Overload Injury Research Articles

Lipid peroxidation mediates the association between iron overload and liver injury: cross-sectional and longitudinal analyses in general Chinese urban adults.

Iron overload has been associated with acute/chronic organ failure, but whether iron overload induces liver injury remains unclear. The objectives of this study were to assess the relationship between urinary iron and serum alanine aminotransferase (ALT, a biomarker for liver injury), and investigate the potential mediating roles of lipid peroxidation and oxidative DNA damage in such association. Levels of urinary iron, serum ALT, and urinary biomarkers of lipid peroxidation (8-iso-prostaglandin-F2α [8-iso-PGF2α]) and oxidative DNA damage (8-hydroxy-deoxyguano-sine [8-OHdG]) were measured among 5386 observations of 4220 participants from the Wuhan-Zhuhai cohort. The relationships of urinary ironwith serum ALT and risk of hyperALT were evaluated by linear mixed model and logistic regression model, respectively. The mediating roles of 8-iso-PGF2α and 8-OHdG were assessed by mediation analyses. This cross-sectional analysis found that urinary iron was positively associated with ALT (β = 0.032; 95% CI: 0.020, 0.044) and hyperALT prevalence (OR = 1.127; 95% CI: 1.065, 1.192). After 3years of follow-up, participants with persistent high iron levels had increased risk of developing hyperALT (RR = 3.800; 95% CI: 1.464, 9.972) when compared with those with persistent low iron levels. In addition, each 1% increase in urinary iron was associated with a 0.146% (95% CI: 0.128%, 0.164%) increase and a 0.192% (95% CI: 0.154%, 0.229%) increase in 8-iso-PGF2α and 8-OHdG, respectively. Urinary 8-iso-PGF2α (β = 0.056; 95% CI: 0.039, 0.074) was positively associated with ALT, while the association between 8-OHdG and ALT was insignificant. Furthermore, increased 8-iso-PGF2α significantly mediated 22.48% of the urinary iron-associated ALT increment. Our study demonstrated that iron overload was significantly associated with liver injury, which was partly mediated by lipid peroxidation. Controlling iron intake and regulating lipid peroxidation may help in preventing liver injury.

Dual genetic tracing reveals a unique fibroblast subpopulation modulating cardiac fibrosis.

After severe heart injury, fibroblasts are activated and proliferate excessively to form scarring, leading to decreased cardiac function and eventually heart failure. It is unknown, however, whether cardiac fibroblasts are heterogeneous with respect to their degree of activation, proliferation and function during cardiac fibrosis. Here, using dual recombinase-mediated genetic lineage tracing, we find that endocardium-derived fibroblasts preferentially proliferate and expand in response to pressure overload. Fibroblast-specific proliferation tracing revealed highly regional expansion of activated fibroblasts after injury, whose pattern mirrors that of endocardium-derived fibroblast distribution in the heart. Specific ablation of endocardium-derived fibroblasts alleviates cardiac fibrosis and reduces the decline of heart function after pressure overload injury. Mechanistically, Wnt signaling promotes activation and expansion of endocardium-derived fibroblasts during cardiac remodeling. Our study identifies endocardium-derived fibroblasts as a key fibroblast subpopulation accounting for severe cardiac fibrosis after pressure overload injury and as a potential therapeutic target against cardiac fibrosis.

Current concepts in tourniquet uses

<h2>Abstract</h2> Tourniquets have been around for many years, providing surgeons with a bloodless operative field and saving lives in the pre-hospital care of major limb trauma. However, their use does come with risk. It is therefore extremely important that we, as surgeons, fully understand the physiological influence they impose on patients, the complications associated with their use and, moreover, how to minimize the incidence of these complications. Most tourniquets are now electronically controlled pneumatic devices with built-in pressure sensors and timers. Classically, inflation to 250 mmHg in the upper limb and 300 mmHg in the lower limb is used, but a move towards patient-specific limb occlusion pressures is suggested, although it is more difficult due to the requirement of more time-consuming set-up. Complications from tourniquets can occur, such as nerve injury, pain, venous thromboembolism or even cardiac overload and reperfusion injury. Limiting use to key parts of an operation or using alternatives such as adrenaline infiltration and tranexamic acid can be of benefit. As such, any use of a tourniquet during an operation must be treated with caution and be deployed taking into account the specific characteristics of that particular patient.

