Comparison of transient elastography and shear wave elastography in patients with MAFLD: A single-center experience.

BACKGROUND: Metabolic-associated fatty liver disease and liver fibrosis are intimately linked to insulin resistance, type 2 diabetes, obesity, and metabolic syndrome. Transient elastography (TE) and point shear wave elastography (pSWE) were used to measure liver stiffness in patients who met the ultrasound criteria for steatotic liver diseases (SLD). This study compared two methods for estimating liver stiffness in patients with SLD, which in turn correlated with liver fibrosis. METHOD: Ultrasound B-mode imaging was used to identify SLD. In total, 250 MAFLD patients were recruited. Patient characteristics, laboratory investigations, and liver stiffness measurements using TE and pSWE were assessed on the same day. RESULTS: In the study, 56.0% of the patients were male, with a mean age of 41.5 ± 10.7 years. The correlation between TE and pSWE was significant (Spearman's r = 0.867*, p < .001). The Bland-Altman Plot analysis confirmed this, with 97.5% of variations in LSM falling within 95% agreement ranges. Cohen's κ was used to assess the agreement between TE and pSWE fibrosis stages, showing almost perfect agreement (83.5% kappa agreement) and a strong association between pSWE and TE in the assessment fibrosis stages. CONCLUSION: In patients with MAFLD, TE, and SWE are reliable methods for measuring liver stiffness and can be used as non-invasive screening tools for the assessment of fibrosis in SLD.

Dysregulation of kidney proteases in the pathogenesis of hypertension following unilateral nephrectomy in juvenile mice.

BACKGROUND: Unliteral nephrectomy (UNX) results in the reduction of kidney mass. The remaining kidney undergoes compensatory renal growth via hypertrophy of the glomeruli and renal tubules to maintain a normal glomerular filtration rate (GFR). These compensatory mechanisms result in increased capillary pressure and glomerular hyperfiltration to increase single nephron GFR. Over time, hyperfiltration may lead to kidney scarring and the development of hypertension. OBJECTIVES: The first objective of this study was to test the hypothesis that a 50% reduction in functioning nephrons in juvenile mice leads to increased blood pressure over a 24-hour phase. The second objective was to test the hypothesis that UNX leads to changes in the expression and activity of kidney proteases in juvenile mice. METHODS: Eight male C57B6 juvenile wild-type mice were subject to UNX and an equal number of mice were subject to sham (SH) surgery. Metabolic cage studies were performed for 5 weeks to collect urine produced during the inactive and active phases. Blood pressure was measured using the tail cuff method twice weekly and tail blood was collected on different days during the inactive or active phase of each animal. The mice were euthanized at the age of 9 weeks. Western blotting and immunohistochemistry were performed to investigate changes in renal protein expression of various cathepsins and renal kallikrein 1 (KLK1) between the two groups. Protease activity assays were performed using kidney lysates and urine samples from each group. RESULTS: Compared to the SH group, UNX mice showed a persistent increase in blood pressure at week 3 which progressed toward the end of the study at week 5 of age. Cathepsin B, D, and S expression and activity were up-regulated in kidney cortex lysates from UNX mice compared to the SH control group. KLK1 protein expression was down-regulated and urinary nitric oxide excretion was decreased in UNX mice compared to the SH control group. CONCLUSION: UNX results in the development of persistent and progressive hypertension. Down-regulation of KLK1 and up-regulation of various cathepsins may contribute to the development of hypertension via multiple mechanisms including a decrease in nitric oxide (NO) production.

Functional and metabolomic analysis of urinary extracellular vesicles from juvenile mice with renal compensatory hypertrophy.

