Clearance Levels Research Articles

Obicetrapib Alone and in Combination with Ezetimibe Reduces Non-HDL-Cholesterol by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion in ApoE*3-Leiden.CETP Mice

Background and Aims: Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and cardiovascular risk. It reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, also reducing LDL-C levels. The current study elucidates the mechanism for decreases in non-HDL-C by obicetrapib alone and with ezetimibe in a mouse model for hyperlipidemia and atherosclerosis.Methods: Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib (2 mg/kg/day), ezetimibe (1 mg/kg/day), or obicetrapib with ezetimibe.Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-42%, -23% and -62%).Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 (98% and 81%). Obicetrapib, ezetimibe, and the combination enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice was observed, and was more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss.Conclusions: Obicetrapib alone and with ezetimibe reduced non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels, and enhanced fecal bile acid and neutral sterol excretion.

Evaluation of Inflammatory Status in COVID-19 Patients with Chronic Kidney Disease: A Comparative Analysis Based on Creatinine Clearance Levels

Background and Objectives: Patients with chronic kidney disease (CKD) are at increased risk of severe COVID-19 outcomes due to their compromised immune systems and chronic inflammatory state. This study aimed to evaluate and compare the inflammatory status of COVID-19 patients with CKD, stratified by creatinine clearance (CrCl) levels: CrCl < 30 mL/min, CrCl 30–60 mL/min, and CrCl > 60 mL/min. Multiple inflammatory scores combining laboratory parameters were assessed, including novel scores and established indices. Methods: In this retrospective cohort study, 223 patients admitted with confirmed COVID-19 were included and divided into three groups based on CrCl levels: CrCl < 30 (n = 41), CrCl 30–60 (n = 78), and CrCl > 60 (n = 104). Laboratory parameters including C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil-to-lymphocyte ratio (NLR), ferritin, platelet count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and serum albumin were collected. Multiple inflammatory scores were calculated, including inflammation scores (IS1–IS4), the systemic inflammatory index (SII), the C-reactive protein-to-albumin ratio (CAR), the lymphocyte-to-C-reactive protein ratio (LCR), and the prognostic nutritional index (PNI). Statistical analyses were performed to compare inflammatory scores among groups and assess correlations with clinical outcomes. Results: The CrCl < 30 group exhibited significantly higher levels of inflammatory markers and inflammatory scores compared with the other groups (p < 0.001). Among the additional scores, CAR and SII were significantly elevated in patients with lower CrCl levels, while LCR and PNI were decreased. CAR showed a strong positive correlation with COVID-19 severity (r = 0.65, p < 0.001), and PNI was inversely correlated with mortality (r = −0.58, p < 0.001). Multivariate regression analysis indicated that lower CrCl levels, higher IS3 and CAR, and lower PNI were independent predictors of severe COVID-19 outcomes. Conclusions: CKD patients with lower CrCl levels have an amplified inflammatory response during COVID-19 infection, as evidenced by elevated inflammatory scores. The additional inflammatory scores, particularly CAR and PNI, may serve as valuable tools for risk stratification and management of COVID-19 in CKD patients. Early identification of patients with high CAR and low PNI could improve clinical outcomes through timely therapeutic interventions.

Disequilibrium in natural decay series in samples from Czech water treatment plants: Uranium, radium and thorium isotopes determination