The transfusion-associated dyspnea prospective observation and laboratory assessment study: a protocol for investigating and disambiguating cardiopulmonary and high-grade febrile transfusion reactions in adults

Background: Cardiorespiratory transfusion reactions drive most transfusion-related morbidity and mortality. Transfusion-associated circulatory overload and transfusion-related acute lung injury have established causes, important impacts, mitigation options, and revised definitions, while non-conforming CRTRs fall into a category known as transfusion-associated dyspnea. Though procedures to investigate high-risk febrile transfusion reactions are typically rooted in detecting incompatibility or bacterial contamination, a common standard for examining CRTRs is lacking. CRTRs are further challenged by charting limitations, confounding (or enhanced susceptibility) by comorbidities, and/or overlapping insults. Deeper profiling of CRTRs could improve categorizations, reveal best-value diagnostics, and decipher the nature of (and/or minimize) reactions coded as TAD. Methods: The primary objective of this multi-center study is to reduce uncertainty in final conclusions drawn on CRTRs (cases), defined by dyspnea with objective disturbances and/or significant hemodynamic insults, with/without fever (±F). HRFTRs (controls) represent higher-grade F (T≥39°C or chills/rigors or lower-grade F (≥38°C by +Δ1°C) with non-respiratory effects). Patients (goal: 200) consent to additional sampling (≤24h post-TR) to identify contributing factors in case/control presentations, and in diagnostic groups (TRALI, TACO±F, TAD). Mechanistic axes of interest are cardiorenal, hemolytic, leukoagglutinating, biolipid, vasoactive, and inflammatory. Secondary goals include elucidation of real-life “insult-multiplicity” in CRTRs, tests of greatest yield, and distinguishing features in TRALI/TACO/TAD. Conclusions: A deep systematic CRTR probe may not only reduce diagnostic uncertainty but frame biomarker performance and pathologic signatures in definition-specific CRTRs. The re-classifiability or biology of TAD may be better understood. High-quality, mechanistic, true-to-quantity hemovigilance better exposes burdens and management options. Trial Registration: The trial is registered with ClinicalTrials.gov. with registry number NCT04267029.

Duration of Invasive Mechanical Ventilation Post-Liver Transplantation: Does One Size Fit All?

Duration of Invasive Mechanical Ventilation Post-Liver Transplantation: Does One Size Fit All?

The impact of revised definitions for transfusion-associated circulatory overload and transfusion-related acute lung injury on haemovigilance reporting.

Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are serious adverse transfusion reactions. Standardized surveillance definitions are important to ensure consistent reporting of cases. Recently, revised definitions have been developed for TACO and TRALI, the latter of which has not yet been widely implemented. This study aimed to assess the impact of the new TACO and TRALI definitions on haemovigilance reporting. The Australian Red Cross Lifeblood Adverse Transfusion Reaction database was accessed to identify all cases of suspected or confirmed TACO and TRALI referred from 1 July 2015 to 30 June 2019. Cases were assessed against both the former and new definitions and the results were compared. A total of 73 cases were assessed. There were 48 TACO cases identified. Only 26 of 48 cases strictly met the former 2011 International Society of Blood Transfusion (ISBT) definition of TACO; 6 cases did not meet the definition and 16 cases lacked sufficient clinical details. In comparison, 46 cases met the revised 2018 ISBT definition, with only 2 cases having insufficient details. There were 24 cases of TRALI according to the existing 2004 Canadian Consensus Conference (CCC) definition compared with 25 cases according to the proposed 2019 revised definition. The revised TACO definition captured more cases than the former definition. No significant differences were observed in the number of TRALI cases under the proposed new definition. This is the first study to provide validation data for the revised TRALI definition.

Retracted: LncXIST Facilitates Iron Overload and Iron Overload-Induced Islet Beta Cell Injury in Type 2 Diabetes through miR-130a-3p/ALK2 Axis.

[This retracts the article DOI: 10.1155/2022/6390812.].

