurements. The ADALINE and retrained ADALINE are used along with PID and 2-DOF-PID leading to APID, A2PID, RAPID and RA2PID inferential controllers. Further the parameters of 2-DOF-PID are optimized using Non-dominated sorted genetic algorithm-II and used with retrained ADALINE soft sensor which leads to RAN2PID inferential controller. Simulation results demonstrate that performance of proposed RAN2PID controller is better in comparison to other designed controllers in terms of qualitative and quantitative performance indices. Copyright © 2017 ISA. Published by Elsevier Ltd. All rights reserved.

  16. [Chronic myeloid leukemia in an adult with common variable immunodeficiency].

    PubMed

    O'Farrill-Romanillos, Patricia María; Galindo-Pacheco, Lucy Vania; Amaya-Mejía, Adela Sisy; Campos-Romero, Freya Helena; Mendoza-Reyna, Laura Dafne; Pérez-Rocha, Fernando; Segura-Méndez, Nora Hilda

    2014-01-01

    Common variable immunodeficiency is a primary immunodeficiency, in which from 70 to 80 % of patients have tumors and 25 % of cases are associated with autoimmune diseases. Common variable immunodeficiency patients have a higher incidence of neoplasms, with a risk 12-18 times higher than the general population. There are few cases of common variable immunodeficiency patients with leukemia. Female of 36 years old, with left upper quadrant pain, early satiety, weight loss of 8 kg in three months and splenomegaly. The complete blood count showed: leukocytosis 206 000/mL, with 8 % blasts, platelets 530 000/mL and hemoglobin 8 mg/dL. Abdominal ultrasound: 19??12 cm splenomegaly. Karyotype BCR/ABL IS 64.20 %, 100 % Philadelphia chromosome. The diagnosis was of chronic myeloid leukemia. Given the presence of recurrent respiratory tract infection, frequent diarrheas and reduced concentrations of IgG, IgM and IgA, common variable immunodeficiency was diagnosed and human immunoglobulin was used successfully. The association between chronic myeloid leukemia and common variable immunodefficiency is unusual. Given the high frequency of hematological neoplasm in common variable immunodeficiency patients, we suggest that hematological patients with repeated infections and decreased concentrations of immunoglobulin be referred to an immunological evaluation.

  17. Immunodeficiency and autoimmune enterocolopathy linked to NFAT5 haploinsufficiency.

    PubMed

    Boland, Brigid S; Widjaja, Christella E; Banno, Asoka; Zhang, Bing; Kim, Stephanie H; Stoven, Samantha; Peterson, Michael R; Jones, Marilyn C; Su, H Irene; Crowe, Sheila E; Bui, Jack D; Ho, Samuel B; Okugawa, Yoshinaga; Goel, Ajay; Marietta, Eric V; Khosroheidari, Mahdieh; Jepsen, Kristen; Aramburu, Jose; López-Rodríguez, Cristina; Sandborn, William J; Murray, Joseph A; Harismendy, Olivier; Chang, John T

    2015-03-15

    The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

  18. Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency

    PubMed Central

    Boland, Brigid S.; Widjaja, Christella E.; Banno, Asoka; Zhang, Bing; Kim, Stephanie H.; Stoven, Samantha; Peterson, Michael R.; Jones, Marilyn C.; Su, H. Irene; Crowe, Sheila E.; Bui, Jack D.; Ho, Samuel B.; Okugawa, Yoshinaga; Goel, Ajay; Marietta, Eric V.; Khosroheidari, Mahdieh; Jepsen, Kristen L.; Aramburu, Jose; Lopez-Rodriguez, Cristina; Sandborn, William J.; Murray, Joseph A.; Harismendy, Olivier; Chang, John T.

    2015-01-01

    The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of natural killer (NK) cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency. PMID:25667416

  19. Immunodeficiencies caused by infectious diseases.

    PubMed

    Sykes, Jane E

    2010-05-01

    Immunodeficiencies caused by infectious agents may result from disruption of normal host barriers or dysregulation of cellular immunity, the latter serving to promote survival of the infectious agent through immune evasion. Such infections may be followed by opportunistic infections with a variety of other microorganisms. Classic infectious causes of immunodeficiency in companion animals are the immunodeficiency retroviruses, including feline immunodeficiency virus and feline leukemia virus. Other important causes include canine distemper virus; canine parvovirus 2; feline infectious peritonitis virus; rickettsial organisms that infect leukocytes; Leishmania; and fungal pathogens, such as Cryptococcus. Considerable research effort has been invested in understanding the mechanisms of pathogen-induced immunosuppression, with the hope that effective therapies may be developed that reverse the immunodeficiencies developed and in turn assist the host to clear persistent or life-threatening infectious diseases.

  20. Space Flight Immunodeficiency

    NASA Technical Reports Server (NTRS)

    Shearer, William T.

    1999-01-01

    The National Aeronautics and Space Administration (NASA) has had sufficient concern for the well-being of astronauts traveling in space to create the National Space Biomedical Research Institute (NSBRI), which is investigating several areas of biomedical research including those of immunology. As part of the Immunology, Infection, and Hematology Team, the co-investigators of the Space Flight Immunodeficiency Project began their research projects on April 1, 1998 and are now just into the second year of work. Two areas of research have been targeted: 1) specific immune (especially antibody) responses and 2) non-specific inflammation and adhesion. More precise knowledge of these two areas of research will help elucidate the potential harmful effects of space travel on the immune system, possibly sufficient to create a secondary state of immunodeficiency in astronauts. The results of these experiments are likely to lead to the delineation of functional alterations in antigen presentation, specific immune memory, cytokine regulation of immune responses, cell to cell interactions, and cell to endothelium interactions.

  1. Space Flight Immunodeficiency

    NASA Technical Reports Server (NTRS)

    Shearer, William T.

    1999-01-01

    The National Aeronautics and Space Administration (NASA) has had sufficient concern for the well-being of astronauts traveling in space to create the National Space Biomedical Research Institute (NSBRI), which is investigating several areas of biomedical research including those of immunology. As part of the Immunology, Infection, and Hematology Team, the co-investigators of the Space Flight Immunodeficiency Project began their research projects on April 1, 1998 and are now just into the second year of work. Two areas of research have been targeted: 1) specific immune (especially antibody) responses and 2) non-specific inflammation and adhesion. More precise knowledge of these two areas of research will help elucidate the potential harmful effects of space travel on the immune system, possibly sufficient to create a secondary state of immunodeficiency in astronauts. The results of these experiments are likely to lead to the delineation of functional alterations in antigen presentation, specific immune memory, cytokine regulation of immune responses, cell to cell interactions, and cell to endothelium interactions.

  2. [HIV infection and acquired immunodeficiency syndrome].

    PubMed

    Takamatsu, J

    1997-05-01

    On June 4, 1981, MMWR published a report about Pneumocystis carinii pneumonia in homosexual men in Los Angeles. This was the first published report. A years later, this disease was named acquired immunodeficiency syndrome (AIDS). In the following year, Montangier et al in France discovered the causative agent, which they called lymphadenopathy virus (LAV), now known as human immunodeficiency virus (HIV). In 1985, solid-phase enzymeimmunoassay for the detection of the antibody to HIV was developed. Since then, other new techniques for the identification of HIV infection have been become available. These include more sensitive methods (for example; polymerase chain reaction techniques). Although these techniques facilitate early and definite diagnosis of infection, these tests may fail to detect the antibody in sera during window period of infection or overdiagnose infection in sera contaminated with genes not related to HIV. Although preventing blood exposure is the primary means of preventing occupationally acquired human immunodeficiency virus (HIV) infection, appropriate post-exposure management is an important element of workplace safety. Information suggesting that zidovudine (ZDV) postexposure prophylaxis (PEP) may reduce the risk for HIV transmission after occupational exposure to HIV infected blood prompted a Public Health Service (PHS) interagency working group, with expert consultation, and recommendations on PEP and management of occupational exposure to HIV in relation to these findings were discussed.

  3. T-cell receptor αβ(+) and CD19(+) cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency.

    PubMed

    Shah, Ravi M; Elfeky, Reem; Nademi, Zohreh; Qasim, Waseem; Amrolia, Persis; Chiesa, Robert; Rao, Kanchan; Lucchini, Giovanna; Silva, Juliana M F; Worth, Austen; Barge, Dawn; Ryan, David; Conn, Jane; Cant, Andrew J; Skinner, Roderick; Abd Hamid, Intan Juliana; Flood, Terence; Abinun, Mario; Hambleton, Sophie; Gennery, Andrew R; Veys, Paul; Slatter, Mary

    2017-08-03

    Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants. We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αβ CD3(+) cells from the graft. CD3(+)TCRαβ(+)/CD19(+) depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis. Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%). CD3(+)TCRαβ(+) and CD19(+) cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. All rights reserved.

  4. Pelvic inflammatory disease and salpingitis: incidence of primary and repeat episodes in England.

    PubMed

    Price, M J; Ades, A E; Welton, N J; Simms, I; Horner, P J

    2017-01-01

    Pelvic inflammatory disease (PID) and more specifically salpingitis (visually confirmed inflammation) is the primary cause of tubal factor infertility and is an important risk factor for ectopic pregnancy. The risk of these outcomes increases following repeated episodes of PID. We developed a homogenous discrete-time Markov model for the distribution of PID history in the UK. We used a Bayesian framework to fully propagate parameter uncertainty into the model outputs. We estimated the model parameters from routine data, prospective studies, and other sources. We estimated that for women aged 35-44 years, 33·6% and 16·1% have experienced at least one episode of PID and salpingitis, respectively (diagnosed or not) and 10·7% have experienced one salpingitis and no further PID episodes, 3·7% one salpingitis and one further PID episode, and 1·7% one salpingitis and ⩾2 further PID episodes. Results are consistent with numerous external data sources, but not all. Studies of the proportion of PID that is diagnosed, and the proportion of PIDs that are salpingitis together with the severity distribution in different diagnostic settings and of overlap between routine data sources of PID would be valuable.

