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Summary: Microalgae are considered as attractive expression systems for the production of biologics. As photosynthetic unicellular organisms, they do not require costly and complex media for growing and are able to secrete proteins and perform protein glycosylation. Some biologics have been successfully produced in the green microalgae Chlamydomonas reinhardtii. However, post‐translational modifications like glycosylation of these Chlamydomonas‐made biologics have poorly been investigated so far. Therefore, in this study, we report on the first structural investigation of glycans linked to human erythropoietin (hEPO) expressed in a wild‐type C. reinhardtii strain and mutants impaired in key Golgi glycosyltransferases. The glycoproteomic analysis of recombinant hEPO (rhEPO) expressed in the wild‐type strain demonstrated that the three N‐glycosylation sites are 100% glycosylated with mature N‐glycans containing four to five mannose residues and carrying core xylose, core fucose and O‐methyl groups. Moreover, expression in C. reinhardtii insertional mutants defective in xylosyltransferases A and B and fucosyltransferase resulted in drastic decreases of core xylosylation and core fucosylation of glycans N‐linked to the rhEPOs, thus demonstrating that this strategy offers perspectives for humanizing the N‐glycosylation of the Chlamydomonas‐made biologics. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Context: Many clinicians, trainers, and athletes do not have a true understanding of the effects of commonly used performance-enhancing drugs (PEDs) on performance and health. Objective: To provide an evidence-based review of 7 commonly used pharmacological interventions for performance enhancement in athletes. Data Sources: PubMed and Scopus databases were searched on April 8, 2022. Study Selection: Systematic reviews (SRs) and meta-analyses (MAs) assessing the performance-enhancing effects of the following interventions were included: androgenic anabolic steroids (AAS), growth hormone (GH), selective androgen receptor modulators (SARMs), creatine, angiotensin-converting enzyme (ACE)-inhibitors, recombinant human erythropoietin (rHuEPO), and cannabis. Study Design: Umbrella review of SRs and MAs. Level of Evidence: Level 4. Data Extraction: Primary outcomes collected were (1) body mass, (2) muscle strength, (3) performance, and (4) recovery. Adverse effects were also noted. Results: A total of 27 papers evaluating 5 pharmacological interventions met inclusion criteria. No studies evaluating SARMs or ACE-inhibitors were included. AAS lead to a 5% to 52% increase in strength and a 0.62 standard mean difference in lean body mass with subsequent lipid derangements. GH alters body composition, without providing a strength or performance benefit, but potential risks include soft tissue edema, fatigue, arthralgias, and carpel tunnel syndrome. Creatine use during resistance training can safely increase total and lean body mass, strength, and performance in high-intensity, short-duration, repetitive tasks. Limited evidence supports rHuEPO benefit on performance despite increases in both VO2max and maximal power output, and severe cardiovascular risks are documented. Cannabis provides no performance benefit and may even impair athletic performance. Conclusion: In young healthy persons and athletes, creatine can safely provide a performance-enhancing benefit when taken in controlled doses. AAS, GH, and rHuEPO are associated with severe adverse events and do not support a performance benefit, despite showing the ability to change bodily composition, strength, and/or physiologic measures. Cannabis may have an ergolytic, instead of ergogenic, effect. [ABSTRACT FROM AUTHOR]

Background and Purpose: Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. Experimental Approach: By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short‐term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long‐term haemoglobin responses. Key Results: The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. Conclusions and Implications: The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency‐mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment. [ABSTRACT FROM AUTHOR]

Background: Erythropoietin resistance is present in some patients with chronic kidney disease, especially in those undergoing hemodialysis, and is often treated using roxadustat rather than iron supplements and erythropoiesis-stimulating agents (ESAs). However, some patients cannot afford full doses of roxadustat. This retrospective study investigated the efficacy of low-dose roxadustat combined with recombinant human erythropoietin (rhuEPO) therapy in 39 patients with erythropoietin-resistant renal anemia undergoing maintenance hemodialysis (3-4 sessions/week). Methods: The ability of the combination of low-dose roxadustat and rhuEPO to increase the hemoglobin concentration over 12 weeks was assessed. Markers of iron metabolism were evaluated. Eligible adults received 50-60% of the recommended dose of roxadustat and higher doses of rhuEPO. Results: The mean hemoglobin level increased from 77.67 ± 11.18 g/dL to 92.0 ± 8.35 g/dL after treatment, and the hemoglobin response rate increased to 72%. The mean hematocrit level significantly increased from 24.26 ± 3.99% to 30.04 ± 3.69%. The soluble transferrin receptor level increased (27.29 ± 13.60 mg/L to 38.09 ± 12.78 mg/L), while the total iron binding capacity (49.22 ± 11.29 mg/L to 43.91 ± 12.88 mg/L) and ferritin level (171.05 ± 54.75 ng/mL to 140.83 ± 42.03 ng/mL) decreased. Conclusion: Therefore, in patients with ESA-resistant anemia who are undergoing hemodialysis, the combination of low-dose roxadustat and rhuEPO effectively improves renal anemia and iron metabolism. [ABSTRACT FROM AUTHOR]

Background: Pure red cell aplasia (PRCA) in neuromyelitis optica spectrum disorder (NMOSD) has not been reported before. This study presents a patient with NMOSD who developed PRCA. Case presentation: A 54-year-old female was admitted in January 2023 for dysuria and progressive numbness and weakness of lower limbs. She had difficulty standing and walking in a straight line. Both lower limbs were positive for the Babinski and Chaddock signs. MRI showed abnormal signals in the spinal cord. Aquaporin-4-IgG (AQP-4-IgG) was positive (1:320), and NMOSD was confirmed. Intravenous immunoglobulin and methylprednisolone were given, and the symptoms improved. She received maintenance treatment with methylprednisolone tablets, and the dosage was gradually reduced. She was readmitted for fatigue, palpitations, and shortness of breath in May 2023. Bone marrow aspiration and biopsy showed elevated erythroid precursors and erythroid hypoplasia, with normal megakaryocytes and myeloid precursors. Chest CT showed no mediastinal lymph node enlargement or thymoma. PRCA secondary to NMOSD was diagnosed. Recombinant human erythropoietin was given. Her condition improved after 1.5 months, as indicated by blood cell count and imaging. Conclusions: This case suggests that PRCA can be secondary to NMOSD. A comprehensive immune function and bone marrow evaluation might be necessary if abnormal blood cells are found while managing NMOSD. [ABSTRACT FROM AUTHOR]

Objective To investigate the overall and subgroup efficacy, subgroup differences, predictors of efficacy and safety of roxadustat in the treatment of refractory non-severe aplastic anemia (NSAA) and low-risk myelodysplastic syndromes (LR-MDS). Methods Patients with refractory NSAA and LR-MDS who were admitted to the Department of Hematology, Peking Union Medical College Hospital from August 2020 to December 2022 were enrolled. All patients received first-line standard treatment, including recombinant human erythropoietin (rhEPO) for at least 3 months before roxadustat treatment. All patients received roxadustat 2.5 mg/kg every other day for at least 3 months, and were followed up for at least 8 months. The clinical characteristics of patients, roxadustat efficacy, predictors of efficacy, adverse effects,relapse and disease clonal evolution were analyzed. Results A total of 40 patients including 24 refractory NSAA and 16 LR-MDS were included. median age was 56 (18 - 81) years and 40% were males. 65% of the patients were transfusion dependent. Median follow-up was 21 (9 -34) months. 22.5%, 25.0%, 47.5%, 55.0%, 57.5%, 60.0% and 50.0% of the patients achieved haematological improvement-erythroid (HI-E) at months 1, 2, 3, 4, 5, 6, and end of the follow-up period, respectively, and no factors affecting HI-E were identified.The hemoglobin change from baseline was statistically different between the two groups at the end of the follow-up period. 50% of patients were relieved from transfusion dependence. Adverse reactions were reported in 22.5% of patients. 28.5% of patients relapsed after achieving HI-E, with a median time to relapse of 7 (4 - 12) months. No clonal evolution was observed at the end of the follow-up period. Conclusions Our preliminary findings suggested that Roxadustat may be effective for patients with NSAA or LR-MDS refractory to conventional therapies and rhEPO, with mild adverse effects and low relapse rate.The degree of hemoglobin improvement may be better in the refractory NSAA patients. [ABSTRACT FROM AUTHOR]