In the Czech Republic, underground or mixed source water treatment plants are classified as the workplaces with possible increased exposure from a natural source of radiation. When releasing waste materials or residues from these NORM workplaces into the environment, the content of natural radionuclides is measured and compared with the clearance levels established by Czech legislation. The content of natural radionuclides in solid samples is determined primarily by high-resolution gamma-ray spectrometry. Six radionuclides, 238U, 228Th, 226Ra, 228Ra, 210Pb, 40K, are measured directly or by their measurable decay products (assuming equilibrium), the activity concentration of the other four radionuclides, 234U, 230Th, 210Po, 232Th is conservatively estimated. The study is focused on mapping the properties of NORM arising from the treatment of groundwater and, based on the real samples measurement, verification of new proposed assessment approach. It was tested whether the knowledge of the content of natural radionuclides in water can be practically used to estimate the content in NORM. Samples of water, filter material or sludge were taken from 16 different water treatment plants. Combination of gamma-ray spectrometry and radiochemical methods were applied to determine the content of radionuclides 234U, 238U, 226Ra, 228Ra, 228Th, 230Th and 232Th in solid NORM, and radionuclides 234U, 238U, 226Ra, 228Ra in water. Based on the results the proposed modification of the assessment was verified.

Vertebral Fracture Prediction from MRI-based Vertebral Bone Quality Scores in Postmenopausal Women

Study Design. A longitudinal cohort study Objective. The study aims to assess the lumbar MRI-based vertebral bone quality (VBQ) score and dual energy x-ray absorptiometry (DXA) T score in a longitudinal cohort of postmenopausal women and to evaluate the performance of these scores in predicting VF over 5 years of follow-up. Summary of Background Data. VBQ scores can be used for osteoporosis screening and identification of vertebral fractures (VFs). However, due to limitations in prior cross-sectional studies, definitive conclusions about the causal associations between the VBQ score and incident VF have not been drawn. Methods. Postmenopausal women with baseline DXA and lumbar MRI data were enrolled. Follow-up assessments were conducted over 5 years after the baseline examination; both anteroposterior- and lateral-view thoracolumbar spine radiographs were captured to evaluate incident VF. At baseline, correlation analyses between the VBQ score and osteoporosis or preexisting VF were performed. A Cox regression model for multivariate logistic regression was used to analyze the risk factors for incident VF. The hazard ratio (HR) was calculated. Results. 137 postmenopausal women were included. The VBQ score was moderately correlated with lumbar bone mineral density at baseline (r=0.4, P<0.001). Patients with incident VF had significantly lower T scores (-3.4 vs. -1.87, P<0.001) and higher VBQ scores (4.62 vs. 4.03, P<0.001) at baseline than those without incident VF. After adjusting for age, weight, creatinine clearance, and alkaline phosphatase levels, the HRs for the VBQ score and T score were 1.93 and 0.71, respectively. After adjusting for the T score, an increased VBQ score was independently associated with an increased risk of incident VF, with an HR of 1.87. Conclusion. The VBQ score was moderately correlated with DXA T score and was a predictor of incident VF risk independent of bone mineral density in postmenopausal women.

EVALUATION OF SERUM PERIOSTIN AND PIIINP AS BIOMARKERS OF RENAL FIBROSIS AND FUNCTION DECLINE IN RENAL TRANSPLANT PATIENTS

This study aimed to evaluate the potential of serum periostin and N-terminal propeptide of type III procollagen (PIIINP) as biomarkers for predicting renal fibrosis and functional decline in renal transplant patients. We conducted a two-visit observational study among 86 renal allograft patients, reduced to 35 at the two-year follow-up due to the COVID-19 pandemic. Blood samples were collected at baseline and follow-up, while urine samples were collected only at follow-up. Serum levels of PIIINP and periostin were measured using ELISA kits, and various renal function parameters were assessed. Serum PIIINP levels showed a significant decrease over two years (p<0.001, Wilcoxon test), while periostin levels significantly increased (p<0.001, Wilcoxon test). These changes correlated with declines in renal function, as indicated by decreased serum albumin and creatinine clearance levels, and increased serum creatinine levels. Significant correlations were found between changes in PIIINP and creatinine clearance (Spearman coefficient = 0.352, p<0.05), as well as between changes in periostin and creatinine clearance (Spearman coefficient = 0.626, p<0.001). Our findings suggest that serum periostin and PIIINP levels are valuable biomarkers for assessing renal fibrosis and functional decline in renal transplant patients. These biomarkers may provide insights into disease progression and guide therapeutic interventions.

