The effect of genetic polymorphisms in STIM1 and ORAI1 on erythropoietin resistance in Egyptian patients with end-stage renal disease.

Chronic renal failure (CRF) is an incurable disease with unique challenges. Anemia is a frequent complication affecting dialysis patients. Erythropoietin (EPO) is used to treat anemia, but a poor response may result. We investigated genetic polymorphisms of store-operated calcium channel (SOC) signaling, an important erythropoietin-activated pathway that may induce EPO resistance in patients with renal failure. A total of 108 end stage renal disease (ESRD) patients were selected for this study. Patients were divided into two groups according to their erythropoietin resistance index (ERI): 39 patients with an ERI>10 and 69 patients with an ERI<10. We selected four tagging single nucleotide polymorphisms (tSNPs) in STIM1 and five in ORAI1 in our study. A polymerase chain reaction was performed, and genotyping against EPO resistance was correlated. Patients with the AG genotype of rs1561876 in STIM1, the TC genotype of rs6486795 in ORAI1, and the TG or GG genotypes of rs12320939 in ORAI1 were associated with an increased risk of erythropoietin resistance. Overall, we reported a moderately significant relationship between genetic polymorphisms of STIM1 and EPO resistance. We also reported a highly significant relationship between genetic polymorphisms of ORAI1 and EPO resistance. The (A-A-G) haplotype of STIM1 and the (G-T-G-T-A, G-C-G-C-G, or G-T-T-C-G) haplotypes of ORAI1 were significantly associated with EPO resistance.

Erythropoietin-induced hepatocyte receptor A2 regulates effect of pyroptosis on gastrointestinal colorectal cancer occurrence and metastasis resistance.

Erythropoietin-induced hepatocyte receptor A2 (EphA2) is a receptor tyrosine kinase that plays a key role in the development and progression of a variety of tumors. This article reviews the expression of EphA2 in gastrointestinal (GI) colorectal cancer (CRC) and its regulation of pyroptosis. Pyroptosis is a form of programmed cell death that plays an important role in tumor suppression. Studies have shown that EphA2 regulates pyrodeath through various signaling pathways, affecting the occurrence, development and metastasis of GI CRC. The overexpression of EphA2 is closely related to the aggressiveness and metastasis of GI CRC, and the inhibition of EphA2 can induce pyrodeath and improve the sensitivity of cancer cells to treatment. In addition, EphA2 regulates intercellular communication and the microenvironment through interactions with other cytokines and receptors, further influencing cancer progression. The role of EphA2 in GI CRC and its underlying mechanisms provide us with new perspectives and potential therapeutic targets, which have important implications for future cancer treatment.

Effect of perioperative erythropoietin on postoperative morbidity and mortality after cardiac surgery: A meta-analysis of randomized controlled trials.

OBJECTIVE: Cardiac surgery is known to have high rates of perioperative red blood cell (RBC) transfusions which are associated with increased postoperative mortality and morbidity. Perioperative erythropoietin (EPO) has been suggested to lower perioperative RBC transfusions, and the effect on postoperative morbidity or mortality is unknown. METHODS: The registered study protocol is available on PROSPERO (CRD42022314538). We searched the Pubmed, EMbase, and Cochrane CENTRAL databases for randomized controlled trials (RCT) of EPO in cardiac surgery. Outcomes were short-term mortality, acute kidney injury (AKI), re-operation, cerebrovascular accident (CVA), perioperative myocardial infarction (MI), infectious complications, and RBC transfusions. RCT studies of perioperative EPO that reported at least one prespecified outcome of interest were included. RESULTS: A total of 21 RCT's (n = 2,763 patients) were included. Mortality analysis included 17 studies (EPO 1,272 patients, control 1,235) and showed no significant difference (risk difference (RD) 0.0004, 95%CI: -0.016, 0.009). EPO did not reduce the incidence of AKI (RD -0.006, 95% CI: -0.038, 0.026) and reoperation (RD 0.001, 95% CI: -0.013, 0.015). The incidence of CVA (RD -0.004, 95% CI: -0.015, 0.007) and perioperative MI (RD -0.008, 95% CI: -0.021, 0.005) was similar between the groups. CONCLUSIONS: Although EPO had been proven to reduce perioperative RBC transfusions, we did not find that it reduces the incidence of postoperative short-term mortality, AKI, and reoperation. The study results support that perioperative EPO is also safe, with no rise in thrombotic events, including CVA and perioperative MI.

