X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by the clinical triad of increased susceptibility to primary Epstein-Barr virus (EBV) infection, dysgammaglobulinaemia and lymphoma. Most cases are caused by germline mutations in the SH2D1A gene, which encodes the adaptor molecule Signalling Lymphocytic Activation Molecule (SLAM)-associated protein (SAP). Recently, a subset of patients with an XLP-like phenotype was found to carry mutations in XIAP, the gene encoding the X-linked inhibitor of apoptosis protein (XIAP). Studies of XLP patients and Sap-/- mice reveal that loss of SAP expression impairs immune cell activities, such as natural killer and CD8+ T cell cytotoxicity, T cell cytokine production, activation-induced cell death, germinal centre formation and natural killer T cell development. Efforts to dissect the diverse roles of SAP and XIAP are enhancing our understanding of immune cell biology and defining how genetic defects in these molecules predispose to EBV-specific as well as more general cellular and humoral immune dysfunction. These studies are also highlighting critical signalling pathways that might be amenable to pharmacological targeting to improve the treatment of XLP and other disorders associated with impaired antiviral and antitumour immunity.     

Safety and efficacy of clopidogrel reloading in patients on chronic clopidogrel therapy who present with an acute coronary syndrome and undergo percutaneous coronary intervention

The clinical safety and efficacy of clopidogrel reloading in patients receiving long-term clopidogrel therapy who present with acute coronary syndromes and undergo percutaneous coronary intervention have not yet been evaluated. The study cohort comprised 1,368 consecutive patients receiving long-term clopidogrel therapy (75 mg/day) who had presented with acute coronary syndromes and underwent coronary artery stent implantation. In total, 926 patients were given a 600-mg clopidogrel loading dose (reload cohort) before cardiac catheterization, while 442 patients were not reloaded (no-reload cohort). Patients who had presented with cardiogenic shock or stable angina were excluded. The 2 cohorts were well matched for the conventional risk factors for coronary artery disease. The analyzed clinical end points of death (1.1% vs 0.9%, p = 0.77), death or Q-wave myocardial infarction (0.9% vs 0.9%, p = 1.0), target lesion revascularization (0.2% vs 0.8%, p = 0.45), target vessel revascularization (1.1% vs 1.1%, p = 1.0), and major adverse cardiac events (2.0% vs 1.8%, p = 0.8) were similar between the no-reload and reload groups at 30 days. The in-hospital rates of major bleeding and gastrointestinal bleeding were also similar between the 2 cohorts. There were no cases of definite stent thrombosis. In conclusion, patients receiving long-term clopidogrel therapy who present with acute coronary syndromes do not gain any clinical benefit from additional reloading with clopidogrel.     

Doppler Vortography: A Color Doppler Approach to Quantification of Intraventricular Blood Flow Vortices

We propose a new approach to quantification of intracardiac vorticity based on conventional color Doppler images —Doppler vortography. Doppler vortography relies on the centrosymmetric properties of the vortices. Such properties induce particular symmetries in the Doppler flow data that can be exploited to describe the vortices quantitatively. For this purpose, a kernel filter was developed to derive a parameter, the blood vortex signature (BVS), that allows detection of the main intracardiac vortices and estimation of their core vorticities. The reliability of Doppler vortography was assessed in mock Doppler fields issued from simulations and in vitro data. Doppler vortography was also tested in patients and compared with vector flow mapping by echocardiography. Strong correlations were obtained between Doppler vortography-derived and ground-truth vorticities (in silico: r² = 0.98, in vitro: r² = 0.86, in vivo: r² = 0.89). Our results indicate that Doppler vortography is a potentially promising echocardiographic tool for quantification of vortex flow in the left ventricle.     

Monoclonal antibody conjugated magnetic nanoparticles could target MUC‐1‐positive cells in vitro but not in vivo

MUC1 antigen is recognized as a high‐molecular‐weight glycoprotein that is unexpectedly over‐expressed in human breast and other carcinomas. In contrast, C595 a monoclonal antibody (mAb) against the protein core of the human urinary epithelial machine, is commonly expressed in breast carcinomas. The aim of this study was to conjugate ultra‐small super paramagnetic iron oxide nanoparticles (USPIO) with C595 mAb, in order to detect in vivo MUC1 expression. A dual contrast agent (the C595 antibody‐conjugated USPIO labeled with 99mTc) was prepared for targeted imaging and therapy of anti‐MUC1‐expressing cancers. The C595 antibody‐conjugated USPIO had good stability and reactivity in the presence of blood plasma at 37 °C. No significant differences were observed in immunoreactivity results between conjugated and nonconjugated nanoparticles. The T₁ and T₂ measurements show >79 and 29% increments (for 0.02 mg/ml iron concentrations) in T₁ and T₂ values for USPIO‐C595 in comparison with USPIO, respectively. The nanoprobes showed the interesting targeting capability of finding the MUC1‐positive cell line in vitro. However, we found disappointing in vivo results (i.e. very low accumulation of nanoprobes in the targeted site while >80% of the injected dose per gram was taken up by the liver and spleen), not only due to the coverage of targeting site by protein corona but also because of absorption of opsonin‐based proteins at the surface of nanoprobes. Copyright © 2014 John Wiley & Sons, Ltd.     

