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Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis.

March 28, 2019 By Manish Butte

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Synovial Inflammation in Rheumatoid Arthritis.

Med Sci Monit. 2019 Mar 27;25:2246-2256

Authors: Xiong Y, Mi BB, Liu MF, Xue H, Wu QP, Liu GH

Abstract
BACKGROUND Rheumatoid arthritis (RA) has a high prevalence in the elderly population. The genes and pathways in the inflamed synovium in patients with RA are poorly understood. This study aimed to identify differentially expressed genes (DEGs) linked to the progression of synovial inflammation in RA using bioinformatics analysis. MATERIAL AND METHODS Gene expression profiles of datasets GSE55235 and GSE55457 were acquired from the Gene Expression Omnibus (GEO) database. DEGs were identified using Morpheus software, and co-expressed DEGs were identified with Venn diagrams. Protein-protein interaction (PPI) networks were assembled with Cytoscape software and separated into subnetworks using the Molecular Complex Detection (MCODE) algorithm. The functions of the top module were assessed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed. RESULTS DEGs that were upregulated were significantly enhanced in protein binding, the cell cytosol, organization of the extracellular matrix (ECM), regulation of RNA transcription, and cell adhesion. DEGs that were downregulated were associated with control of the immune response, B-cell and T-cell receptor signaling pathway regulation. KEGG pathway analysis showed that upregulated DEGs enhanced pathways associated with the cell adherens junction, osteoclast differentiation, and hereditary cardiomyopathies. Downregulated DEGs were enriched in primary immunodeficiency, cell adhesion molecules (CAMs), cytokine-cytokine receptor interaction, and hematopoietic cell lineages. CONCLUSIONS The findings from this bioinformatics network analysis study identified molecular mechanisms and the key hub genes that may contribute to synovial inflammation in patients with RA.

PMID: 30916045 [PubMed – in process]

Fast and Quantitative Identification of Ex Vivo Precise Genome Targeting-Induced Indel Events by IDAA.

March 27, 2019 By Manish Butte

Fast and Quantitative Identification of Ex Vivo Precise Genome Targeting-Induced Indel Events by IDAA.

Methods Mol Biol. 2019;1961:45-66

Authors: König S, Yang Z, Wandall HH, Mussolino C, Bennett EP

Abstract
Recent developments in gene targeting methodologies such as ZFNs, TALENs, and CRISPR/Cas9 have revolutionized approaches for gene modifications in cells, tissues, and whole animals showing great promise for translational applications. With regard to CRISPR/Cas9, a variety of repurposed systems have been developed to achieve gene knock-out, base editing, targeted knock-in, gene activation/repression, epigenetic modulation, and locus-specific labeling. A functional communality of all CRISPR/Cas9 applications is the gRNA-dependent targeting specificity of the Cas9/gRNA complex that, for gene knock-out (KO) purposes, has been shown to dictate the indel formation potential. Therefore, the objective of a CRISPR/Cas9 KO set up is to identify gRNA designs that enable maximum out-of-frame insertion and/or deletion (indel) formation and thus, gRNA design becomes a proxy for optimal functionality of CRISPR/Cas9 KO and repurposed systems. To this end, validation of gRNA functionality depends on efficient, accurate, and sensitive identification of indels induced by a given gRNA design. For in vitro indel profiling the most commonly used methods are based on amplicon size discrimination or sequencing. Indel detection by amplicon analysis (IDAA™) is an alternative sensitive, fast, and cost-efficient approach ideally suited for profiling of indels induced by Cas9/gRNA with similar sensitivity, specificity, and resolution, down to single base discrimination, as the preferred next-generation sequencing-based indel profiling methodologies. Here we provide a protocol that is based on complexed Cas9/gRNA RNPs delivered to primary peripheral blood mononuclear cells (PBMCs) isolated from healthy individuals followed by quantitative IDAA indel profiling. Importantly, the protocol described benefits from a short “sample-to-data” turnaround time of less than 5 h. Thus, this protocol describes a methodology that provides a suitable and effective solution to validate and quantify the extent of ex vivo CRISPR/Cas9 targeting in primary cells.

PMID: 30912039 [PubMed – in process]

Nasal Nitric Oxide in Primary Immunodeficiency and Primary Ciliary Dyskinesia: Helping to Distinguish Between Clinically Similar Diseases.

March 27, 2019 By Manish Butte

Nasal Nitric Oxide in Primary Immunodeficiency and Primary Ciliary Dyskinesia: Helping to Distinguish Between Clinically Similar Diseases.