The Weakened Interaction Between HECTD4 and GluN2B in Ischemic Stroke Promotes Calcium Overload and Brain Injury Through a Mechanism Involving the Decrease of GluN2B and MALT1 Ubiquitination.

Glutamate receptor ionotropic NMDA 2B (GluN2B) plays an essential role in calcium overload during excitotoxicity. Reverse-phase nano-liquid chromatography-tandem mass spectrometry has revealed an interaction between GluN2B and HECT domain E3 ubiquitin protein ligase 4 (HECTD4), an E3 ubiquitin ligase highly expressed in the brain. As a potential substrate for HECTD4, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) acts as a scaffold with hydrolysis activity. This study explores the relationship between HECTD4, GluN2B, and MALT1, focusing on their role in brain injury in ischemic stroke. Rats were subjected to 2h-ischemia followed by 24-h reperfusion to establish an ischemic stroke model. We observed the downregulation of HECTD4 and the upregulation of MALT1. Additionally, an increased GluN2B phosphorylation was concomitant with weakened interactions between HECTD4 and GluN2B, followed by decreased striatal-enriched protein phosphatase (STEP61). Knockdown of HECTD4 exacerbated hypoxia- or NMDA-induced injury in nerve cells coincident with a decrease in GluN2B and MALT1 ubiquitination, and an increase in GluN2B phosphorylation as well as an increase in intracellular calcium level, which were counteracted by MALT1 siRNA. Blockage of MALT1 with its inhibitor or siRNA reduced STEP61 degradation, accompanied by a decrease in GluN2B phosphorylation, intracellular calcium concentration, and brain cell injury, which were reversed by overexpression of MALT1. Based on these observations, we conclude that the downregulation of HECTD4 in ischemic stroke rat brain accounts for calcium overload and brain injury due to activating GluN2B directly and indirectly through a mechanism involving the reduced ubiquitination of GluN2B and MALT1, respectively.

Synergistic association of fluid overload and acute kidney injury on outcomes in pediatric cardiac ECMO: a retrospective analysis of the KIDMO database.

Acute kidney injury (AKI) and fluid overload (FO) are associated with poor outcomes in children receiving extracorporeal membrane oxygenation (ECMO). Our objective is to evaluate the impact of AKI and FO on pediatric patients receiving ECMO for cardiac pathology. We performed a secondary analysis of the six-center Kidney Interventions During Extracorporeal Membrane Oxygenation (KIDMO) database, including only children who underwent ECMO for cardiac pathology. AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. FO was defined as < 10% (FO-) vs. ≥ 10% (FO +) and was evaluated at ECMO initiation, peak during ECMO, and ECMO discontinuation. Primary outcomes were mortality and length of stay (LOS). Data from 191 patients were included. Non-survivors (56%) were more likely to be FO + than survivors at peak ECMO fluid status and ECMO discontinuation. There was a significant interaction between AKI and FO. In the presence of AKI, the adjusted odds of mortality for FO + was 4.79 times greater than FO- (95% CI: 1.52-15.12, p = 0.01). In the presence of FO + , the adjusted odds of mortality for AKI + was 2.7 times higher than AKI- [95%CI: 1.10-6.60; p = 0.03]. Peak FO + was associated with a 55% adjusted relative increase in LOS [95%CI: 1.07-2.26, p = 0.02]. The association of peak FO + with mortality is present only in the presence of AKI + . Similarly, AKI + is associated with mortality only in the presence of peak FO + . FO + was associated with LOS. Studies targeting fluid management have the potential to improve LOS and mortality outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Abstract P2013: Transcription Fidelity Dysregulation In Heart Failure Pathogenesis

