Research

Recurrent infections in a patient with psoriatic arthritis and hypogammaglobulinemia, treated with conventional and biologic disease-modifying anti-rheumatic drugs-a primary or secondary entity?

Clin Rheumatol. 2017 May 09;:

Authors: Więsik-Szewczyk E, Kucharczyk A, Świerkocka K, Rutkowska E, Jahnz-Różyk K

Abstract
A 54-year-old man with confirmed psoriatic arthritis, treated with conventional and biologic disease-modifying anti-rheumatic drugs, suffered from severe, recurrent respiratory tract infections. He was found to have hypogammaglobulinemia. Further investigations confirmed the diagnosis of common variable immunodeficiency. Introduction of immunoglobulin G replacement therapy allowed for safe and effective treatment of psoriatic arthritis with etanercept and methotrexate. Patients with a history of recurrent infections on disease-modifying anti-rheumatic drugs and hypogammaglobulinemia should be assessed for primary antibody immunodeficiencies, even in adulthood.

PMID: 28488125 [PubMed – as supplied by publisher]

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An evaluation of the TREC assay with regard to the integration of SCID screening into the Dutch newborn screening program.

Clin Immunol. 2017 May 06;:

Authors: Blom M, Pico-Knijnenburg I, Veen MS, Boelen A, Bredius R, van der Burg M, Schielen P

Abstract
Newborn screening of severe combined immunodeficiency through the detection of T-cell receptor excision circles will provide the opportunity of treating before the occurrence of life-threatening infections. With the EnLite Neonatal TREC assay (PerkinElmer) and end-point PCR, 39 samples (3.0%) of 1295 heel prick cards of the Dutch newborn screening program required a retest after initial analysis. After retest, 21 samples (1.62%) gave TREC levels below cut-off. A significant reduction in TREC levels was observed in heel prick cards stored for three months (n=33) and one year (n=33). Preterm newborns (n=155) showed significantly lower TREC levels and a higher retest-rate than full-term newborns. Peripheral blood spots of 22 confirmed SCID patients and 17 primary immunodeficiency patients showed undetectable or low TREC-levels. These findings suggest that the EnLite Neonatal TREC assay is a suitable method for SCID-screening in the Netherlands, thereby providing guidance in the decisions concerning implementation into the Dutch program.

PMID: 28487086 [PubMed – as supplied by publisher]

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Genetic Engineering and Manufacturing of Hematopoietic Stem Cells.

Mol Ther Methods Clin Dev. 2017 Jun 16;5:96-105

Authors: Wang X, Rivière I

Abstract
The marketing approval of genetically engineered hematopoietic stem cells (HSCs) as the first-line therapy for the treatment of severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) is a tribute to the substantial progress that has been made regarding HSC engineering in the past decade. Reproducible manufacturing of high-quality, clinical-grade, genetically engineered HSCs is the foundation for broadening the application of this technology. Herein, the current state-of-the-art manufacturing platforms to genetically engineer HSCs as well as the challenges pertaining to production standardization and product characterization are addressed in the context of primary immunodeficiency diseases (PIDs) and other monogenic disorders.

PMID: 28480310 [PubMed – in process]

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

J Clin Immunol. 2017 May 08;:

Authors: Veramendi-Espinoza LE, Zafra-Tanaka JH, Pérez-Casquino GA, Córdova-Calderón WO

Abstract
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.

PMID: 28484900 [PubMed – as supplied by publisher]

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Hypoxic preconditioning of myoblasts implanted in a tissue engineering chamber significantly increases local angiogenesis via upregulation of myoblast VEGF-A expression, and downregulation of miRNA-1, miRNA-206 and Angiopoietin 1.

J Tissue Eng Regen Med. 2017 May 06;:

Authors: Taylor CJ, Church JE, Williams MD, Gerrand YW, Keramidaris E, Palmer JA, Galea LA, Penington AJ, Morrison WA, Mitchell GM