Chronic Administration of Recombinant Human Erythropoietin Induces Angiogenesis in Healthy Mouse Brain.

Introduction The hematopoietic growth factor erythropoietin (EPO) plays an important role in apoptosis and oxidative stress attenuation as well as the promotion of angiogenesis in several tissues. Systemically administered EPO has beneficial effects on rabbits subjected to subarachnoid hemorrhage or stroke. So far, the angiogenic effect of EPO has been documented after an experimentally induced stroke or subarachnoid hemorrhage. In our study, we examined the possible angiogenic effect of chronic treatment with recombinant human erythropoietin (rHuEPO) under normal conditions, in an attempt to clarify if the existence of a lesion or oxygen deprivation is necessary to initiate the angiogenic effect of EPO. Materials & methods BALB/c mice were used and were divided into three groups as follows: group A (no treatment), group B (saline only), and group C (7000 U rHuEPO per week for three weeks by intraperitoneal injection). The number of CD31- and CD34-positive endothelial cells was assessed in mouse brain preparations under control conditions and after treatment with rHuEPO. Results There was no difference between the mean numbers of CD31 and CD34 cells among the different groups. The mean number of vessels in group A and group B was almost the same (18 ± 2 vessels per optical field). However, the number of brain vessels in group C (EPO treatment) increased significantly by 44% compared to controls (26 ± 4 vessels per optical field, P < 0.05). Conclusion These data indicate that no lesion or oxygen deprivation is needed to initiate the angiogenic effect of EPO in healthy mouse brains.

Emerging therapies for immunomodulation in traumatic brain injury: A systematic review and meta-analysis.

Background: Traumatic brain injury (TBI) represents a significant global health burden, often leading to significant morbidity and mortality. Mounting evidence underscores the intricate involvement of dysregulated immune responses in TBI pathophysiology, highlighting the potential for immunomodulatory interventions to mitigate secondary injury cascades and enhance patient outcomes. Despite advancements in treatment modalities, optimizing therapeutic strategies remains a critical challenge in TBI management. To address this gap, this systematic review and meta-analysis aimed to rigorously evaluate the efficacy and safety of emerging immunomodulatory therapies in the context of TBI. Methods: We searched electronic databases such as PubMed, Scopus, Web of Science and CENTRAL for relevant studies investigating the efficacy of immunomodulatory therapies in TBI that were meticulously selected for inclusion. Two independent reviewers meticulously performed data extraction and quality assessment, adhering to predefined criteria. Both randomized controlled trials (RCTs) and observational studies reporting clinically relevant outcomes, such as mortality rates, the Glasgow coma scale, and adverse events, were meticulously scrutinized. Meta-analysis techniques were employed to assess treatment effects across studies quantitatively and analyzed using the Review Manager software (version 5.2). Results: Fourteen studies (n = 1 observational and n = 13 RCTs) were included in our study. Meta-analysis showed no significant overall mortality difference, but erythropoietin (EPO) significantly reduced mortality (odds ratio = 0.49; 95% confidence interval: 0.31-0.78, P = 0.002). The adverse event meta-analysis revealed no significant differences. Conclusion: Immunomodulatory therapies did not significantly affect overall mortality, but EPO demonstrated promising results. Adverse events did not significantly differ from controls. Further research is warranted to refine TBI treatment protocols.

Potential therapeutic effects of topical recombinant human erythropoietin on burn wound healing: A preliminary randomized double-blind controlled clinical trial.

BACKGROUND: Burn injuries can cause significant mortality and morbidity. This study aimed to evaluate the efficiency of topical recombinant human erythropoietin (rhEPO) on enhancing burn wound healing. METHODS: In this randomized double-blind controlled clinical trial, we enrolled 40 participants aged 18 years and older who were referred to a burn center during the first 24 h of burning. The participants with no concurrent comorbidities had superficial and deep second-degree burns, no respiratory burns, no face and perineum burns, no keloid formation, or a healed, fully epithelialized, hypertrophic burn scar. Topical rhEPO or nitrofurazone/Vitamin A was administered every other day, and the patients were scheduled for follow-up visits to receive wound cleansing, debridement, and dressing changes. Burn wound healing response to treatment was measured as the study main outcome. RESULTS: At the second follow-up visit, all parameters were significantly lower in the rhEPO group compared with the control group except for itchiness. The results of the next two follow-up sessions were also the same. The total value of the modified Vancouver Scar Scale (VSS) at days 5, 7, and 14 was significantly lower in the rhEPO group compared with the routine of care group. Trial Registry Date: 2022-03-02, Trial Registry number: IRCT20190810044500N23 CONCLUSIONS: The results of the present study suggested that topical rhEPO is a potential option in burn wounds and patient satisfaction, without causing intolerable side effects.