Using deep sequencing combined with computational biology, we found that the failing human hearts (n=3) contain a significant amount of aberrant transcripts arising from widespread spurious intragenic transcription initiations. The same phenomenon was detected in failing mouse hearts (n=3) induced by pressure overload and ischemia injury. Therefore, we hypothesize that spurious transcripts accumulation is a causative factor promoting heart failure (HF). The SET domain containing 2 (Setd2), an H3K36 tri-methylase, is a key regulator for transcription fidelity. The Setd2 modified H3K36me3 prevents RNA polymerase II (Pol II) entry from the gene body and the subsequent cryptic transcription initiation. In the same cohort of failing human and mouse hearts, we found that the SETD2 and H3K36me3 levels were concurrently reduced. To further test our hypothesis, we generated cardiac-specific Setd2-Knockout mice. The mice (n≥8) developed a typical HF progression phenotype: initial compensatory hypertrophy followed by a gradually deteriorating HF with chamber dilation. Transcriptome analysis revealed an accumulation of spurious transcripts in pre-hypertrophic Setd2 -/- cardiomyocytes (n=3). New intragenic transcription initiation sites were identified by DECAP-seq in the knockout (n=3), confirming that the increased aberrant transcripts resulted from spurious Pol II entry. Using ribosome footprinting assay (n=3) to map the translation initiation sites, we found that the aberrant transcripts were partially translated into micro peptides in the Setd2 -/- heart, suggesting that the accumulated aberrant transcripts and micro peptides together promote cardiac hypertrophy. Finally, we developed transgenic mice overexpressing human SETD2 (Tg-MHC-SETD2) in the heart. SETD2 overexpression repressed TAC-induced accumulation of spurious transcripts in cardiomyocytes (n=3). The transgenic mice (n≥6) were resistant to pressure overload stress with less cardiac hypertrophy and improved cardiac contractility. Together, we report that dysregulated transcription fidelity causes adverse aberrant transcripts accumulation leading to cardiac hypertrophy and heart failure. This new mechanism provides potential new therapeutic targets for HF.

Abstract P3066: Macrophage-derived Ccl24 Worsens Cardiac Dysfunction Following Pressure-overload

Heart failure (HF) is the leading cause of death worldwide. Systemic inflammation is associated with HF and is considered an independent predictor of adverse cardiac outcomes. Macrophages are the most abundant immune cells in the heart and have integral roles in cardiac homeostasis and remodeling. Despite their unique identity and homeostatic functions, the precise role of cardiac macrophages during cardiac remodeling is poorly understood. We have previously reported that cardiac resident macrophages expand early in response to pressure overload injury and provide cardioprotection. Using single-cell mRNA sequencing, we revealed that these macrophages consist of distinct subsets including a population that highly expresses C-C Motif Chemokine Ligand 24 (CCL24). CCL24 is a chemokine that promotes immune cell trafficking and activation through its receptor expressed on immune cells, fibroblasts, and cardiomyocytes. Here, we tested whether CCL24 regulates cardiac adaptation to pressure overload by performing transverse aortic constriction (TAC) in whole-body CCL24 knockout (CCL24KO) mice. Aortic constriction during TAC increases the pressure overload in ventricular chambers leading to an early compensated hypertrophy and diastolic dysfunction followed by systolic dysfunction and decompensated heart failure. Despite no differences at steady state, CCL24KO mice showed an improved cardiac function after TAC-induced pressure overload. Compared with WT controls, CCL24KO mice had a higher ejection fraction and fractional shortening. Furthermore, CCL24KO mice had increased hypertrophy but improved diastolic function. These results suggest that CCL24 worsens cardiac dysfunction leading to decompensated HF in response to pressure overload. Interestingly, CCL24KO mice have higher proportions of neutrophils and eosinophils at steady state, suggesting that the presence of these cells may facilitate cardiac repair. Overall, our findings indicate that macrophage-derived CCL24 is detrimental to cardiac function in response to pressure overload injury. The results of this study uncover CCL24 as a central mechanism by which cardiac resident macrophages promote cardiac inflammation and HF.

Protective effect of fucoidan against iron overload and ferroptosis-induced liver injury in rats exposed to alcohol