Abstract
Vascularization is a major hurdle for growing 3 dimensional tissue engineered constructs. This study investigated the mechanisms involved in hypoxic preconditioning of primary rat myoblasts in vitro and their influence on local angiogenesis post-implantation. Primary rat myoblast cultures were exposed to 90 minutes hypoxia at < 1% oxygen followed by normoxia for 24 hours. RT PCR evaluation indicated that 90 min. hypoxia resulted in significant downregulation of miRNA-1 and miRNA-206 (p < 0.05), and Angiopoietin-1 (p < 0.05) with upregulation of VEGF-A (p < 0.05). The miRNA-1 and Angiopoietin 1 responses remained significantly downregulated after a 24 hour rest phase. In addition, direct inhibition of miR-206 in L6 myoblasts caused a significant increase in VEGF-A expression (p < 0.05), further establishing that changes in VEGF-A expression are influenced by miR-206. Of the myogenic genes examined, MyoD, was significantly upregulated, only after 24 hours rest (p < 0.05). Preconditioned or control myoblasts were implanted with Matrigel™ into isolated bilateral tissue engineering chambers incorporating a flow-through epigastric vascular pedicle, in severe combined immunodeficiency mice, and chamber tissue harvested 14 days later. Chambers implanted with preconditioned myoblasts had a significantly increased percent volume of blood vessels (p = 0.0325) compared to chambers implanted with control myoblasts. Hypoxic preconditioned myoblasts promote vascularization of constructs via VEGF upregulation, and downregulation of Angiopoietin 1, miRNA-1 and miRNA-206. The relatively simple strategy of hypoxic pre-conditioning of implanted cells – including non-stem cell types has broad, future applications in tissue engineering of skeletal muscle and other tissues, as a technique to significantly increase implant site angiogenesis.

PMID: 28477583 [PubMed – as supplied by publisher]

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Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency.

BMC Res Notes. 2017 May 05;10(1):177

Authors: Al-Hammadi S, Alsuwaidi AR, Alshamsi ET, Ghatasheh GA, Souid AK

Abstract
BACKGROUND: The Bacillus Calmette-Guérin (BCG) preparations are live-attenuated derivatives of Mycobacterium bovis. These products are used to vaccinate infants at birth, a practice that may result in a disseminated infection in those patients who have an unidentified immunodeficiency.
CASE PRESENTATION: Patients who were immunized at birth with BCG and who developed a disseminated infection are reported here to emphasize the importance of taking an extensive medical history before ‎giving the BCG vaccine. Patient 1 has a sibling who had familial hemophagocytic lymphohistiocytosis. Patient 2 has a severe immunodeficiency with profound lymphopenia. Patient 3 has a sibling who had a disseminated BCG infection. Patient 4 has two siblings with an immunodeficiency disorder; one sibling passed away in infancy and one is receiving regular immunoglobulin infusions. Patient 5 has profound lymphopenia and his brother had cytomegalovirus (CMV) pneumonitis and passed away in infancy.
CONCLUSIONS: These unfortunate events could have been avoided by compiling the relevant clinical and laboratory information. These cases also underscore the importance of a strict adherence to the BCG vaccine policies. Local and international registries that estimate the birth prevalence of primary immune deficiencies are needed prior to implementing universal BCG vaccination administration.

PMID: 28476145 [PubMed – in process]

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Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression.

Oncotarget. 2017 Apr 17;:

Authors: Andrlová H, Mastroianni J, Madl J, Kern JS, Melchinger W, Dierbach H, Wernet F, Follo M, Technau-Hafsi K, Has C, Mittapalli VR, Idzko M, Herr R, Brummer T, Ungefroren H, Busch H, Boerries M, Narr A, Ihorst G, Vennin C, Schmitt-Graeff A, Minguet S, Timpson P, Duyster J, Meiss F, Römer W, Zeiser R

Abstract
Novel targeted and immunotherapeutic approaches have revolutionized the treatment of metastatic melanoma. A better understanding of the melanoma-microenvironment, in particular the interaction of cells with extracellular matrix molecules, may help to further improve these new therapeutic strategies.We observed that the extracellular matrix molecule biglycan (Bgn) was expressed in certain human melanoma cells and primary fibroblasts when evaluated by microarray-based gene expression analysis. Bgn expression in the melanoma tissues correlated with low overall-survival and low progression-free-survival in patients. To understand the functional role of Bgn we used gene-targeted mice lacking functional Bgn. Here we observed that melanoma growth, metastasis-formation and tumor-related death were reduced in Bgn-/- mice compared to Bgn+/+ mice. In vitro invasion of melanoma cells into organotypic-matrices derived from Bgn-/- fibroblasts was reduced compared to melanoma invasion into Bgn-proficient matrices. Tissue stiffness as determined by atomic-force-microscopy was reduced in Bgn-/- matrices. Isolation of melanoma cells and fibroblasts from the stiffer Bgn+/+ matrices revealed an increase in integrin-β1 expression compared to the Bgn-/- fibroblast matrices. Overexpression of integrin-β1 in B16-melanoma cells abolished the survival benefit seen in Bgn-/- mice. Consistent with the studies performed in mice, the abundance of Bgn-expression in human melanoma samples positively correlated with the expression of integrin-β1, which is in agreement with results from the organotypic invasion-assay and the in vivo mouse studies.This study describes a novel role for Bgn-related tissue stiffness in the melanoma-microenvironment via regulation of integrin-β1 expression by melanoma cells in both mice and humans.