Background: Left ventricular hypertrophy (LVH) is highly prevalent in haemodialysis (HD) patients and is associated with an increased risk of death. Roxadustat and recombinant human erythropoietin (rHuEPO, abbreviated as EPO) are the main treatment strategies for renal anaemia in HD patients, but it has not been clear whether there is a difference in their effect on LVH. Methods: In this multi‐centre, prospective, randomized trial of 12‐month duration, study participants were randomized in a 1:1 ratio to the roxadustat group or the EPO group. The doses of both treatment regimens were adjusted so that the patients had a haemoglobin level of 10.0–12.0 g per dL. The primary study endpoint was the change from baseline to 12 months in the left ventricular mass index (LVMI, g/m2) measured by echocardiography. Results: In total, 114 patients were enrolled. The mean age was 50 years, and the median dialysis duration was 33 months. Sixty‐one patients were men, and 24 were diabetic. LVMI decreased from 116.18 ± 27.84 to 110.70 ± 25.74 g/m2 in the roxadustat group. However, it increased from 109.35 ± 23.41 to 114.99 ± 28.46 g/m2 in the EPO group, with a significant difference in the change in LVMI between the two groups [−5.48 (−11.60 to 0.65) vs. 5.65 (0.74 to 10.55), p < 0.05]. Changes in left ventricular mass, end‐diastolic volume and 6‐min walk test seemed superior in the roxadustat group. There were no significant differences in other cardiac geometry, biochemical parameters and major adverse cardiovascular events between the two groups. Conclusions: Compared to EPO, roxadustat is more helpful in the regression of LVH in HD patients. [ABSTRACT FROM AUTHOR]

Anaemia is one of the most common complications of chronic kidney disease (CKD), having a significant impact on quality of life, and is also associated with a number of adverse clinical outcomes. Its pathogenesis is multifactorial, caused largely by an inadequate production of erythropoietin from the diseased kidneys, with iron deficiency, inflammation, shortened red cell lifespan and enhanced blood loss also being contributory factors. The management of this condition was transformed in the late 1980s by the advent of recombinant human erythropoietin (epoetin), and treatment paradigms have developed over the last three decades, largely focusing on a combination of epoetin or its analogues (erythropoiesis-stimulating agents; ESAs) along with iron supplementation, often administered intravenously due to increased hepcidin levels limiting iron absorption from the gut. Indeed, in patients with early CKD and iron deficiency, iron per se may be sufficient to improve the anaemia, delaying the need for ESA therapy. Other causes of anaemia should be excluded and corrected (if possible) before resorting to treatment with ESAs and iron. More recently, the hypoxia-inducible factor–prolyl hydroxylase inhibitors have entered the therapeutic arena; these are orally active agents that upregulate endogenous erythropoietin production as well as a number of iron-regulatory genes which may also enhance erythropoiesis. The latter drugs are highly efficacious, and may have advantages in inflammatory conditions causing resistance to conventional ESA therapy, but concerns exist regarding their safety, particularly in the longer term. This article reviews the current standards of treatment, as well as recent novel developments in the management of anaemia in CKD. [ABSTRACT FROM AUTHOR]

Recombinant human proteoglycan 4 (rhPRG4) is a macromolecular mucin‐like glycoprotein that is classically studied as a lubricant within eyes and joints. Given that endogenously produced PRG4 is present within atherosclerotic lesions and genetic PRG4 deficiency increases atherosclerosis susceptibility in mice, in the current study we investigated the anti‐atherogenic potential of chronic rhPRG4 treatment. Female low‐density lipoprotein receptor knockout mice were fed an atherogenic Western‐type diet for 6 weeks and injected three times per week intraperitoneally with 0.5 mg rhPRG4 or PBS as control. Treatment with rhPRG4 was associated with a small decrease in plasma‐free cholesterol levels, without a change in cholesteryl ester levels. A marked increase in the number of peritoneal foam cells was detected in response to the peritoneal rhPRG4 administration, which could be attributed to elevated peritoneal leukocyte MSR1 expression levels. However, rhPRG4‐treated mice exhibited significantly smaller aortic root lesions of 278 ± 21 × 103 μm2 compared with 339 ± 15 × 103 μm2 in the aortic root of control mice. The overall decreased atherosclerosis susceptibility coincided with a shift in the monocyte and macrophage polarization states towards the patrolling and anti‐inflammatory M2‐like phenotypes, respectively. Furthermore, rhPRG4 treatment significantly reduced macrophage gene expression levels as well as plasma protein levels of the pro‐inflammatory/pro‐atherogenic cytokine TNF‐alpha. In conclusion, we have shown that peritoneal administration and subsequent systemic exposure to rhPRG4 beneficially impacts the inflammatory state and reduces atherosclerosis susceptibility in mice. Our findings highlight that PRG4 is not only a lubricant but also acts as an anti‐inflammatory agent. Key points: Endogenously produced proteoglycan 4 is found in atherosclerotic lesions and its genetic deficiency in mice is associated with enhanced atherosclerosis susceptibility.In this study we investigated the anti‐atherogenic potential of chronic treatment with recombinant human PRG4 in hypercholesterolaemic female low‐density lipoprotein receptor knockout mice.We show that recombinant human PRG4 stimulates macrophage foam cell formation, but also dampens the pro‐inflammatory state of monocyte/macrophages, eventually leading to a significant reduction in plasma TNF‐alpha levels and a lowered atherosclerosis susceptibility.Our findings highlight that peritoneal recombinant human PRG4 treatment can execute effects both locally and systemically and suggest that it will be of interest to study whether rhPRG4 treatment is also able to inhibit the progression and/or induce regression of previously established atherosclerotic lesions. [ABSTRACT FROM AUTHOR]

In orthopaedics, erythropoietin (EPO) is applied in the preoperative management of anaemic patients, but also as a stimulating factor to assist bone regeneration due to its angiogenic and osteoinductive potential. Since orthopaedists mainly rely on their clinical experience to assess bone healing, additional and more objective methods such as studying the dynamics of bone markers are needed. Therefore, the aim of this study was to investigate the plasma activity of bone-specific alkaline phosphatase (BALP), the N-terminal propeptide of type I collagen (PINP), the C-terminal telopeptide of type I collagen (CTX), and deoxypyridinoline (DPD) during the first 2 months of healing of comminuted fractures in cats, either non-stimulated or locally stimulated with recombinant human erythropoietin (rhEPO). The study included twelve cats of mixed breeds, aged 7.2 ± 4 months, weighing 2.11 ± 1.1 kg, with comminuted diaphyseal fractures of the femur. Surgical treatment with plate osteosynthesis was performed in all animals. The cats were randomly divided into two groups—a control (n = 6) and an EPO group (n = 6). The locally applied EPO leads to the increased activity of bone formation markers (BALP and PINP) during the second week after the osteosynthesis, preceding the peaks in the control group by two weeks. The studied bone resorption markers (DPD, CTX) varied insignificantly during the studied period. In conclusion, erythropoietin could serve as a promoter of bone healing in comminuted fractures in cats. [ABSTRACT FROM AUTHOR]

