Serum eosinophil-derived neurotoxin: a new promising biomarker for cow's milk allergy diagnosis.

BACKGROUND: Cow's Milk Allergy (CMA) diagnosis is often a challenge due to the non-specific nature of symptoms and lack of a confirmatory diagnostic test. To our knowledge no previous studies investigated serum Eosinophil-Derived Neurotoxin (sEDN) in CMA. So, we aimed to assess the role of sEDN in CMA diagnosis. METHODS: Forty-five infants with CMA were compared to 45 infants with functional gastrointestinal disorders (FGIDs) and 45 healthy controls. For all participants, Cow's Milk-related Symptom Score (CoMiSS) was documented, and sEDN level with hematological parameters were measured before starting elimination diet. RESULTS: Receiver operation characteristic (ROC) curve identified sEDN > 14 ng/mL and CoMiSS > 9 as the optimal cut-off points to discriminate CMA from other groups with sensitivity 86.67%, 97.78% and specificity 60.00%, 78.89% respectively. Additionally, absolute neutrophil count (ANC) showed the highest sensitivity and specificity (80.0% and 78.89%) among hematological parameters. Although CoMiSS and ANC showed a significant positive correlation with sEDN in CMA group, CoMiSS was the only significant predictor for sEDN in multivariate linear regression. CONCLUSIONS: sEDN showed high sensitivity in discriminating infants with and without CMA. Therefore, it is suggested as a potential biomarker for CMA diagnosis. Also, ANC should be closely monitored in these infants. IMPACT: CMA presents with high heterogeneity, which complicates the diagnosis especially non-IgE-mediated and mixed types. So, oral food challenge continues to be the gold standard for its diagnosis. ROC curve identified CoMiSS > 9 as the best cut-off point to identify CMA. However, CoMiSS is a good awareness tool for CMA but not a diagnostic tool. sEDN level was significantly higher in infants with CMA with a good diagnostic performance in differentiating them than those without CMA. So, it is suggested as a potential biomarker for CMA diagnosis. ANC could have a role in CMA diagnosis and differentiating it from FGIDs.

Evaluation of Circular RNA SMARCA5 as a Novel Biomarker for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth most prevalent type of cancer in Egypt and the sixth globally. Most patients with HCC are typically diagnosed during the advanced stages of the disease due to the absence of biomarkers for early detection. Consequently, these patients miss the optimal timeframe for receiving therapy. OBJECTIVE: we aimed to assess the circular RNA SMARCA5 level and SMARCA5 mRNA gene expression as a potential biomarker for early detection of HCC. METHODS: The present study utilized a case-control design comprising 159 participants. Participants were selected from both inpatient and outpatient hepatology and gastroenterology clinics at the National Liver Institute Hospital, Menoufia University. They were evenly distributed among three groups: Group I: 53 control subjects, Group II: 53 HCV cirrhotic patients, and Group III: 53 HCC patients. Tumor staging was done using BCLC staging system. Each patient underwent a thorough clinical examination, radiological examination, complete history taking, and serum Alpha-fetoprotein (AFP) assessment and detection of circular RNASMARCA5 and SMARCA5mRNA gene sutilizing quantitative real-time polymerase chain reaction. RESULTS: Statistically substantial differences were observed in the examined groups in terms of AFP, SMARCA5, and CircSMARCA5 (P-value = 0.001, 0.001 & 0.001). CircSMARCA5 and SMARCA5mRNA were markedly down regulated in the HCC group compared to HCV cirrhotic patients and controls. ROC analysis for early HCC diagnosis demonstrated that the CircSMARCA5 area under the curve (AUC) at cut-off point 4.55 yielded a specificity of 83.8% and sensitivity of 91.7%. The AUC for AFP at a cut-off point of 515ng/ml yielded a specificity of 89.2% and a sensitivity of 91.3%. CONCLUSION: CircSMARCA5 has the potential to be a more sensitive predictor of HCC disease compared to AFP.