PMID: 28476030 [PubMed – as supplied by publisher]

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Immunodeficiency-Associated Lymphoid Hyperplasia As a Cause of Intussusception in a Case of Activated PI3K-δ Syndrome.

Front Pediatr. 2017;5:71

Authors: Mettman D, Thiffault I, Dinakar C, Saunders C

Abstract
Activated PI3K-δ syndrome refers to a recently described primary immunodeficiency syndrome consisting of recurrent sinopulmonary infections, lymphadenopathy, mucosal lymphoid aggregates, increased susceptibility to Epstein-Barr virus and cytomegalovirus, and increased incidence of B-cell lymphomas. Variants in PIK3CD, which encodes the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform, enhance membrane association and kinase activity, resulting in increased signal transduction through the PI3K-Akt pathway. Whole-exome sequencing revealed a pathogenic PIK3CD variant in a patient with history of immunologic impairment, recurrent sinopulmonary infections, and lymphoid hyperplasia presenting as intussusception. This case illustrates that while lymphoid hyperplasia secondary to immunodeficiency is most often unsurprising and non-threatening, it can present as an emergency-like intussusception.

PMID: 28469999 [PubMed – in process]

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Identifying dynamic pathway interactions based on clinical information.

Comput Biol Chem. 2017 Apr 24;68:260-265

Authors: Kim S

Abstract
In this paper, we introduce approaches for inferring dynamic pathway interactions by converting static datasets into dynamic datasets using patients’ clinical information. One approach uses survival time-based dynamic datasets, and the other uses grade- and stage-based dynamic datasets. Based on cancer grades and stages, we generated six dynamic levels and obtained two pairs of significant pathways out of twelve enriched pathways. One pair of the pathways included CELL ADHESION MOLECULES CAMS and SYSTEMIC LUPUS ERYTHEMATOSUS (correlation coefficient=1.00), in which CD28, CD86, HLA-DOA, and HLA-DOB were identified as common genes in the pathways. The other pair of the pathways included SPLICEOSOME and PRIMARY IMMUNODEFICIENCY (correlation coefficient=0.94) with no common genes identified.

PMID: 28463775 [PubMed – as supplied by publisher]

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Reference values for B-cell surface markers and co-receptors associated with primary immune deficiencies in healthy Turkish children.

Int J Immunopathol Pharmacol. 2017 Apr 01;:394632017707609

Authors: Azarsiz E, Karaca NE, Aksu G, Kutukculer N

Abstract
In order to evaluate B-lymphocyte subsets of patients with primary immunodeficiencies, the normal values for national healthy children have to be used as a reference. Recently, B-cell co-receptor markers (CD19, CD21, and CD81) and CD20, CD22, and CD27 deficiencies have been reported in relation with different primary immunodeficiency diseases. The objective of this study was to establish national reference values for B-lymphocyte co-receptors and some surface markers, CD20, CD22, CD27, as well as classic lymphocyte subsets in the peripheral blood of healthy children. A total of 90 healthy children were included in this study. Complete blood counts were performed and cells with CD3, CD4, CD8, CD19, CD16/56, CD20, CD21, CD22, CD27, and CD81 surface markers were simultaneously detected by flow cytometry. The children were evaluated in three age subgroups, 0-1, 1-6, and >6 years, and minimum, maximum, mean, mean minus standard deviation, and 2.5-97.5 percentile values were all determined. By establishing reliable reference ranges for these surface markers, we hoped to help identifying and classifying some primary immunodeficiency patients, especially those defined as unclassified hypogammaglobulinemia and those without definite diagnosis.

PMID: 28449602 [PubMed – as supplied by publisher]

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