Nephroprotective effects of the soluble guanylyl cyclase stimulator, riociguat in doxorubicin-induced acute kidney injury in rats

This study aimed to investigate the potential protective effects of riociguat, a soluble guanylyl cyclase (sGC) stimulator, on kidney function and structure in rats with acute kidney injury (AKI) induced by the chemotherapeutic drug doxorubicin (DX). Rats were subjected to a single intraperitoneal injection of DX (13.5 mg/kg) on the 5th day, either alone or in combination with low-dose riociguat (3 mg/kg/day), or high-dose riociguat (10 mg/kg/day) for 8 consecutive days. Various markers related to kidney function, oxidative stress, and inflammation were measured in plasma and urine. Kidney tissues were examined histopathologically. DX-induced nephrotoxicity was characterized by increased plasma urea, creatinine, uric acid and neutrophil gelatinase-associated lipocalin (NGAL). DX also decreased creatinine clearance and albumin levels and increased urinary N-acetyl-β-D-glucosaminidase (NAG) activity. Furthermore, DX increased the inflammatory markers interleukin 1 beta (IL-1 β), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). DX further induced oxidative stress injury evidenced by decreased glutathione reductase (GR) activity, total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase levels and increased malondialdehyde (MDA) levels. Concomitant treatment with riociguat ameliorated these DX-induced changes with parallel histopathological improvements but the effects were more favorable with high-dose riociguat. The observed renoprotective effects of riociguat can be partly attributed to the anti-inflammatory and anti-oxidant properties of this drug.

Differential gene expression of immune response in COVID-19 and its relationship with progression of COVID-19

Human immune response evolved in virus clearance and gene expression levels of immune response may be associated with progression of Coronavirus disease 2019 (COVID-19). Our current study aims to investigate the relationship between differential gene expression of immune response and progression of COVID-19. A total of 50 participants of COVID-19 group were studied, compared with 39 participants of healthy control group. There were different gene expression profiles in pathways of activation of neutrophil, defense response and adaptive immune response for COVID-19 group before treatment compared to the healthy control group. Distinct gene expression profiles showed that pathways of chemotaxis, immune response and antibacterial humoral response involved in rehabilitation of severe COVID-19 group while pathways of immune system process, defense response to virus and negative regulation of viral genome replication involved in rehabilitation of moderate COVID-19 group. Both protein expression of ATP-binding cassette transporter A1 levels and protein expression of low affinity Fc-receptor FcγRIIIb levels were significantly and positively correlated with COVID-19-IgM levels and might be suitable as biomarkers for monitoring of COVID-19. This study showed that differential gene expression of immune response predicted onset and rehabilitation of COVID-19.

Disease-Modifying Treatment of Psoriasis in Children

Advances in understanding the mechanisms underlying chronic inflammatory skin diseases, such as psoriasis vulgaris, have led to implementation of new treatment options aimed at symptoms relieving. Moreover, this data may become the basis for new strategies to achieve sustained or treatment-free remission, that is disease modification with potential impact on comorbid conditions. However, achieving this goal requires further study of such crucial aspects as the terms of disease modification and disease activity indicators, deeper understanding of pathogenesis mechanisms, etiology, and systemic side effects, possible opportunities, biomarkers for successful patient stratification and intervention, as well as the adequate study design. Early intervention with genetically engineered biologic drugs such as secukinumab represents new paradigm shift in improvement of immune-mediated diseases outcomes. However, new evidence is needed to determine its efficacy in psoriasis. High level of sustained skin clearance observed on secukinumab therapy compared to standard treatment and phototherapy indicates the potential benefit of early biologic drugs treatment to achieve complete skin clearance and improvement in quality of life, education, and daily activities. It can also become a background for changing treatment strategies for patients with newly diagnosed moderate-to-severe plaque psoriasis. Keywords: psoriasis, children, secukinumab, disease-modifying treatment