Disruption of the Circulating Proteome in Neonates Receiving Extracorporeal Membrane Oxygenation Following Congenital Heart Disease Surgery: A Nested Case-Control Study.

This nested case-control study identified broad dysregulation of the circulating proteome in neonates receiving postoperative extracorporeal membrane oxygenation support after congenital heart disease surgery, including differential responses in those not surviving to hospital discharge. Tissue hypoxia and mitochondrial-associated proteins may represent novel candidate biomarkers for poor extracorporeal membrane oxygenation outcomes.

Bloodless Total Hip Arthroplasty in Jehovah's Witness Patients: Contemporary Strategies and Outcomes.

BACKGROUND: Reported blood transfusion rates in total hip arthroplasty (THA) range between 3 and 22%. Jehovah's Witnesses (JW) do not accept blood transfusions and make conscience decisions to accept blood derivatives. This study reports on strategies and outcomes for bloodless THA. METHODS: All JW patients undergoing primary THA at our institution between 2011 and 2022 were included in this study (94 of 110 THA). The indications for THA were osteoarthritis (92%), femoral neck fracture (6%), rheumatoid arthritis (1%), and failed open reduction and internal fixation (1%). Strategies used to optimize outcomes included erythropoietin, tranexamic acid (TXA), cell savers, intra-iliac artery tourniquets, and minimizing phlebotomy. RESULTS: The mean estimated blood loss was 201.2 ± 122.2 ml. Preoperative hemoglobin (Hgb) levels were 13.4 ± 1.4 g/dl, which decreased to 11.0 ± 1.3 g/dl on postoperative day 1 (POD1, P < 0.001), 10.3 ± 1.5 g/dl on POD2 (P = 0.001), and 9.8 ± 1.1 g/dl on POD3 (P = 0.171). The use of TXA significantly decreased Hgb on POD1 (P = 0.04). Subgroup analysis showed that preoperatively anemic patients (Hgb < 12 g/dl) had significantly less Hgb drop postoperatively (P = 0.003). No patients met the recommended transfusion threshold (Hgb < 7 g/dl). There were two 90-day readmissions due to falls. There was zero 90-day mortality. CONCLUSION: A THA can be safely performed on JW patients. Preoperatively anemic patients had a decreased Hgb drop postoperatively. JW patients make a conscious decision to accept blood derivatives, which may be present in medications including erythropoietin. Cell savers can be utilized when anticipating intraoperative blood loss greater than 500 mL. We recommend maintaining a Hgb above 11 g/dl prior to surgery, as a Hgb drop of 3.1 g/dl can be expected. These findings highlight the efficacy of a multimodal approach to optimizing bloodless primary THAs.

Erythropoietin Reduces Inflammation, Oxidative Stress, and Apoptosis in a Rat Model of Bleomycin-Induced Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial disease with unknown etiology and no effective cure, posing a great health burden to society. Erythropoietin (EPO) has been demonstrated to have protective roles in various tissues such as brain, spinal cord, heart, kidney and lung tissues. In this study, we investigate the specific anti-inflammatory, antioxidant and antiapoptotic effects of erythropoietin on lung tissue in a bleomycin-induced rat model of idiopathic pulmonary fibrosis. METHODS: Recombinant human EPO or saline was injected, and the animals were monitored for 14 days after bleomycin instillation. Their hematocrit and serum EPO levels were determined. Histological and immunohistochemical analyses were performed. RESULTS: The extent of tissue injury, determined through morphometric analysis, was significantly decreased in size in animals treated with erythropoietin. An immunohistochemical analysis of the expression of cyclooxygenase-2 (COX-2), inducible synthase of nitric oxide (i-NOS), metalloproteinase-9 (MMP-9), erythropoietin receptor (EPO-R), and cytochrome-C (cyt-C) found these enzymes to be decreased in a statistically significant manner in animals treated with erythropoietin when compared to a non-treated group. CONCLUSIONS: The reduced expression of COX-2, i-NOS, MMP-9, EPO-R, and i-NOS in the lung tissues of animals treated with EPO indicates the anti-inflammatory, antioxidant and antiapoptotic action of erythropoietin, suggesting its potential therapeutic role in pulmonary fibrosis.