This study was aimed to explore the effects of fucoidan on iron overload and ferroptosis-induced liver injury, and the underlying mechanisms in rats exposed to alcohol. Sprague-Dawley rats were used to establish alcoholic liver injury model by intragastric administration with alcohol for 16 weeks. The results showed that fucoidan treatment reversed alcohol-induced increases in reactive oxygen species and malondialdehyde levels, and increased glutathione peroxidase and glutathione levels, thus protecting against liver damage. Long-term alcohol feeding resulted in abnormal increase of serum ferritin, liver total iron and the "free" iron levels. Fucoidan treatment reduced serum ferritin level and alleviated liver iron deposition. Fucoidan reversed the reduction of hepcidin induced by alcohol exposure and decreased divalent metal transporter 1 (DMT1) and ferroportin1 (FPN1) expressions in the duodenum. Electron microscope observation of liver tissues showed that alcohol exposure induced ferroptosis changes in the liver. However, fucoidan treatment could alleviate alcohol-induced ferroptosis via upregulating the expressions of p62, Nrf2, SLC7A11 and GPX4. The liver endogenous metabolites analysis by liquid chromatography and mass spectrometry showed that after fucoidan intervention, mineral absorption, biosynthesis of amino acids pathways and lipid metabolism were changed. Fucoidan intervention reduced the levels of oxidized glutathione and regulated the levels of phosphatidylethanolamines in liver tissues. Our data showed that fucoidan supplementation could inhibit iron load via regulating hepcidin-intestinal DMT1/FPN1 axis, alleviate the liver oxidative damage and protect hepatocytes from ferroptosis induced by long-term alcohol exposure through upregulating p62/Nrf2/SLC7A11 pathway in rats.

LncXIST Facilitates Iron Overload and Iron Overload-Induced Islet Beta Cell Injury in Type 2 Diabetes through miR-130a-3p/ALK2 Axis.

Iron overload is directly associated with diabetes mellitus, loss of islet beta cell, and insulin resistance. Likewise, long noncoding RNA (lncRNA) is associated with type 2 diabetes (T2D). Moreover, lncRNAs could be induced by iron overload. Therefore, we are going to explore the molecular mechanism of lncRNA XIST in iron overload-related T2D. Real-time quantitative PCR and Western blot were used to detect gene and protein levels, respectively. TUNEL and MTT assay were performed to examine cell survival. The glucose test strip, colorimetric analysis kit, ferritin ELISA kit, and insulin ELISA kit were performed to examine the levels of glycolic, iron, and total iron-binding capacity, ferritin, and insulin in serum. Fluorospectrophotometry assay was used to examine labile iron pool level. XIST was higher expressed in T2D and iron overload-related T2D rat tissues and cells, and iron overload-induced promoted XIST expression in T2D. Higher XIST expression was associated with iron overload in patients with T2D. Knockdown of XIST alleviated iron overload and iron overload-induced INS-1 cells injury. Further, we found that XIST can sponge miR-130a-3p to trigger receptor-like kinase 2 (ALK2) expression. Moreover, knockdown of ALK2 alleviated iron overload and iron overload-induced INS-1 cells injury by inhibiting bone morphogenetic protein 6 (BMP6)/ALK2/SMAD1/5/8 axis but reversed with XIST upregulation, which was terminally boosted by overexpression of miR-130a-3p. XIST has the capacity to promote iron overload and iron overload-related T2D initiation and development through inhibition of ALK2 expression by sponging miR-130a-3p, and that targeting this axis may be an effective strategy for treating patients with T2D.

Osteochondral allograft transplantation in the football player (knee and ankle)

Articular cartilage defects in the knee and ankle are frequently seen in football (soccer) players and are often a result of trauma, but occasionally are the consequence of occult underlying conditions such as osteochondritis dissecans. Symptoms such as pain, swelling, and inability to ramp up may limit an athlete's performance and ability to compete. Initial evaluation includes a careful history and physical exam, including assessment of overall limb and joint alignment, ligamentous stability, meniscal damage, as well as associated degenerative change. Though nonoperative management serves as the mainstay for treatment in high-level athletes, surgical options are indicated in situations where symptoms persist. Osteochondral allograft (OCA) transplantation, in particular, allows for restoration of hyaline cartilage with predictable healing and accelerated return to activity. With appropriate indications and surgical technique, graft survival following OCA transplantation can exceed 90% at 10 years postoperatively, allow for predictable (70%-80%) return to sport, and produce clinically meaningful improvements in patient-reported outcomes. Full return to sports is often possible between 4 and 10 months postoperatively. Careful attention to postoperative rehabilitation and strength progression prior to return to sport is imperative to prevent graft overload, joint inflammation, or secondary injury to other knee structures such as meniscus or ligamentous structures. This article reviews the overall indications, technique, and outcomes of OCA transplantation in the athletic population.