Evaluation of <Emphasis Type="Italic">DNMT1</Emphasis> gene expression profile and methylation of its promoter region in patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is an autoimmune disease with a chronic inflammatory arthritis. The critical role of methylation in the biology of immunocytes has increasingly been surveyed to discover disease etiology. DNA methyltransferase 1 (DNMT1) is an enzyme, which establishes and regulates patterns of methylated cytosine residues. The aim of the current investigation was to unveil if methylation circumstances of CpG sites in DNMT1 promoter could affect the mRNA expression level of this gene in peripheral blood mononuclear cells (PBMCs) from AS patients. PBMCs were isolated from whole blood of 40 AS patients and 40 healthy individuals. Total RNA and DNA contents of leukocytes were extracted. Afterward, quantitative analysis was carried out by real-time PCR using the SYBR Green PCR Master Mix. Finally, to determine the methylation level, PCR products of bisulfite-treated DNA from patients and controls were sequenced. Compared with healthy controls, expression level of DNMT1 in AS patients was significantly downregulated. Methylation of DNMT1 promoter was significantly higher in AS patients in comparison to controls. While a negative correlation between methylation and expression level of DNMT1 was observed in AS patients, both methylation and expression level of DNMT1 did not correlate with clinical manifestations. Considering the observation that decreased expression level of DNMT1 was associated with hypermethylation of DNMT1 promoter in PBMCs from AS patients, this survey suggests that dysregulation of DNMT1 expression through altered methylation level of other target genes would probably contribute to AS development.     

Phosphatidylinositide 3-kinase is important in late-stage fibroblast growth factor-1-mediated angiogenesis in vivo

We previously reported that overexpression of a secreted version of fibroblast growth factor-1 (sp-FGF-1) has the ability to induce angiogenesis in the chicken chorioallantoic membrane (CAM). In our current study, we examine the effects of sp-FGF-1 through a time course analysis of angiogenesis in the chicken CAM on days 3, 4, and 5 after gene transfection. Significant angiogenesis was observed on days 4 and 5 after gene transfection in the CAM assay. To evaluate the role of phosphatidylinositide 3-kinase (PI3K) signaling in sp-FGF-1-induced angiogenesis, we analyzed mRNA expression levels of PI3K and protein activity through its immediate downstream target, AKT-1. We found upregulation of both PI3K and AKT mRNA expression levels in day 5 sp-FGF-1 versus day 5 vector control-transfected CAMs. Furthermore, by blocking PI3K phosphorylation using the specific inhibitor, LY294002, we found that downstream phosphorylation of AKT-1 was inhibited. More importantly, the blockade of the PI3K pathway via LY294002 in sp-FGF-1-transfected CAMs significantly inhibited angiogenesis. These results further elucidate the molecular mechanisms of the sp-FGF-1 signaling pathway and it underscores the importance of PI3K signaling in FGF-1-stimulated angiogenesis in vivo. It also provides a basis for the role of sp-FGF-1 in the development of therapeutic treatments to combat vascular insufficiencies and angiogenesis-dependent cancers.     

Evaluation of the Iranian versions of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Patient Acceptable Symptom State (PASS) in patients with ankylosing spondylitis

The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI) are widely used instruments in assessment of patients suffering from ankylosing spondylitis (AS). The Patient Acceptable Symptom State (PASS) is regarded as a target for patients' well-being. The aim of this study was to translate and adapt BASDAI, BASFI and PASS into the Iranian official language, Farsi, and evaluate their reliability and validity. Ninety patients with AS were included in this study. The questionnaires were translated into Farsi and back translated into English, modified until the final versions were approved with minor adaptations and the VAS was changed to numerical rating scales from 0 to 10. Forty-eight-hour test-retest agreement showed good reliability: interclass correlation coefficient (ICC) for BASDAI was 0.93 (CI at 95%, 0.90-0.95), for BASFI was 0.96 (CI at 95%, 0.94-0.97) and for PASS was 0.87 (CI at 95%, 0.79-0.92). Chronbach's alpha was 0.95, 0.96 and 0.87 for BASDAI, BASFI and PASS, respectively. BASDAI showed a significant correlation with patient global disease activity index, nocturnal back pain, total back pain, number of swollen joints, number of enthesites, morning stiffness, Bath Ankylosing Spondylitis Global Score (BAS-G), BASFI and BASMI. A significant correlation was also found between BASFI and occiput-to-wall distance, mentum-to-sternum distance, chest expansion, finger-to-floor distance, number of swollen joints, number of enthesites, nocturnal back pain, total back pain, BAS-G, BASDAI and BASMI. Patients who answered "no" to PASS (found their condition unsatisfactory) reported significantly increased pain scores, patient global disease activity scores, BAS-G, BASDAI and BASFI scores. The results showed that the Iranian versions of BASDAI, BASFI and PASS are adequately reliable and valid in patients with AS.     

