Manish Butte

Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy.

Viruses. 2014;6(11):4140-4164

Authors: Niederer HA, Bangham CR

Abstract
Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety.

PMID: 25365582 [PubMed – as supplied by publisher]

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Hyper-IgE syndromes: reviewing PGM3 deficiency.

Curr Opin Pediatr. 2014 Dec;26(6):697-703

Authors: Yang L, Fliegauf M, Grimbacher B

Abstract
PURPOSE OF REVIEW: The hyper-IgE syndromes have been recognized as a group of primary immunodeficiencies characterized by eczema, recurrent skin and lung infections, and elevated serum IgE. Recently, mutations in phosphoglucomutase 3 (encoding PGM3, which is involved in the protein glycosylation pathway) have been identified in autosomal recessive forms of hyper-IgE syndromes.
RECENT FINDINGS: Autosomal recessive, hypomorphic PGM3 mutations cause a multisystem disorder, characterized by both a congenital glycosylation disease and a hyper-IgE syndrome. The reported mutations in PGM3 led to an impaired biosynthesis of UDP-GlcNAc and impaired tri-antennary and tetra-antennary N-glycan structures. Laboratory results in patients showed eosinophilia, a T-cell proliferation defect, and a reversed CD4/CD8 ratio. The impaired glycosylation in PGM3-mutant patients will not only affect proteins involved in the immune system, and thus causes a multisystem phenotype.
SUMMARY: The identification of hyper-IgE syndromes-associated mutations in PGM3 provides the basis for future studies on the pathophysiology and the molecular mechanisms of eczema, IgE dysregulation, and increased susceptibility to infections.

PMID: 25365149 [PubMed – in process]

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Invasive pneumococcal disease in children can reveal a primary immunodeficiency.

Pediatrics. 2014 Nov;134 Suppl 3:S180-1

Authors: Fleisher TA

PMID: 25363989 [PubMed – in process]

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Survey of early complications of primary skin graft and secondary skin graft (delayed) surgery after resection of burnwaste in hospitalized burn patients.

Glob J Health Sci. 2014;6(7 Spec No):38456

Authors: Enshaei A, Masoudi N

Abstract
INTRODUCTION: Burning is the second most common cause of home injuries in Iran that is often the cause of conflicts between children and young adults. Burning can lead to early and late complications that scar and contracture are the most common. Burn waste treatment is done by two methods: excision and then skin graft after the formation of granulation tissue; and excision and graft simultaneously that in this study, these two methods are compared.
METHODS: This was performed as a quasi-experimental analysis and retrospective study on all patients who were hospitalized for burn scar. All patients who have associated with weak eningimmune diseases such as diabetes, acquired immunodeficiency or congenital, taking steroids and patients undergoing chemotherapy etc. are excluded. The method of grafting in patients is primary graft procedure that was compared with patients who are treated using secondary graft. Data collected through review of patients’ hospital and clinic chart.
RESULTS: The mean burn percentage in the primary repair group was 14.4% and in the delayed repair group was 16.6%, respectively. The incidence of hematoma in both groups was zero. Skin necrosis and graft rejection and infection in the primary repair group was in 3.7% of patients and in the delayed repair group was in 1.2% of cases (P=0.5) CONCLUSION: Based on the findings of this study, no difference was observed between the two methods of excision and primary graft with delayed graft in the incidence of graft rejection. Due to the shorter treatment of primary graft and patient satisfaction and also according to the findings of this study excision and primary graft method seems appropriate method for treating old waste burning. 

PMID: 25363185 [PubMed – in process]

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Recurrent meningitis in a child with IgG3 subclass deficiency.

J Pak Med Assoc. 2014 Aug;64(8):963-5

Authors: Vehapoglu A, Ozgurhan G, Demir AD, Uzuner S, Nursoy MA, Turkmen S

Abstract
Recurrent meningitis is an uncommon life-threatening condition. Here, the case of a 6-year-old boy is reported who had two episodes of meningitis with an IgG3 subclass deficiency. The boy had aseptic meningitis at the age of 3 years, followed by bacterial meningitis at the age of 4 years. Primary immunoglobulin deficiencies are a group of disorders associated with an increased incidence and/or severity of infection. Recurrent infections, sinusitis, bronchitis, and pneumonia are the most frequently observed illnesses in patients with IgG subclass deficiencies, of which an IgG3 subclass deficiency is the most common, especially in adults. Although cases of recurrent viral or bacterial meningitis have been reported, herein a patient is presented with recurrence of aseptic and bacterial meningitis 1 year after the initial episode. Some researchers recommend that all children with episodes of recurrent meningitis should be screened for primary immunoglobulin or complement deficiencies.

PMID: 25252530 [PubMed – indexed for MEDLINE]

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Addressing diagnostic challenges in primary immunodeficiencies: laboratory evaluation of Toll-like receptor- and NF-κB-mediated immune responses.

Crit Rev Clin Lab Sci. 2014 Apr;51(2):112-23

Authors: Frans G, Meyts I, Picard C, Puel A, Zhang SY, Moens L, Wuyts G, Van der Werff Ten Bosch J, Casanova JL, Bossuyt X

Abstract
Toll-like receptors (TLRs) play an important role in immunity and mediate their actions via multiple signaling pathways, in particular, the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) pathway. Rare inherited defects of TLR- and NF-κB-dependent responses have recently been recognized. These primary immunodeficiencies predispose children to life-threatening infections and often remain undiagnosed. Establishing a sensitive, specific, cost-effective and simple method for diagnosis is therefore important. In this article, we review the known defects of TLR- and NF-κB-mediated pathways and the assays that can be used to screen for such defects.