  5. Neural Network Based PID Gain Tuning of Chemical Plant Controller

    NASA Astrophysics Data System (ADS)

    Abe, Yoshihiro; Konishi, Masami; Imai, Jun; Hasegawa, Ryusaku; Watanabe, Masamori; Kamijo, Hiroaki

    In these years, plant control systems are highly automated and applied to many industries. The control performances change with the passage of time, because of the deterioration of plant facilities. This is why human experts tune the control system to improve the total plant performances. In this study, PID control system for the oil refining chemical plant process is treated. In oil refining, there are thousands of the control loops in the plant to keep the product quality at the desired value and to secure the safety of the plant operation. According to the ambiguity of the interference between control loops, it is difficult to estimate the plant dynamical model accurately. Using neuro emulator and recurrent neural networks model (RNN model) for emulation and tuning parameters, PID gain tuning system of chemical plant controller is constructed. Through numerical experiments using actual plant data, effect of the proposed method was ascertained.

  6. An improved PID switching control strategy for type 1 diabetes.

    PubMed

    Marchetti, Gianni; Barolo, Massimiliano; Jovanovic, Lois; Zisser, Howard; Seborg, Dale E

    2006-01-01

    In order for an "artificial pancreas" to become a reality for ambulatory use, a practical closed-loop control strategy must be developed and critically evaluated. In this paper, an improved PID control strategy for blood glucose control is proposed and evaluated in silico using a physiologic model of Hovorka et al. The key features of the proposed control strategy are: (i) a switching strategy for initiating PID control after a meal and insulin bolus; (ii) a novel time-varying setpoint trajectory, (iii) noise and derivative filters to reduce sensitivity to sensor noise, and (iv) a systematic controller tuning strategy. Simulation results demonstrate that the proposed control strategy compares favorably to alternatives for realistic conditions that include meal challenges, incorrect carbohydrate meal estimates, changes in insulin sensitivity, and measurement noise.

  7. Two-level tuning of fuzzy PID controllers.

    PubMed

    Mann, G I; Hu, B G; Gosine, R G

    2001-01-01

    Fuzzy PID tuning requires two stages of tuning; low level tuning followed by high level tuning. At the higher level, a nonlinear tuning is performed to determine the nonlinear characteristics of the fuzzy output. At the lower level, a linear tuning is performed to determine the linear characteristics of the fuzzy output for achieving overall performance of fuzzy control. First, different fuzzy systems are defined and then simplified for two-point control. Non-linearity tuning diagrams are constructed for fuzzy systems in order to perform high level tuning. The linear tuning parameters are deduced from the conventional PID tuning knowledge. Using the tuning diagrams, high level tuning heuristics are developed. Finally, different applications are demonstrated to show the validity of the proposed tuning method.

  8. An improved PID switching control strategy for type 1 diabetes.

    PubMed

    Marchetti, Gianni; Barolo, Massimiliano; Jovanovic, Lois; Zisser, Howard; Seborg, Dale E

    2008-03-01

    In order for an "artificial pancreas" to become a reality for ambulatory use, a practical closed-loop control strategy must be developed and validated. In this paper, an improved PID control strategy for blood glucose control is proposed and critically evaluated in silico using a physiologic model of Hovorka et al. [1]. The key features of the proposed control strategy are: 1) a switching strategy for initiating PID control after a meal and insulin bolus; 2) a novel time-varying setpoint trajectory; 3) noise and derivative filters to reduce sensitivity to sensor noise; and 4) a practical controller tuning strategy. Simulation results demonstrate that proposed control strategy compares favorably to alternatives for realistic conditions that include meal challenges, incorrect carbohydrate meal estimates, changes in insulin sensitivity, and measurement noise.

  9. Experimental results from a network-assisted PID controller

    SciTech Connect

    Curtiss, P.S.

    1996-11-01

    The results presented here are a continuation of studies on a neural-network-based controller. Part 1 is a summary of the previous studies, and Part 2 presents new results and offers some novel techniques used for training the network and making the entire package easier to use. The two major additions are (1) efficient use of training data for dramatically reducing memory requirements and (2) incorporation of a PID algorithm for performing control during training periods.

  10. Tuning of PID controllers for boiler-turbine units.

    PubMed

    Tan, Wen; Liu, Jizhen; Fang, Fang; Chen, Yanqiao

    2004-10-01

    A simple two-by-two model for a boiler-turbine unit is demonstrated in this paper. The model can capture the essential dynamics of a unit. The design of a coordinated controller is discussed based on this model. A PID control structure is derived, and a tuning procedure is proposed. The examples show that the method is easy to apply and can achieve acceptable performance.

  11. Adaptive PID control based on orthogonal endocrine neural networks.

    PubMed

    Milovanović, Miroslav B; Antić, Dragan S; Milojković, Marko T; Nikolić, Saša S; Perić, Staniša Lj; Spasić, Miodrag D

    2016-12-01

    A new intelligent hybrid structure used for online tuning of a PID controller is proposed in this paper. The structure is based on two adaptive neural networks, both with built-in Chebyshev orthogonal polynomials. First substructure network is a regular orthogonal neural network with implemented artificial endocrine factor (OENN), in the form of environmental stimuli, to its weights. It is used for approximation of control signals and for processing system deviation/disturbance signals which are introduced in the form of environmental stimuli. The output values of OENN are used to calculate artificial environmental stimuli (AES), which represent required adaptation measure of a second network-orthogonal endocrine adaptive neuro-fuzzy inference system (OEANFIS). OEANFIS is used to process control, output and error signals of a system and to generate adjustable values of proportional, derivative, and integral parameters, used for online tuning of a PID controller. The developed structure is experimentally tested on a laboratory model of the 3D crane system in terms of analysing tracking performances and deviation signals (error signals) of a payload. OENN-OEANFIS performances are compared with traditional PID and 6 intelligent PID type controllers. Tracking performance comparisons (in transient and steady-state period) showed that the proposed adaptive controller possesses performances within the range of other tested controllers. The main contribution of OENN-OEANFIS structure is significant minimization of deviation signals (17%-79%) compared to other controllers. It is recommended to exploit it when dealing with a highly nonlinear system which operates in the presence of undesirable disturbances.

  12. Empirically characteristic analysis of chaotic PID controlling particle swarm optimization.

    PubMed

    Yan, Danping; Lu, Yongzhong; Zhou, Min; Chen, Shiping; Levy, David

    2017-01-01

    Since chaos systems generally have the intrinsic properties of sensitivity to initial conditions, topological mixing and density of periodic orbits, they may tactfully use the chaotic ergodic orbits to achieve the global optimum or their better approximation to given cost functions with high probability. During the past decade, they have increasingly received much attention from academic community and industry society throughout the world. To improve the performance of particle swarm optimization (PSO), we herein propose a chaotic proportional integral derivative (PID) controlling PSO algorithm by the hybridization of chaotic logistic dynamics and hierarchical inertia weight. The hierarchical inertia weight coefficients are determined in accordance with the present fitness values of the local best positions so as to adaptively expand the particles' search space. Moreover, the chaotic logistic map is not only used in the substitution of the two random parameters affecting the convergence behavior, but also used in the chaotic local search for the global best position so as to easily avoid the particles' premature behaviors via the whole search space. Thereafter, the convergent analysis of chaotic PID controlling PSO is under deep investigation. Empirical simulation results demonstrate that compared with other several chaotic PSO algorithms like chaotic PSO with the logistic map, chaotic PSO with the tent map and chaotic catfish PSO with the logistic map, chaotic PID controlling PSO exhibits much better search efficiency and quality when solving the optimization problems. Additionally, the parameter estimation of a nonlinear dynamic system also further clarifies its superiority to chaotic catfish PSO, genetic algorithm (GA) and PSO.

  13. Optimal Pid Controller Design Using Adaptive Vurpso Algorithm

    NASA Astrophysics Data System (ADS)

    Zirkohi, Majid Moradi

    2015-04-01

    The purpose of this paper is to improve theVelocity Update Relaxation Particle Swarm Optimization algorithm (VURPSO). The improved algorithm is called Adaptive VURPSO (AVURPSO) algorithm. Then, an optimal design of a Proportional-Integral-Derivative (PID) controller is obtained using the AVURPSO algorithm. An adaptive momentum factor is used to regulate a trade-off between the global and the local exploration abilities in the proposed algorithm. This operation helps the system to reach the optimal solution quickly and saves the computation time. Comparisons on the optimal PID controller design confirm the superiority of AVURPSO algorithm to the optimization algorithms mentioned in this paper namely the VURPSO algorithm, the Ant Colony algorithm, and the conventional approach. Comparisons on the speed of convergence confirm that the proposed algorithm has a faster convergence in a less computation time to yield a global optimum value. The proposed AVURPSO can be used in the diverse areas of optimization problems such as industrial planning, resource allocation, scheduling, decision making, pattern recognition and machine learning. The proposed AVURPSO algorithm is efficiently used to design an optimal PID controller.

  14. PID1 increases chemotherapy-induced apoptosis in medulloblastoma and glioblastoma cells in a manner that involves NFκB.

    PubMed

    Xu, Jingying; Ren, Xiuhai; Pathania, Anup Singh; Fernandez, G Esteban; Tran, Anthony; Zhang, Yifu; Moats, Rex A; Shackleford, Gregory M; Erdreich-Epstein, Anat

    2017-04-11

    Phosphotyrosine Interaction Domain containing 1 (PID1; NYGGF4) inhibits growth of medulloblastoma, glioblastoma and atypical teratoid rhabdoid tumor cell lines. PID1 tumor mRNA levels are highly correlated with longer survival in medulloblastoma and glioma patients, suggesting their tumors may have been more sensitive to therapy. We hypothesized that PID1 sensitizes brain tumors to therapy. We found that PID1 increased the apoptosis induced by cisplatin and etoposide in medulloblastoma and glioblastoma cell lines. PID1 siRNA diminished cisplatin-induced apoptosis, suggesting that PID1 is required for cisplatin-induced apoptosis. Etoposide and cisplatin increased NFκB promoter reporter activity and etoposide induced nuclear translocation of NFκB. Etoposide also increased PID1 promoter reporter activity, PID1 mRNA, and PID1 protein, which were diminished by NFκB inhibitors JSH-23 and Bay117082. However, while cisplatin increased PID1 mRNA, it decreased PID1 protein. This decrease in PID1 protein was mitigated by the proteasome inhibitor, bortezomib, suggesting that cisplatin induced proteasome dependent degradation of PID1. These data demonstrate for the first time that etoposide- and cisplatin-induced apoptosis in medulloblastoma and glioblastoma cell lines is mediated in part by PID1, involves NFκB, and may be regulated by proteasomal degradation. This suggests that PID1 may contribute to responsiveness to chemotherapy.