Unilateral nephrectomy, a procedure reducing kidney mass, triggers a compensatory response in the remaining kidney, increasing its size and function to maintain a normal glomerular filtration rate (GFR). Recent research has highlighted the role of extracellular vesicles (EVs) in renal physiology and disease, although their involvement in unilateral nephrectomy has been underexplored. In this study, unilateral nephrectomy was performed on young mice, and urinary extracellular vesicles (uEVs) characterization and cargo were analyzed. Kidney volume increased significantly post-nephrectomy, demonstrating compensatory hypertrophy. Serum creatinine, cystatin C, and urinary electrolytes concentrations were similar in both nephrectomized and control groups. Western blot analysis revealed upregulation of sodium-glucose cotransporter 2 (SGLT2) and sodium chloride cotransporter (NCC), and downregulation of sodium­potassium-chloride co-transporter (NKCC2) and epithelial sodium channel (ENaC) in the nephrectomized group. Metabolomic analysis of uEVs showed an enrichment of certain metabolites, including citrate and stachydrine. Interestingly, uEVs from the nephrectomized group demonstrated a protective effect, downregulating signal transducer and activator of transcription 3 (STAT3) and reducing reactive oxygen species (ROS) in renal proximal cells, compared to uEVs from the control group. This study suggests that uEVs contain bioactive components capable of inducing protective, anti-inflammatory, anti-fibrinolytic, and antioxidative effects in renal cells. These findings contribute to our understanding of uEVs' role in renal compensatory mechanisms after unilateral nephrectomy and may hold promise for future therapeutic interventions in renal diseases.

Severe hypertriglyceridemia in an infant on chronic hemodialysis.

Severe hyperlipidemia is a risk factor for cardiovascular disease. Children with chronic kidney disease and end stage renal disease are at risk for development of hyperlipidemia. In this report, we describe a 7-month-old male infant with Denys-Drash syndrome who was found to have a "milky-layer" floating on the deaerator of the hemodialysis machine. Investigations showed severe hypertriglyceridemia of >1000 mg/dl. The patient had been on chronic continuous manual peritoneal dialysis until 6 months of age and recently had been switched to hemodialysis. Management included lowering of caloric intake and addition of medium chain triglyceride with reduction of the serum triglyceride levels to 300-400 mg/dl. Close monitoring of serum lipids and timely intervention is important to prevent serious complications associated with dyslipidemia. Observation of the "milky layer" in the deaerator of the hemodialysis machine may be an interesting visual clue of underlying severe hypertriglyceridemia.

Enhancing the Occurrence Variance Reporting System Implementation at one of the Hospitals of the Egyptian Universal Health Insurance.

Background: Identifying, reporting, measuring, and tracking events provide an opportunity to study system issues, motivate learning, measure the frequency and severity of events, and manage high-risk ones which refer to a safety culture that is focused on valuing the input of working staff and improving the quality of care. Aim: Enhance the implementation of the occurrence variance reporting (OVR) system at the Obstetrics and Gynecological Hospital in Port Said Governorate, Egypt. Design: A quasi-experimental research design for one group (pre-posttest) and a mixed-methods approach was conducted in this study. Method: This study was carried out at an Obstetrics and Gynecological Hospital in Port Said Governorate, Egypt. Study subjects included a convenient sample of 100 doctors and nurses. The study used three tools: OVR Knowledge, Attitude, and Practice (KAP) questionnaire, the OVR trend analysis clinical audit checklist, and barriers that hinder staff to report patient safety events through two open-ended questions. Results: Significant improvements were detected in the OVR system post-program implementation than pre-program implementation phase. A statistically significant increase in nurses' and doctors' total knowledge score from 0.74 to 3.39 and a statistically significant decrease in nurses' and doctors' total negative attitude score from 3.87 to 3.27. Also, a statistically significant increase in total practice score from 2.35 to 2.45. Conclusion: There were significant improvements in the hospital OVR system postprogram implementation than preprogram implementation. Relevance to clinical practice: To maintain performance and make sure that the original result is not lost, the health care facilities should emphasize the ongoing monthly and quarterly monitoring and analysis of data. Meetings, lectures, and training sessions are used for ongoing education.

Extracellular vesicles from focal segmental glomerulosclerosis pediatric patients induce STAT3 activation and mesangial cell proliferation.