Suppressor of Cytokine Signaling-3 Gene Polymorphisms and the Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Patients in Egypt.

BACKGROUND: Hepatocellular carcinoma (HCC) contributes significantly to cancer mortalities worldwide. The association between a specific single nucleotide polymorphism (SNP) located within the SOCS3 gene as well as the likelihood of hepatocellular carcinoma (HCC) progression in individuals with chronic hepatitis C virus (CHC) was found to be significant. We aimed to study SOCS3 gene polymorphisms at rs4969168 and rs4969170and HCC susceptibility in individuals with CHC. METHODS: The current prospective study involved 111 subjects divided in to three groups (HCC, HCV with and with no cirrhosis, and apparently healthy individuals). Tumor staging was done using BCLC staging system. SOCS3 (rs4969168 and rs4969170) gene polymorphisms' analysis was done utilizing real-time polymerase chain reaction (RT-PCR) (via DNA extracted from all subjects). All subjects underwent a complete history, medical examination, and laboratory and radiological data collection. RESULTS: Compared to healthy controls, homozygous AA genotypes and heterozygous GA genotypes were substantially overrepresented in  HCC patients as well as those with CHCaccompanied by cirrhosis.AFP, smoking, glucose level, and AA genotype of rs4969170 might be critical significant parameters for HCC development. CONCLUSION: SOCS3 gene polymorphisms at rs4969168 and rs4969170 are associated with HCC and liver fibrosis progression in the Egyptian population with CHC infection.

The Potential Role of Circulating Long Miscellaneous RNAs in the Diagnosis and Prognosis of Hepatitis C Related Hepatocellular Carcinoma.

Ribonucleic acids (RNAs) are important regulators of gene expression and crucial for the progression of hepatocellular carcinoma (HCC). This study was designed to determine the diagnostic and prognostic utility of the circulating long miscellaneous RNAs; LINC01419, AK021443, and AF070632 in HCV-related HCC patients. Real-time PCR was used to measure their relative expression levels in the plasma of 194 HCV patients, 120 HCV-related HCC patients and 120 healthy controls. LINC01419 and AK021443 expression levels had significantly increasing linear trend estimates while AF070632 was dramatically downregulated in HCC compared to HCV. Interestingly, LINC01419 and AK021443 served as more significant diagnostic biomarkers for HCC than AF070632 and AFP. Multivariate analysis with cox regression revealed that the high expression of AK021443 [HR = 10.06, CI95%: 3.36-30.07], the high expression of LINC01419 [HR 4.13, CI95%: 1.32-12.86], and the low expression of AF070632 [HR = 2.70, CI95%: 1.07-6.81] were significant potential prognostic factors for HCC. Besides, the Kaplan-Meier analysis showed that HCC patients with high LIN01419 and AK021443 and low AF070632 expression levels had shorter OS. The circulating LINC01419 and AK021443 can be used as noninvasive potential biomarkers for diagnosis and prognosis of HCV-related HCC patients than AF070632 providing new targets for limiting the progression of the disease.

Cytotoxic T Cell Expression of Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) in Viral Hepatitis C-Mediated Hepatocellular Carcinoma.