  15. Feline immunodeficiency virus latency

    PubMed Central

    2013-01-01

    Despite highly effective anti-retroviral therapy, HIV is thought to persist in patients within long-lived cellular reservoirs in the form of a transcriptionally inactive (latent) integrated provirus. Lentiviral latency has therefore come to the forefront of the discussion on the possibility of a cure for HIV infection in humans. Animal models of lentiviral latency provide an essential tool to study mechanisms of latency and therapeutic manipulation. Of the three animal models that have been described, the feline immunodeficiency virus (FIV)-infected cat is the most recent and least characterized. However, several aspects of this model make it attractive for latency research, and it may be complementary to other model systems. This article reviews what is known about FIV latency and chronic FIV infection and how it compares with that of other lentiviruses. It thereby offers a framework for the usefulness of this model in future research aimed at lentiviral eradication. PMID:23829177

  16. An Attitude Control of Flexible Spacecraft Using Fuzzy-PID Controller

    NASA Astrophysics Data System (ADS)

    Park, Jong-Oh; Im, Young-Do

    This primary objective of this study is to demonstrate simulation and ground-based experiment for the attitude control of flexible spacecraft. A typical spacecraft structure consists of the rigid body and flexible appendages which are large flexible solar panels, parabolic antennas built from light materials in order to reduce their weight. Therefore the attitude control has a big problem because these appendages induce structural vibration under the excitation of external forces. A single-axis rotational simulator with a flexible arm is constructed with on-off air thrusters and reaction wheel as actuation. The simulator is also equipped with payload pointing capability by simultaneous thruster and DC servo motor actuation. The experiment of flexible spacecraft attitude control is performed using only the reaction wheel. Using the reaction wheel the performance of the fuzzy-PID controller is illustrated by simulation and experimental results for a single-axis rotational simulator.

  17. Pediatric human immunodeficiency virus and acquired immunodeficiency syndrome: an overview.

    PubMed

    Layton, T L; Davis-McFarland, E

    2000-01-01

    This article covers the epidemiological manifestations of human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) in children, demographic statistics, and information on the three modes of virus transmission. The various opportunistic diseases and neurological dysfunction that characterize pediatric HIV are described. The Center for Disease Control pediatric HIV classification system is presented, and the developmental disorders often found in children with HIV are discussed. The Universal Disease Precautions of the American Speech and Hearing Association (ASHA) for clinicians is also presented.

  18. Comparison of PID and Fuzzy Controller for Position Control of AR.Drone

    NASA Astrophysics Data System (ADS)

    Prayitno, A.; Indrawati, V.; Trusulaw, I. I.

    2017-04-01

    This paper describes the implementation of the PID Controller to control the position of the AR.Drone in the x-y-z. This position control scheme uses three PID controllers to maintain the position of x, y and z using the signal control pitch, roll and vertical rate. PID Controller implemented on AR.Drone 2.0 and then tested in an indoor space. The performance of the controller will be compared with Fuzzy Logic Controller schemes that have been implemented previously. The results show that the PID Controller generate a response with rise time less than 3 seconds at the x and y position with around 25% overshoot. The result for z position give better result without overshoot. The comparison between fuzzy logic and PID Controller indicates that the results of the PID controller is better although there is overshoot.

  19. PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas.

    PubMed

    Erdreich-Epstein, Anat; Robison, Nathan; Ren, Xiuhai; Zhou, Hong; Xu, Jingying; Davidson, Tom B; Schur, Mathew; Gilles, Floyd H; Ji, Lingyun; Malvar, Jemily; Shackleford, Gregory M; Margol, Ashley S; Krieger, Mark D; Judkins, Alexander R; Jones, David T W; Pfister, Stefan M; Kool, Marcel; Sposto, Richard; Asgharzadeh, Shahab; Asgharazadeh, Shahab

    2014-02-15

    We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets, PID1 mRNA was lower in glioblastomas (GBM), the most malignant gliomas, compared with other astrocytomas, oligodendrogliomas and nontumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared with classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients whose tumors had higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in patients with glioma and GBM. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolaization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT, and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization. These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors. ©2013 AACR

  20. PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas

    PubMed Central

    Erdreich-Epstein, Anat; Robison, Nathan; Ren, Xiuhai; Zhou, Hong; Xu, Jingying; Davidson, Tom B.; Schur, Mathew; Gilles, Floyd H.; Ji, Lingyun; Malvar, Jemily; Shackleford, Gregory M.; Margol, Ashley S.; Krieger, Mark D.; Judkins, Alexander R.; Jones, David T.W.; Pfister, Stefan; Kool, Marcel; Sposto, Richard; Asgharazadeh, Shahab

    2014-01-01

    Purpose We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. Experimental Design and Results Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (Groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets PID1 mRNA was lower in glioblastomas (GBMs), the most malignant gliomas, compared to other astrocytomas, oligodendrogliomas and non-tumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared to classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients with higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in glioma and GBM patients. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT) and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolarization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization. Conclusions These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors. PMID:24300787

  1. Mutation particle swarm optimization of the BP-PID controller for piezoelectric ceramics

    NASA Astrophysics Data System (ADS)

    Zheng, Huaqing; Jiang, Minlan

    2016-01-01

    PID control is the most common used method in industrial control because its structure is simple and it is easy to implement. PID controller has good control effect, now it has been widely used. However, PID method has a few limitations. The overshoot of the PID controller is very big. The adjustment time is long. When the parameters of controlled plant are changing over time, the parameters of controller could hardly change automatically to adjust to changing environment. Thus, it can't meet the demand of control quality in the process of controlling piezoelectric ceramic. In order to effectively control the piezoelectric ceramic and improve the control accuracy, this paper replaced the learning algorithm of the BP with the mutation particle swarm optimization algorithm(MPSO) on the process of the parameters setting of BP-PID. That designed a better self-adaptive controller which is combing the BP neural network based on mutation particle swarm optimization with the conventional PID control theory. This combination is called the MPSO-BP-PID. In the mechanism of the MPSO, the mutation operation is carried out with the fitness variance and the global best fitness value as the standard. That can overcome the precocious of the PSO and strengthen its global search ability. As a result, the MPSO-BP-PID can complete controlling the controlled plant with higher speed and accuracy. Therefore, the MPSO-BP-PID is applied to the piezoelectric ceramic. It can effectively overcome the hysteresis, nonlinearity of the piezoelectric ceramic. In the experiment, compared with BP-PID and PSO-BP-PID, it proved that MPSO is effective and the MPSO-BP-PID has stronger adaptability and robustness.

  2. Late Onset Combined Immunodeficiency Presenting with Recurrent Pneumocystis jiroveci Pneumonia

    PubMed Central

    Baraboutis, Ioannis G.; Karnesis, Lazaros

    2014-01-01

    Late onset combined immunodeficiency (LOCID) is a recently described variant of common variable immunodeficiency (CVID), involving adult patients presenting with opportunistic infections and/or low CD4+ lymphocyte counts. A 36-year-old male with unremarkable past medical history presented with fever, respiratory failure, and lymphocytopenia. He was found to have Pneumocystis jiroveci pneumonia (PJP), subsequently complicated by recurrent hospital-acquired Pseudomonas aeruginosa pneumonia and immune reconstitution phenomena, attributed to restoration of immunoglobulin levels. Clinicians should be aware of LOCID, which could be confused with HIV infection/AIDS or idiopathic CD4 lymphocytopenia. In the English bibliography there is only one case report, where PJP was the initial presentation of CVID (that case would probably be classified as LOCID). Phenomena of immune reconstitution are described in various settings, including primary immunodeficiency, manifesting as temporary clinical and radiologic deterioration and leading to misperceptions of therapeutic failure and/or presence of alternative/additional diagnoses. PMID:24799913

  3. Fuzzy PID control algorithm based on PSO and application in BLDC motor

    NASA Astrophysics Data System (ADS)

    Lin, Sen; Wang, Guanglong

    2017-06-01

    A fuzzy PID control algorithm is studied based on improved particle swarm optimization (PSO) to perform Brushless DC (BLDC) motor control which has high accuracy, good anti-jamming capability and steady state accuracy compared with traditional PID control. The mathematical and simulation model is established for BLDC motor by simulink software, and the speed loop of the fuzzy PID controller is designed. The simulation results show that the fuzzy PID control algorithm based on PSO has higher stability, high control precision and faster dynamic response speed.

  4. Fuzzy Auto-adjust PID Controller Design of Brushless DC Motor

    NASA Astrophysics Data System (ADS)

    Yuanxi, Wang; Yali, Yu; Guosheng, Zhang; Xiaoliang, Sheng

    Using conventional PID control method, to guarantee the rapidity and small overshoot dynamic and static performance of the BLDCM (brushless DC motor) system is out of the question. The control method to combine fuzzy control with PID control was fit the multivariable strong coupling nonlinear characteristic of BLDCM system. Matlab/Simulink simulation model had been built. The result of computer simulation shows that, compared with the conventional PID controller, the dynamic and static performance of fuzzy auto-adjust PID controller are put forward to optimize. The research work of this paper has profound significance for high precision controller design.

  5. Rudder-roll stabilization using fgs-pid controller for sigma-e warship

    NASA Astrophysics Data System (ADS)

    Santoso, M. Y.; Munadhif, I.; Wahidin, A.; Ruddianto; Fathulloh; Soelistijono, R. T.