Circulating retinol-binding protein 4 concentrations in patients with coronary artery disease and patients with type 2 diabetes mellitus

Circulating Retinol-Binding Protein 4 (RBP4) has recently been identified as a marker of insulin resistance. We tested this hypothesis in patients with coronary artery disease (CAD), patients with type 2 diabetes mellitus (T2DM), and in non-diabetic control subjects. We studied plasma RBP4 levels and RBP4-to-transthyrethin (TTR) ratio, estimating the excess circulating RBP4 in proportion to TTR, in 45 individuals divided into three groups (15 CAD, 15 T2DM, and 15 controls). Plasma RBP4 levels were significantly lower in patients with T2DM than in non-diabetic control subjects (P?=?0.05). The RBP4/TTR ratio was not statistically different between the groups. There was no difference in plasma RBP4 levels and RBP4/TTR ratio between non-diabetic CAD patients and control subjects or those with and without metabolic syndrome. No significant associations were found between RBP4 and RBP4/TTR ratio, as dependent parameters, with markers of the metabolic syndrome and lipid metabolism. RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in patients with T2DM or CAD.     

The impact of intra-aortic balloon counter-pulsation on in-hospital mortality in patients presenting with anterior ST-elevation myocardial infarction without cardiogenic shock

ObjectivesThis study aimed to determine whether the elective insertion of an intra-aortic balloon counter pulsation (IABP) device at the time of myocardial revascularization in patients presenting with an acute anterior ST-elevation myocardial infarction (STEMI) without cardiogenic shock has any impact on the in-hospital rate of cardiac mortality.BackgroundThe role of IABP in patients presenting with an acute MI without cardiogenic shock remains ill defined.MethodsThe present study comprised 605 consecutive patients who underwent primary percutaneous coronary intervention for an anterior STEMI without cardiogenic shock. Patients who received IABP at the time of their coronary revascularization (n = 105) were compared to those who had not (n = 500). Patients with stable angina, unstable angina, non-STEMI, non-anterior STEMI, and cardiogenic shock were excluded.ResultsThe two cohorts were well matched for the conventional risk factors for coronary artery disease. Although the left ventricular ejection fraction was significantly lower in the patients who received IABP (0.32 ± 0.11 vs. 0.39 ± 0.12; P < 0.001), the two cohorts were well matched for history of MI, coronary revascularization, and chronic renal impairment. Following propensity scoring, the in-hospital rate of cardiac death was similar between the two cohorts (5.6% vs. 0%; P = .12) as was the rate of vascular complications. Major bleeding was significantly greater in the IABP cohort (10.0% vs. 0%; P = .01) leading to a greater transfusion requirement (14.9% vs. 2.9%; P = .01).ConclusionThe adjunctive use of an IABP in patients presenting with an acute anterior STEMI without cardiogenic shock may not be associated with an in-hospital mortality benefit.     

Analysis of killer cell immunoglobulin-like receptors (KIRs) and their HLA ligand genes polymorphisms in Iranian patients with systemic sclerosis

Genetic factors have a great role in the pathogenesis of autoimmune diseases by cooperating with environmental stimuli. Killer immunoglobulin-like receptors (KIRs) are cell surface proteins on NK cells whose association with major histocompatibility complex-I regulates their killing function. The aim of this study was to provide information on the possible association between KIR and human leukocyte antigen (HLA) genes with systemic sclerosis disease in Iranian population. A total of 279 systemic sclerosis patients and 451 healthy controls were enrolled in this case-control study in order to determine the presence or absence of 19 KIR genes and 6 specific HLA class I ligands. DNA was analyzed by polymerase chain reaction using the specific sequence primer method (PCR-SSP). Among 11 discovered KIR genotypes, 6 genotypes showed a considerable role and 4 genotypes could preclude the risk of systemic sclerosis (SSc) disease. The gene-gene interactions were also analyzed, and significant confounding effects were seen between involved genes in these two combinations: “KIR3DL1; HLA-BW4-Thr80” and “KIR3DL1 -HLA-BW4-A1.” None of single KIR genes showed significant effect on the risk of SSc. We conclude that there is an important relationship between KIR genes and their HLA ligands with incidence rate of systemic sclerosis in Iranian population. The powerful role of a number of discovered KIR/HLA compounds such as activating KIR genotype 3 and HLA-BW4-A1 confirmed the provocative hypothesis of the interplay between activating or inhibitory KIR genes with HLA ligands as a critical index of systemic sclerosis predisposition.