Virus-related hepatocellular carcinoma (HCC) pathogenesis involves liver inflammation, therefore, despite successful treatment, hepatitis C virus (HCV) may progress to HCC from initiated liver cirrhosis. Cytotoxic T cells (Tcs) are known to be involved in HCV-related cirrhotic complications and HCC pathogenesis. The inhibitory checkpoint leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is expressed on Tcs. Therefore, we aimed to determine whether the Tc expression level of LAIR-1 is associated with HCC progression and to evaluate LAIR-1 expression as a noninvasive biomarker for HCC progression in the context of liver cirrhosis related to HCV genotype 4 (G4) in Egyptian patients' peripheral venous blood liquid biopsy. A total of 64 patients with HCC and 37 patients with liver cirrhosis were enrolled in this case-controlled study, and their LAIR-1 expression on Tc related to the progression of liver cirrhosis was examined and compared to that of the apparently healthy control group (n = 20). LAIR-1 expression was analyzed using flow cytometry. Results: The HCC group had significantly higher LAIR-1 expression on Tc and percentage of Tc positive for LAIR-1 (LAIR-1+Tc%) than the HCV G4-related liver cirrhosis group. LAIR-1+Tc% was correlated with the HCC surrogate tumor marker AFP (r = 0.367, p = 0.001) and insulin resistance and inflammation prognostic ratios/indices. A receiver operating characteristic (ROC) curve revealed that adding LAIR-1+Tc% to AFP can distinguish HCC transformation in the Egyptian patients' cohort. Upregulated LAIR-1 expression on Tc could be a potential screening noninvasive molecular marker for chronic inflammatory HCV G4 related liver cirrhosis. Moreover, LAIR-1 expression on Tc may be one of the players involved in the progression of liver cirrhosis to HCC.

Impact of indirect bilirubin and uric acid on outcomes of sepsis-associated acute kidney injury (sAKI).

BACKGROUND: Acute kidney injury (AKI) is one of the most frequent pathophysiologic disorders encountered in hospitalized patients, with sepsis frequently implicated in pathogenesis. Reactive oxygen species (ROS) seem to have a significant contribution to sepsis-induced AKI. Proposed mechanisms include induction of cell membrane lipid peroxidation, protein denaturing, and direct DNA damage, all of which have deleterious effect. These changes constitute oxidative injury to the kidneys. OBJECTIVE: To evaluate the antioxidant actions of indirect bilirubin and uric acid on outcomes of sepsis-associated AKI. METHODS: Ninety-eight patients admitted to the intensive care unit (ICU), at a large tertiary center, with sepsis and AKI were evaluated for serum levels of uric acid, bilirubin (primarily indirect), and procalcitonin. The primary endpoints studied were the need for hemodialysis and death. RESULTS: Thirty-two (33%) patients developed AKI requiring hemodialysis (HD). These patients had higher SOFA scores (p < 0.001) and lower levels of indirect bilirubin (p < 0.001) compared to those not requiring HD. There was no statistically significant difference in serum uric acid levels. Logistic regression analysis identified creatinine level, total and indirect bilirubin levels, and leukocyte count as significant predictors of patient death. CONCLUSION: Higher leukocyte counts and creatinine levels were independently associated with poor outcomes in ICU patients with sepsis. Additionally, lower indirect bilirubin levels were also noted to be associated with similar outcomes. The latter provides insights into oxidative stress as a major player in the pathogenesis of sepsis-induced AKI, with a potential protective role of indirect bilirubin.

Predictive Role of AURKA rs 1047972 Gene Polymorphism and the Risk of Development of Hepatocellular Carcinoma.

ABBREVIATION: AFP: alpha-fetoprotein; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; AURKA: aurora kinase A; BCLC: Barcelona- Clinic Liver Cancer; CBC: complete blood count; CT: computed tomography; DM: diabetes mellitus; DNA: deoxyribonucleic acid; EDTA: ethylene diamine tetraacetic acid; GGT: gamma-glutamyl transferase; HB: hemoglobin; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; INR: international normalized ratio; mRNA: messenger ribonucleic acid; OR: odds ratio; PVT: portal vein thrombosis; RT-PCR: real-time polymerase chain reaction; SNP: single nucleotide polymorphism; WBCs: white blood cells.

Endothelial Activation and Immune Thrombocytopenia: An Engagement Waiting for Consolidation.