    2017-06-01

    The aim of rudder-roll stabilization (RSS) is controlling ship heading and reducing roll motion simultaneously using one actuator, rudder. In this paper, RSS using FGS-PID for SIGMA-e warship was performed, both in normal and disturbed sea conditions. The fuzzy system for determining PID controller are constructed from SIGMA-e linear mathematical model. The wave disturbances are generated based on the WMO. The results show that FGS-PID has superior performance compared to conventional PID controller in heading control and roll damping. It means that the proposed control method can encounter the environmental changes.

  6. Simple PID parameter tuning method based on outputs of the closed loop system

    NASA Astrophysics Data System (ADS)

    Han, Jianda; Zhu, Zhiqiang; Jiang, Ziya; He, Yuqing

    2016-05-01

    Most of the existing PID parameters tuning methods are only effective with pre-known accurate system models, which often require some strict identification experiments and thus infeasible for many complicated systems. Actually, in most practical engineering applications, it is desirable for the PID tuning scheme to be directly based on the input-output response of the closed-loop system. Thus, a new parameter tuning scheme for PID controllers without explicit mathematical model is developed in this paper. The paper begins with a new frequency domain properties analysis of the PID controller. After that, the definition of characteristic frequency for the PID controller is given in order to study the mathematical relationship between the PID parameters and the open-loop frequency properties of the controlled system. Then, the concepts of M-field and θ-field are introduced, which are then used to explain how the PID control parameters influence the closed-loop frequency-magnitude property and its time responses. Subsequently, the new PID parameter tuning scheme, i.e., a group of tuning rules, is proposed based on the preceding analysis. Finally, both simulations and experiments are conducted, and the results verify the feasibility and validity of the proposed methods. This research proposes a PID parameter tuning method based on outputs of the closed loop system.

  7. Multi-loop decentralized PID control based on covariance control criteria: an LMI approach.

    PubMed

    Huang, Xin; Huang, Biao

    2004-01-01

    PID control is well known and widely applied in industry and many design algorithms are readily available in the literature. However, systematic design of multi-loop or decentralized PID control for multivariable processes to meet certain objectives simultaneously is still a challenging task. Designing multi-loop PID controllers such that the process variables satisfy the generalized covariance constraints is studied in this paper. A convergent computational algorithm is proposed to calculate the multi-loop PID controller for a process with stable disturbances. This algorithm is then extended to a process with random-walk disturbances. The feasibility of the proposed algorithm is verified by applying it to several simulation examples.

  8. The application of neural network PID controller to control the light gasoline etherification

    NASA Astrophysics Data System (ADS)

    Cheng, Huanxin; Zhang, Yimin; Kong, Lingling; Meng, Xiangyong

    2017-06-01

    Light gasoline etherification technology can effectively improve the quality of gasoline, which is environmental- friendly and economical. By combining BP neural network and PID control and using BP neural network self-learning ability for online parameter tuning, this method optimizes the parameters of PID controller and applies this to the Fcc gas flow control to achieve the control of the final product- heavy oil concentration. Finally, through MATLAB simulation, it is found that the PID control based on BP neural network has better controlling effect than traditional PID control.

  9. Empirically characteristic analysis of chaotic PID controlling particle swarm optimization

    PubMed Central

    Yan, Danping; Lu, Yongzhong; Zhou, Min; Chen, Shiping; Levy, David

    2017-01-01

    Since chaos systems generally have the intrinsic properties of sensitivity to initial conditions, topological mixing and density of periodic orbits, they may tactfully use the chaotic ergodic orbits to achieve the global optimum or their better approximation to given cost functions with high probability. During the past decade, they have increasingly received much attention from academic community and industry society throughout the world. To improve the performance of particle swarm optimization (PSO), we herein propose a chaotic proportional integral derivative (PID) controlling PSO algorithm by the hybridization of chaotic logistic dynamics and hierarchical inertia weight. The hierarchical inertia weight coefficients are determined in accordance with the present fitness values of the local best positions so as to adaptively expand the particles’ search space. Moreover, the chaotic logistic map is not only used in the substitution of the two random parameters affecting the convergence behavior, but also used in the chaotic local search for the global best position so as to easily avoid the particles’ premature behaviors via the whole search space. Thereafter, the convergent analysis of chaotic PID controlling PSO is under deep investigation. Empirical simulation results demonstrate that compared with other several chaotic PSO algorithms like chaotic PSO with the logistic map, chaotic PSO with the tent map and chaotic catfish PSO with the logistic map, chaotic PID controlling PSO exhibits much better search efficiency and quality when solving the optimization problems. Additionally, the parameter estimation of a nonlinear dynamic system also further clarifies its superiority to chaotic catfish PSO, genetic algorithm (GA) and PSO. PMID:28472050

  10. An analytical method for PID controller tuning with specified gain and phase margins for integral plus time delay processes.

    PubMed

    Hu, Wuhua; Xiao, Gaoxi; Li, Xiumin

    2011-04-01

    In this paper, an analytical method is proposed for proportional-integral/proportional-derivative/proportional-integral-derivative (PI/PD/PID) controller tuning with specified gain and phase margins (GPMs) for integral plus time delay (IPTD) processes. Explicit formulas are also obtained for estimating the GPMs resulting from given PI/PD/PID controllers. The proposed method indicates a general form of the PID parameters and unifies a large number of existing rules as PI/PD/PID controller tuning with various GPM specifications. The GPMs realized by existing PID tuning rules are computed and documented as a reference for control engineers to tune the PID controllers.

  11. Using PIDs to Support the Full Research Data Publishing Lifecycle

    NASA Astrophysics Data System (ADS)

    Waard, A. D.

    2016-12-01

    Persistent identifiers can help support scientific research, track scientific impact and let researchers achieve recognition for their work. We discuss a number of ways in which Elsevier utilizes PIDs to support the scholarly lifecycle: To improve the process of storing and sharing data, Mendeley Data (http://data.mendeley.com) makes use of persistent identifiers to support the dynamic nature of data and software, by tracking and recording the provenance and versioning of datasets. This system now allows the comparison of different versions of a dataset, to see precisely what was changed during a versioning update. To present research data in context for the reader, we include PIDs in research articles as hyperlinks: https://www.elsevier.com/books-and-journals/content-innovation/data-base-linking. In some cases, PIDs fetch data files from the repositories provide that allow the embedding of visualizations, e.g. with PANGAEA and PubChem: https://www.elsevier.com/books-and-journals/content-innovation/protein-viewer; https://www.elsevier.com/books-and-journals/content-innovation/pubchem. To normalize referenced data elements, the Resource Identification Initiative - which we developed together with members of the Force11 RRID group - introduces a unified standard for resource identifiers (RRIDs) that can easily be interpreted by both humans and text mining tools. https://www.force11.org/group/resource-identification-initiative/update-resource-identification-initiative, as can be seen in our Antibody Data app: https://www.elsevier.com/books-and-journals/content-innovation/antibody-data To enable better citation practices and support robust metrics system for sharing research data, we have helped develop, and are early adopters of the Force11 Data Citation Principles and Implementation groups (https://www.force11.org/group/dcip) Lastly, through our work with the Research Data Alliance Publishing Data Services group, we helped create a set of guidelines (http

  12. Progress on Development of the New FDIRC PID Detector

    SciTech Connect

    Vavra, Jerry

    2012-08-03

    We present a progress status of a new concept of PID detector called FDIRC, intended to be used at the SuperB experiment, which requires {pi}/K separation up to a few GeV/c. The new photon camera is made of the solid fused-silica optics with a volume 25x smaller and speed increased by a factor of ten compared to the BaBar DIRC, and therefore will be much less sensitive to electromagnetic and neutron background

  13. Stable visual PID control of a planar parallel robot

    NASA Astrophysics Data System (ADS)

    Garrido Moctezuma, Ruben; Soria López, Alberto; Trujano Cabrera, Miguel

    2008-11-01

    In this paper, we study an image-based PID control of a redundant planar parallel robot using a fixed camera configuration. The control objective is to move the robot end effector to the desired image reference position. The control law has a PD term plus an integral term with a nonlinear function of the position error. The proportional and integral actions use image loop information whereas the derivative action adds task space damping using joint level measurements. The Lyapunov method and the LaSalle invariance principle allow assessing asymptotic closed loop stability. Experiments show the feasibility of the proposed approach.

  14. Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

    PubMed Central

    Lobachevsky, Pavel; Woodbine, Lisa; Hsiao, Kuang-Chih; Choo, Sharon; Fraser, Chris; Gray, Paul; Smith, Jai; Best, Nickala; Munforte, Laura; Korneeva, Elena; Martin, Roger F.; Jeggo, Penny A.; Martin, Olga A.

    2016-01-01

    Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. PMID:26151233

  15. Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity.

    PubMed

    Lobachevsky, Pavel; Woodbine, Lisa; Hsiao, Kuang-Chih; Choo, Sharon; Fraser, Chris; Gray, Paul; Smith, Jai; Best, Nickala; Munforte, Laura; Korneeva, Elena; Martin, Roger F; Jeggo, Penny A; Martin, Olga A

    2015-09-01

    Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects.