Background: The bone regeneration potential of erythropoietin (EPO) is not yet fully investigated, but some previous experimental studies demonstrated that its application activated the differentiation of osteoblasts and promoted bone formation. Aim: The aim of the present study was to evaluate the effects of recombinant human erythropoietin (rhEpo) on bone healing in cats with fragmented long bone fractures. Methods: Twelve cats were divided into two groups--control (n = 6) in which physiological saline was applied at the fracture gap site and EPO (n = 6) with the application of 1,000 IU rhEpo. The effects of EPO on blood erythrocyte counts, hemoglobin content, and hematocrit were monitored by serial complete blood cell tests, whereas bone formation was evaluated by clinical and radiographic examinations on post-operative weeks 1, 2, 3, 4, 6, and 8. Results: All tested blood parameters were within the reference range. A faster fracture healing and full limb weight-bearing were observed in the EPO group, with statistically significant differences with respect to the control group. Conclusion: The obtained results confirmed that the local application of rhEpo promoted bone healing in cats with fragmented femoral fractures and increased bone callus strength without having significant systemic effects. [ABSTRACT FROM AUTHOR]

Aim: Patients undergoing dialysis are at high risk for coronavirus disease 2019 (COVID‐19). Haemoglobin (Hb) levels may be changed in patients infected with the Omicron variant of COVID‐19 who are undergoing peritoneal dialysis (PD). Therefore, we aimed to explore the effect of anti‐anaemia treatment on such patients. Methods: This study enrolled patients undergoing PD who were infected with the Omicron variant of COVID‐19 at our centre between November 2022 and February 2023. We retrospectively analysed changes in Hb levels and explored the effectiveness of roxadustat and recombinant human erythropoietin (rhEPO) for patients infected with the Omicron variant of COVID‐19. Results: Among 125 enrolled patients, 83 (66.4%) were infected with the Omicron variant and 75 (90.4%) patients mainly experienced mild or moderate disease. During infection, C‐reactive protein (CRP) levels were higher than those before infection (p <.001). Additionally, their CRP levels were negatively correlated with Hb levels (p =.002). However, Hb levels were decreased 1 month after infection (109.61 ± 10.64 g/L vs. 115.69 ± 12.04 g/L; p <.001). The roxadustat treatment group did not exhibit significantly decreased Hb levels 1 month after infection (114.57 ± 14.11 vs. 117.51 ± 10.74 g/L; p =.225). Conversely, the rhEPO treatment group experienced a mild decrease in Hb levels (108.69 ± 11.20 vs. 115.03 ± 12.23 g/L; p =.001). Ferritin levels increased in both groups during infection (p =.495). Two months after infection, ferritin levels (median, 205.0 ng/mL) were significantly decreased compared with during infection (median, 377.4 ng/mL) (p <.001) in the roxadustat treatment group. Conclusion: Roxadustat was effective than rhEPO for treating anaemia in patients undergoing PD who were infected with the Omicron variant of COVID‐19. [ABSTRACT FROM AUTHOR]

With the aging of the population, an increasing number of elderly patients are opting for artificial joint replacement, leading to the exploration of various rapid rehabilitation programs in the perioperative period. In this study, we aimed to investigate the effectiveness of combining recombinant human erythropoietin and iron sucrose in altering the range and trend of postoperative hemoglobin in patients undergoing arthroplasty. Specifically, we will examine whether this combination can effectively alter the rise and fall of postoperative haemoglobin, identify the inflection point of haemoglobin change or recovery after arthroplasty, and assess the effect of treatment on serum iron in postoperative blood. We conducted a retrospective study of 138 patients who underwent unilateral total joint arthroplasty by the same surgeon in the same hospital before July 2022. The results of this study may provide valuable insights for the development of effective rehabilitation programs for patients undergoing arthroplasty. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (EPO) is a biopharmaceutical frequently used in the treatment of anemia. It is a heavily glycosylated protein with a diverse and complex glycome. EPO N-glycosylation influences important pharmacological parameters, prominently serum half-life. Therefore, EPO N-glycosylation analysis is of the utmost importance in terms of controlling critical quality attributes. In this work, we performed an interlaboratory study of glycoanalytical techniques for profiling and in-depth characterization, namely (1) hydrophilic interaction liquid chromatography with fluorescence detection after 2-aminobenzamide labeling (HILIC-FLD(2AB)) and optional weak anion exchange chromatography (WAX) fractionation and exoglycosidase digestion, (2) HILIC-FLD after procainamide labeling (PROC) optionally coupled to electrospray ionization-MS and (3) matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-MS). All techniques showed good precision and were able to differentiate the unique N-glycosylation profiles of the various EPO preparations. HILIC-FLD showed higher precision, while MALDI-TOF-MS covered the most analytes. However, HILIC-FLD differentiated isomeric N-glycans, i.e., N-acetyllactosamine repeats and O-acetylation regioisomers. For routine profiling, HILIC-FLD methods are more accessible and cover isomerism in major structures, while MALDI-MS covers more minor analytes with an attractively high throughput. For in-depth characterization, MALDI-MS and HILIC-FLD(2AB)/WAX give a similar amount of orthogonal information. HILIC-FLD(PROC)-MS is attractive for covering isomerism of major structures with a significantly less extensive workflow compared to HILIC-FLD(2AB)/WAX. [ABSTRACT FROM AUTHOR]

Anemia induced by chronic kidney disease (CKD) has multiple underlying mechanistic causes and generally worsens as CKD progresses. Erythropoietin (EPO) is a key endogenous protein which increases the number of erythrocyte progenitors that mature into red blood cells that carry hemoglobin (Hb). Recombinant human erythropoietin (rHuEPO) in its native and re-engineered forms is used as a therapeutic to alleviate CKD-induced anemia by stimulating erythropoiesis. However, due to safety risks associated with erythropoiesisstimulating agents (ESAs), a new class of drugs, prolyl hydroxylase inhibitors (PHIs), has been developed. Instead of administering exogenous EPO, PHIs facilitate the accumulation of HIF-a, which results in the increased production of endogenous EPO. Clinical trials for ESAs and PHIs generally involve balancing decisions related to safety and efficacy by carefully evaluating the criteria for patient selection and adaptive trial design. To enable such decisions, we developed a quantitative systems pharmacology (QSP) model of erythropoiesis which captures key aspects of physiology and its disruption in CKD. Furthermore, CKD virtual populations of varying severities were developed, calibrated, and validated against public data. Such a model can be used to simulate alternative trial protocols while designing phase 3 clinical trials, as well as an asset for reverse translation in understanding emerging clinical data. [ABSTRACT FROM AUTHOR]

Background: NeuroEPO plus is a recombinant human erythropoietin without erythropoietic activity and shorter plasma half-life due to its low sialic acid content. NeuroEPO plus prevents oxidative damage, neuroinflammation, apoptosis and cognitive deficit in an Alzheimer's disease (AD) models. The aim of this study was to assess efficacy and safety of neuroEPO plus. Methods: This was a double-blind, randomized, placebo-controlled, phase 2–3 trial involving participants ≥ 50 years of age with mild-to-moderate AD clinical syndrome. Participants were randomized in a 1:1:1 ratio to receive 0.5 or 1.0 mg of neuroEPO plus or placebo intranasally 3 times/week for 48 weeks. The primary outcome was change in the 11-item cognitive subscale of the AD Assessment Scale (ADAS-Cog11) score from baseline to 48 weeks (range, 0 to 70; higher scores indicate greater impairment). Secondary outcomes included CIBIC+, GDS, MoCA, NPI, Activities of Daily Living Scales, cerebral perfusion, and hippocampal volume. Results: A total of 174 participants were enrolled and 170 were treated (57 in neuroEPO plus 0.5 mg, 56 in neuroEPO plus 1.0 mg and 57 in placebo group). Mean age, 74.0 years; 121 (71.2%) women and 85% completed the trial. The median change in ADAS-Cog11 score at 48 weeks was −3.0 (95% CI, −4.3 to −1.7) in the 0.5 mg neuroEPO plus group, −4.0 (95% CI, −5.9 to −2.1) in the 1.0 mg neuroEPO plus group and 4.0 (95% CI, 1.9 to 6.1) in the placebo group. The difference of neuroEPO plus 0.5 mg vs. placebo was 7.0 points (95% CI, 4.5–9.5) P = 0.000 and between the neuroEPO plus 1.0 mg vs. placebo was 8.0 points (95% CI, 5.2–10.8) P = 0.000. NeuroEPO plus treatment induced a statistically significant improvement in some of clinical secondary outcomes vs. placebo including CIBIC+, GDS, MoCA, NPI, and the brain perfusion. Conclusions: Among participants with mild-moderate Alzheimer's disease clinical syndrome, neuroEPO plus improved the cognitive evaluation at 48 weeks, with a very good safety profile. Larger trials are warranted to determine the efficacy and safety of neuroEPO plus in Alzheimer's disease. Trial registration: https://rpcec.sld.cu Identifier: RPCEC00000232. [ABSTRACT FROM AUTHOR]