Assessment of radiological risk to workers and members of the public from the operation of a groundwater treatment plant in Jordan

ABSTRACT The study aimed to evaluate the radiation doses received by workers at a pilot water treatment plant (WTP) in Jordan. It also examined the concentrations of gross alpha, gross beta, and radium activities in both groundwater and treated water, along with a radiological risk assessment for the waste generated by the treatment process. The radioactivity levels of gross alpha and gross beta in the groundwater were found to exceed the established drinking water limits. In the pilot WTP, two methods were applied for water treatment, namely, ceramic ultra-filtration (CUF) and reverse osmosis (RO), both of which produced treated water that met drinking water quality standards. The annual effective dose from external radiation exposure to the WTP workers was found to be less than 0.007 mSv y−1 (during the filters backwash operation). However, the average annual dose from internal radiation due to inhalation of radon released from groundwater reached 3.2 mSv y−1, exceeding the 1 mSv y−1 limit. Therefore, monitoring radon levels in workplaces is recommended. Radioisotope concentrations in the waste (sludge) stockpiles exceeded clearance levels, requiring them to be treated as radioactive waste. Overall, the WTP successfully produced drinking water that met quality standards, and the methods used could be replicated in other locations.

Clove Aqueous Extract Alleviates Acute Kidney Injury Induced by Folic Acid in Rats

Background: Acute Kidney Injury (AKI) is a common clinical disease that has a high incidence and mortality rate. Clove, a robust natural source of bioactive chemicals and rich in secondary metabolites, plays a wide range of biological roles. Aim: The present study aimed to assess the ameliorative efficacy of clove extract against acute renal damage induced by folic acid in rats. Methods: Gas Chromatography/Mass Spectrometry (GC/MS) was used to investigate the main components of clove extract. Folic acid, at a dose of 250 mg/kg, was delivered intraperitoneally to rats to induce AKI. Eighteen rats were divided into three groups: control, AKI, and AKI + clove extract (500 mg/kg). Results: The administration of clove extract significantly restored the levels of creatine, urea, uric acid, sodium, potassium, chloride, creatinine clearance, and microalbumin to nearly normal levels. Also, clove water extract inhibited oxidative stress by decreasing concentrations of Malondialdehyde (MDA) and Nitric Oxide (NO). Furthermore, clove extract elevated the levels of Glutathionereduced (GSH), Catalase (CAT), and Glutathione S-transferase (GST). Kidney section histology showed notable improvements after the administration of clove extract. Conclusion: The clove water extract has been found to contain many bioactive components possessing antioxidant and anti-inflammatory properties, effectively protecting against acute renal injury.

Reno-protective potential of poncirin against polyethylene microplastics instigated kidney damage in rats via regulating Nrf-2/Keap-1 pathway

Polyethylene microplastics (PEMPs) are noxious environmental pollutants that are documented to cause organ damage including the kidneys. Poncirin (PON) is a naturally occurring flavonoid which demonstrates a wide range of pharmacological properties. This experiment was conducted to evaluate the palliative potential of PON against PEMPs induced renal toxicity by examining a range of biochemical and physiological parameters. Twenty-four male albino rats were randomly apportioned into four distinct groups including the control, PEMPs (1.5 mgkg−1), PEMPs (1.5 mgkg−1) + PON (20 mgkg−1) and only PON (20 mgkg−1). Our results displayed that PEMPs intoxication escalated the levels of urea, KIM-1, creatinine and NGAL while reducing the creatinine clearance level. Besides reduction in the activities of GPx, GST, HO-1, CAT, GSR & upsurge in the levels of MDA and ROS were detected in PEMPs group. Conversely, the levels of inflammatory markers including COX-2, IL-6, IL-1β, NF-kB and TNF-α were augmented following the PEMPs intoxication. Besides, the results of the current research demonstrated that the expressions of Bax and caspase-3 were esclated whereas the Bcl-2 expression was lowered from its standard value due to PEMPs provision. However, PON treatment significantly restored the PEMPs-induced aforementioned impairments. Therefore, PON could be used as a therapeutic compound to ameliorate PEMPs-induced kidney impairments in rats, possibly due to its tremendous pharmacotherapeutic potential.