J Clin Immunol. 2019 Mar 26;:

Authors: Zysman-Colman ZN, Kaspy KR, Alizadehfar R, NyKamp KR, Zariwala MA, Knowles MR, Vinh DC, Shapiro AJ

Abstract
PURPOSE: Primary ciliary dyskinesia (PCD) is a rare disorder of the mucociliary clearance leading to recurrent upper and lower respiratory tract infections. PCD is difficult to clinically distinguish from other entities leading to recurrent oto-sino-pulmonary infections, including primary immunodeficiency (PID). Nasal nitric oxide (nNO) is a sensitive and specific diagnostic test for PCD, but it has not been thoroughly examined in PID. Past publications have suggested an overlap in nNO levels among subjects with PCD and PID. We sought to determine if nNO measurements among patients diagnosed with PID would fall significantly above the established PCD diagnostic cutoff value of 77 nL/min.
METHODS: Children > 5 years old and adults with definitive PID or PCD diagnoses were recruited from outpatient subspecialty clinics. Participants underwent nNO testing by standardized protocol using a chemiluminescence analyzer and completed a questionnaire concerning their chronic oto-sino-pulmonary symptoms, including key clinical criteria specific to diagnosed PCD (neonatal respiratory distress at term birth, year-round cough or nasal congestion starting before 6 months of age, any organ laterality defect).
RESULTS: Participants included 32 patients with PID, 27 patients with PCD, and 19 healthy controls. Median nNO was 228.9.1 nL/min in the PID group, 19.7 nL/min in the PCD group, and 269.4 in the healthy controls (p < 0.0001). Subjects with PCD were significantly more likely to report key clinical criteria specific to PCD, but approximately 25% of PID subjects also reported at least 1 of these key clinical criteria (mainly year-round cough or nasal congestion).
CONCLUSIONS: While key clinical criteria associated with PCD often overlap with the symptoms reported in PID, nNO measurement by chemiluminescence technology allows for effective discrimination between PID and PCD.

PMID: 30911954 [PubMed – as supplied by publisher]

Treatment of antibody immunodeficiency.

March 27, 2019 By Manish Butte

Treatment of antibody immunodeficiency.

Vnitr Lek. 2019;65(2):126-130

Authors: Litzman J

Abstract
The basis of treatment of patients with hypogammaglobulinemia, primary or secondary, is immunoglobulin replacement. Current immunoglobulin derivates contain highly purified IgG from healthy human donors. Intravenous or subcutaneous route are almost exclusively used at present. The treatment must be individualized. Adequate doses of immunoglobulin derivates must be administered to avoid frequent and severe infections of the respiratory tract. Antibiotic prophylaxis may be alternative and complementary treatment to immunoglobulin substitution.

PMID: 30909702 [PubMed – in process]

Primary immunodeficiencies in adults.

March 27, 2019 By Manish Butte

Primary immunodeficiencies in adults.

Vnitr Lek. 2019;65(2):109-116

Authors: Litzman J

Abstract
In contrast to general opinion, the issue of primary immunodeficiency is far from just a pediatric medicine; a large number of patients with primary immunodefciencies are not only treated, but also diagnosed in adulthood. The most important manifestation of these diseases are serious, unusual or ill-treatable infections. Some primary immune deficiency diseases manifest themselves in adulthood – mainly common variable immunodeficiency (CVID) and Goods syndrome (hypogammaglobulinemia with thymoma). Due to successful treatment, adults also suffer from illnesses manifestation of which begin in early infancy. Among these, the most common are patients with disorders of antibody production – for example, X-linked agammaglobulinemia or T-cell defect – Di George syndrome (thymus deficiency, morphological heart abnormalities, hypoparathyroidism). Another important group of primary immunodeficiencies are patients with hereditary angioedema (C1-INH deficiency). These patients do not suffer from an increased incidence of infections, but from swelling of the subcutaneous and submucosal tissues.

PMID: 30909700 [PubMed – in process]

Managing costs in primary immunodeficiency: minimal immunophenotyping and three national references.

March 26, 2019 By Manish Butte

Managing costs in primary immunodeficiency: minimal immunophenotyping and three national references.

APMIS. 2019 Apr;127(4):228-235

Authors: Dias ALA, da Silva RG, Cunha FGP, Morcillo AM, Lorand-Metze I, Vilela MMDS, Riccetto AGL

Abstract
Our aim was to evaluate the cost-effectiveness of a minimal lymphocyte subset quantification (LSQ) by flow cytometry as the first screening in children with clinically suspected primary immunodeficiency (PID). Two hundred sixty-eight Brazilian patients (0-21 years old) were studied. They were divided by clinical and phenotypical features into those fulfilling criteria for PID (PID phenotype) according to the 2017 International Union of Immunological Societies (IUIS) classification and those not fulfilling these criteria (non-PID phenotype). We evaluated how many patients had values below the 10th percentile for five lymphocyte subsets in peripheral blood, (suggestive of PID) according to reference values for Brazil, Italy and USA. Three lymphocyte subsets (T CD3/CD4, B CD19 and NK CD16/CD56) had p-value < 0.05 and Odds Ratio (OR) indicating a risk at least two times higher for the diagnosis of a PID phenotype. The application of Kappa coefficient (k) on Brazilian vs Italian and Brazilian vs US data sets resulted in k compatible with strong or excellent level of agreement between the three classification systems. The authors conclude that a number of CD3+ /CD4+ , CD19+ and CD16+ /CD56+ (NK) cells in peripheral blood <10th percentile represented a significant risk for the diagnosis of PID in this cohort. Natural killer (NK) deficiency is quite rare and has a very specific clinical profile. So, the analysis of these cells could be requested only in some cases, saving even more costs. The minimal immunophenotyping, with quantification of T CD4+ , CD19+ and in some cases CD16+ /CD56+ cells, may be a useful tool for the first screening of PID, saving costs, especially in developing countries.