Copyright of Egyptian Journal of Histology is the property of Egyptian Journal of Histology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The polymorphism of the angiotensin-converting enzyme (ACE) gene and interleukin-1 beta (IL-1b) gene could be associated with resistance in the treatment of anemia in dialysis patients with recombinant human erythropoietin (rHuEPO). The aim of the study was to evaluate the association between the polymorphism of the ACE and IL-1b genes and the response to rHuEPO therapy in dialysis patients with anemia. The study investigated 69 patients on dialysis with anemia treated with recombinant human erythropoietin for 12 months. Genotyping of ACE and IL-1b polymorphism was done in all study patients at the initiation of the study. The patient's demographic characteristics, dialysis vintage, and laboratory parameters were also evaluated as factors associated with rHuEPO resistance. The erythropoietin resistance index (ERI) was calculated as the weekly rHuEPO dose per kg of body weight, divided by the hemoglobin (Hb) concentration in g/dl. The Hb ≥ 110 g/l was registered in 37 (53.6%) patients. Patients with Hb ≥ 110 g/l were characterized by significantly higher serum levels of albumin, cholesterol, and iron than those with Hb < 110 g/l. The serum level of the CRP, the weekly dose of rHuEPO, and ERI were significantly higher in patients with Hb < 110 g/l compared to patients with Hb ≥ 110 g/l. The ERI value of ≥ 10 IUkg/weekly/g/dl was present in 27 (39.1%) patients. The serum levels of ferritin and CRP, and weekly dose of rHuEPO were significantly higher in patients with ERI value ≥ 10 IU kg/weekly/g/dl compared with the patients with ERI value < 10 IUkg/weekly/g/dl. There was no significant association between the ERI and polymorphism of the ACE and IL-1b genes in study patients. The polymorphism of the ACE and IL-1b genes was not significantly associated with the response to erythropoietin therapy in dialysis patients with anemia. Iron deficiency, malnutrition, and inflammation were factors associated with anemia and resistance to erythropoietin therapy in dialysis patients. [ABSTRACT FROM AUTHOR]

Polytrauma involving traumatic brain injury poses serious threats like hemorrhagic shock and consumption coagulopathy. Blood and blood components are a necessity for maintenance of homeostasis in these patients. Elizabeth Topley and R. Clarke, in their study, demonstrated a considerable drop in red cell volume following a major trauma, nearly 11% in the next 14 days. Use of extensive perioperative blood salvage techniques, recombinant erythropoietin, iron complex injections, and antifibrinolytic agents cannot replace the benefits of blood and blood component transfusion. The real challenge of blood transfusion arises in Jehovah's Witness (JW) patients where a licensed medical practitioner (LMP) is caught in the loop of protecting the sanctity of faith over saving a patient's life. This case report highlights the successful management of a 19-year-old JW patient without transfusion of blood or blood products despite an absolute indication for transfusion. We also discuss the legal and ethical perspectives necessary for a legal medical practitioner, when treating patients of JW faith. [ABSTRACT FROM AUTHOR]

Anemia in chronic kidney disease (CKD) occurs due to insufficient production of erythropoietin to compensate for the decrease in hemoglobin. Anemia in CKD has traditionally been treated with periodic injections of erythropoiesis-stimulating agents (ESAs), which are recombinant human erythropoietin preparations. Although ESA improved anemia in CKD and dramatically improved the quality of life of patients, there are some patients who are hyporesponsive to ESA, and the use of large doses of ESA in these patients may have a negative impact on patient prognosis. Currently, HIF prolyl hydroxylase (HIF-PH) inhibitors have been approved in Japan as a new treatment for anemia in CKD. HIF-PH inhibitors activate HIF and promote the production of endogenous erythropoietin. The 2019 Nobel Prize in Physiology or Medicine was awarded for groundbreaking research that uncovered the HIF pathway. Because HIF-PH inhibitors improve both erythropoietin production and iron metabolism, they are expected to be effective in treating ESA hyporesponsiveness and solve the inconvenience of injectable preparations. On the other hand, its effects are systemic and multifaceted, and long-term effects must be closely monitored. [ABSTRACT FROM AUTHOR]

With the aging of the population, an increasing number of elderly patients are opting for artificial joint replacement, leading to the exploration of various rapid rehabilitation programs in the perioperative period. In this study, we aimed to investigate the effectiveness of combining recombinant human erythropoietin and iron sucrose in altering the range and trend of postoperative hemoglobin in patients undergoing arthroplasty. Specifically, we will examine whether this combination can effectively alter the rise and fall of postoperative haemoglobin, identify the inflection point of haemoglobin change or recovery after arthroplasty, and assess the effect of treatment on serum iron in postoperative blood. We conducted a retrospective study of 138 patients who underwent unilateral total joint arthroplasty by the same surgeon in the same hospital before July 2022. The results of this study may provide valuable insights for the development of effective rehabilitation programs for patients undergoing arthroplasty. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to evaluate the effectiveness and cost-effectiveness of recombinant human erythropoietin (rHuEPO) and Roxadustat in treating renal anemia, particularly in athletic patients undergoing regular hemodialysis. Methods: Between January 2020 and December 2021, 150 athletic patients on continuous ambulatory regular hemodialysis were enrolled. They were divided equally into rHuEPO and Roxadustat groups. We assessed hemoglobin (Hb), hematocrit (Hct), serum ferritin (SF), and transferrin (TRF) levels, along with adverse reactions, allergic responses, coagulation function, and liver and kidney function parameters (ALT, CCr) before and after treatment. The study also compared the cost-effectiveness of these treatments. Results: Basic demographic information (gender, duration of illness, weight, dialysis method, age) showed no significant difference between groups (P > 0.05). The Roxadustat group demonstrated a significantly higher total effective rate (92.00%) compared to the rHuEPO group (74.67%), with P < 0.05. Posttreatment, improvements in Hb, Hct, SF, TRF, and coagulation and liver and kidney function indices were observed in both groups, with Roxadustat showing superior outcomes (P < 0.05). Adverse reactions were lower in the Roxadustat group (9.33%) compared to the rHuEPO group (24.00%), P < 0.05. Roxadustat's Incremental Cost-Effectiveness Ratio (ICER) was 41,134.10 yuan, deemed tolerable against the backdrop of thrice the per capita GDP. Conclusion: Both Roxadustat and rHuEPO are effective in treating renal anemia in athletes. However, Roxadustat shows superior efficacy, safety, ease of oral administration, patient acceptance, and cost-effectiveness. It becomes the preferred choice for athletic patients with a willingness to pay exceeding 41,134.10 yuan, marking it as the most economically viable option. [ABSTRACT FROM AUTHOR]

