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Reduced-intensity conditioning for hematopoietic cell transplantation of chronic granulomatous disease.

Pediatr Blood Cancer. 2014 Aug 30;

Authors: Oshrine B, Morsheimer M, Heimall J, Bunin N

Abstract
Hematopoietic cell transplantation (HCT) is the only available curative therapy for chronic granulomatous disease (CGD), but its use is limited by transplant-related mortality (TRM) in patients who often come to transplant with existing infections or organ dysfunction. Reduction in the intensity of the preparative regimen mitigates these risks, but increases the potential for mixed donor-recipient chimerism (MC) that may progress to graft loss. Recently a busulfan-based reduced-intensity conditioning (RIC) regimen has been described with excellent survival and little MC. We report our experience with a similar RIC regimen at our institution, demonstrating problems with donor chimerism and graft loss. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.

PMID: 25175046 [PubMed – as supplied by publisher]

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Medical History, Lifestyle, Family History, and Occupational Risk Factors for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project.

J Natl Cancer Inst Monogr. 2014 Aug;2014(48):41-51

Authors: Slager SL, Benavente Y, Blair A, Vermeulen R, Cerhan JR, Costantini AS, Monnereau A, Nieters A, Clavel J, Call TG, Maynadié M, Lan Q, Clarke CA, Lightfoot T, Norman AD, Sampson JN, Casabonne D, Cocco P, de Sanjosé S

Abstract
BACKGROUND: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two subtypes of non-Hodgkin lymphoma. A number of studies have evaluated associations between risk factors and CLL/SLL risk. However, these associations remain inconsistent or lacked confirmation. This may be due, in part, to the inadequate sample size of CLL/SLL cases.
METHODS: We performed a pooled analysis of 2440 CLL/SLL cases and 15186 controls from 13 case-control studies from Europe, North America, and Australia. We evaluated associations of medical history, family history, lifestyle, and occupational risk factors with CLL/SLL risk. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: We confirmed prior inverse associations with any atopic condition and recreational sun exposure. We also confirmed prior elevated associations with usual adult height, hepatitis C virus seropositivity, living or working on a farm, and family history of any hematological malignancy. Novel associations were identified with hairdresser occupation (OR = 1.77, 95% CI = 1.05 to 2.98) and blood transfusion history (OR = 0.79, 95% CI = 0.66 to 0.94). We also found smoking to have modest protective effect (OR = 0.9, 95% CI = 0.81 to 0.99). All exposures showed evidence of independent effects.
CONCLUSIONS: We have identified or confirmed several independent risk factors for CLL/SLL supporting a role for genetics (through family history), immune function (through allergy and sun), infection (through hepatitis C virus), and height, and other pathways of immune response. Given that CLL/SLL has more than 30 susceptibility loci identified to date, studies evaluating the interaction among genetic and nongenetic factors are warranted.

PMID: 25174025 [PubMed – as supplied by publisher]

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Interpret and manage (not only autoimmune) cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment.

Blood. 2014 Aug 27;

Authors: Seidel MG

Abstract
Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PID). Especially when cytopenia is the initial symptom of PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and contain not only the exclusion of systemic lupus erythematosus, common variable immunodeficiency, autoimmune lymphoproliferative syndromes, but also hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, LRBA (lipopolysaccharide-responsive beige-like anchor) deficiency, activated PI3KD syndrome (APDS), XMEN disease (MAGT1 deficiency) and others. Immunosuppressive treatment often needs to be initiated urgently, impeding relevant further immunologic laboratory analyses aimed to define the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial to identify a certain proportion of PID pheno- and genotypes among rather 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 of cytopenias in PID is provided to facilitate the essential multidisciplinary management and to bridge approaches.

PMID: 25163701 [PubMed – as supplied by publisher]

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IgA deficiency in primary antiphospholipid syndrome.

Joint Bone Spine. 2014 Jan;81(1):97-8

Authors: Bonin CC, Rodrigues CE, de Carvalho JF

PMID: 23809213 [PubMed – indexed for MEDLINE]

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The Value of Family History in Diagnosing Primary Immunodeficiency Disorders.

Case Rep Pediatr. 2014;2014:516256

Authors: Hendaus MA, Alhammadi A, Adeli MM, Al-Yafei F

Abstract
Eliciting proper family medical history is critical in decreasing morbidity and mortality in patients with primary immunodeficiency disorders (PIDs). Communities with a common practice of consanguinity have a high rate of PIDs. We are presenting 2 cases where digging deeply into the family medical history resulted in the diagnosis of Omenn syndrome, a possibly fatal entity if not managed in a reasonable period.

PMID: 25161792 [PubMed – as supplied by publisher]

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Malakoplakia and Primary Immunodeficiency.

J Pediatr. 2014 Aug 22;

Authors: Archer SR, Abramowsky CR, Kobrynski L, Simoneaux S, Vogler LB, Ricketts RR, Parker C, Elawahbdeh N, Shehata BM

Abstract
Malakoplakia, a rare granulomatous disease caused by impaired macrophage response, has been reported only rarely in children. We report 3 unique cases, with lesions occurring in unusual locations in children with primary immune deficiencies.

PMID: 25155967 [PubMed – as supplied by publisher]

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Cryptococcal meningoencephalitis in a patient with hyper immunoglobulin M (IgM) syndrome: a case report.