PMID: 30908772 [PubMed – in process]

Oral features of Griscelli syndrome type II: A rare case report.

March 26, 2019 By Manish Butte

Oral features of Griscelli syndrome type II: A rare case report.

Spec Care Dentist. 2018 Nov;38(6):421-425

Authors: Tewari N, Rajwar A, Mathur VP, Chaudhari PK

Abstract
Griscelli syndrome (GS) is an autosomal-recessive disorder of the vesicle transport and membrane trafficking system first identified by Griscelli et al in 1978. The three types of GS have specific genetic defects and systemic manifestations apart from classic partial pigmentary dilution, resulting in hypopigmentation of skin and silvery hair. GS-II occurs due to a defect in the Rab27a gene and is characterized by primary immune deficiency along with accelerated phases of a hemophagocytic lymphohistiocytosis (HLH) crisis. This rare disorder has been widely studied for dermatological, hematological, and neurological manifestations; however, the oral features and presentations have not been elucidated in detail. This report presents a case of a 4-year-old male with known mutation c.550C > T or p.R184X mutation (ENST00000396307) in Rab27a with oral features.

PMID: 30207398 [PubMed – indexed for MEDLINE]

Castleman Disease in a Patient with Common Variable Immunodeficiency.

March 25, 2019 By Manish Butte

Castleman Disease in a Patient with Common Variable Immunodeficiency.

Case Reports Immunol. 2019;2019:5476383

Authors: Ricciardi L, Furci F, Ieni A, Macrì A

Abstract
Common variable immunodeficiency (CVID) is a primary immunodeficiency due to a disorder of the adaptive immune system which causes hypogammaglobulinemia and therefore an increased susceptibility to infection; noninfectious, inflammatory conditions including systemic autoimmunity and lymphoproliferative complications are also commonly associated with CVID. Castleman disease (CD) is a systemic disease clinically characterized by diffuse lymphadenopathy, splenomegaly, anemia, and systemic inflammatory symptoms. This makes CD a great mimicker of more common benign and malignant masses in the neck, chest, abdomen, and pelvis. A novel case of primary immunodeficiency (CVID) in a middle-aged woman, who developed multicentric CD (MDC) with splenomegaly, is described. The authors suggest that the onset of MCD and of the correlated splenomegaly was due to incorrect management of the hypogammaglobulinemia as immunoglobulin G (IgG) levels were not kept within normal ranges. Correct management of the hypogammaglobulinemia allowed splenectomy to be performed without any infectious surgical complications. MCD is reported for the first time in association with an adult case of CVID. The above reported case highlights the need for a timely correct diagnosis and treatment of CVID to avoid complications, which could cause recourse to splenectomy, such as in our case or development of malignancies.

PMID: 30906603 [PubMed]

Correction to: Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group.

March 25, 2019 By Manish Butte

Correction to: Imaging of Bronchial Pathology in Antibody Deficiency: Data from the European Chest CT Group.

J Clin Immunol. 2019 Mar 23;:

Authors: Schütz K, Alecsandru D, Grimbacher B, Haddock J, Bruining A, Driessen G, de Vries E, van Hagen PM, Hartmann I, Fraioli F, Milito C, Mitrevski M, Quinti I, Serra G, Kelleher P, Loebinger M, Litzman J, Postranecka V, Thon V, Babar J, Condliffe AM, Exley A, Kumararatne D, Screaton N, Jones A, Bondioni MP, Lougaris V, Plebani A, Soresina A, Sirignano C, Spadaro G, Galal N, Gonzalez-Granado LI, Dettmer S, Stirling R, Chapel H, Lucas M, Patel S, Farber CM, Meyts I, Banerjee AK, Hackett S, Hurst JR, Warnatz K, Gathmann B, Weidemann J, Berthold D, Baumann U, Chest CT in Antibody Deficiency Group

Abstract
In the original version of this article unfortunately two authors were missing: Dr. Jürgen Weidemann and Dr. Daniel Berthold. The correct list of authors is presented above.

PMID: 30905051 [PubMed – as supplied by publisher]

Revisiting Fatal Granulomatous Disease of Childhood Through an Autopsy: Still Lethal in the Developing World!

March 25, 2019 By Manish Butte

Revisiting Fatal Granulomatous Disease of Childhood Through an Autopsy: Still Lethal in the Developing World!

J Clin Immunol. 2019 Mar 21;:

Authors: Pilania RK, Prithvi A, Nambiyar K, Gupta K, Rawat A

PMID: 30903458 [PubMed – as supplied by publisher]