Interferon-λ3 rs12979860 can regulate inflammatory cytokines production in pulmonary fibrosis.

Pulmonary fibrosis (PF) is the last phase of interstitial lung diseases (ILDs), which are a collection of pulmonary illnesses marked by parenchymal remodeling and scarring. Treatment can only halt the functional decline of the lung, raising the necessity of identifying the basic processes implicated in lung fibrogenesis. The Interferon lambda-3 (IFNL3) gene variant, rs12979860, was determined to be related to an elevated risk of fibrosis in different organs, but the mechanism through which it mediates fibrogenesis is not clear. In the current research, we aim to figure out some of the mechanistic pathways by which IFN-λ3 mediates ILDs. 100 healthy controls and 74 ILD patients were genotyped for IFNL3 rs12979860. Then the mRNA expression of IFNL3 and some other proinflammatory mediators was examined according to genotype in the peripheral blood mononuclear cells (PBMCs) of ILDs patients. The IFNL3 rs12979860 genotype distribution of healthy individuals and ILDs patients was shown to be in Hardy-Weinberg equilibrium (HWE) with a minor allele frequency (MAF) of 0.293 and 0.326, respectively. Furthermore, the CC genotype was demonstrated to be linked to enhanced IFNL3 expression. Also, the CC genotype was linked to an increase in the mRNA expression of TLR4 (P = 0.03) and the inflammatory cytokines IL-1ß and TNF-α (P = 0.01 and 0.04, respectively) and had no effect on the NF-kB level (P = 0.3). From these results, we can deduce that IFN-λ3 may mediate tissue fibrosis via increasing the expression of IFN-λ3 itself and other proinflammatory mediators. This stimulates a self-sustaining loop mechanism which includes a reciprocal production of IFN-λ3, TLR4, IL-1ß, and TNF-α leading to persistent inflammation and fibrosis.

Influence of Different Antiseizure Medications on Vascular Risk Factors in Children with Epilepsy.

Many studies have proposed that plasma homocysteine levels are increased as a side effect with the prolonged use of antiseizure medications. This is associated with an increase in carotid intima media thickness; hence, it increases the threat of atherosclerosis at a young age. We aimed to assess serum levels of homocysteine in epileptic children on long-standing antiseizure medications and its association with increased occurrence of cardiovascular disease. The study included 60 epileptic children aged between 2 and 15 years old who visited our pediatric neurology outpatient clinic and 25 apparently healthy children served as a control group. All included children were subjected to careful history taking, clinical examination, anthropometric measures, laboratory investigations including serum homocysteine levels and lipid profile, along with radiological assessment involving carotid intima media thickness and carotid stiffness. Results demonstrated a significant increase in the serum levels of homocysteine, carotid intima media thickness, and carotid stiffness in children on monotherapy of old generation antiseizure medications and polytherapy than that in children on monotherapy of new generation antiseizure medications and control children. Epileptic children on old generation and polytherapy antiseizure medications have an increased risk for cardiovascular diseases and need follow up for early intervention when needed.

Occult HCV infection in liver transplanted patients: frequency and consequences.

Aim of the study: Occult hepatitis C virus (HCV) infection (OCI) is a potential source of relapse after liver transplantation with subsequent graft damage. The aim of the study was to detect OCI in patients with living donor liver transplantation (LDLT) who achieved sustained virological response (SVR) after sofosbuvir-based antiviral treatment, and to detect risk factors associated with the development of OCI as well as to determine the effect of direct acting antiviral (DAA) therapy after liver transplantation. Material and methods: 41 patients with living donor liver transplantation who did not receive DAAs before with recurrent HCV infection who achieved a SVR with sofosbuvir-based therapy for 12-24 weeks were recruited. These patients were tested for OCI by HCV-RNA in peripheral blood mononuclear cells (PBMNCs). Those patients with OCI were followed up every 6 months with alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum HCV-RNA by PCR for 2 years. Results: 92.7% of treated patients achieved HCV SVR 12 weeks. OCI was detected in 4 patients. After follow-up for 18 months, 3 patients continued to have OCI, but one patient presented with progressive elevation of liver enzymes and developed overt HCV infection with positive HCV-RNA PCR in the serum. This patient was retreated with sofosbuvir 400 mg + ledipasvir 90 mg for 12 weeks with resultant negative HCV-RNA PCR in both serum and PBMNCs in addition to normalization of liver enzymes. Conclusions: Occult HCV infection is a potential source of HCV relapse after liver transplantation which should be investigated for in PBMNCs or liver biopsy.