  16. Primary Immune Deficiencies – Principles of Care

    PubMed Central

    Chapel, Helen; Prevot, Johan; Gaspar, Hubert Bobby; Español, Teresa; Bonilla, Francisco A.; Solis, Leire; Drabwell, Josina

    2014-01-01

    Primary immune deficiencies (PIDs) are a growing group of over 230 different disorders caused by ineffective, absent or an increasing number of gain of function mutations in immune components, mainly cells and proteins. Once recognized, these rare disorders are treatable and in some cases curable. Otherwise untreated PIDs are often chronic, serious, or even fatal. The diagnosis of PIDs can be difficult due to lack of awareness or facilities for diagnosis, and management of PIDs is complex. This document was prepared by a worldwide multi-disciplinary team of specialists; it aims to set out comprehensive principles of care for PIDs. These include the role of specialized centers, the importance of registries, the need for multinational research, the role of patient organizations, management and treatment options, the requirement for sustained access to all treatments including immunoglobulin therapies and hematopoietic stem cell transplantation, important considerations for developing countries and suggestions for implementation. A range of healthcare policies and services have to be put into place by government agencies and healthcare providers, to ensure that PID patients worldwide have access to appropriate and sustainable medical and support services. PMID:25566243

  17. Pid1 induces insulin resistance in both human and mouse skeletal muscle during obesity.

    PubMed

    Bonala, Sabeera; McFarlane, Craig; Ang, Jackie; Lim, Radiance; Lee, Marcus; Chua, Hillary; Lokireddy, Sudarsanareddy; Sreekanth, Patnam; Leow, Melvin Khee Shing; Meng, Khoo Chin; Shyong, Tai E; Lee, Yung Seng; Gluckman, Peter D; Sharma, Mridula; Kambadur, Ravi

    2013-09-01

    Obesity is associated with insulin resistance and abnormal peripheral tissue glucose uptake. However, the mechanisms that interfere with insulin signaling and glucose uptake in human skeletal muscle during obesity are not fully characterized. Using microarray, we have identified that the expression of Pid1 gene, which encodes for a protein that contains a phosphotyrosine-interacting domain, is increased in myoblasts established from overweight insulin-resistant individuals. Molecular analysis further validated that both Pid1 mRNA and protein levels are increased in cell culture models of insulin resistance. Consistent with these results, overexpression of phosphotyrosine interaction domain-containing protein 1 (PID1) in human myoblasts resulted in reduced insulin signaling and glucose uptake, whereas knockdown of PID1 enhanced glucose uptake and insulin signaling in human myoblasts and improved the insulin sensitivity following palmitate-, TNF-α-, or myostatin-induced insulin resistance in human myoblasts. Furthermore, the number of mitochondria in myoblasts that ectopically express PID1 was significantly reduced. In addition to overweight humans, we find that Pid1 levels are also increased in all 3 peripheral tissues (liver, skeletal muscle, and adipose tissue) in mouse models of diet-induced obesity and insulin resistance. An in silico search for regulators of Pid1 expression revealed the presence of nuclear factor-κB (NF-κB) binding sites in the Pid1 promoter. Luciferase reporter assays and chromatin immunoprecipitation studies confirmed that NF-κB is sufficient to transcriptionally up-regulate the Pid1 promoter. Furthermore, we find that myostatin up-regulates Pid1 expression via an NF-κB signaling mechanism. Collectively these results indicate that Pid1 is a potent intracellular inhibitor of insulin signaling pathway during obesity in humans and mice.

  18. Retraction: Pid1 Induces Insulin Resistance in Both Human and Mouse Skeletal Muscle during Obesity

    PubMed Central

    Bonala, Sabeera; McFarlane, Craig; Ang, Jackie; Lim, Radiance; Lee, Marcus; Chua, Hillary; Lokireddy, Sudarsanareddy; Sreekanth, Patnam; Shing Leow, Melvin Khee; Meng, Khoo Chin; Shyong, TAI E; Lee, Yung Seng; Gluckman, Peter D.; Sharma, Mridula

    2013-01-01

    Obesity is associated with insulin resistance and abnormal peripheral tissue glucose uptake. However, the mechanisms that interfere with insulin signaling and glucose uptake in human skeletal muscle during obesity are not fully characterized. Using microarray, we have identified that the expression of Pid1 gene, which encodes for a protein that contains a phosphotyrosine-interacting domain, is increased in myoblasts established from overweight insulin-resistant individuals. Molecular analysis further validated that both Pid1 mRNA and protein levels are increased in cell culture models of insulin resistance. Consistent with these results, overexpression of phosphotyrosine interaction domain-containing protein 1 (PID1) in human myoblasts resulted in reduced insulin signaling and glucose uptake, whereas knockdown of PID1 enhanced glucose uptake and insulin signaling in human myoblasts and improved the insulin sensitivity following palmitate-, TNF-α-, or myostatin-induced insulin resistance in human myoblasts. Furthermore, the number of mitochondria in myoblasts that ectopically express PID1 was significantly reduced. In addition to overweight humans, we find that Pid1 levels are also increased in all 3 peripheral tissues (liver, skeletal muscle, and adipose tissue) in mouse models of diet-induced obesity and insulin resistance. An in silico search for regulators of Pid1 expression revealed the presence of nuclear factor-κB (NF-κB) binding sites in the Pid1 promoter. Luciferase reporter assays and chromatin immunoprecipitation studies confirmed that NF-κB is sufficient to transcriptionally up-regulate the Pid1 promoter. Furthermore, we find that myostatin up-regulates Pid1 expression via an NF-κB signaling mechanism. Collectively these results indicate that Pid1 is a potent intracellular inhibitor of insulin signaling pathway during obesity in humans and mice. PMID:23927930

  19. Immunodeficiency in Patients With 49,XXXXY Chromosomal Variation

    PubMed Central

    Keller, Michael D.; Sadeghin, Teresa; Samango-Sprouse, Carole; Orange, Jordan S.

    2016-01-01

    Boys affected with 49,XXXXY sex chromosomal variation have been described to have high incidence of recurrent otitis media and asthma, the cause of which is unknown. We hypothesized that primary immunodeficiency occurs in patients with XXXXY aneuploidy. To investigate this, 31 boys with known 49,XXXXY were evaluated through a multidisciplinary clinic. Screening history was performed using the “10 Warning Signs of primary immunodeficiency” (Jeffrey Modell Foundation), as well as by history of atopic and autoimmune conditions. Of the 31 boys, 20 had at least two warning signs of primary immunodeficiency, and five had four or more signs. Sixteen had history of recurrent pneumonia, and 15 carried the diagnosis of asthma. Of the 10 who underwent immunologic screening, eight showed some evidence of impaired antibody responses to polysaccharide antigens, and one was diagnosed with specific antibody deficiency. These preliminary results suggest a high incidence of both atopy and antibody deficiency in boys with 49,XXXXY. PMID:23345259

  20. Improved automatic tuning of PID controller for stable processes.

    PubMed

    Kumar Padhy, Prabin; Majhi, Somanath

    2009-10-01

    This paper presents an improved automatic tuning method for stable processes using a modified relay in the presence of static load disturbances and measurement noise. The modified relay consists of a standard relay in series with a PI controller of unity proportional gain. The integral time constant of the PI controller of the modified relay is chosen so as to ensure a minimum loop phase margin of 30( composite function). A limit cycle is then obtained using the modified relay. Hereafter, the PID controller is designed using the limit cycle output data. The derivative time constant is obtained by maintaining the above mentioned loop phase margin. Minimizing the distance of Nyquist curve of the loop transfer function from the imaginary axis of the complex plane gives the proportional gain. The integral time constant of the PID controller is set equal to the integral time constant of the PI controller of the modified relay. The effectiveness of the proposed technique is verified by simulation results.

  1. Study of fuzzy PID controller for velocity circuit of optical-electronic theodolite

    NASA Astrophysics Data System (ADS)

    Li, GengXin; Yang, XiaoJun; He, SaiXian

    2017-02-01

    Two-axis stabilized turntable is an important part of optical-electronic theodolite, it carries various of measuring instruments. In order to improve the response speed of the optical-electronic theodolite when tracking high speed target. In the same time, improve the stability and precision when tracking low speed target. The traditional servo controller is double close-loop structure. On the basis of traditional structure, we use the fuzzy control theory to design the servo control speed loop adjuster as a fuzzy PID controller, and the position loop is designed as a traditional first order adjuster. We introduce the theory and characteristics of PID control and fuzzy control, and discussed the structure of the speed loop fussy controller and the tuning method of the PID parameters. The fuzzy PID controller was studied with simulation on the MATLAB/Simulink platform, the performance indexes and the anti-jamming abilities of the fussy PID controller and the traditional PID controller were compared. The experiment results show that the fussy PID controller has the ability of parameter self-tuning, and its tacking ability is much better than the traditional PID controller.

  2. Screening for Human Immunodeficiency Virus (HIV)

    MedlinePlus

    Understanding Task Force Recommendations Screening for Human Immunodeficiency Virus (HIV) The U.S. Preventive Services Task Force (Task ... final recommendation statement on Screening for Human Immunodeficiency Virus (HIV) . This final recommendation statement applies to all ...

  3. Human immunodeficiency virus infection and pneumothorax

    PubMed Central

    Terzi, Eirini; Zarogoulidis, Konstantinos; Kougioumtzi, Ioanna; Dryllis, Georgios; Kioumis, Ioannis; Pitsiou, Georgia; Machairiotis, Nikolaos; Katsikogiannis, Nikolaos; Tsiouda, Theodora; Madesis, Athanasios; Karaiskos, Theodoros

    2014-01-01

    Pneumothorax is a serious and relatively frequent complication of human immunodeficiency virus (HIV) infection that may associate with increased morbidity and mortality and may prove difficult to manage, especially in patients with acquired immunodeficiency syndrome (AIDS). PMID:25337392

  4. Design of incomplete derivative fuzzy PID control system for fast-steering mirror

    NASA Astrophysics Data System (ADS)

    Ai, Zhiwei; Tan, Yi; Wu, Qiongyan; Ren, Ge; Tan, Yufen; Zhu, Nengbing; Zhu, Fuyin

    2016-10-01

    The structure parameters of fast-steering mirror (FSM) might change with time goes by. In order to reduce the impact of this change on the output performance of FSM system, an incomplete derivative fuzzy PID control system is proposed. This control system can effectively improve the time domain quality of FSM system by optimizing the PID control parameters online. First, the dynamic model of FSM is established. Second, the initial parameters of the incomplete derivative PID control system are designed according to the frequency domain quality of the closed-loop system. Then, the rules and related factors of the fuzzy controller are designed on the basis of the initial parameters. Finally, simulation experiments are carried out. The results show that the incomplete derivative PID control system has shorter adjustment time, less overshoot and lower dependence on the parameters of FSM when compared with the fixed parameters PID control system.