Extended long-term efficacy and safety of velmanase alfa treatment up to 12 years in patients with alpha-mannosidosis.

Enzyme replacement therapy (ERT) using velmanase alfa previously showed promising efficacy and safety outcomes for up to 4 years of therapy in patients with alpha-mannosidosis. This pooled analysis from two multicenter, open-label phase IIIb extension trials rhLAMAN-07 (N = 13; NCT01908712) and rhLAMAN-09 (N = 8; NCT01908725) evaluated the long-term effects of velmanase alfa. Sixteen patients who previously completed phase I-III rhLAMAN-02/-03/-04/-05/-08 trials and five ERT-naïve patients were enrolled. Patients received 1 mg/kg velmanase alfa once weekly. Endpoints included changes from treatment baseline (before initial dose of velmanase alfa in any trial) in serum oligosaccharides, 6-minute walk test (6MWT), 3-minute stair climb test (3MSCT), pulmonary function (forced vital capacity [FVC], % predicted), serum immunoglobulin G (IgG) levels, and adverse events. The overall cohort comprised 21 patients, divided by age at treatment baseline into pediatric (n = 14) and adult subgroups (n = 7). Distance walked according to 6MWT increased or stabilized in pediatric patients, while in adults either stabilization or slight decline was observed. Similarly, pediatric patients performed better in the 3MSCT. Changes in FVC, % predicted, were comparable in both subgroups up to ~6 years of observation, diverging thereafter. Overall, sustained serum oligosaccharide clearance and serum IgG level increase was observed upon treatment initiation and persisted until last common observation. Velmanase alfa treatment was generally well tolerated, with the majority of reported adverse events being of mild-to-moderate intensity. With follow-up of up to 12 years, long-term efficacy and safety outcomes indicate continued benefits of velmanase alfa in patients with alpha-mannosidosis.

Biofabricated adipose-derived mesenchymal cell sheets recover cryo-injured kidneys in rats.

This study aimed to develop a treatment for chronic kidney disease (CKD) by investigating whether transplantation of biofabricated adipose-derived mesenchymal cell (AMC) sheets could improve renal tissue and function. Thirty-nine 10-week-old male Sprague-Dawley rats underwent the harvesting of adipose tissues and right nephrectomy. AMCs that were collected from adipose tissues were labeled and cultured on temperature-responsive dishes, and applied to a gelatin hydrogel sheet. Subsequently, two identical AMC-gelatin sheets were attached together to biofabricate a bilayered AMC-gelatin sheet. Further, 3 weeks after nephrectomy, the renal artery and vein of the left kidney were clamped, and the kidney was sprayed with liquid nitrogen for 60 seconds. The biofabricated AMC sheet was autologously transplanted into the renal capsule of the cryo-injured region (n = 14). Control rats were given acellular sheet (n = 25). One day before and four weeks after transplantation, blood and 24-hour urinary specimens were collected. Histological analysis of the experimental kidneys was performed four weeks after transplantation. Four weeks after transplantation, in the acellular control-transplanted rats, creatinine clearance levels tended to increase, while serum creatinine levels significantly increased. However, in the biofabricated AMC sheet-transplanted rats, creatinine clearance levels significantly increased, and serum creatinine levels remained unchanged and were significantly lower than that of the control rats. The ratio of damaged to undamaged renal tubules in the AMC sheet-transplanted rats was lower than that in the control rats. In addition, the occupancy rate of fibrotic areas in the renal cortex under the AMC sheet-transplanted regions was significantly lower than that in the control regions. After transplantation, while the expressions of transforming growth factor-beta 1 and hypoxia-inducible factor-1 alpha were observed in both the control- and AMC sheet-transplanted regions, these expressions tended to be lower in the AMC sheet-transplanted rats than in the control rats. The labeled transplanted AMCs were detected in the transplanted regions, with some of them also showing positive staining for the vascular endothelial growth factor antibody. In conclusion, the biofabricated AMC sheets improved renal functions by ameliorating renal tubule disorders and renal fibrosis. Therefore, biofabricated AMC sheets would serve as a potential treatment for CKD.