BMC Res Notes. 2014 Aug 26;7(1):566

Authors: Malheiro L, Xerinda S, Sarmento A, Pinheiro MD, Lazzara D

Abstract
BACKGROUND: Cryptococcal meningoencephalitis is an opportunistic infection that predominantly affects immunocompromised patients. Hyper immunoglobulin M syndrome is a primary immunodeficiency syndrome that increases susceptibility to several opportunistic infections. Here, we report a case of cryptococcal meningoencephalitis in the context of hyper immunoglobulin M syndrome, a situation that has been reported very few times and whose management is not clearly defined. We describe our management of this case and the outcome of the patient to help in future similar situations.
CASE PRESENTATION: The patient is a 19-year-old Caucasian male student diagnosed with X-linked hyper immunoglobulin M syndrome and treated chronically with weekly intravenous immunoglobulin and daily sulfamethoxazole-trimethoprim. He was admitted to the infectious diseases ward because of headache, diplopia and a cerebral-spinal fluid analysis revealing cryptococcal meningoencephalitis. The patient was treated with liposomal amphotericin and flucytosine with a favorable outcome. Maintenance therapy with fluconazole has continued and will be sustained for 6 months following his upcoming bone marrow transplantation.
CONCLUSION: Monitoring for cryptococcal meningoencephalitis should be considered in patients with primary immunodeficiencies, as clinical manifestations may go unnoticed. In these patients, it is expected that chronic treatment with fluconazole will be the only treatment that will prevent reinfection or reactivation, and therefore should be kept at least until bone marrow transplant, the only curative treatment, is performed. It may, however, lead to intolerable side effects and hepatic toxicity.

PMID: 25155248 [PubMed – as supplied by publisher]

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Contribution of high-throughput DNA sequencing to the study of primary immunodeficiencies.

Eur J Immunol. 2014 Aug 22;

Authors: Picard C, Fischer A

Abstract
Primary immunodeficiencies (PIDs) are inborn errors of the immune system. PIDs have been characterized immunologically for the last 60 years and genetically, principally by Sanger DNA sequencing, over the last 30 years. The advent of next-generation sequencing (NGS) in 2011, with the development of whole-exome sequencing (WES) in particular, has facilitated the identification of previously unknown genetic lesions. NGS is rapidly generating a stream of candidate variants for an increasing number of genetically undefined PIDs. The use of NGS technology is ushering in a new era, by facilitating the discovery and characterization of new PIDs in patients with infections and other phenotypes, thereby helping to improve diagnostic accuracy. This review provides a historical overview of the identification of PIDs before NGS, and the advances and limitations of the use of NGS for the diagnosis and characterization of PIDs. This article is protected by copyright. All rights reserved.

PMID: 25154746 [PubMed – as supplied by publisher]

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Evolution of puma lentivirus in bobcats (Lynx rufus) and mountain lions (Puma concolor) in North America.

J Virol. 2014 Jul;88(14):7727-37

Authors: Lee JS, Bevins SN, Serieys LE, Vickers W, Logan KA, Aldredge M, Boydston EE, Lyren LM, McBride R, Roelke-Parker M, Pecon-Slattery J, Troyer JL, Riley SP, Boyce WM, Crooks KR, VandeWoude S

Abstract
Mountain lions (Puma concolor) throughout North and South America are infected with puma lentivirus clade B (PLVB). A second, highly divergent lentiviral clade, PLVA, infects mountain lions in southern California and Florida. Bobcats (Lynx rufus) in these two geographic regions are also infected with PLVA, and to date, this is the only strain of lentivirus identified in bobcats. We sequenced full-length PLV genomes in order to characterize the molecular evolution of PLV in bobcats and mountain lions. Low sequence homology (88% average pairwise identity) and frequent recombination (1 recombination breakpoint per 3 isolates analyzed) were observed in both clades. Viral proteins have markedly different patterns of evolution; sequence homology and negative selection were highest in Gag and Pol and lowest in Vif and Env. A total of 1.7% of sites across the PLV genome evolve under positive selection, indicating that host-imposed selection pressure is an important force shaping PLV evolution. PLVA strains are highly spatially structured, reflecting the population dynamics of their primary host, the bobcat. In contrast, the phylogeography of PLVB reflects the highly mobile mountain lion, with diverse PLVB isolates cocirculating in some areas and genetically related viruses being present in populations separated by thousands of kilometers. We conclude that PLVA and PLVB are two different viral species with distinct feline hosts and evolutionary histories. Importance: An understanding of viral evolution in natural host populations is a fundamental goal of virology, molecular biology, and disease ecology. Here we provide a detailed analysis of puma lentivirus (PLV) evolution in two natural carnivore hosts, the bobcat and mountain lion. Our results illustrate that PLV evolution is a dynamic process that results from high rates of viral mutation/recombination and host-imposed selection pressure.

PMID: 24741092 [PubMed – indexed for MEDLINE]

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A nonsense mutation in IKBKB causes combined immunodeficiency.

Blood. 2014 Aug 18;

Authors: Mousallem T, Yang J, Urban T, Wang H, Adeli M, Parrott RE, Roberts JL, Goldstein D, Buckley RH, Zhong XP

Abstract
Identification of the molecular etiologies of primary immunodeficiencies has led to important insights into the development and function of the immune system. We report here the cause of Combined Immunodeficiency in 4 patients from 2 different consanguineous Qatari families with similar clinical and immunologic phenotypes. The patients presented at an early age with fungal, viral and bacterial infections and hypogammaglobulinemia. Although their B- and T-cell numbers were normal, they had low regulatory T-cell and NK-cell numbers. Moreover, patients’ T-cells were mostly CD45RA(+) naíve cells and defective in activation following TCR stimulation. All patients contained the same homozygous nonsense mutation in IKBKB (R286X) revealed by whole-exome sequencing with undetectable IKKβ and severely decreased NEMO proteins. Mutant IKKβ(R286X) was unable to complex with IKKα/NEMO. Immortalized patient B-cells displayed impaired IκBα phosphorylation and NFκB nuclear translocation. These data indicate that mutated IKBKB is the likely cause of immunodeficiency in these four patients.

PMID: 25139357 [PubMed – as supplied by publisher]

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