Extracellular Biomarkers of Inner Ear Disease and Their Potential for Point-of-Care Diagnostics.

Rapid diagnostic testing has become a mainstay of patient care, using easily obtained samples such as blood or urine to facilitate sample analysis at the point-of-care. These tests rely on the detection of disease or organ-specific biomarkers that have been well characterized for a particular disorder. Currently, there is no rapid diagnostic test for hearing loss, which is one of the most prevalent sensory disorders in the world. In this review, potential biomarkers for inner ear-related disorders, their detection, and quantification in bodily fluids are described. The authors discuss lesion-specific changes in cell-free deoxyribonucleic acids (DNAs), micro-ribonucleic acids (microRNAs), proteins, and metabolites, in addition to recent biosensor advances that may facilitate rapid and precise detection of these molecules. Ultimately, these biomarkers may be used to provide accurate diagnostics regarding the site of damage in the inner ear, providing practical information for individualized therapy and assessment of treatment efficacy in the future.

IL-23/Th17 pathway and IL-17A gene polymorphism in Egyptian children with immune thrombocbytopenic purpura.

BACKGROUND: Immune thrombocytopenic purpura (ITP) is an acquired complex autoimmune thrombocytopenia. Uncontrolled cellular immune response is one of the key triggers for the loss of immune tolerance in ITP patients. The purpose of this study was to investigate the association of IL-23/Th17, IL-17A and IL-17A rs2275913 gene polymorphism with ITP in Egyptian children. METHODS: 60 patients with ITP and 50 healthy control children from Minia city- Egypt were involved. Serum levels of IL-23 and IL-17A were determined by enzyme-linked immunosorbent assay. The frequency of Th17 cells was measured using flow cytometer. Genotyping for IL-17A was performed via polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Comparing children with ITP to controls, serum levels of IL-23 and IL-17A as well as Th17 cells percentage were significantly increased (p <  0.001). Also, higher levels of these ILs and Th17 cells percentage were associated with decreased platelet count within ITP patients (p <  0.001). Analysis of genotype frequencies for IL-17A rs2275913 polymorphism and its alleles (A, G) showed no significant difference between cases and controls. Likewise, no significant differences were demonstrated between acute and chronic ITP regarding both IL-17A rs2275913 polymorphism prevalence and levels of IL-23, IL-17A plus Th17 cells percentage. The frequency of A alleles was 85 and 86% within patients and controls, respectively. CONCLUSIONS: Elevated levels of IL-23, IL-17A and Th17 cells may be involved in ITP pathogenesis while IL-17A polymorphism rs2275913 is not prevalent in Egyptian children with ITP.

Expression analysis of selected genes involved in tryptophan metabolic pathways in Egyptian children with Autism Spectrum Disorder and learning disabilities.