INTRODUCTION: Primary focal segmental glomerulosclerosis (FSGS), a major cause of end-stage kidney disease (ESKD) in adolescents and young adults, is attributable to recognized genetic mutations in a minority of cases. For the majority with idiopathic primary FSGS, the cause of the disease is unknown. We hypothesize that extracellular vesicle (EVs), that carry information between podocytes and mesangial cells, may play a key role in disease progression. MATERIAL & METHODS: A total of 30 participants (20 primary nephrotic syndrome/ 10 healthy controls) were enrolled in this study. Primary nephrotic syndrome subjects were grouped based on pathologic diagnosis. The FSGS group was compared to healthy control subjects based on demographic and clinical findings. EVs were isolated from the urine of each group before being characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis. The effects of the EVs from each group on normal human mesangial cells and activation of certain pathways were then investigated. RESULTS: Based on demographic and clinical findings, mean serum creatinine was significantly higher in the FSGS group than the normal healthy control group. The mean size of the EVs in the FSGS group was significantly higher than the healthy control group. The mesangial cells that were challenged with EVs isolated from FSGS patients showed significant upregulation of STAT-3, PCNA, Ki67, and cell proliferation. DISCUSSION: Our data demonstrate that EVs from FSGS patients stimulate mesangial cell proliferation in association with upregulation of the phospho-STAT-3 pathway. Additional studies are planned to identify the molecular cargo within the EVs from FSGS patients that contribute to the pathogenesis of FSGS.

Polyethylene Glycol 3350 Crystal Nephropathy in Association With Glomerular Mesangial Immunoglobin A Deposition.

Polyethylene glycol (PEG) 3350, an active ingredient of over-the-counter MiraLAX, is a commonly used laxative in children and is produced by polymerization of ethylene glycol (EG). Masked EG toxicity secondary to contamination of PEG 3350 could occur. We present a 7-year-old child with developmental delay who presented with altered mental status and acute kidney injury (AKI) following intake of generic PEG 3350 for few days prior to presentation. There was high anion gap metabolic acidosis, hypernatremia, elevated osmolar gap, lactic acidosis, and AKI. Urinalysis showed tubular proteinuria, microscopic hematuria, and calcium oxalate crystals. Prior urinalyses were normal without hematuria or proteinuria. Renal biopsy revealed evidence of mesangial dominant immunoglobulin A (IgA) and complement 3 (C3) deposits along with dense tubular deposition of calcium oxalate crystals. He subsequently developed worsening oliguric AKI and required hemodialysis (HD) for several sessions. The AKI resolved within 2 weeks and further HD was not required. Mental status improved in few days. Follow-up urinalyses showed resolution of microscopic hematuria and crystalluria. We hypothesized that the generic PEG 3350 most likely was contaminated with EG leading to the presentation. A high index of suspicion of contamination of PEG 3350 with EG is required in patients presenting with unexplained high anion gap metabolic acidosis, elevated osmolar gap, lactic acidosis, AKI, calcium oxalate crystalluria, and oxalate crystals on renal biopsy. Further studies are needed to determine whether there is an association between transient glomerular mesangial IgA deposition and crystal nephropathy.

Drug-Induced Lupus Secondary to Ethosuximide in Association with Acute Tubulointerstitial Nephritis and Nephrotic Syndrome.

Background. Drug-induced lupus (DIL) is an autoimmune phenomenon where the patient develops lupus-like symptoms after exposure to a long-term medication. Case Summary. Here we describe a 10-year-old female with absence seizures who developed a lupus-like syndrome after being on ethosuximide for three months. She presented with nephrotic syndrome (NS) and acute kidney injury. Four weeks prior to presentation, she had been prescribed a seven-day course of oral amoxicillin for submental swelling after dental extraction. Investigations showed high titer of antinuclear antibody (ANA) and anti-double stranded DNA, elevated serum IgE level, and positive Coombs' test, along with positive anti-histone antibodies. Renal biopsy showed features of acute tubulointerstitial nephritis (TIN) and partial podocyte foot process effacement without evidence of lupus nephritis. The patient had an excellent response to the steroid therapy with remission within two weeks. The patient remained in remission for two months as evaluated during the most recent follow-up; the autoimmune antibodies and immunoglobulin E trended down. Ethosuximide has been reported to cause DIL, however its possible association with TIN has not been reported. Although amoxicillin could have caused the TIN and NS in this patient, a possible novel association of ethosuximide with this nephrotic-nephritic presentation (NNP) cannot be ruled out. Conclusions. A renal histology is important to determine the accurate etiology of NNP in patients with DIL. Further studies are necessary to determine any possible causal effect of ethosuximide with NNP.

Delayed Onset Minimal Change Disease as a Manifestation of Lupus Podocytopathy.