Problems of management of patient biological waste in radionuclide diagnostics

Biological excretion from patients (urine) generated during radionuclide diagnostics enters directly into the hospital sewage system. The establishment of new clearance level according to Resolution of the Government of the Russian Federation No. 1069 of October 19, 2012 may entail amendments to regulatory documents for radionuclide diagnostics departments. One of these requirements is a mandatory dedicated sewage system. Establishment of the requirement may lead to an increase the cost of the radionuclide diagnostic examinations, and to a decrease the accessibility of radionuclide diagnostic. The aim of this study was to estimate the activity of radionuclides in patient urine after radionuclide diagnostic and activity concentration in sewage water in the hospital and in the transport tank of toilet for evaluation of paths of waste manage. Based on published literature data, models of biological excretion were constructed for the following radiopharmaceuticals: 99mTc-pyrophosphate, 64Cu-Labeled Monoclonal Antibody, 18F-FDG, 68Ga-PSMA-617. The activity of radionuclides in the patient waste in the hospital and in public transport during the patient transportation to home was calculated. Various scenarios of patient transportation were considered. The values of the excreted activity, activity concentration and dose rate at 1 m from the tank with sewage water for each type of transport were calculated. The calculated values of the radionuclide activity concentration in sewage water in transport tank of toilet for the majority scenarios exceed the clearance level (up to 180 times for 68Ga-PSMA-617 when traveling by bus). According the regulatory requirements, it is necessary to collect patient excretions after radionuclide diagnostic examinations and hold it for decay. However, estimated effective doses of individuals from the public from contact with biological patient waste do not exceed the acceptable value. This is due to the short half-life of diagnostic radionuclides. The paths of management system of biological patient waste were proposed.

A study on in-situ characterization technology development for clearance verification of radioactive waste from nuclear decommissioning

Although the clearance level of every radioactive nuclide was published by the IAEA to promote the recycling and reuse of decontaminated radioactive waste worldwide, technical and regulatory issues have always been raised around the application of the criteria. Therefore, several countries are developing in-situ characterization equipment or apparatus for on-site verification to check if the clearance criteria is met.In this study authors developed a pilot radiation detection and measurement system using in-situ characterization technology to solve the issues, which consists of a 3D scanning camera system and a built-in Monte Carlo simulation program. Measurement results show that MDA (Minimum Detectable Activity) of the current design was indisputably below the clearance level and built-in Monte Carlo simulation package closely predicts the measurements results with the error of less than 5%. This implicates that it can determine with enough margin whether the radioactivity level of decontaminated metallic components meets the clearance criteria at decommissioning site or not.Practically when we measure the radioactivity from gamma ray source mass attenuation always takes place during the photon transports through the medium. In fact, the reduction depends on the material, shapes, and radioactive sources. In this study the reduction factors were experimentally examined according to the influencing parameters and the results were saved as DCF (Density Correction Factor) in the data base. As expected, it turned out that the factor is somewhat affected by medium material and radioactive sources, but it is basically proportional to the distance of gamma ray passage.It is expected that upgraded design with more accurate and reliable instruments can make it easier for regulators to accept the application of the in-situ characterization technology on-site.

Monitoring clonal burden as an alternative to blast count for myelodysplastic neoplasm treatment response.