  5. Study of fuzzy adaptive PID controller on thermal frequency stabilizing laser with double longitudinal modes

    NASA Astrophysics Data System (ADS)

    Mo, Qingkai; Zhang, Tao; Yan, Yining

    2016-10-01

    There are contradictions among speediness, anti-disturbance performance, and steady-state accuracy caused by traditional PID controller in the existing light source systems of thermal frequency stabilizing laser with double longitudinal modes. In this paper, a new kind of fuzzy adaptive PID controller was designed by combining fuzzy PID control technology and expert system to make frequency stabilizing system obtain the optimal performance. The experiments show that the frequency stability of the designed PID controller is similar to the existing PID controller (the magnitude of frequency stability is less than 10-9 in constant temperature and 10-7 in open air). But the preheating time is shortened obviously (from 10 minutes to 5 minutes) and the anti-disturbance capability is improved significantly (the recovery time needed after strong interference is reduced from 1 minute to 10 seconds).

  6. An improved robust fuzzy-PID controller with optimal fuzzy reasoning.

    PubMed

    Li, Han-Xiong; Zhang, Lei; Cai, Kai-Yuan; Chen, Guanrong

    2005-12-01

    Many fuzzy control schemes used in industrial practice today are based on some simplified fuzzy reasoning methods, which are simple but at the expense of losing robustness, missing fuzzy characteristics, and having inconsistent inference. The concept of optimal fuzzy reasoning is introduced in this paper to overcome these shortcomings. The main advantage is that an integration of the optimal fuzzy reasoning with a PID control structure will generate a new type of fuzzy-PID control schemes with inherent optimal-tuning features for both local optimal performance and global tracking robustness. This new fuzzy-PID controller is then analyzed quantitatively and compared with other existing fuzzy-PID control methods. Both analytical and numerical studies clearly show the improved robustness of the new fuzzy-PID controller.

  7. [Immunological alterations in common variable immunodeficiency].

    PubMed

    Berrón-Ruiz, Laura

    2017-01-01

    Common variable immunodeficiency (CVID) is the largest group of symptomatic primary immune deficiencies; it is characterized by hypogammaglobulinemia, poor response to vaccines and increased susceptibility to infections. Cellular phenotypes and abnormalities have been described both in adaptive and innate immune response. Several classifications of common variable immunodeficiency are based on defects found on T and B cells, which have been correlated with clinical manifestations. In recent years, significant progress has been made in elucidating the genetic mechanisms that result in a IDCV phenotype. Massive sequencing technologies have favored the description of mutations in several genes, but only in 2 % to 10 % of patients. These monogenetic defects are: ICOS, TNFRSF13B (TACI), TNFRS13C (BAFFR), TNRFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), (CD27), LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R, VAV1, RAC1, BLK, IKZF1 (IKAROS) and IRF2BP2. These findings have provided a possible explanation for the pathogenesis of IDCV, since these molecules play an important role in the co-operation between B and T cells in the germinal center, as well as in intrinsic signaling pathways of both.

  8. Neonatal Screening for Severe Combined Immunodeficiency (SCID)

    PubMed Central

    Puck, Jennifer M.

    2012-01-01

    Purpose of review Population-based newborn screening for severe combined immunodeficiency (SCID) and related disorders has been instituted in five states, with several more planning to add this testing to their newborn screening panels. This review summarizes the rationale, development, and implementation of SCID screening programs to date and highlights current and future challenges. Recent findings Early results of T-cell receptor excision circle (TREC) testing newborns in pilot states indicate that this addition to the newborn screening panel can be successfully integrated into state public health programs. The TREC test has clinical validity and TRECs, as predicted, are an excellent biomarker of poor T-cell lymphocyte production in the thymus or increased lymphocyte loss resulting in T-cell lymphopenia. A variety of cases with typical SCID genotypes and other conditions have been detected in a timely manner and referred for appropriate early treatment. Summary Early detection of primary immunodeficiency is recognized as important for avoiding infectious complications that compromise outcomes. Routine screening of all newborns with the TREC test, implemented as part of an integrated public health program, can achieve pre-symptomatic diagnosis of SCID and other disorders with T-cell lymphopenia, allowing prompt and effective treatment and leading to a better understanding of the spectrum of these disorders and how to manage them. PMID:22001765

  9. Severe combined immunodeficiency--an update.

    PubMed

    Cirillo, Emilia; Giardino, Giuliana; Gallo, Vera; D'Assante, Roberta; Grasso, Fiorentino; Romano, Roberta; Di Lillo, Cristina; Galasso, Giovanni; Pignata, Claudio

    2015-11-01

    Severe combined immunodeficiencies (SCIDs) are a group of inherited disorders responsible for severe dysfunctions of the immune system. These diseases are life-threatening when the diagnosis is made too late; they are the most severe forms of primary immunodeficiency. SCID patients often die during the first two years of life if appropriate treatments to reconstitute their immune system are not undertaken. Conventionally, SCIDs are classified according either to the main pathway affected by the molecular defect or on the basis of the specific immunologic phenotype that reflects the stage where the blockage occurs during the differentiation process. However, during the last few years many new causative gene alterations have been associated with unusual clinical and immunological phenotypes. Many of these novel forms of SCID also show extra-hematopoietic alterations, leading to complex phenotypes characterized by a functional impairment of several organs, which may lead to a considerable delay in the diagnosis. Here we review the biological and clinical features of SCIDs paying particular attention to the most recently identified forms and to their unusual or extra-immunological clinical features.

  10. Chronic Giardiasis in a Case of Common Variable Immunodeficiency (CVID): A Case Report

    PubMed Central

    Koticha, Avani; Mehta, Preeti R

    2016-01-01

    Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by low antibody levels and recurrent infections. This makes an individual more prone to recurrent respiratory and gastrointestinal tract infections. In cases where there is persistent positive finding of intestinal parasites in stool, a high index of suspicion should be raised to rule out immunodeficiency state. Early diagnosis of such cases will help in reducing the morbidity and better management of the patient. A case of CVID in 18-year-old male with recurrent lower respiratory tract infection and chronic diarrhoea due to Giardia lamblia is reported herewith. PMID:27630845

  11. Chronic Giardiasis in a Case of Common Variable Immunodeficiency (CVID): A Case Report.

    PubMed

    Paranjpe, Supriya M; Koticha, Avani; Mehta, Preeti R

    2016-07-01

    Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by low antibody levels and recurrent infections. This makes an individual more prone to recurrent respiratory and gastrointestinal tract infections. In cases where there is persistent positive finding of intestinal parasites in stool, a high index of suspicion should be raised to rule out immunodeficiency state. Early diagnosis of such cases will help in reducing the morbidity and better management of the patient. A case of CVID in 18-year-old male with recurrent lower respiratory tract infection and chronic diarrhoea due to Giardia lamblia is reported herewith.

  12. Human Immunodeficiency Virus Envelope (gp120) Binding to DC-SIGN and Primary Dendritic Cells Is Carbohydrate Dependent but Does Not Involve 2G12 or Cyanovirin Binding Sites: Implications for Structural Analyses of gp120-DC-SIGN Binding

    PubMed Central

    Hong, Patrick W.-P.; Flummerfelt, Karen B.; de Parseval, Aymeric; Gurney, Kevin; Elder, John H.; Lee, Benhur

    2002-01-01

    The calcium-dependent lectin, DC-SIGN, binds to human immunodeficiency virus (HIV) (and simian immunodeficiency virus) gp120 and mediates the binding and transfer of HIV from monocyte-derived dendritic cells (MDDCs) to permissive T cells. However, it has been recently reported that DC-SIGN binding to HIV gp120 may be carbohydrate independent. Here, we formally demonstrate that gp120 binding to DC-SIGN and MDDCs is largely if not wholly carbohydrate dependent. Endo-β-N-glucosaminidase H (EndoH) treatment of gp120-Fc under conditions that maintained wild-type CD4 binding—and the full complement of complex glycans—significantly decreased (>90%) binding to DC-SIGN expressing cell lines, as well as to MDDCs. Any residual binding of EndoH-treated gp120-Fc to DC-SIGN was completely competed off with mannan. Mutational analysis indicated that no single glycosylation site affected the ability of gp120-Fc to bind DC-SIGN. To further guide our efforts in mapping the DC-SIGN binding sites on gp120, we used two well-characterized HIV inhibitory agents (2G12 monoclonal antibody and cyanovirin) that bind to high-mannose sugars on gp120. We showed that 2G12 and DC-SIGN bound to nonoverlapping sites in gp120 because (i) 2G12 did not block soluble gp120 or virion binding to DC-SIGN, (ii) 2G12 bound to gp120-Fc that was prebound to cell surface DC-SIGN, and (iii) gp120-Fc mutants that lack glycosylation sites involved in 2G12's epitope were also fully capable of binding DC-SIGN. These data were substantiated by the inability of cyanovirin to block gp120-Fc binding to DC-SIGN. Cyanovirin has been shown to effectively compete for 2G12 binding to gp120. Indeed, high concentrations of cyanovirin dramatically enhanced gp120-Fc binding to cell surfaces in the presence or absence of DC-SIGN. We provide evidence that this enhancement may be due to cyanovirin's ability to bridge gp120 to mannosylated cell surface proteins. These results have implications for antiviral therapeutics and

  13. Mathematical Modeling: Immune System Dynamics in the Presence of Cancer and Immunodeficiency in vivo

    DTIC Science & Technology

    2016-05-11

    public release; its distribution is UNLIMITED. 13. SUPPLEMENTARY NOTES 14. ABSTRACT The Human Immunodeficiency Virus (HIV) targets CD4 T-cells...During HIV-1 primary infection, we know that the virus concentration increases, reaches a peak, and then decreases until it reaches a set point. We...Mathematical Modeling, Human Immunodeficiency Virus , Cancer, Stability, Numerical Simulations, Time Delay, Optimal Control 16. SECURITY CLASSIFICATION OF

  14. Disseminated Bacille Calmette-Guerin (BCG) disease in an infant with severe combined immunodeficiency.

    PubMed

    Sohail, Shagufta; Afzal, Muhammad; Anwar, Vaqas; Shama, Quratulain

    2014-11-01

    Bacille Calmette-Guerin (BCG) vaccine is administered to all newborns in countries where tuberculosis is still endemic. It is a live attenuated vaccine and considered quite safe in immunocompetent children. Disseminated BCG disease is the most serious complication seen only in individuals with underlying primary or secondary immunodeficiencies. We report a case of disseminated BCG disease in an infant with Severe Combined Immunodeficiency (SCID) who received BCG administration prior to diagnosis of SCID.