Separation of recombinant erythropoietin and human serum albumin without the use of sophisticated equipment.

A number of drugs based on recombinant erythropoietin contain human serum albumin as an auxiliary component. The presence of this protein hinders the proper control of the drug quality in accordance with the requirements of regulating agencies. We propose the novel method for separation of recombinant erythropoietin (epoetin beta) and human serum albumin. It is based on the subsequent use of hydrophobic sorbent and anion exchange resin placed in gravity flow columns (without the use of spin-columns). The proposed approach makes it possible to concentrate and purify the preparations containing the epoetin beta both at high and at minimal concentrations (the ratio of the amount of albumin and erythropoietin in the used preparations can reach 125:1). The average yield of epoetin beta after the use of hydrophobic sorbent and anion exchange resin was 75% and 97%, respectively. It was shown that the determined conditions of sample preparation had no affect on the content of the epoetin beta in the product.

Utility of next-generation sequencing in identifying congenital erythrocytosis in patients with idiopathic erythrocytosis.

Background: Congenital erythrocytosis (CE) is increasingly recognized as the cause of erythrocytosis in patients in whom polycythemia vera and secondary acquired causes have been excluded. The aim of our study was to determine possible genetic background in patients with idiopathic erythrocytosis. Methods: 40 patients with idiopathic erythrocytosis, referred to our institution in a 5-year period, were analyzed. We collected data on erythropoietin (Epo) levels, hemoglobin (Hgb), hematocrit (Hct), erythrocyte count, age, gender, past thrombotic events, concomitant diseases, and smoking status. CE was tested using next-generation sequencing (NGS), in the majority of patients also measurement of P50 and Hgb electrophoresis were performed. Patients with signs of iron overload were tested for genetic variants in the HFE gene. Results: The median patient age at analysis was 46.5 years (range 22-73), with 37 out of 40 being males (93 %). The median Hgb, Hct and red blood cells count were 180 g/L, 0.51, 5.985 x 1012/L in men and 171 g/L, 0.50 and 5.68 x 1012/L in women, respectively. Epo levels were decreased in three, increased in one patient and within the normal range in the rest (median 7.55 mIU/mL; range 2.90-19.50). Eight patients (20 %) smoked. 32 (80 %) were treated with low-dose aspirin, and 20 (50 %) underwent at least one phlebotomy. Thromboembolic events were recorded in 2 patients (5 %). P50 was measured in 20 out of 40 patients, and it was above 24 mm Hg (3.12 kPa) in all of them. Hemoglobin electrophoresis was performed in 73 % of patients, with no abnormal Hgb detected. Variants in the HFE gene were found in 8 out of 40 patients (20 %), but in only one patient the results were associated with an increased risk for hemochromatosis. Although no pathogenic variants for CE were detected by NGS, two variants of uncertain significance, namely EGLN1 (NM_022051.2):c.1072C>T (p.(Pro358Ser)) and EGLN1 (NM_022051.2):c.1124A>G (p.(Glu375Gly)) were identified as strong etiologic candidates. Conclusion: CE is an extremely rare condition. Genetic testing is advised in young individuals with a long-standing persistent erythrocytosis, possibly with a family history and after exclusion of more frequent secondary causes and polycytemia vera.

Discovery of Biomarkers of a Recombinant Human Erythropoietin Administration to Thoroughbred Geldings by Label-Free Proteomics.