Accurate assessment of therapy response in myelodysplastic neoplasm (MDS) has been challenging. Directly monitoring mutational disease burden may be useful, but is not currently included in MDS response criteria, and the correlation of mutational burden and traditional response endpoints is not completely understood. Here, we used genome-wide and targeted next-generation sequencing (NGS) to monitor clonal and subclonal molecular disease burden in 452 samples from 32 patients prospectively treated in a clinical trial. Molecular responses were compared with International Working Group (IWG) 2006-defined response assessments. We found that myeloblast percentage consistently underestimates MDS molecular disease burden and that mutational clearance patterns for marrow complete remission (mCR), which depends on myeloblast assessment, was not different than stable disease or bone marrow aplasia, underscoring a major limitation of using mCR. In contrast, achieving a complete remission (CR) was associated with the highest level of mutation clearance and lowest residual mutational burden in higher-risk MDS patients. A targeted gene panel approach was inferior to genome-wide sequencing in defining subclones and their molecular responses but may be adequate for monitoring molecular disease burden when a targeted gene is present in the founding clone. Our work supports incorporating serialNGS-based monitoring into prospective MDS clinical trials.

Outcome and Prognostic Factors of Class V Membranous Nephropathy (Pure and Mixed Form) in a Cohort of Egyptian Patients with Systemic Lupus Erythematosus

Abstract Background Renal disease is a frequent and severe cause of morbidity in systemic lupus erythematosus (SLE). Lupus membranous nephropathy (LMN), which is an uncommon subtype of lupus nephritis, is usually associated with nephrotic syndrome and can have a variable course; some patients maintain stable kidney function or show a slow progression, while others can have renal flares and transformation to more severe proliferative forms eventually leading to ESRD or to life-threatening extrarenal complications, including thrombotic events, cardiovascular disease (CVD), or infections. In many cases, a combination of membranous and proliferative lesions may be seen in renal biopsies. Objective To study the clinical presentation, course, outcome and prognostic factors of class V membranous nephropathy (pure and mixed) in a cohort of Egyptian patients with SLE. Methods This was an observational study which was conducted on ninety six (96) adult Egyptian patients diagnosed with LMN recruited from the outpatient clinic and inpatient department of rheumatology, at Ain Shams university hospitals, during a period of 12 months. Results In this study, the univariate logistic regression analysis shows that (low level of WBCs, low level of hemoglobin, high level creatinne, high level of urine, Protein / Cr ratio, low level of Creatinine clearance) were found significantly associated with poor outcome in patients with mixed type. Also, the multivariate logistic regression analysis shows that the most important factors associated with poor outcome in patients with mixed type was found WBCs level ≤3. WBC of urine analysis>10, that ESR >28, partial remission and SLEDAI score >13 were found significantly associated with poor outcome among patients with pure MLN. Also, the multivariate logistic regression analysis shows that the most important factor associated with poor outcome in patients with pure type was found partial remission. Conclusion The present study can burden the knowledge and shed some light on future prospective studies with larger sample sizes and longer follow up to reassess our findings.

Lactoferrin alleviates gentamicin-induced acute kidney injury in rats by suppressing ferroptosis: Highlight on ACSL4, SLC7A11, NCOA4, FSP1 pathways and miR-378a-3p, LINC00618 expression

The use of gentamicin (GNT) is associated with acute kidney injury (AKI). Ferroptosis is a newly recognized iron-dependent, non-apoptotic cell death that can lead to AKI. Lactoferrin (LF), an iron-binding glycoprotein, was previously reported to be renoprotective. Nonetheless, LF's impact on GNT-induced AKI and ferroptosis has not yet been investigated. Accordingly, we assessed the dose-dependent effect of LF on GNT-induced AKI and its influence on ferroptosis. Thirty-six male rats were allocated as control, LF, GNT (100 mg/kg/day, i.p.), and groups given LF (100, 200, and 300 mg/kg, p.o.) for 14 days prior concurrently with GNT (Day 8–14). The high dose of LF (300 mg/kg) showed better histopathological picture, higher creatinine clearance, reduced serum and urine levels of kidney injury markers when compared to the GNT group and the lower two doses. These nephroprotective effects of LF can be attributed to the observed reduction in renal ferrous iron, 4-HNE, and MDA, miR-378a-3p and ALOX15 expression, TFR1, NCOA4, and ACSL4 protein expression and the increased LINC00618 expression, GSH levels, GPX4, SLC7A11, and FSP1 protein expression. In conclusion, LF high dose was the most renoprotective against GNT-induced AKI, in which suppression of ferroptosis pathways was a likely contributor to its protective mechanism.