Few effective therapies are available to treat patients with relapsed/refractory myelodysplastic neoplasms (MDS). Luspatercept was shown to display good efficacy in a phase 3 clinical trial for lower-risk MDS (LR-MDS) patients, yet real-world data are limited, especially in China. Therefore, data from patients diagnosed as having MDS with low blasts and SF3B1 mutation (MDS-SF3B1) and MDS with SF3B1 mutation and thrombocytosis were retrospectively analyzed. Of the 23 enrolled patients, 17 (73.9%) were males (median age 67 years: range 29 to 80 years). Previously, a total of 22 (95.7%) patients had received recombinant human erythropoietin (rhEPO), 9 (39.1%) roxadustat, 7 (30.4%) lenalidomide and 3 (13.0%) hypomethylating agents (HMA). The median treatment time was 22.9 weeks (9.0–32.4). At week 12, 60.9% (14/23) of the patients achieved a hematologic improvement–erythroid (HI-E) response. Red blood cell transfusion independence (RBC-TI) for ≥ 8 weeks was found in 57.1% (8/14) of transfusion-dependent patients. The median hemoglobin concentration was 84 g/L, and patients had significantly higher hemoglobin concentrations after 12 weeks of treatment (P < 0.001). It is noteworthy that responders had a greater reduction in serum ferritin (P = 0.021). Those with serum EPO < 500 IU/L at baseline tended to have a higher HI-E rate (P = 0.081), but only patients in non-transfusion and low transfusion burden (LTB) subgroups had statistical differences (P = 0.024). The most commonly occurring adverse events were blood bilirubin increase (17.4%), fatigue (13.0%) and dizziness (13.0%). Luspatercept was effective and tolerated well in refractory LR-MDS-SF3B1 patients. In particular, baseline non-transfusion and LTB patients exhibited a greater response rate to treatment. [ABSTRACT FROM AUTHOR]

Background: Recombinant human erythropoietin (rhEPO) lost its role in minimizing red blood cell transfusion in very preterm infants after it had been associated with severe retinopathy of prematurity (ROP). Previous systematic reviews did not stratify ROP by gestation and birth weight (BW). Objectives: The aim of this study was to investigate the effect of early prophylactic rhEPO on ROP in a stratified meta-analysis of randomized controlled trials (RCTs). Methods: The databases EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched in January 2022 and complemented by citation searching. RCTs comparing early rhEPO treatment with no treatment or placebo were selected if they were published in a peer-reviewed journal and reported ROP outcomes. Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW. Data were extracted and analyzed using the standard methods of the Cochrane Neonatal Review Group. Pre-specified outcomes were "ROP stage ≥3" (primary outcome) and "any ROP." Results: Fourteen RCTs, comprising 2,040 infants of <29 weeks of GA, were included for meta-analysis. Data syntheses showed no effects of rhEPO on ROP stage ≥3 or on any ROP, neither in infants of <29 weeks GA, nor in infants of <1,000 g BW, nor in any GA strata. The risk ratio (95% confidence interval) for ROP stage ≥3 in infants of <29 weeks of GA was 1.13 (0.84, 1.53), p = 0.41 (quality of evidence: moderate). Conclusions: The present meta-analysis detected no effects of early rhEPO on ROP in any comparison, but most stratified analyses were limited by low statistical power. [ABSTRACT FROM AUTHOR]

The discovery and development of erythropoiesis-stimulating agents was a journey lasting more than a century, leading to the cloning and approval of recombinant human erythropoietin (rHuEpo). This was an impressive clinical advance, providing the possibility of correcting the symptoms associated with anaemia in chronic kidney disease. Associated iron use was needed to produce new haemoglobin-containing blood red cells. Partial anaemia correction became the standard of care since trials aiming for near-normal haemoglobin levels showed a higher risk of adverse cardiovascular events. Hoping to reduce the cardiovascular risks, a new category of drugs was developed and tested. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are small molecules than can be formulated into orally active pills. They simulate reduced tissue oxygen pressure, thus stimulating the production of endogenous erythropoietin (Epo) by the kidneys and liver. Clinical trials with these compounds demonstrated that HIF-PHIs are at least as effective as rHuEpo in treating or correcting anaemia in non-dialysis and dialysis patients. Trials with HIF-PHIs did not demonstrate superiority in safety outcomes and in some trials, outcomes were worse. There was also a focus on oral delivery, a possible beneficial iron-sparing effect and the ability to overcome Epo resistance in inflamed patients. A negative effect is possible iron depletion, which may explain adverse outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Bleeding and transfusion remain important concerns during surgical correction of scoliosis even when multiple conservative strategies, such as preoperative recombinant erythropoietin and/or antifibrinolytic agents, are used. The current work aimed to determine the impact of other potential risk factors, especially the volume of intraoperative fluid intake, on the perioperative risk of allogenic transfusion during surgical correction of adolescent idiopathic scoliosis. Methods: This prospective study included all cases of adolescent idiopathic scoliosis operated in a single center during 2 years (2018–2020). Predictors analyzed were as follows: body mass index, preoperative hemoglobin concentration, thoracoplasty, preoperative halo‐gravity, volume of intraoperative crystalloid administration, use of esophageal Doppler (for goal‐directed fluid therapy), and duration of surgery. Statistical analyses were performed using a multivariable logistic regression model. Results: Two hundred patients were included in the analysis. Multivariable analysis found: an increased volume of intraoperative crystalloid administration as a significant predictor of allogenic blood transfusion. Receiving operator characteristics analysis found the model exhibiting an area under the curve of 0.85 (95% confidence interval: 0.75–0.95). Optimizing stroke volume using esophageal Doppler was associated with a decrease in intraoperative crystalloid intake. Conclusion: These results indicate a statistical association between the increase in crystalloid intake and the risk of allogenic blood transfusion during surgical correction of adolescent idiopathic scoliosis. Controlled studies are needed to address the causative relation between intraoperative fluid intake and the risk of allogenic transfusion. [ABSTRACT FROM AUTHOR]

Patients with renal anaemia are usually treated with recombinant human erythropoietin (EPO) because of insufficient renal EPO secretion. The establishment of a good haemoglobin (Hgb) response model is a necessary condition for dose optimization design. The purpose of this paper is to apply physics‐informed neural networks (PINN) to build the Hgb response model under EPO treatment. Neural network training is guided by a physiological model to avoid overfitting problems. During the training process, the parameters of the physiological model can be estimated simultaneously. To handle differential equations with impulse inputs and time delays, we propose approximate model equations for the pharmacokinetic (PK) model and the pharmacodynamic (PD) model, respectively. The modified PK/PD model was incorporated into PINN for training. Tests on simulated data and clinical data show that the proposed method has better performance than data‐driven modelling methods and the traditional physiological modelling based on the least squares method. [ABSTRACT FROM AUTHOR]

Background: Administration of recombinant erythropoietin (EPO), a kidneyproduced hormone with erythropoietic functions, has been shown to have multiple immunoregulatory effects in mice and humans, but whether physiological levels of EPO regulate immune function in vivo has not been previously evaluated. Methods: We generated mice in which we could downregulate EPO production using a doxycycline (DOX)-inducible, EPO-specific silencing RNA (shEPOrtTAPOS), and we crossed them with B6.MRL-Faslpr/J mice that develop spontaneous lupus. We treated these B6.MRL/lpr shEPOrtTAPOS with DOX and serially measured anti-dsDNA antibodies, analyzed immune subsets by flow cytometry, and evaluated clinical signs of disease activity over 6 months of age in B6.MRL/lpr shEPOrtTAPOS and in congenic shEPOrtTANEG controls. Results: In B6.MRL/lpr mice, Epo downregulation augmented anti-dsDNA autoantibody levels and increased disease severity and percentages of germinal center B cells compared with controls. It also increased intracellular levels of IL-6 and MCP-1 in macrophages. Discussion: Our data in a murine model of lupus document that endogenous EPO reduces T- and B-cell activation and autoantibody production, supporting the conclusion that EPO physiologically acts as a counterregulatory mechanism to control immune homeostasis. [ABSTRACT FROM AUTHOR]