Immune thrombocytopenia (ITP) appears to be a heterogeneous disease. In some patients, autoimmunity may be associated with an inflammatory process, and in other patients, low platelets may interfere with other aspects of the coagulation system. Either may predispose to thrombosis or bleeding. Further investigation of the interactions of platelets, with inflammatory cytokines and endothelial biomarkers, may help us to better understand the disease, and to recognize those patients at risk of bleeding, or conversely thrombosis. The aim of this work is to estimate von Willebrand factor (vWF) and vascular cellular adhesion molecule (V-CAM) serum levels in adult immune thrombocytopenic patients (ITP) and to decipher their possible clinical correlates. Eighty adults (≥ 18 years) were enrolled in the study; naive newly diagnosed 40 patients with primary ITP (according to the ASH 2019) and 40 sex and age-matched healthy controls, all groups are subjected for complete blood count (CBC), liver, and renal function tests, ESR, CRP, V-CAM, and VWF-Ag by enzyme-linked immunosorbent assay (ELISA). There was a highly statistically significant difference between case and control as regards to the mean level of VWF-Ag and V-CAM. vWF and V-CAM could serve as biomarkers for endothelial alterations and should be investigated as a predictor of thrombocytopenic bleeding and tailor patient management accordingly.

Potential Value of TNF-α (-376 G/A) Polymorphism and Cystatin C (CysC) in the Diagnosis of Sepsis Associated Acute Kidney Injury (S-AK I) and Prediction of Mortality in Critically Ill patients.

Sepsis Associated Kidney Injury represents a major health concern as it is frequently associated with increased risk of mortality and morbidity. We aimed to evaluate the potential value of TNF-α (-376 G/A) and cystatin C in the diagnosis of S-AKI and prediction of mortality in critically ill patients. This study included 200 critically ill patients and 200 healthy controls. Patients were categorized into 116 with acute septic shock and 84 with sepsis, from which 142 (71%) developed S-AKI. Genotyping of TNF-α (-376 G/A) was performed by RT-PCR and serum CysC was assessed by Enzyme Linked Immunosorbent Assay. Our results showed a highly significant difference in the genotype frequencies of TNF-α (-376 G/A) SNP between S-AKI and non-AKI patients (p < 0.001). Additionally, sCysC levels were significantly higher in the S-AKI group (p = 0.011). The combination of both sCysC and TNF-α (-376 G/A) together had a better diagnostic ability for S-AKI than sCysC alone (AUC = 0.610, 0.838, respectively). Both GA and AA genotypes were independent predictors of S-AKI (p= < 0.001, p = 0.002 respectively). Additionally, sCysC was significantly associated with the risk of S-AKI development (Odds Ratio = 1.111). Both genotypes and sCysC were significant predictors of non-survival (p < 0.001), suggesting their potential role in the diagnosis of S-AKI and prediction of mortality.

Biocompatible and functional inorganic magnesium ceramic particles for biomedical applications.

Magnesium ceramics hold promise for numerous biological applications. This review covers the synthesis of magnesium ceramic particles with specific morphologies and potential modification techniques. Magnesium ceramic particles possess multiple characteristics directly applicable to human biology; they are anti-inflammatory, antibacterial, antiviral, and offer anti-cancer effects. Based on these advantages, magnesium hydroxide nanoparticles have been extensively utilized across biomedical fields. In a vascular stent, the incorporation of magnesium ceramic nanoparticles enhances re-endothelialization. Additionally, tissue regeneration for bone, cartilage, and kidney can be promoted by magnesium ceramics. This review enables researchers to identify the optimum synthetic conditions to prepare magnesium ceramics with specific morphologies and sizes and select the appropriate modification protocols. It is also intended to elucidate the desirable physicochemical properties and biological benefits of magnesium ceramics.

Janus Kinase-2 Mutation Associated Portal Vein Thrombosis Complicating Liver Cirrhosis and Hepatocellular Carcinoma.