  15. Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency

    PubMed Central

    Bacalhau, Sílvia; Freitas, Cristina; Valente, Rosalina; Barata, Deolinda; Neves, Conceição; Schäfer, Katrin; Lubatschofski, Annelie; Schulz, Ansgar; Neves, João Farela

    2011-01-01

    In high-burden countries, Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine is administered in newborn to prevent severe Mycobacterium tuberculosis infection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burden countries. We report the case of a patient with X-linked severe combined immunodeficiency (SCID) who developed disseminated BCG disease, highlighting the specific strategies adopted. PMID:22110512

  16. CB-19PID1, A NEW GROWTH-INHIBITORY GENE, SENSITIZES MEDULLOBLASTOMA AND GLIOMA CELL LINES TO CHEMOTHERAPY

    PubMed Central

    Xu, Jingying; Ren, Xiuhai; Tran, Anthony; Erdreich-Epstein, Anat

    2014-01-01

    BACKGROUND: Phosphotyrosine Interaction Domain containing protein-1 (PID1) was discovered in 2006. We recently showed that PID1 inhibits growth of brain tumor cell lines and its mRNA level is directly correlated with survival in glioma and medulloblastoma patients (Erdreich-Epstein et al, Clin Cancer Res). The growth-inhibitory effect of PID1 was due to decreased proliferation and increased cell death. METHODS/RESULTS: We hypothesized that PID1 sensitizes brain tumors to therapy, thus accounting for the longer survival in patients with higher PID1 mRNA. Indeed, while cisplatin (10 µg/ml) or transient PID1 overexpression each increased apoptosis of glioma and medulloblastoma cell lines, combining cisplatin with PID1 resulted in markedly higher apoptosis. Moreover, knockdown of PID1 by siRNA inhibited the cisplatin-induced mitochondrial membrane depolarization and apoptosis, suggesting that PID1 is partially required for cisplatin-induced apoptosis. Taken together, this suggests that PID1 sensitizes both glioma and medulloblastoma cell lines to cisplatin. Intriguingly, PID1 mRNA increased in response to chemotherapy in a time- and dose-dependent manner in brain tumor cell lines. The chemotherapy-induced increase in PID1 mRNA was blocked by inhibitors of NFkB, suggesting that regulation of PID1 mRNA increase may be an NF-kB-dependent process. Consistent with this, cisplatin increased activity of an NF-kB promoter reporter. Surprisingly, despite the chemotherapy-induced increase in PID1 mRNA, PID1 protein decreased in response to cisplatin, suggesting post-translational modification(s) of PID1 induced by cisplatin. Ongoing work is focusing on the mechanism and role of PID1 in response to chemotherapy, and examining the effect of PID1 on the response of tumors to chemotherapy in vivo. CONCLUSIONS: Our data show that PID1 sensitizes glioma and medulloblastoma cell lines to chemotherapy, possibly explaining the correlation between higher PID1 mRNA and longer patient

  17. Aerogel RICH for the Belle II forward PID

    NASA Astrophysics Data System (ADS)

    Nishida, S.; Adachi, I.; Hamada, N.; Hara, K.; Iijima, T.; Iwata, S.; Kakuno, H.; Kawai, H.; Korpar, S.; Kriz^an, P.; Ogawa, S.; Pestotnik, R.; Ŝantelj, L.; Seljak, A.; Sumiyoshi, T.; Tabata, M.; Tahirovic, E.; Yoshida, K.; Yusa, Y.

    2014-12-01

    The Belle II spectrometer, a follow up of the very successful Belle experiment, is under construction at the SuperKEKB electron-positron collider at KEK in Japan. For the PID system in the forward region of the spectrometer, a proximity focusing ring-imaging Cherenkov (RICH) counter with an aerogel radiator is being developed. The counter will provide a 4σ separation of pions and kaons up to momenta of 4 GeV/c. For the position sensitive photon sensor, a 144-channel Hybrid Avalanche Photo-Detector (HAPD) has been developed with Hamamatsu Photonics K.K. The readout electronics is based on the custom developed ASIC. The design of the components is currently being finalized and part of their mass production have already started. Herein, we report the final design of the counter and a prototype test conducted with test beams at DESY.

  18. PID controller design for trailer suspension based on linear model

    NASA Astrophysics Data System (ADS)

    Kushairi, S.; Omar, A. R.; Schmidt, R.; Isa, A. A. Mat; Hudha, K.; Azizan, M. A.

    2015-05-01

    A quarter of an active trailer suspension system having the characteristics of a double wishbone type was modeled as a complex multi-body dynamic system in MSC.ADAMS. Due to the complexity of the model, a linearized version is considered in this paper. A model reduction technique is applied to the linear model, resulting in a reduced-order model. Based on this simplified model, a Proportional-Integral-Derivative (PID) controller was designed in MATLAB/Simulink environment; primarily to reduce excessive roll motions and thus improving the ride comfort. Simulation results show that the output signal closely imitates the input signal in multiple cases - demonstrating the effectiveness of the controller.

  19. Severe Combined Immunodeficiency (For Parents)

    MedlinePlus

    ... a doctor will test for SCID or other types of immune deficiency. Parents who have a child with SCID or a family history of immunodeficiency might want to consider genetic counseling and early blood testing, since early diagnosis can lead to prompt ...

  20. Persistent papillomatosis associated with immunodeficiency.

    PubMed

    Duncan, J R; Corbeil, L B; Davies, D H; Schultz, R D; Whitlock, R H

    1975-04-01

    A case report of a young bull with persistent papillomatosis associated with immunodeficiency is presented. Humoral immune responses were normal but cell mediated immunity was deficient. The possible significance of the findings to pathogenesis and therapy of the disease is discussed.

  1. Severe Combined Immunodeficiency (For Parents)

    MedlinePlus

    ... immune deficiency. Parents who have a child with SCID or a family history of immunodeficiency might want to consider genetic counseling ... screening for newborns. Children without a known family history of the disease are often not diagnosed until 6 months of age or ... Treating SCID SCID is a pediatric emergency. When a child ...

  2. Enteroaggregative Escherichia coli in Venda, South Africa: distribution of virulence-related genes by multiplex polymerase chain reaction in stool samples of human immunodeficiency virus (HIV)-positive and HIV-negative individuals and primary school children.

    PubMed

    Samie, Amidou; Obi, Chikwelu Larry; Dillingham, Rebecca; Pinkerton, Relana C; Guerrant, Richard L

    2007-07-01

    We used a multiplex polymerase chain reaction (PCR) and a quantitative real-time PCR to determine the distribution of three enteroaggregative Escherichia coli (EAEC) virulence-related genes in stool samples from hospital patients and school children in the Venda region of South Africa. At least one gene was found in 52 (16.5%) samples, 50 (19.6%) from hospitals and 2 (3%) from schools. The AA probe was found in 36 (69%), the aggR gene was found in 41 (79%), and the aap gene was found in 49 (94%) of all positive samples. EAEC was significantly associated with diarrhea and intestinal inflammation and was significantly higher (chi(2) = 5.360, P = 0.021) in human immunodeficiency virus (HIV)-positive persons (29.5%) than in HIV-negative persons (13.7%). The presence of EAEC genes was significantly associated with occult blood (chi(2) = 30.543, P < 0.0001) in the stool samples. This study suggests that the clinical presentation of EAEC infection may be directly related to the bacterial load as well as to the genetic characteristics of the strains involved.

  3. Human immunodeficiency virus type 1 induces cellular polarization, intercellular adhesion molecule-1 redistribution, and multinucleated giant cell generation in human primary monocytes but not in monocyte-derived macrophages.

    PubMed

    Fais, S; Borghi, P; Gherardi, G; Logozzi, M; Belardelli, F; Gessani, S

    1996-12-01

    In this study, we evaluated the effects of human immunodeficiency virus type 1 (HIV-1) on some morphologic and functional changes in cultured human monocytes/macrophages at different stages of differentiation. Freshly isolated monocytes infected with HIV-1 24 hours after seeding exhibited marked morphologic changes such as uropod formation, polarization of intercellular adhesion molecule-1 (ICAM-1) on the cytoplasmic projection, the redistribution of alpha-actinin on cell-membrane dots, and an increased release of soluble ICAM-1. These changes preceded the increase in monocyte-monocyte fusion and the formation of multinucleated giant cells. In contrast, HIV-1 infection did not affect monocyte-derived macrophages in terms of either cellular polarization or multinucleated giant cell formation. Immunocytochemistry showed that HIV-1 matrix protein was present mostly in bi- and trinucleated cells, which suggests that multinucleated giant cells may represent a long-lived and highly productive cellular source of HIV. The treatment of the HIV-1-infected monocytes with azidodeoxythymidine virtually abolished all viral-induced morphofunctional changes. On the whole, these results indicate that blood monocytes and differentiated macrophages may be affected differently by HIV infection, as monocytes seem to be much more prone to polarize, undergo homotypic fusion, and form multinucleated giant cells. These changes may confer to HIV-infected monocytes an increased ability to transmigrate through endothelia into tissues, whereas differentiated macrophages may have a predominant role as a widespread reservoir of HIV.

  4. Bacterial Respiratory Infections Complicating Human Immunodeficiency Virus.

    PubMed

    Feldman, Charles; Anderson, Ronald

    2016-04-01

    Opportunistic bacterial and fungal infections of the lower respiratory tract, most commonly those caused by Streptococcus pneumoniae (the pneumococcus), Mycobacterium tuberculosis, and Pneumocystis jirovecii, remain the major causes of mortality in those infected with human immunodeficiency virus (HIV). Bacterial respiratory pathogens most prevalent in those infected with HIV, other than M. tuberculosis, represent the primary focus of the current review with particular emphasis on the pneumococcus, the leading cause of mortality due to HIV infection in the developed world. Additional themes include (1) risk factors; (2) the predisposing effects of HIV-mediated suppression on pulmonary host defenses, possibly intensified by smoking; (3) clinical and laboratory diagnosis, encompassing assessment of disease severity and outcome; and (4) antibiotic therapy. The final section addresses current recommendations with respect to pneumococcal immunization in the context of HIV infection, including an overview of the rationale underpinning the current "prime-boost" immunization strategy based on sequential administration of pneumococcal conjugate vaccine 13 and pneumococcal polysaccharide vaccine 23.