Lupus podocytopathy (LP) is an uncommon manifestation of systemic lupus erythematosus (SLE) and is not included in the classification of lupus nephritis. The diagnosis of LP is confirmed by the presence of diffuse foot process effacement in the absence of capillary wall deposits with or without mesangial immune deposits in a patient with SLE. Here we describe a 13-year-old female who presented with nephrotic syndrome (NS) seven years after the diagnosis of SLE. The renal function had been stable for seven years since the SLE diagnosis, as manifested by the normal serum creatinine, serum albumin and absence of proteinuria. Renal biopsy showed evidence of minimal change disease without immune complex deposits or features of membranous nephropathy. Renal function was normal. The patient had an excellent response to steroid therapy with remission within two weeks. The patient remained in remission five months later during the most recent follow-up. This report highlights the importance of renal histology to determine the accurate etiology of NS in patients with SLE. Circulating factors, including cytokines such as interleukin 13, may play a role in the pathophysiology of LP and needs to be studied further in future larger studies.

MELD-Sarcopenia is Better than ALBI and MELD Score in Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation.

BACKGROUND: The albumin bilirubin (ALBI) score and model of end stage liver disease (MELD) are prognostic in patients with hepatocellular carcinoma (HCC). Aim was to compare MELD-sarcopenia to MELD and ALBI scores in patients with HCC awaiting liver transplantation. METHODS: patients with HCC (n=262) were included and followed up for 12 months. Baseline MELD, ALBI and MELD-sarcopenia models were calculated. RESULTS: The average age was 59.61 ±8.09 years. Most patients were males (69.5%), CTP class A (55.7%) and BCLC stage B (54.2%). Hepatitis C virus was the main cause of liver cirrhosis in most patients (88.9%). The average MELD, MELD-sarcopenia and median ALBI score were 10.65 ±2.54, 15.11 ±6.22 and -2.12 (0.74) respectively. Sarcopenia patients had higher MELD, ALBI and MELD-sarcopenia values. Patients with sarcopenia had lower survival (10.09 months) than those without (11.72 months). The ALBI, MELD and MELD-sarcopenia were associated with mortality. ALBI had AUROC of 0.717 (95% CI: 0.659 - 0.771), MELD had AUROC of 0.656 (95% CI: 0.595 - 0.713) and MELD-sarcopenia had AUROC of 0.798 (95% CI: 0.744 - 0.845). The ALBI and MELD scores had comparable AUROC (p=0.081). The MELD-sarcopenia had superior AUROC than MELD (p=0.001) and ALBI (p=0.05). CONCLUSION: MELD-sarcopenia is better prognostic model than the ALBI and MELD scores in HCC patients awaiting liver transplantation.
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Renal Transplant Hydroureteronephrosis as a Manifestation of Rejection: An Under-Recognized Entity?

Hydroureteronephrosis (HUN) of the renal transplant (RT) can be obstructive or non-obstructive, refluxing or non-refluxing, and can cause allograft dysfunction. HUN of the RT as a manifestation of rejection is uncommon and has not been described in children. We describe two pediatric RT recipients who presented with late-onset HUN, 5 and 10 years after transplantation. Both had new-onset HUN which occurred at the time of rejection; HUN resolved in both patients after treatment of rejection. Renal function stabilized in both patients without the need for stent or nephrostomy tube placement. There was no obstruction or vesicoureteral reflux (VUR). Edema of the uroepithelial cells leading to transient obstruction causing HUN is a most likely explanation. We conclude that treatment of rejection in patients without obstruction or VUR may lead to resolution of HUN without the need for urological interventions.

Antineoplastic activity of Salmonella Typhimurium outer membrane nanovesicles.