Pharmacological assessment of delphinidin in counteracting polystyrene microplastic induced renal dysfunction in rats

Polystyrene microplastics (PSMP) are toxic environmental contaminants which can damage various body organs including kidneys. Delphinidin (DEL) is a potential anthocyanidin flavonoid with significant pharmacological benefits. This research was conducted to analyze the protective effect of DEL to avert PSMP prompted renal dysfunction. Rats (n = 24) were divided into 4 separate groups: Control, PSMP (0.01 mgkg−1), PSMP (0.01 mgkg−1) + DEL (25 mgkg−1) and only DEL (25 mgkg−1). Our results showed that PSMP exposure reduced the expressions of Nrf-2 and antioxidant genes while increasing the expression of Keap1. Besides, PSMP intoxication escalated the level of kidney injury markers (urea, KIM-1, creatinine and NGAL) while inducing substantial reduction in the levels of creatinine clearance. Moreover, PSMP significantly reduced the levels of GSH, GST, SOD, HO-1, CAT, GSR, GPx while escalating MDA and ROS. Conversely, inflammatory biomarkers including IL-1β, TNF-α, NF-kB, IL-6 and COX-2 activity were increased due to PSMP intoxication. Our results showed that PSMP administration increased the expressions of Bax and caspase-3 while decreasing the expression of Bcl-2. However, DEL treatment significantly restored the PSMP-induced renal impairments. Therefore, it is suggested that DEL could be used as a therapeutic compound to alleviate PSMP-induced kidney damage in rats, possibly due to its strong pharmacological properties.

Risk factors for linezolid - induced haematological toxicity in patients: a retrospective study.

This single-center, observational cohort study aimed to investigate the risk factors associated with linezolid-induced hematological toxicity by analyzing the linezolid trough concentration (Cmin) obtained from patients undergoing treatment between January 2020 and December 2021. A total of 111 eligible individuals were included in the study, of which 47 were diagnosed with linezolid-induced thrombocytopenia and 18 were diagnosed with linezolid-induced hemoglobin decrease. Binary logistic regression analysis revealed that creatinine clearance level (Ccr) < 50 mL/min/1.73 m2 (OR, 5.463; 95% CI, 1.249-23.888, p = 0.024) and Cmin > 7 mg/L (OR, 62.660; 95% CI, 14.293-274.708, p = 0.001) were risk factors associated with linezolid-induced thrombocytopenia. Area under the ROC curve for Cmin was 0.955, with a maximum Youden index of 0.837. The corresponding critical value was 6.94 mg/L (sensitivity 91.5%; specificity 92.2%). Ccr < 50 mL/min/1.73 m2 (OR, 7.282; 95% CI, 1.765-30.048, p = 0.006) and Cmin > 7mg/L (OR, 6.364; 95% CI, 1.937-20.910, p = 0.020) were found to be associated with linezolid-induced hemoglobin reduction. The area under the ROC curve for Cmin was 0.755, Youden index was 0.477 at the maximum, and the corresponding critical value was 7.53 mg/L (sensitivity 77.8%; specificity 69.9%). Renal insufficiency is a related risk factor for linezolid-induced hematological toxicity. Patients receiving linezolid treatment should be closely monitored with blood routine and plasma concentration, particularly in patients with moderate or severe renal insufficiency. The plasma trough concentration of linezolid could be a suitable predictor for linezolid-induced thrombocytopenia and anemia.