Erythropoiesis-stimulating agents (ESAs) continue to be a significant threat to the integrity of human and equine sports. Besides conventional direct testing, monitoring the biomarkers associated with the effects of ESAs may provide a complementary approach via indirect detection to enhance doping control. In this study, we applied label-free proteomics to discover plasma protein biomarkers in Thoroughbred geldings after administration with a long-acting form of recombinant human erythropoietin (rhEPO), methoxy polyethylene glycol epoetin beta, Mircera. Increased haematocrit, haemoglobin and red blood cell (RBC) levels were evidenced as early as 4 days post-administration in all three horses to varying extents. Tryptic peptides were obtained from plasma samples and analysed by nanoflow ultra-high-performance liquid chromatography-high-resolution tandem mass spectrometry (nano-UHPLC-HRMSMS) using data-independent acquisition. Differential protein abundance analysis has shortlisted seven protein biomarker candidates that showed significant changes specifically after Mircera administration in the treated but not in the control geldings, which comprised downregulation of two proteins, haptoglobin (HP) and haemopexin (HPX), and upregulation of five proteins, transferrin receptor 1 (TFR1), phospholipid transfer protein (PLTP), tenascin C (TNC), vascular cell adhesion molecule 1 (VCAM1) and galectin 3 binding protein (LGALS3BP). Multivariate analysis of plasma proteome has allowed the classification of control and treated samples. This is the first report on the discovery of plasma protein biomarkers of rhEPO administration to geldings. The results lay a foundation for applications of protein biomarkers for controlling the misuse of ESAs.

Insoluble HIFa protein aggregates by cadmium disrupt hypoxia-prolyl hydroxylase (PHD)-hypoxia inducible factor (HIFa) signaling in renal epithelial (NRK-52E) and interstitial (FAIK3-5) cells.

The kidney is the main organ that senses changes in systemic O2 pressure by hypoxia-PHD-HIFa (HPH) signaling, resulting in adaptive target gene activation, including erythropoietin (EPO). The non-essential transition metal cadmium (Cd) is nephrotoxic and disrupts the renal HPH pathway, which may promote Cd-associated chronic renal disease (CKD). A deeper molecular understanding of Cd interference with renal HPH signaling is missing, and no data with renal cell lines are available. In rat kidney NRK-52E cells, which model the proximal tubule, and murine fibroblastoid atypical interstitial kidney (FAIK3-5) cells, which mimic renal EPO-producing cells, the chemical hypoxia mimetic dimethyloxalylglycine (DMOG; 1 mmol/l) or hypoxia (1% O2) activated HPH signaling. Cd2+ (2.5-20 µmol/l for ≤ 24 h) preferentially induced necrosis (trypan blue uptake) of FAIK3-5 cells at high Cd whereas NRK-52E cells specially developed apoptosis (PARP-1 cleavage) at all Cd concentrations. Cd (12.5 µmol/l) abolished HIFa stabilization and prevented upregulation of target genes (quantitative real-time polymerase chain reaction and immunoblotting) induced by DMOG or hypoxia in both cell lines, which was caused by the formation of insoluble HIFa aggregates. Strikingly, hypoxic preconditioning (1% O2 for 18 h) reduced apoptosis of FAIK3-5 and NRK-52E cells at low Cd concentrations and decreased insoluble HIFa proteins. Hence, drugs mimicking hypoxic preconditioning could reduce CKD induced by chronic low Cd exposure.

Diagnostic Performance of Serum Erythropoietin to Discriminate Polycythemia Vera from Secondary Erythrocytosis through Established Subnormal Limits.

Serum erythropoietin (sEPO) is an initial screening tool for distinguishing polycythemia vera (PV) from secondary erythrocytosis (SE), but defining 'subnormal' sEPO levels for PV diagnosis remains contentious, complicating its clinical utility. This study compares the diagnostic performance of sEPO across established subnormal limits, including reference interval (RI), clinical decision limit (CDL), and functional reference limit. sEPO levels were analyzed in 393 healthy donors (HDs) and 90 patients (41 PV and 49 SE), who underwent bone marrow biopsy and genetic tests due to erythrocytosis. The RI (2.5-97.5 percentile from HDs) of sEPO was 5.3-26.3 IU/L. A CDL of 3.1 IU/L, determined by ROC analysis in erythrocytosis patients, had a sensitivity of 80.5% and specificity of 87.8% for diagnosing PV. A functional reference limit of 7.0 IU/L, estimated based on the relationship between sEPO and hemoglobin, hematocrit, and WBC, increased sensitivity to 97.6% but decreased specificity to 46.7%. Using 5.3 IU/L as a 'subnormal' limit identified all three JAK2-negative PV cases, increasing the sensitivity and negative predictive value to 97.6% and 97.0%, respectively. Combining the RI, CDL, and functional reference limit may improve PV diagnostic accuracy.

Renoprotective Effects of Daprodustat in Patients with Chronic Kidney Disease and Renal Anemia.