Nano-sized Gram-negative bacterial outer membrane vesicles possess unique structural and immunostimulatory effects that could be exploited to regress tumors by alerting the host immune system and reversing the immunosuppressive tumor microenvironment. The current study was conducted to investigate the antitumor activity of the outer membrane vesicles (ST-OMVs) of Salmonella Typhimurium ATCC 14028, in vitro in human colorectal carcinoma (HTC116), breast cancer (MCF-7), and hepatocellular carcinoma (HepG2) cell lines and in vivo in Ehrlich solid carcinoma-bearing mice model either as a mono-immunotherapy or as an adjuvant to a commonly used conventional chemotherapy. In addition, we investigated the safety of ST-OMVs. Adult Swiss albino female mice with transplanted Ehrlich solid carcinoma were treated with either ST-OMVs, paclitaxel or a combination of both. Tumor volume, growth inhibition rate, quantitative RT-PCR of Bax and VEGF genes expression, histopathology and immune-expression of caspase-3, Beclin-1, CD49b and Ki-67 were all analyzed. Our results showed that ST-OMVs significantly decreased tumor volume, significantly increased tumor growth inhibition rate, up-regulated the immunohistochemical expression of caspase-3, Beclin-1, and CD49b (enhanced recruitment of NK cells). Furthermore, ST-OMVs down-regulated the expression of Ki-67, increased Bax gene expression and decreased VEGF gene expression as detected by qRT-PCR analysis. Histologically, ST-OMVs promoted apoptosis, decreased tumor invasion and mitotic activities. Moreover, ST-OMVs showed a remarkable cytotoxic activity in various investigated in vitro cancer cell lines. Our findings demonstrate potential antitumor activity of ST-OMVs that might be used as a promising safe antitumor immunotherapy or an adjuvant to conventional chemotherapeutic drugs, resolving some of their problems.

Baseline Sarcopenia is Associated with Lack of Response to Therapy, Liver Decompensation and High Mortality in Hepatocellular Carcinoma Patients.

OBJECTIVE: hepatocellular carcinoma (HCC) is a dreadful complication of liver cirrhosis. Aim was to study the effect of sarcopenia on the survival in patients with HCC. METHODS: we included 262 patients and were followed up for 12 months. Sarcopenia was calculated by skeletal muscle index (SMI). Sarcopenia was defined by SMI ≤39 cm2/m2 for women and ≤50 cm2/m2 for men. RESULTS: patients with sarcopenia (n= 113, 43.1%) were older, mainly males, Child-Pugh class B and smokers. Patients with sarcopenia had lower survival than those without (10.09 vs. 11.72 months). Survival was also lower in Barcelona clinic liver cancer stage C than B and A (9.02 vs. 11.21 vs. 11.89 months). Age and sarcopenia were hazardous of mortality (p <0.05). There was statistically significant difference of serial SMI in patients without baseline sarcopenia unlike patients with baseline sarcopenia. On follow up patients with sarcopenia had higher incidence of ascites (45% vs. 20.4%), spontaneous bacterial peritonitis (21.7% vs. 11.6%), hepatic encephalopathy (28% vs. 11.5%) and bleeding (22.9% vs. 12.7%). Totally patients with sarcopenia had higher incidence of progressive HCC (39% vs. 25.5%). CONCLUSION: Sarcopenia is associated with lack of response to therapy, liver decompensation and higher mortality in hepatocellular carcinoma patients.
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Novel quinoline-3-carboxamides (Part 2): Design, optimization and synthesis of quinoline based scaffold as EGFR inhibitors with potent anticancer activity.

EGFR has a key role in cell growth. Its mutation and overexpression share in epithelial malignancies and tumor growth. Quinazoline and quinoline derivatives are common anticancer intracellular inhibitors of EGFR kinase, and their optimization is an important issue for development of potent targeted anticancer agents. Based on these facts, different strategies were used for optimizing our reported quinoline-3-carboxamide compound III (EGFR IC50 = 5.283 µM and MCF-7 IC50 = 3.46 µM) through different molecular modeling techniques. The optimized compounds were synthesized and subjected to EGFR binding assay and accordingly some more potent inhibitors were obtained. The most potent quinoline-3-carboxamides were the furan derivative 5o; thiophene derivative 6b; and benzyloxy derivative 10 showing EGFR IC50 values 2.61, 0.49 and 1.73 µM, respectively. Furthermore, the anticancer activity of compounds eliciting potent EGFR inhibition (5o, 5p, 6b, 8a, 8b, and 10) was evaluated against MCF-7 cell line where they exhibited IC50 values 3.355, 3.647, 5.069, 3.617, 0.839 and 10.85 µM, respectively. Compound 6b was selected as lead structure for further optimization hoping to produce more potent EGFR inhibitors.