  5. Autoimmune Cytopenias In Common Variable Immunodeficiency

    PubMed Central

    Podjasek, Jenna C.; Abraham, Roshini S.

    2012-01-01

    Common variable immunodeficiency (CVID) is a humoral immunodeficiency whose primary diagnostic features include hypogammaglobulinemia involving two or more immunoglobulin isotypes and impaired functional antibody responses in the majority of patients. While increased susceptibility to respiratory and other infections is a common thread that binds a large cross-section of CVID patients, the presence of autoimmune complications in this immunologically and clinically heterogeneous disorder is recognized in up to two-thirds of patients. Among the autoimmune manifestations reported in CVID (20–50%; Chapel et al., 2008; Cunningham-Rundles, 2008), autoimmune cytopenias are by far the most common occurring variably in 4–20% (Michel et al., 2004; Chapel et al., 2008) of these patients who have some form of autoimmunity. Association of autoimmune cytopenias with granulomatous disease and splenomegaly has been reported. The spectrum of autoimmune cytopenias includes thrombocytopenia, anemia, and neutropenia. While it may seem paradoxical “prima facie” that autoimmunity is present in patients with primary immune deficiencies, in reality, it could be considered two sides of the same coin, each reflecting a different but inter-connected facet of immune dysregulation. The expansion of CD21 low B cells in CVID patients with autoimmune cytopenias and other autoimmune features has also been previously reported. It has been demonstrated that this unique subset of B cells is enriched for autoreactive germline antibodies. Further, a correlation has been observed between various B cell subsets, such as class-switched memory B cells and plasmablasts, and autoimmunity in CVID. This review attempts to explore the most recent concepts and highlights, along with treatment of autoimmune hematological manifestations of CVID. PMID:22837758

  6. Cardiac-specific PID1 overexpression enhances pressure overload-induced cardiac hypertrophy in mice.

    PubMed

    Liu, Yaoqiu; Shen, Yahui; Zhu, Jingai; Liu, Ming; Li, Xing; Chen, Yumei; Kong, Xiangqing; Song, Guixian; Qian, Lingmei

    2015-01-01

    PID1 was originally described as an insulin sensitivity relevance protein, which is also highly expressed in heart tissue. However, its function in the heart is still to be elucidated. Thus this study aimed to investigate the role of PID1 in the heart in response to hypertrophic stimuli. Samples of human failing hearts from the left ventricles of dilated cardiomyopathy (DCM) patients undergoing heart transplants were collected. Transgenic mice with cardiomyocyte-specific overexpression of PID1 were generated, and cardiac hypertrophy was induced by transverse aortic constriction (TAC). The extent of cardiac hypertrophy was evaluated by echocardiography as well as pathological and molecular analyses of heart samples. A significant increase in PID1 expression was observed in failing human hearts and TAC-treated wild-type mouse hearts. When compared with TAC-treated wild-type mouse hearts, PID1-TG mouse showed a significant exacerbation of cardiac hypertrophy, fibrosis, and dysfunction. Further analysis of the signaling pathway in vivo suggested that these adverse effects of PID1 were associated with the inhibition of AKT, and activation of MAPK pathway. Under pathological conditions, over-expression of PID1 promotes cardiac hypertrophy by regulating the Akt and MAPK pathway. © 2015 S. Karger AG, Basel.

  7. Do short-term markers of treatment efficacy predict long-term sequelae of PID?

    PubMed Central

    Trautmann, Gail M.; Kip, Kevin E.; Richter, Holly E.; Soper, David E.; Peipert, Jeffrey F.; Nelson, Deborah B.; Trout, Wayne; Schubeck, Dianne; Bass, Debra C.; Ness, Roberta B.

    2008-01-01

    Objective To assess whether short-term markers, often used to measure clinical cure after treatment for pelvic inflammatory disease (PID), predict sequelae of lack of pregnancy, recurrent PID, and chronic pelvic pain. Study Design Women with mild-to-moderate PID were assessed after treatment initiation at five days for tenderness (n=713) and at thirty days for tenderness, cervical infections and endometritis (n=298). Pregnancy, recurrent PID and chronic pelvic pain were evaluated after 84 months, on average. Results Pelvic tenderness at five and at thirty days significantly elevated the risk for developing chronic pelvic pain; tenderness at thirty days was also significantly associated with recurrent PID. However, pelvic tenderness at five and at thirty days were only modestly clinically predictive of chronic pelvic pain or recurrent PID (positive predictive values 22.1–66.9%). No short-term marker significantly influenced the likelihood of achieving a pregnancy. Conclusion Tenderness at 5 or 30 days did not accurately predict the occurrence of PID-related reproductive morbidities. CONCISE Tenderness at 5 or 30 days and microbiologic cure post-pelvic inflammatory disease treatment did not accurately predict long-term sequelae including chronic pelvic pain, fertility, and recurrence. PMID:18166300

  8. Black box modeling of PIDs implemented in PLCs without structural information: a support vector regression approach.

    PubMed

    Salat, Robert; Awtoniuk, Michal

    In this report, the parameters identification of a proportional-integral-derivative (PID) algorithm implemented in a programmable logic controller (PLC) using support vector regression (SVR) is presented. This report focuses on a black box model of the PID with additional functions and modifications provided by the manufacturers and without information on the exact structure. The process of feature selection and its impact on the training and testing abilities are emphasized. The method was tested on a real PLC (Siemens and General Electric) with the implemented PID. The results show that the SVR maps the function of the PID algorithms and the modifications introduced by the manufacturer of the PLC with high accuracy. With this approach, the simulation results can be directly used to tune the PID algorithms in the PLC. The method is sufficiently universal in that it can be applied to any PI or PID algorithm implemented in the PLC with additional functions and modifications that were previously considered to be trade secrets. This method can also be an alternative for engineers who need to tune the PID and do not have any such information on the structure and cannot use the default settings for the known structures.

  9. Interval type-2 fuzzy PID controller for uncertain nonlinear inverted pendulum system.

    PubMed

    El-Bardini, Mohammad; El-Nagar, Ahmad M

    2014-05-01

    In this paper, the interval type-2 fuzzy proportional-integral-derivative controller (IT2F-PID) is proposed for controlling an inverted pendulum on a cart system with an uncertain model. The proposed controller is designed using a new method of type-reduction that we have proposed, which is called the simplified type-reduction method. The proposed IT2F-PID controller is able to handle the effect of structure uncertainties due to the structure of the interval type-2 fuzzy logic system (IT2-FLS). The results of the proposed IT2F-PID controller using a new method of type-reduction are compared with the other proposed IT2F-PID controller using the uncertainty bound method and the type-1 fuzzy PID controller (T1F-PID). The simulation and practical results show that the performance of the proposed controller is significantly improved compared with the T1F-PID controller. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

  10. Modelling and Control of the Qball X4 Quadrotor System based on Pid and Fuzzy Logic Structure

    NASA Astrophysics Data System (ADS)

    Bodrumlu, Tolga; Turan Soylemez, Mehmet; Mutlu, Ilhan

    2017-01-01

    This work focuses on a quadrocopter model, which was developed by QuanserTM and named as Qball X4. First, mathematical model of the Qball X4 is obtained. Then, a conventional PID control technique is presented. This PID control parameters come from Qball user manual. After the presentation of conventional PID control, as an extension of the conventional PID control theory, a different fuzzy controller structure is given. The proposed fuzzy controller structure is based on fuzzy logic and its name is PID type fuzzy controller. All of the simulations are done in MATLABTM environment.

  11. Application of adaptive PID control based on RBF-NN for the supercritical main steam

    NASA Astrophysics Data System (ADS)

    Li, Yun-Juan; Fang, Yan-jun

    2012-01-01

    The traditional PID control with RBF function the nerve network integration and made based on RBF the nerve network the PID controller. the controller for the supercritical main system, the network for temperature control system RBF an on-line to identify and build up the reference in the line and PID controller model for providing information and controllers of the online study to their control, adjust the parameter from online, the performance indicators. MATLAB simulation results show that the controller for temperature system has good control, not only keep track of good performance and robustness better.

  12. Application of adaptive PID control based on RBF-NN for the supercritical main steam

    NASA Astrophysics Data System (ADS)

    Li, Yun-Juan; Fang, Yan-Jun

    2011-12-01

    The traditional PID control with RBF function the nerve network integration and made based on RBF the nerve network the PID controller. the controller for the supercritical main system, the network for temperature control system RBF an on-line to identify and build up the reference in the line and PID controller model for providing information and controllers of the online study to their control, adjust the parameter from online, the performance indicators. MATLAB simulation results show that the controller for temperature system has good control, not only keep track of good performance and robustness better.

  13. Variable Gain Type Internal Model Control-PID Speed Control for Ultrasonic Motors

    NASA Astrophysics Data System (ADS)

    Tanaka, Kanya; Yoshimura, Yoshie; Wakasa, Yuji; Akashi, Takuya

    Ultrasonic motors (USM) causes serious characteristic changes during operation. It is difficult for the conventional internal model control (IMC) proportional integral differential (PID) control to compensate such characteristic changes of the plant. To solve these problems, we propose a method of variable gain type IMC-PID control. In the proposed method, plant parameters are identified on line and these estimated parameters are used for adjusting three gains of PID. Then the proposed method makes it possible to compensate characteristic changes of the plant. The effectiveness of the proposed control method have been confirmed by experiments using the existing ultrasonic motors servo system.

  14. Improvement of speed control performance using PID type neurocontroller in an electric vehicle system