BACKGROUND: Portal vein thrombosis (PVT) might be a catastrophic event complicating liver cirrhosis and hepatocellular carcinoma (HCC). AIM: role of JAK2 RS V617F mutation as a risk factor for PVT development in liver cirrhosis and HCC. METHODS: A case control study conducted on 100 PVT patients (76 HCC and 24 liver cirrhosis) additionally, 100 healthy individuals used as a control group. PVT was diagnosed incidentally by Doppler ultrasound during routine follow-up HCC screening. Prothrombin G20210A mutation, MTHFR mutation, Factor V Leiden mutation (VFL), antithrombin III (ATIII), protein C, S, and antiphospholipid antibodies, along with JAK2 RS V617F  mutation by real-time polymerase chain reaction all were analyzed. RESULTS: Patients with PVT were significantly older (p <0.001), thrombocytopenic (p <0.001), with high alkaline phosphatase (p <0.001). JAK2 RS V617F mutation was found in 28/100 (28%) in idiopathic PVT complicating liver cirrhosis and hepatocellular carcinoma. Cases with positive JAK2 rs V617F mutation were significantly accompanied by protein S deficiency (P 0.03), LA absence (p 0.06), and high frequency of ascites (P 0.03). While, the MTHFR heterozygous mutation (p0.001), ATIII (P 0.02), and VFL (P 0.01) were more frequent with negative JAK2 rs V617F mutation. The comparison between demographic data and thrombophilic parameters in PVT cases revealed that no significant differences were recorded except for male gender, Diabetes Mellitus, splenomegaly significantly increased among HCC cases (p <0.05). CONCLUSIONS: JAK2 rs V617F mutation must be considered in any case of PVT with liver cirrhosis and hepatocellular carcinoma without identified thrombophilic risk factors, with potential considerations of evolving myeloproliferative disorders. New diagnostic and therapeutic implications are still awaited.

Matrix Metalloproteinase-11 Gene Polymorphisms as a Risk for Hepatocellular Carcinoma Development in Egyptian Patients.

BACKGROUND: Chronic hepatitis C (CHC) virus infection is one of major risk factors of hepatocellular carcinoma (HCC) in Egypt, which is a major cause of cancer mortalityin the world. Matrix metalloproteinase-11 (MMP-11) has an important role in tumor migration and metastasis. Therefore, this study aimed to determine relation between MMP-11 gene polymorphisms and risk of HCC development among Egyptian cirrhotic patients. SUBJECTS AND METHODS: Two hundred and sixty patients were included, 140 of them with HCC on top of CHC and 120 patients with post CHC liver cirrhosis (LC) as well as 140 subjects were enrolled in the study as healthy controls. Two single nucleotide polymorphisms (SNPs) rs738791 and rs738792 for MMP-11 gene were done using real-time PCR. RESULTS: Combination of CT and TT allele of rs738791 genotypes was more significantly frequent in HCC compared to LC patients and controls, however, a higher frequency of T allele was found in HCC patients compared to LC and controls. In spite of lake of significant difference between patient groups regarding the rs738792 genotypes, the CC genotype was considered a risk of developing portal vein thrombosis, and was associated with advanced tumor stage, increased tumor size, higher Cancer of the Liver Italian Program [CLIP] score, more advanced Barcelona stage [D] and with child Pugh class [C]. CONCLUSION: Genetic variations in MMP-11 may be implicated in post HCV-HCC development and might be dependable biomarkers for HCC progression.

Magnesium hydroxide-incorporated PLGA composite attenuates inflammation and promotes BMP2-induced bone formation in spinal fusion.