Autism Spectrum Disorder (ASD) and learning disabilities are neurodevelopmental disabilities characterized by dramatically increasing incidence rates, yet the exact etiology for these disabilities is not identified. Impairment in tryptophan metabolism has been suggested to participate in the pathogenesis of ASD, however, further validation of its involvement is required. Additionally, its role in learning disabilities is still uninvestigated. Our objective was to evaluate some aspects of tryptophan metabolism in ASD children (N = 45) compared to children with learning disabilities (N = 44) and healthy controls (N = 40) by measuring the expression levels of the MAOA, HAAO and AADAT genes using real-time RT-qPCR. We also aimed to correlate the expression patterns of these genes with parental ages at the time of childbirth, levels of serum iron, and vitamin D3 and zinc/copper ratio, as possible risk factors for ASD. Results demonstrated a significant decrease in the expression of the selected genes within ASD children (p < 0.001) relative to children with learning disabilities and healthy controls, which significantly associated with the levels of our targeted risk factors (p < 0.05) and negatively correlated to ASD scoring (p < 0.001). In conclusion, this study suggests that the expression of the MAOA, HAAO and AADAT genes may underpin the pathophysiology of ASD.

Diagnostic Role of Cell-free DNA Integrity in Thyroid Cancer Particularly for Bethesda IV Cytology.

BACKGROUND: The cell-free DNA integrity index (cfDI) is promising for the differentiation between malignant and benign tumors, but little data has been reported on thyroid cancer (TC). We explored its diagnostic role in TC, mainly in cases of Bethesda category IV. METHODS: cfDI was evaluated by quantitative real-time polymerase chain reaction using 2 primer sets to identify cell-free DNAs (cfDNAs) Alu83 and Alu244. Blood samples were collected from 85 patients with thyroid nodules (18 papillary [PTC], 21 follicular [FTC], 21 medullary, and 25 benign thyroid nodules [BTN]) before fine-needle aspiration cytology and surgical treatment and also from 25 patients with autoimmune thyroid disease (ATD) and 25 healthy subjects (HS). RESULTS: cfDNA Alu244 concentration ≥6.95 ng/mL and cfDI ≥0.3 were excellent sensitive and specific tests to discriminate TC particularly cytologically indeterminate thyroid nodules (Bethesda IV) from the control groups (BTN, ATD, and HS). The levels of both cfDNA Alu83 and Alu244 were decreased while cfDI was increased significantly in medullary compared with FTC and PTC, with a nonsignificant difference between the latter subgroups. There was a significantly positive correlation between both cfDNA Alu83 and Alu244 with the T-classification of TNM staging and capsular invasion among PTC and FTC patients and between cfDI with Bethesda categories. Additionally, ATD had significantly higher cfDNA Alu83 and lower cfDI than HS. CONCLUSION: cfDI is a useful noninvasive molecular biomarker in TC that correlates with the Bethesda classification and histopathology. Tumor size and capsular invasion were correlated with quantitative cfDNA among PTC and FTC.

Serum and ascitic fluid interleukin-17 in spontaneous bacterial peritonitis in Egyptian patients with HCV-related liver cirrhosis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a potentially lethal complication of ascites. The inflammatory response is very intense in case of SBP despite low concentration of bacteria in the ascitic fluid with IL-17A overproduced by intestinal Paneth cells and may have role in host immune defense and inflammatory response. AIMS: To study the diagnostic performance of serum and ascitic fluid IL-17A as a marker of SBP and its correlation with renal function. METHODS: 120 cirrhotic patients including 80 patients with HCV-induced cirrhotic ascites but not with SBP and 40 patients with HCV-induced cirrhotic ascites with SBP were recruited. Serum and ascitic fluid IL17A were measured before and after treatment. RESULTS: The mean serum and ascitic fluid levels of IL-17 in cirrhotic patients with SBP were significantly higher than in patients with cirrhosis without SBP (p < 0.001). Also, we found significant decline in both serum and ascitic fluid IL17 levels with successful treatment of SBP (p < 0.001). The sensitivity and specificity of serum IL17 was 100 % when using 92 pg/mL as cutoff. Meanwhile, sensitivity and specificity of ascitic fluid IL-17were 100 % when using 132 pg/mL as cutoff. CONCLUSIONS: IL-17 could be used as a possible diagnostic biomarker for SBP especially in culture negative and non-neutrocytic SBP and in monitoring therapeutic response. Also, it was shown to be related to hepatic and renal functions deterioration.