PMID: 24533908 [PubMed – indexed for MEDLINE]

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

Biol Blood Marrow Transplant. 2014 Feb;20(2):243-9

Authors: Lane JP, Evans PT, Nademi Z, Barge D, Jackson A, Hambleton S, Flood TJ, Cant AJ, Abinun M, Slatter MA, Gennery AR

Abstract
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.

PMID: 24225641 [PubMed – indexed for MEDLINE]

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Do Immunocompromised Children Benefit from Having Surgical Lung Biopsy Performed?

Acta Haematol. 2014 Oct 29;133(2):205-209

Authors: Goldstein G, Keller N, Bilik R, Bielorai B, Toren A

Abstract
Background: Surgical lung biopsy is considered a gold standard for the evaluation of pulmonary disease in immunocompromised children. However, in the literature, its accuracy and the rate of complications vary. Objective: We aimed to evaluate the yield of surgical lung biopsies in the management of persistent pulmonary findings in immunocompromised children. Methods: We performed a retrospective review of clinical records of immunocompromised children who underwent surgical lung biopsies, and evaluated the impact that preoperative factors had on outcomes. Results: Twenty-five patients underwent 27 surgical lung biopsies. The underlying immunodeficiency included allogeneic stem cell transplantation (n = 12), chemotherapy for solid tumors (n = 6), hematologic malignancy (n = 4), primary immunodeficiency (n = 4) and chronic steroid use (n = 1). Biopsies provided a specific histopathologic or microbiologic diagnosis in 10 cases (37%). No preoperative factor predicted a diagnostic biopsy. Five of the 27 biopsies were beneficial for the patients (18%). A major complication related to the procedure was reported for 1 biopsy (4%). Conclusions: We conclude that surgical lung biopsy in pediatric immunocompromised patients appears to be safe, but has a relatively low diagnostic yield and an even lower yield with regards to the benefit it provides. © 2014 S. Karger AG, Basel.

PMID: 25358357 [PubMed – as supplied by publisher]

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Refractory invasive aspergillosis controlled with posaconazole and pulmonary surgery in a patient with chronic granulomatous disease: case report.

Ital J Pediatr. 2014;40:2

Authors: Kepenekli E, Soysal A, Kuzdan C, Ermerak NO, Yüksel M, Bakır M

Abstract
Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Among primary immunodefiencies, chronic granulomatous disease (CGD) has the highest prevalence of invasive fungal diseases. Voriconazole is recommended for the primary treatment of invasive aspergillosis in most patients. In patients whose aspergillosis is refractory to voriconazole, therapeutic options include changing class of antifungal, for example using an amphotericin B formulation, an echinocandin, combination therapy, or further use of azoles. Posaconazole is a triazole derivative which is effective in Aspergillosis prophylaxis and treatment. Rarely, surgical therapy may be needed in some patients. Lesions those are contiguous with the great vessels or the pericardium, single cavitary lesion that cause hemoptysis, lesions invading the chest wall, aspergillosis that involves the skin and the bone are the indications for surgical therapy.Chronic granulomatous disease (CGD) is an inherited immundeficiency caused by defects in the phagocyte nicotinamide adenine dinucleotidephosphate (NADPH) oxidase complex which is mainstay of killing microorganisms. CGD is characterized by recurrent life-threatening bacterial and fungal infections and by abnormally exuberant inflammatory responses leading to granuloma formation, such as granulomatous enteritis, genitourinary obstruction, and wound dehiscence. The diagnosis is made by neutrophil function testing and the genotyping.Herein, we present a case with CGD who had invasive pulmonary aspergillosis refractory to voriconazole and liposomal amphotericine B combination therapy that was controlled with posaconazole treatment and pulmonary surgery.

PMID: 24401677 [PubMed – indexed for MEDLINE]

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Identification of Two Novel Mutations in Patients With X-Linked Primary Immunodeficiencies.

Fetal Pediatr Pathol. 2014 Oct 29;

Authors: Yu L, Wang X, Wang Y, Wang J

Abstract
Primary immunodeficiency diseases (PID) are a heterogeneous group of inherited disorders with defects in one or more component of the immune system. In this study, we analyzed gene mutations in four X-linked PID pedigrees, which include one X- linked agammaglobulinemia (XLA) pedigree, one X-linked chronic granulomatous disease (XCGD) pedigree, and two X-linked Hyper IgM syndrome (XHIGM) pedigrees. Sequence analysis of the BTK gene revealed a novel mutation (c.1802_1803delinsGCC, p.Phe601CysfsX3) which results in the developmental arrest of B cells in the bone marrow. Sequence analysis of the CYBB gene revealed a recurrent frameshift mutation (c.1313_1314delinsT) in exon 10, which generates a premature stop codon (p.Lys438IlefsX63). One novel frameshift mutation (c.114delG, p.Ser39GlnfsX14) and one recurrent missense mutation (c.499G>C, p.Gly167Arg) were found in the CD40LG gene and cause defective T cell functioning. In conclusion, our study identified two novel mutations on the BTK and CD40LG genes in Chinese patients and established accurate and simple genetic diagnostic methods for three X-linked PID.

PMID: 25353698 [PubMed – as supplied by publisher]

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