Many large-scale studies revealed that exogenous erythropoietin, erythropoiesis-stimulating agents, have no renoprotective effects. We reported the renoprotective effects of endogenous erythropoietin production on renal function in ischemic reperfusion injury (IRI) of the kidney using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat. The purpose of this study was to investigate the effects of daprodustat on the progression of chronic renal failure. We retrospectively investigated the effects of daprodustat on the progression of chronic renal failure and renal anemia in patients with stages 3a-5 chronic kidney diseases (estimated glomerular filtration rate, eGFR < 60 mL/min/1.73 m2). The results show that daprodustat largely slowed the reduction in eGFR. The recovery of renal function was observed in some patients. Daprodustat is useful not only for renal anemia but also for the preservation of renal function. The renoprotective effect of daprodustat was small in patients with serum creatinine larger than 3-4 mg/dL because of low residual renal function. The appearance of renal anemia would be a sign of the time to start using daprodustat.

The Neuroprotective Effect of Erythropoietin on the Optic Nerve and Spinal Cord in Rats with Experimental Autoimmune Encephalomyelitis through the Activation of the Extracellular Signal-Regulated Kinase 1/2 Signaling Pathway.

Experimental autoimmune encephalomyelitis is a demyelinating disease that causes paralysis in laboratory rats. This condition lacks treatment that reverses damage to the myelin sheaths of neuronal cells. Therefore, in this study, treatment with EPO as a neuroprotective effect was established to evaluate the ERK 1/2 signaling pathway and its participation in the EAE model. EPO was administered in 5000 U/Kg Sprague Dawley rats. U0126 was used as an inhibitor of the ERK 1/2 pathway to demonstrate the possible activation of this pathway in the model. Spinal cord and optic nerve tissues were evaluated using staining techniques such as H&E and the Luxol Fast Blue myelin-specific technique, as well as immunohistochemistry of the ERK 1/2 protein. The EPO-treated groups showed a decrease in cellular sampling in the spinal cord tissues but mainly in the optic nerve, as well as an increase in the expression of the ERK 1/2 protein in both tissues. The findings of this study suggest that EPO treatment reduces cellular death in EAE-induced rats by regulating the ERK pathway.

Challenges and recent advances in erythropoietin stability.

Erythropoietin (EPO) is a pivotal hormone that regulates red blood cell production, predominantly synthesized by the kidneys and also produced by the liver. Since the introduction of recombinant human EPO (rh-EPO) in 1989 through recombinant DNA technology, the therapeutic landscape for anemia has been improved. rh-EPO's market expansion has been substantial, with its application extending across various conditions such as chronic kidney disease, cancer-related anemia, and other disorders. Despite its success, significant concerns remain regarding the stability of EPO, which is critical for preserving its biological activity and ensuring therapeutic efficacy under diverse environmental conditions. Instability issues, including degradation and loss of biological activity, challenge both drug development and treatment outcomes. Factors contributing to EPO instability include temperature fluctuations, light exposure, and interactions with other substances. To overcome these challenges, pharmaceutical research has focused on developing innovative strategies such as stabilizing agents, advanced formulation techniques, and optimized storage conditions. This review article explores the multifaceted aspects of EPO stability, examining the impact of instability on clinical efficacy and drug development. It also provides a comprehensive review of current stabilization strategies, including the use of excipients, lyophilization, and novel delivery systems.

Silk fibroin/chitosan/montmorillonite sponge dressing: Enhancing hemostasis, antimicrobial activity, and angiogenesis for advanced wound healing applications.

Open wounds present a significant challenge in healthcare, requiring careful management to prevent infection and promote wound healing. Advanced wound dressings are critical need to enhance their hemostatic capabilities, antimicrobial properties, and ability to support angiogenesis and sustained moisture for optimal healing. This study introduces a flexible hemostatic dressing designed for open wounds, integrating chitosan (CS) for hemostasis and biocompatibility, silk fibroin (SF) for mechanical strength, and montmorillonite (MMT) for enhanced drug transport. The CSSF@MMT dressings showed promising mechanical strength and swift hemostasis. The CIP-loaded CSSF@MMT demonstrated sustained release for up to one week, exhibiting antibacterial properties against both Gram-positive and Gram-negative bacteria. In vitro cell migration assay demonstrated that erythropoietin-loaded CSSF@MMT dressings promoted the proliferation and migration of endothelial cells. Similarly, the chick embryo chorioallantoic membrane study indicated the same dressings exhibited a significant increase in vascular regeneration. This research suggests that the CSSF@MMT sponge dressing, incorporated with CIP and erythropoietin, holds promise in effectively halting bleeding, creating a protective environment, diminishing inflammation, and fostering wound tissue regeneration. This potential makes it a significant advancement in open wound care, potentially lowering the need for limb amputation and decreasing wound care burden worldwide.