Renal fibrosis is the final manifestation of chronic kidney disease (CKD); its prevention is vital for controlling CKD progression. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, is produced in the liver via the enzyme sulfotransferase (SULT) 1A1 and accumulates significantly during CKD. We investigated the toxicopathological role of IS in renal fibrosis using Sult1a1-KO mice and the underlying mechanisms. The unilateral ureteral obstruction (UUO) model was created; kidney IS concentrations, inflammation, and renal fibrosis were assessed on day 14. After UUO treatment, inflammation and renal fibrosis were exacerbated in WT mice, with an accumulation of IS in the kidney. However, they were significantly suppressed in Sult1a1-KO mice. CD206+ expression was upregulated, and β-catenin expression was downregulated in Sult1a1-KO mice. To confirm the impact of erythropoietin (EPO) on renal fibrosis, we evaluated the time-dependent expression of EPO. In Sult1a1-KO mice, EPO mRNA expression was improved considerably; UUO-induced renal fibrosis was further attenuated by recombinant human erythropoietin (rhEPO). Thus, UUO-induced renal fibrosis was alleviated in Sult1a1-KO mice with a decreased accumulation of IS. Our findings confirmed the pathological role of IS in renal fibrosis and identified SULT1A1 as a new therapeutic target enzyme for preventing and attenuating renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: In doping control, the presence of the exon5 c.577del variant in the human erythropoietin gene may be a confounding factor in the interpretation of the results from the analytical method currently in force for the detection of human recombinant erythropoietin, based on immunoelectrophoresis on SDSPAGE and/or SAR-PAGE. This variant, determining the transcription of a higher molecular weight protein, can erroneously suggest the presence of recombinant erythropoietin in a biological sample, causing the possibility of a false positive result. Although the variant was now identified only in East Asian populations and with a very low frequency, it can threaten the reliability of current anti-doping tests. Methods: We have implemented a genetic test to identify the presence of this variant in the biological samples that are presently collected for anti-doping analysis (whole blood, urine, and dried blood spots). The test is based on the Sanger sequencing of the human erythropoietin gene exon 5, where the c.577del variant falls. Results and Discussion: The method has a specificity of 100% and allows identification of the possible presence of the variant starting from 100 pg of genomic DNA extracted from each biological sample. The efficacy of the test has been confirmed by the analysis of real samples from subjects showing and not showing the exon c.577del variant. [ABSTRACT FROM AUTHOR]

Purpose: Recombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown. Methods: We conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010–2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5–8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI. Results: Of 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47–1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI - 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2–22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome. Conclusion: EPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) are broadly categorized as lower- and higher-risk with lower-risk dominated by cytopenias and higher-risk plagued by the risk of transformation to acute myeloid leukemia (AML). The management of MDS utilize a risk-adapted approach aimed at ameliorating cytopenias in lower-risk MDS (LR-MDS) and preventing AML transformation in higher-risk MDS. Hematopoietic stem cell transplantation is a potentially curative intent therapy in higher-risk MDS; however, it is not routinely recommended in LR-MDS in view of unfavorable risk/benefit ratio. Therefore, the goal of treatment in LR-MDS is aimed at improving the transfusion burden and health related quality of life. Currently, erythropoiesis stimulating agents (recombinant erythropoietin), erythroid maturation agents (luspatercept), disease modifying agents (lenalidomide) and hypomethylating agents are the agents of choice in the treatment of LR-MDS. This review will discuss the current treatment standards, meaningful clinical outcomes, and emerging therapies in LR-MDS. [ABSTRACT FROM AUTHOR]

Sepsis-induced acute kidney injury (SI-AKI), a common critically ill, represents one of the leading causes of global death. Emerging evidence reveals autophagy as a pivotal modulator of SI-AKI. Autophagy affects the cellular processes of renal lesions, including cell death, inflammation, and immune responses. Herein, we conducted a systematic and comprehensive review on the topic of the proposed roles of autophagy in SI-AKI. Forty-one relevant studies were finally included and further summarized and analyzed. This review revealed that a majority of included studies (24/41, 58.5%) showed an elevation of the autophagy level during SI-AKI, while 22% and 19.5% of the included studies reported an inhibition and an elevation at the early stage but a declination of renal autophagy in SI-AKI, respectively. Multiple intracellular signaling molecules and pathways targeting autophagy (e.g. mTOR, non-coding RNA, Sirtuins family, mitophagy, AMPK, ROS, NF-Kb, and Parkin) involved in the process of SI-AKI, exerting multiple biological effects on the kidney. Multiple treatment modalities (e.g. small molecule inhibitors, temsirolimus, rapamycin, polydatin, ascorbate, recombinant human erythropoietin, stem cells, Procyanidin B2, and dexmedetomidine) have been found to improve renal function, which may be attributed to the elevation of the autophagy level in SI-AKI. Though the exact roles of autophagy in SI-AKI have not been well elucidated, it may be implicated in preventing SI-AKI through various molecular pathways. Targeting the autophagy-associated proteins and pathways may hint towards a new prospective in the treatment of critically ill patients with SI-AKI, but more preclinical studies are still warranted to validate this hypothesis. [ABSTRACT FROM AUTHOR]

Patients with myelodysplastic syndromes and ring sideroblasts (MDS RS) are clinically characterized by severe anemia and transfusion need. Erythropoiesis‐stimulating agents (ESAs), which stimulate hemoglobin production and early maturation of erythroid precursors, are effective only in a portion of patients and for limited time. Luspatercept, an inhibitor of the TGF‐beta pathway, is beneficial in unblocking late‐stage erythropoiesis and has been approved for MDS RS patients failing or not‐candidate to ESAs. ESAs and/or luspatercept failure represents an unmet clinical need and most patients become life‐long transfusion dependent. Here, we describe the clinical combination of luspatercept with ESAs (subcutaneous epoetin alpha 40–80 000 IU/week) in seven MDS RS patients. Two patients had ESAs as pre‐existing therapy, while five were re‐challenged with ESAs as add‐on treatment due to luspatercept failure. Three patients achieved hematologic improvement, and one became transfusion independent. No adverse events were noted. This is the first clinical evidence that stimulating both early and late‐stage erythropoiesis may offer a further option for this challenging patient population. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the effects of early postnatal administration of erythropoietin (EPO) on neurodevelopmental outcomes and morbidities in preterm infants with severe grades of intraventricular hemorrhage (IVH). Methods: We retrospectively reviewed the medical records of preterm infants of gestational age 23+0 weeks to 31+6 weeks, who were diagnosed with severe grades of IVH and received EPO over at least 2 weeks. We compared clinical characteristics, major complications, and neurodevelopmental impairment between the two groups. The primary outcome was severe neurodevelopmental impairment at 18 to 26 months of corrected age. Severe neurodevelopmental impairment was defined as a mental developmental index or psychomotor developmental index of <70 on the Bayley Scales of Infant Development II or diagnosis of cerebral palsy. Results: The study included 33 preterm infants (mean gestational age 25.2±1.6 weeks and mean birth weight 775.1±224.5 g). EPO was administered at a dose of 400 or 1,000 IU/kg thrice weekly and was maintained over a mean period of 58.6± 25.9 days beginning from 10.7±6.9 days after birth. We observed no difference in perinatal characteristics between the EPO (n=14) and the control group (n=19). Similarly, severe neurodevelopmental impairment rates did not differ between the EPO (85.7%) and control groups (78.9%). The incidence of neonatal morbidities including bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity was also similar between the EPO and control groups. Conclusion: Early administration of EPO did not reduce the risk of severe neurodevelopmental impairment in preterm infants with severe IVH. [ABSTRACT FROM AUTHOR]

Germinal matrix-intraventricular hemorrhage (GM-IVH) is among the devastating neurological complications with mortality and neurodevelopmental disability rates ranging from 14.7% to 44.7% in preterm infants. The medical techniques have improved throughout the years, as the morbidity-free survival rate of very-low-birth-weight infants has increased; however, the neonatal and long-term morbidity rates have not significantly improved. To this date, there is no strong evidence on pharmacological management on GM-IVH, due to the limitation of well-designed randomized controlled studies. However, recombinant human erythropoietin administration in preterm infants seems to be the only effective pharmacological management in limited situations. Hence, further high-quality collaborative research studies are warranted in the future to ensure better outcomes among preterm infants with GM-IVH. [ABSTRACT FROM AUTHOR]

Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently translated in clinical trials. The clinical failure of rhuEPOM was thought to be mainly due to its erythropoietic activity-associated side effects. To exploit its tissue-protective property, various EPO derivatives with tissue-protective function only have been developed. Among them, asialo-rhuEPO, lacking terminal sialic acid residues, was shown to be neuroprotective but non-erythropoietic. Asialo-rhuEPO can be prepared by enzymatic removal of sialic acid residues from rhuEPOM (asialo-rhuEPOE) or by expressing human EPO gene in glycoengineered transgenic plants (asialo-rhuEPOP). Both types of asialo-rhuEPO, like rhuEPOM, displayed excellent neuroprotective effects by regulating multiple cellular pathways in cerebral I/R animal models. In this review, we describe the structure and properties of EPO and asialo-rhuEPO, summarize the progress on neuroprotective studies of asialo-rhuEPO and rhuEPOM, discuss potential reasons for the clinical failure of rhuEPOM with acute ischemic stroke patients, and advocate future studies needed to develop asialo-rhuEPO as a multimodal neuroprotectant for ischemic stroke treatment. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) is a glycoprotein hormone that stimulates red blood cell production. It is produced naturally in the body and is used to treat patients with anemia. Recombinant EPO (rEPO) is used illicitly in sports to improve performance by increasing the blood's capacity to carry oxygen. The World Anti-Doping Agency has therefore prohibited the use of rEPO. In this study, we developed a bottom-up mass spectrometric method for profiling the site-specific N-glycosylation of rEPO. We revealed that intact glycopeptides have a site-specific tetra-sialic glycan structure. Using this structure as an exogenous marker, we developed a method for use in doping studies. The profiling of rEPO N-glycopeptides revealed the presence of tri- and tetra-sialylated N-glycopeptides. By selecting a peptide with a tetra-sialic acid structure as the target, its limit of detection (LOD) was estimated to be < 500 pg/mL. Furthermore, we confirmed the detection of the target rEPO glycopeptide using three other rEPO products. We additionally validated the linearity, carryover, selectivity, matrix effect, LOD, and intraday precision of this method. To the best of our knowledge, this is the first report of a doping analysis using liquid chromatography/mass spectrometry-based detection of the rEPO glycopeptide with a tetra-sialic acid structure in human urine samples. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of large bone defects caused by fractures is still a challenge in orthopaedics. In this study, the potential of erythropoietin to promote bone regeneration was investigated in an experimental rat model. Bone healing was monitored through objective radiological, osteodensitometric and histological methods. The assessment suggests that erythropoietin, applied locally on a collagen scaffold alone or in combination with a bone substitute, is capable of inducing bone healing in femoral defects. Critical-size bone defect models are the standard in studies of the osteogenic potential of biomaterials. The present investigation aimed to evaluate the ability of recombinant human erythropoietin (EPO) to induce trabecular bone healing either alone or combined with a xenograft in a rat femoral critical-size defect model. Five-mm bone defects were created in the femoral diaphysis of fifty-six skeletally mature male Wistar albino rats. The animals were divided into six groups: one control group and five experimental groups. The defects in the control group were left empty, whereas an absorbable collagen cone soaked either with saline or erythropoietin (alone or in combination with xenograft) was placed in locally treated groups. The systemic treatment group received EPO subcutaneously. Bone formation was objectively evaluated through radiography, osteodensitometry and histological examination on post-operative days 30 and 90. The results demonstrate that EPO, locally applied on a collagen scaffold, was capable of inducing bone healing, whereas the single systemically administered high EPO dose had only an insignificant effect on bone formation. The combination of EPO with a bone substitute under the form of cancellous granules resulted in more rapid integration between the xenograft and host bone. [ABSTRACT FROM AUTHOR]

Recombinant human erythropoietin (rHuEPO) is one of the most effective drugs for the treatment of anemia in patients with chronic kidney disease. However, EPO-resistance is an important contributor to the increased risk of adverse effects. We previously showed that EPO treatment could induce precursor cell depletion, resulting in EPO-resistance. We further found that the combination of EPO with romiplostim, a thrombopoietin receptor agonist that can stimulate the expansion of hematopoietic stem cells, can treat EPO-resistance. In this study, we performed interspecies pharmacodynamic (PD) scaling of this combination therapy for human dose prediction. The pharmacokinetic parameters of both rHuEPO and romiplostim in humans were obtained from previous studies. The PD parameters obtained in rats were scaled to humans using allometric equations. The relationship between PD parameters of the megakaryocyte lineage from rats, monkeys, and humans was in agreement with those from the literature on allometric scaling. The PD response was translated to humans based on allometric scaling and agreed with the observed data. These parameters were used to simulate hemoglobin and platelet response in humans. RHuEPO 50 IU/kg thrice weekly and romiplostim 1 μg/kg once every 4 weeks from the second week is the recommended combination dosing regimen according to the model prediction. Our work successfully scaled the PD of rHuEPO and romiplostim monotherapy from rats to humans. The predicted dosing regimen of each drug in the combination therapy is less intensive than the approved starting dose of each drug, which supports additional evaluations of the combination therapy in humans. [ABSTRACT FROM AUTHOR]

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Progress in Modern Biomedicine is the property of Publishing House of Progress in Modern Biomedicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Canine pure red cell aplasia (PRCA) is a rare pathological condition in dogs related to a lack of erythroid precursor linages that cause a failure of red blood cell production, leading to severe anemia. Middle-aged dogs, especially females, have a great chance of developing acquired pure red cell aplasia. The clinical signs show pale mucous membrane, systolic murmur, tachypnea, tachycardia, weakness, syncope, and seizure. For diagnosis, the clinical pathological findings show the normocytic normochromic non-regenerative anemia, and the bone marrow pathological findings show a lack of erythroid precursor cells. According to the responsiveness of the immunosuppressive therapy, PRCA is proposed as one form of the immune-mediated anemia. Most PRCA are secondary diseases associated with recombinant human erythropoietin (rhEPO) treatment, infectious disease including parvoviral infection or modified-live parvovirus vaccination, or bone marrow cancer. In case of poor prognosis, the histopathology shows collagenous fibrosis in the bone marrow, and recurrent diseases after withdrawing the treatment commonly occur. In this case study, an 11-year-old non-castrated male Pomeranian dog was presented with a history of syncope. The non-regenerative anemia was found with a decrease of erythroid precursor in the bone marrow. The dog has been successfully treated with prednisolone 2 mg/kg once daily and tapered down every two weeks. The clinical signs of syncope and other blood parameters improved after 2 weeks of treatment. [ABSTRACT FROM AUTHOR]

The use of erythropoietin-stimulating agents (ESAs) as adjunctive therapy in critically ill patients with COVID-19 may have a potential benefit. This study aims to evaluate the effect of ESAs on the clinical outcomes of critically ill COVID-19 patients. A multicenter, retrospective cohort study was conducted from 01-03-2020 to 31-07-2021. We included adult patients who were ≥ 18 years old with a confirmed diagnosis of COVID-19 infection and admitted to intensive care units (ICUs). Patients were categorized depending on ESAs administration during their ICU stay. The primary endpoint was the length of stay; other endpoints were considered secondary. After propensity score matching (1:3), the overall included patients were 120. Among those, 30 patients received ESAs. A longer duration of ICU and hospital stay was observed in the ESA group (beta coef- ficient: 0.64; 95% CI: 0.31-0.97; P=< .01, beta coefficient: 0.41; 95% CI: 0.12-0.69; P=< .01, respectively). In addition, the ESA group's ventilator-free days (VFDs) were significantly shorter than the control group. Moreover, patients who received ESAs have higher odds of liver injury and infections during ICU stay than the control group. The use of ESAs in COVID-19 critically ill patients was associated with longer hospital and ICU stays, with no survival benefits but linked with lower VFDs. [ABSTRACT FROM AUTHOR]