Clinical significances and diagnostic utilities of both miR-215 and squamous cell carcinoma antigen-IgM versus alpha-fetoprotein in Egyptian patients with hepatitis C virus-induced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. It has been widely established that the early detection of HCC enables more treatment options with improvements in prognosis and survival. OBJECTIVES: The aim of this study was to assess the diagnostic accuracy of both circulating miR-215 and squamous cell carcinoma antigen-IgM (SCCA-IgM) as serum biomarkers for HCC by examining their diagnostic sensitivity, specificity, accuracy, and predictive values in hepatitis C virus (HCV)-induced HCC patients. SUBJECTS AND METHODS: This study included 60 patients with HCV-related HCC. In addition, 60 patients with HCV-related liver cirrhosis (LC) and 60 apparently healthy subjects were involved, and served as diseased and healthy control groups, respectively. The relative expression levels of miR-215 were detected using quantitative real-time PCR. SCCA-IgM levels in serum were measured by enzyme immunoassay. We used receiver operating characteristic (ROC) curve to calculate the diagnostic accuracy against alpha-fetoprotein (AFP). RESULTS: Relative miR-215 expression levels increased the most in HCC patients compared to that in healthy or diseased controls (P<0.001). Serum concentration of SCCA-IgM was significantly higher in HCC group than that in the two control groups. We performed multivariate analysis using AFP level, focal lesion size, and portal vein thrombosis as independent variables. ROC curves showed that the optimum diagnostic miR-215 cutoff value for identifying HCC patients from cirrhotic ones was 417 (sensitivity, 97%; specificity, 91%) and for SCCA-IgM was 95 AU/mL (sensitivity, 92%; specificity, 98%). Moreover, the superiority of both miR-215 and SCCA-IgM to AFP is obvious in our study and this superiority is more evident in distinguishing HCC with AFP levels <200 ng/mL and HCC patients with small-sized focal lesions from cirrhotic patients. CONCLUSION: Cell-free miR-215 and serum SCCA-IgM could be used for early diagnosis of HCC either each one as a single marker or with AFP complement measurement.

Assessment of Subclinical Pancreatitis in Epileptic Children With Different Treatment Modalities.

Acute pancreatitis differ in pediatrics and adults. Drug-induced pancreatitis is one of the common causes of pancreatitis in children. This case-control study aimed to assess subclinical pancreatitis in patients with epilepsy treated with different drug regimens. Eighty known patients with epilepsy were enrolled. Forty patients were treated with monotherapy (group I) and 40 were treated with multitherapy (group II) regimens. Twenty age- and sex-matched healthy children were enrolled as control (group III). Serum lipase and amylase were assayed in all included children. Significant differences were found between groups I and III and between groups II and III regarding serum amylase and lipase (P < .001 for all). Significant difference were found between groups I and II (P = .024) and between groups II and III (P = .01) regarding pancreatic duct and body diameters. Significant difference were found between patients with controlled and uncontrolled fits regarding serum amylase (P = .008). In conclusion, subclinical pancreatitis can complicate the treatment with different antiepileptic regimens.

Promoter context determines the role of proteasome in ligand-dependent occupancy of retinoic acid responsive elements.

Retinoid acid receptors are DNA-binding proteins mediating the biological effects of ligands through transcriptional activation. It is known that the activity of the 26S proteasome is important for nuclear receptor-activated gene transcription. However, the molecular mechanism by which the 26S proteasome participates in this process is not well understood. Here we report that the proteasome activity is essential for ligand-dependent interaction of RAR with its co-regulators such as SRC, p300 and RXR. We also determined that the proteasome activity is required for the association of liganded RAR to the genomic DNA and, consequently, for the recruitment of the coactivator complex to the retinoic acid responsive elements. Moreover, the requirement of proteasome activity for the activator activity of RAR is determined by the promoter context. Our study suggests that the 26S proteasome regulates directly the activity of RAR as an activator.