Supplemental Iron and Recombinant Erythropoietin for Anemia in Infants Born Very Preterm: A Survey of Clinical Practice in Europe.

OBJECTIVES: To survey practices of iron and recombinant human erythropoietin (rhEpo) administration to infants born preterm across Europe. STUDY DESIGN: Over a 3-month period, we conducted an online survey in 597 neonatal intensive care units (NICUs) of 18 European countries treating infants born with a gestational age of <32 weeks. RESULTS: We included 343 NICUs (response rate 56.3%) in the survey. Almost all NICUs (97.7%) routinely supplement enteral iron, and 74.3% of respondents to all infants born <32 weeks of gestation. We found that 65.3% of NICUs routinely evaluate erythropoiesis and iron parameters beyond day 28 after birth. Most NICUs initiate iron supplementation at postnatal age of 2 weeks and stop after 6 months (34.3%) or 12 months (34.3%). Routine use of rhEpo was reported in 22.2% of NICUs, and in individual cases in 6.9%. RhEpo was mostly administered subcutaneously (70.1%) and most frequently at a dose of 250 U/kg 3 times a week (44.3%), but the dose varied greatly between centers. CONCLUSIONS: This survey highlights wide heterogeneity in evaluating erythropoietic activity and iron deficiency in infants born preterm. Variation in iron supplementation during infancy likely reflects an inadequate evidence base. Current evidence on the efficacy and safety profile of rhEpo is only poorly translated into clinical practice. This survey demonstrates a need for standards to optimize patient blood management in anemia of prematurity.

Strenuous training combined with erythropoietin induces red cell volume expansion-mediated hypervolemia and alters systemic and skeletal muscle iron homeostasis.

Strenuous physical training increases total blood volume (BV) through expansion of plasma volume (PV) and red cell volume (RCV). In contrast, exogenous erythropoietin (EPO) treatment increases RCV but decreases PV, rendering BV stable or slightly decreased. This study aimed to determine the combined effects of strenuous training and EPO treatment on BV and markers of systemic and muscle iron homeostasis. In this longitudinal study, eight healthy nonanemic males were treated with EPO (50 IU/kg body mass, three times per week, sc) across 28 days of strenuous training (4 days/wk, exercise energy expenditures of 1,334 ± 24 kcal/day) while consuming a controlled, energy-balanced diet providing 39 ± 4 mg/day iron. Before (PRE) and after (POST) intervention, BV compartments were measured using carbon monoxide rebreathing, and markers of iron homeostasis were assessed in blood and skeletal muscle (vastus lateralis). Training + EPO increased (P < 0.01) RCV (13 ± 6%) and BV (5 ± 4%), whereas PV remained unchanged (P = 0.86). The expansion of RCV was accompanied by a large decrease in whole body iron stores, as indicated by decreased (P < 0.01) ferritin (-77 ± 10%) and hepcidin (-49 ± 23%) concentrations in plasma. Training + EPO decreased (P < 0.01) muscle protein abundance of ferritin (-25 ± 20%) and increased (P < 0.05) transferrin receptor (47 ± 56%). These novel findings illustrate that strenuous training combined with EPO results in both increased total oxygen-carrying capacity and hypervolemia in young healthy males. The decrease in plasma and muscle ferritin suggests that the marked upregulation of erythropoiesis alters systemic and tissue iron homeostasis, resulting in a decline in whole body and skeletal muscle iron stores.NEW & NOTEWORTHY Strenuous exercise training combined with erythropoietin (EPO) treatment increases blood volume, driven exclusively by red cell volume expansion. This hematological adaptation results in increased total oxygen-carrying capacity and hypervolemia. The marked upregulation of erythropoiesis with training + EPO reduces whole body iron stores and circulating hepcidin concentrations. The finding that the abundance of ferritin in muscle decreased after training + EPO suggests that muscle may release iron to support red blood cell production.