Spinal fusion has become a common surgical technique to join two or more vertebrae to stabilize a damaged spine; however, the rate of pseudarthrosis (failure of fusion) is still high. To minimize pseudarthrosis, bone morphogenetic protein-2 (BMP2) has been approved for use in humans. In this study, we developed a poly(lactide-co-glycolide) (PLGA) composite incorporated with magnesium hydroxide (MH) nanoparticles for the delivery of BMP2. This study aimed to evaluate the effects of released BMP2 from BMP2-immobilized PLGA/MH composite scaffold in an in vitro test and an in vivo mice spinal fusion model. The PLGA/MH composite films were fabricated via solvent casting technique. The surface of the PLGA/MH composite scaffold was modified with polydopamine (PDA) to effectively immobilize BMP2 on the PLGA/MH composite scaffold. Analyzes of the scaffold revealed that using PLGA/MH-PDA improved hydrophilicity, degradation performance, neutralization effects, and increased BMP2 loading efficiency. In addition, releasing BMP2 from the PLGA/MH scaffold significantly promoted the proliferation and osteogenic differentiation of MC3T3-E1 cells. Furthermore, the pH neutralization effect significantly increased in MC3T3-E1 cells cultured on the BMP2-immobilized PLGA/MH scaffold. In our animal study, the PLGA/MH scaffold as a BMP2 carrier attenuates inflammatory responses and promotes BMP2-induced bone formation in posterolateral spinal fusion model. These results collectively demonstrate that the BMP2-immobilized PLGA/MH scaffold offers great potential in effectively inducing bone formation in spinal fusion surgery.

On-treatment improvement of an emerging psychosomatic depressive disorder among salmonella carriers: a multicenter experience from Egypt.

BACKGROUND: As physicians in a referral hospital, we observed the association between history of enteric fever and somatic disorders associated with low mood. At the Al-Hussein University Hospital, Cairo and the National Liver Institute Hospital, Menoufia, we receive patients from all over Egypt, including rural areas where enteric fever is endemic. AIM: Here in, 60 Egyptian patients referred to us for evaluation of different somatic disorders are reported. METHODS: After extensive evaluations, the patients' symptoms were function-related. Also, their typhoid carrier states were documented, and the severity of depression using Hamilton-D (HAM-D) questionnaire was evaluated and recorded. All patients were treated with ceftriaxone, 2 gm, IV, daily for 15 days. The clinical evaluation and Hamilton score were reassessed at the end of the treatment and 6 weeks thereafter. The patients did not receive any anti-depressant nor anti-anxiety treatment during their course. Typhoid carrier was defined by documenting the history of typhoid fever that was diagnosed by culturing the Salmonella species, and not by serology, isolated from stool culture along with febrile condition, plus the absence of fever in the past 3 weeks. The Widal test was not accepted as a criterion for enrollment. RESULTS: Patients showed clinically significant improvement in the somatic complaints, and their HAM-D score immediately post-treatment that was consolidated for 6 weeks post-treatment completion. CONCLUSION: In this study, the typhoid carrier was associated with the psychosomatic depression that improved by antibiotic therapy.

Persulfated flavonoids accelerated re-endothelialization and improved blood compatibility for vascular medical implants.

Drug-eluting stents (DESs) have been used for the treatment of cardiovascular diseases including stenosis. However, in-stent restenosis, thrombosis, and delayed re-endothelialization represent challenges for their clinical applications. Here, we demonstrate a novel work to overcome these limitations through surface modification technology. The cobalt-chromium (Co-Cr) surface was modified with antioxidants such as gallic acid (GA) and rutin (Ru) and the corresponding persulfates derivatives (i.e., GAS, and RuS) through a simple conjugation procedure. Various analyses tools such as ATR-FTIR, XPS, water contact angle, SEM, and AFM characterized the functionalized surface. The surface characterization confirmed that the antioxidant and the additional persulfates were successfully bonded to the Co-Cr surface. The results of in vitro endothelial cells proved that the persulfates derivatives showed the highest tendency to get rapid re-endothelialization especially RuS. In addition, it showed inhibition to smooth muscle cells (SMCs) as compared to control Co-Cr substrate. The persulfates modified substrates reduced the amount of adsorbed fibrinogen and albumin with higher stability to fetal bovine serum. Moreover, platelet study also demonstrated that Ru and RuS presented lower platelet adhesion with round shape morphology, whereas the control Co-Cr adhere and activate many platelets with pseudopodium morphology. Moreover, these modification processes did not cause any inflammatory responses. In conclusion, it is believed that the persulfates flavonoids have a great potential in the field of drug-eluting stents and blood contacting medical implants to improve blood compatibility, suppress SMCs, and get rapid re-endothelialization.