Purpose: Our study aims to evaluate the effectiveness of intravenous erythropoietin (EPO) in patients with indirect traumatic optic neuropathy (TON), assess the side effects, and compare the visual function results among three groups of patients who had received different treatment options – EPO, steroids, and observation. Methods: Patients with indirect TON presenting to the neuro-ophthalmology clinic from August 2019 to March 2020, were assigned to three groups, with six patients in each group. In group 1, patients were recruited prospectively and received recombinant human erythropoietin, whereas, in groups 2 and 3, patients were recruited retrospectively and received intravenous methylprednisolone followed by oral steroids and multivitamins, respectively. Groups 1 and 2 included patients presenting within 2 weeks of trauma, whereas group 3 included those presenting beyond that. Best-corrected visual acuity, pupillary reaction, color vision, and visual fields following treatment were measured. Results: Initial visual acuity in the EPO group ranged from 20/80 to no perception of light (No PL). The mean initial BCVA (1.82 logMAR, standard deviation [SD] = 0.847) improved to 1.32, SD = 0.93 logMAR after treatment recorded at the third month (P = 0.0375), with no significant adverse effects. The initial BCVA of group 2 ranged from 20/120 to No PL. The mean initial BCVA (1.95, SD = 0.77 logMAR) improved to 1.45 logMAR, SD = 0.97 after treatment (P = 0.0435) but three patients had side effects of steroids. Initial visual acuity in Group 3 ranged from 20/40 to no PL. The mean initial BCVA (1.09 logMAR, SD = 1.10) worsened to 1.19 logMAR, SD = 1.06 after treatment after treatment (P = 0.0193). The improvement in BCVA when compared between the three groups was not significant. Conclusion: Both erythropoietin and steroids are effective in the management of traumatic optic neuropathy. However, erythropoietin shows lesser or no side effects when compared to steroids. [ABSTRACT FROM AUTHOR]

Background: Renal anemia is caused by end-stage renal disease (ESRD) but has a complex etiology. The application of dietary fiber (DF) to regulate the gut microbiota has shown effective therapeutic effects in some diseases, but its role in renal anemia is not clear. The aim of this study was to explore the effect of DF on renal anemia by regulating the gut microbiota and its metabolite, short-chain fatty acids (SCFAs). Methods: A total of 162 ESRD patients were enrolled and randomly distributed into a DF or a control group (received oral DF or potato starch, 10 g/day for 8 weeks). Hemoglobin (Hb), serum iron (Fe2+), serum ferritin (SF), soluble transferrin receptor (sTfR), hepcidin and the dosage of recombinant human erythropoietin (rhEPO) before and after intervention in patients were analyzed. The gut microbiota and SCFAs in both groups were analyzed by 16S rDNA sequencing and gas chromatography–mass spectrometry, respectively. Spearman's correlation test was used to analyze the correlation between the gut microbiota, SCFAs and the hematological indicators. Results: Compared with the control group, (1) the patients in the DF group had higher Hb [117.0 (12.5) g/L vs. 94.0 (14.5) g/L, p < 0.001], Fe2+ [13.23 (4.83) μmol/L vs. 10.26 (5.55) μmol/L, p < 0.001], and SF levels [54.15 (86.66) ng/ml vs. 41.48 (36.60) ng/ml, p = 0.003]. (2) The rhEPO dosage in the DF group was not significantly decreased (p = 0.12). (3) Bifidobacterium adolescentis, Lactobacillus and Lactobacillaceae were increased in the DF group, and Lactobacillus and Lactobacillaceae were positively correlated with Hb (r = 0.44, p < 0.001; r = 0.44, p < 0.001) and Fe2+ levels (r = 0.26, p = 0.016; r = 0.26, p = 0.016) and negatively correlated with rhEPO dosage (r = − 0.45, p < 0.001; r = − 0.45, p < 0.001). (4) Patients in the DF group had elevated serum butyric acid (BA) levels [0.80 (1.65) vs. 0.05 (0.04), p < 0.001] and BA levels were positively correlated with Hb (r = 0.26, p = 0.019) and Fe2+ (r = 0.31, p = 0.005) and negatively correlated with rhEPO dosage (r = − 0.36, p = 0.001). Lactobacillus and Lactobacillaceae were positively correlated with BA levels (r = 0.78, p < 0.001; r = 0.78, p < 0.001). Conclusion: DF may improve renal anemia in ESRD patients by regulating the gut microbiota and SCFAs. Trial registration This study was registered in the China Clinical Trial Registry (www.chictr.org.cn) on December 20, 2018 (ChiCTR1800020232). [ABSTRACT FROM AUTHOR]

Both early correction of anemia and preserving residual renal function (RRF) are reported to improve patient survival. The aim of this study was to explore the efficacy and safety of Roxadustat for treatment of renal anemia in patients new to peritoneal dialysis (PD) and to assess its impact on RRF. A retrospective analysis was performed on 60 initial peritoneal dialysis (PD) patients with renal anemia. Twenty-eight cases were treated with Roxadustat (Roxadustat group) and 32 with recombinant human erythropoietin (control group). Clinical characteristics, hemoglobin (Hb), C-reactive protein, blood lipids, iron metabolism, dialysis adequacy and RRF of the two groups were evaluated and adverse events were recorded. All patients were followed up for at least 40 weeks. After 40 weeks of treatment, mean Hb levels were significantly higher from baseline values in both groups, the mean Hb change in Roxadustat group was higher than control group (3.46 ± 1.59 g/dL vs. 2.28 ± 2.27 g/dL, p < 0.05). At 40 weeks, 92.9% patients met the target level of Hb in Roxadustat group and 84.4% in control group. Total iron binding was higher and ferritin was lower in Roxadustat group from baseline values and Roxadustat-induced Hb increases were independent of baseline C-reactive protein levels and history of rhuEPO administration. RRF decreased over time in both groups, the mean RRF change was lower in Roxadustat group than control group (1.15 ± 1.66 mL/min/1.73 m2 vs. 2.31 ± 1.46 mL/min/1.73 m2, p < 0.01). Compared with control group, patients in Roxadustat group had higher levels of total iron binding, 24 h urine volume, total weekly Ccr, and lower systolic pressure, ferritin, C-reactive protein, total cholesterol, LDL. No serious adverse reactions occurred in either group. In patients new to PD, Roxadustat effectively and safely improved renal anemia and delay the decline of RRF. [ABSTRACT FROM AUTHOR]

Oral iron therapy was ineffective in our patient, and iv iron therapy was required for an optimal erythropoietic response to rHuEPO and to rapidly restore iron.[[1], [3]] Despite the patient being hypersensitive to iron sucrose, we were able to successfully desensitize him by following the aforementioned protocol. At the end of the treatment, the serum hemoglobin and ferritin levels of the patient were above the target value (Hb: 11.4 g/dL Ferritin: 144 /L), and then, the rHuEPO treatment was initiated. However, due to the requirement of serum ferritin level >100 /L for the insurance-related approval of rHuEPO treatment in our country, iv iron treatment was obligatory for the patient. [Extracted from the article]

Anti-erythropoietin (anti-EPO) antibody-mediated pure red cell aplasia (PRCA) is a rarely seen disease. Anti-EPO antibodies were mostly found in patients with chronic kidney disease who received recombinant human erythropoietin (rHuEPO) injections subcutaneously. The treatment against anti-EPO antibody-mediated PRCA included discontinuat ion of rHuEPO, immunosuppressive agents, intravenous immunoglobulin, plasmapheresis, or kidney transplantation. We reported a case of kidney transplant recipient with anti-EPO antibody-mediated PRCA, who had no trend of recovery after stopping rHuEPO, receiving regular induction and maintenance immunosuppressive regimens. He was further given 6 consecutive plasmapheresis sessions, cyclophosphamide, and adjusted maintenance immunosuppressive regimen into cyclosporine, sirolimus and prednisone. We monitored his anti-EPO antibody levels with a self-created simple mixing test. At 10 months post kidney transplant, his anti-EPO antibody finally turned negative, and his reticulocyte count dramatically increased. Cyclosporine, sirolimus and prednisone combined with roxadustat eventually alleviated the patient's anti-EPO antibody-mediated PRCA. Our self-created simple mixing test for anti-EPO antibody titer was very helpful in disease monitoring and therapeutic guidance. [ABSTRACT FROM AUTHOR]