Molecular design and synthesis of certain new quinoline derivatives having potential anticancer activity.

EGFR, which plays a vital role as a regulator of cell growth, is one of the intensely studied TK targets of anticancer inhibitors. The most two common anticancer inhibitors are anilinoquiazolines and anilinoquinolines that inhibit EGFR kinase intracellularly. The present investigation dealt with design (pharmacophore, docking and binding energy) and synthesis of a new series of 4-anilinoquinoline-3-carboxamide derivatives as potential anticancer agents targeting EGFR. All the newly synthesized compounds were screened for their anticancer activity against MCF-7 and compounds 4f, 7a and 7b showed significant activity with IC50 values 13.96 µM, 2.16 µM and 3.46 µM, respectively. Most of the synthesized compounds were subjected to enzyme assay (EGFR TK) for measuring their inhibitory activity with the determination of IC50 values and the preliminary results revealed that compound 7b, which had potent inhibitory activity in tumor growth and had potent activity on the EGFR TK enzyme with 67% inhibition compared to ATP would be a potential anticancer agent.

Metabolic effects of honey in type 1 diabetes mellitus: a randomized crossover pilot study.

The aim of this study was to evaluate the metabolic effects of 12-week honey consumption on patients suffering from type 1 diabetes mellitus (DM). This was a randomized crossover clinical trial done in the National Institute for Diabetes and Endocrinology, Cairo, Egypt. Twenty patients of both sexes aged 4-18 years with type 1 DM and HbA1C<10% participated in the study. They were randomized into two equal groups (intervention to control and control to intervention). The dietary intervention was 12-week honey consumption in a dose of 0.5 mL/kg body weight per day. The main outcome measures were serum glucose, lipids, and C-peptide, and anthropometric measurements. None of participants were lost in follow-up. The intervention resulted in significant decreases in subscapular skin fold thickness (SSFT; P=.002), fasting serum glucose (FSG; P=.001), total cholesterol (P=.0001), serum triglycerides (TG; P=.0001), and low-density lipoprotein (P=.0009), and significant increases in fasting C-peptide (FCP; P=.0004) and 2-h postprandial C-peptide (PCP; P=.002). As possible long-term effects of honey after its withdrawal, statistically significant reductions in midarm circumference (P=.000), triceps skin fold thickness (P=.006), SSFT (P=.003), FSG (P=.005), 2-h postprandial serum glucose (P=.000), TG (P=.003), and HbA1C (P=.043), and significant increases in FCP (P=.002) and PCP (P=.003) were observed. This small clinical trial suggests that long-term consumption of honey might have positive effects on the metabolic derangements of type 1 DM.

Inherited thrombophilia in pediatric ischemic stroke: an Egyptian study.

Pediatric stroke is relatively uncommon, with often subtle clinical presentations. Numerous predisposing risk factors can be both inherited and acquired, including cardiac disease, vascular abnormalities, infectious diseases, collagen tissue diseases, inborn errors of metabolism, anticardiolipin antibody, lupus anticoagulant, deficiencies of protein C, protein S, antithrombin, or plasminogen, and prothrombotic mutations. We explored risk factors, clinical features, and neuroimaging among Egyptian children with ischemic stroke, and estimated the prevalence of inherited thrombophilia. We included 20 children with ischemic stroke, recruited from the Pediatric Neurology Outpatient Clinic (Ain Shams University). Basic clinical evaluations for stroke and genotyping for factor V 1691 G-A (factor V Leiden), prothrombin 20210 G-A mutations, and methylenetetrahydrofolate reductase 677 C-T polymorphisms were performed using real-time polymerase chain reaction, with fluorescent melting curve detection analysis. Ten patients (50%) manifested methylenetetrahydrofolate reductase polymorphisms (six homozygotes and four heterozygotes). Heterozygous factor V Leiden was present in five (25%), whereas prothrombin mutation was present in only one (5%). Five patients (25%) manifested combined prothrombotic abnormalities. Thirteen demonstrated evidence of inherited thrombophilic disorder; 25% manifested more than one mutation. For appropriate risk assessment, even in the presence of overt acquired thrombotic risk factors, physicians should request complete thrombophilia screening for patients with stroke.