Increased exposure to loading is associated with decreased plantar soft tissue hardness in people with diabetes and neuropathy

AimsLiterature indicates that altered plantar loading in people with diabetes could trigger changes in plantar soft tissue biomechanics which, in turn, could affect the risk for ulceration. To stimulate more research in this area, this study uses in vivo testing to investigate the link between plantar loading and tissue hardness. MethodsTissue hardness and plantar pressure distribution were measured for six plantar areas in 39 people with diabetes and peripheral neuropathy. ResultsSpearman correlation analysis revealed that increased pressure time integral at the 1st metatarsal-head region (r = -0.354, n = 39, P = 0.027) or at the heel (r = -0.378, n = 39, P = 0.018) was associated with reduced hardness in the same regions. After accounting for confounding parameters, generalised estimating equations analysis also showed that 10% increase in pressure time integral at the heel was associated with ≈ 1 unit reduction in hardness in the same region. ConclusionsFor the first time, this study reveals that people with diabetes and neuropathy who tend to load their feet more heavily also tend to have plantar soft tissues with lower hardness. The observed difference in tissue hardness is likely to affect the tissue’s vulnerability to overload injury. More research will be needed to explore the implications of the observed association for the risk of ulceration.

Therapeutic hypothermia for acute myocardial infarction: a narrative review of evidence from animal and clinical studies.

Myocardial infarction (MI) is the leading cause of death from coronary heart disease and requires immediate reperfusion therapy with thrombolysis, primary percutaneous coronary intervention, or coronary artery bypass grafting. However, myocardial reperfusion therapy is often accompanied by cardiac ischemia/reperfusion (I/R) injury, which leads to myocardial injury with detrimental consequences. The causes of I/R injury are unclear, but are multifactorial, including free radicals, reactive oxygen species, calcium overload, mitochondria dysfunction, inflammation, and neutrophil-mediated vascular injury. Mild hypothermia has been introduced as one of the potential inhibitors of myocardial I/R injury. Although animal studies have demonstrated that mild hypothermia significantly reduces or delays I/R myocardium damage, human trials have not shown clinical benefits in acute MI (AMI). In addition, the practice of hypothermia treatment is increasing in various fields such as surgical anesthesia and intensive care units. Adequate sedation for anesthetic procedures and protection from body shivering has become essential during therapeutic hypothermia. Therefore, anesthesiologists should be aware of the effects of therapeutic hypothermia on the metabolism of anesthetic drugs. In this paper, we review the existing data on the use of therapeutic hypothermia for AMI in animal models and human clinical trials to better understand the discrepancy between perceived benefits in preclinical animal models and the absence thereof in clinical trials thus far.

Early manifestation of severe plasma leakage with fluid overload and early acute kidney injury and liver injury in dengue haemorrhagic fever and lessons learnt from using N-acetylcysteine and CRRT: A Case Report

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The paradox of thrombotic thrombocytopenic purpura and the TACO challenge!

Thrombotic thrombocytopenic purpura (TTP) is a rare medical emergency characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure, and neurological dysfunction. TTP is an infrequent condition and is a thrombotic microangiopathy. TTP is essentially a clinical diagnosis. As untreated TTP has a high mortality, diagnosis is usually presumptive and prompt treatment with plasma exchange is highly beneficial and reduces mortality significantly. Therapeutic plasma exchange with fresh frozen plasma is the standard treatment of choice for TTP. Transfusion-associated reactions may occur in some patients further complicating the disease picture and prolonging hospital stay and recovery. Transfusion-associated circulatory overload and transfusion-associated acute lung injury are the leading cause of transfusion-related mortality. We present here the diagnostic and therapeutic challenges that we faced with a young male patient who presented with fever, jaundice, and seizures.

Luteoloside protects the vascular endothelium against iron overload injury via the ROS/ADMA/DDAH II/eNOS/NO pathway.

Iron overload injury is considered to be a part of blood stasis syndrome of arthralgia in traditional Chinese medicine. Its primary therapies include clearing heat and detoxification, activating blood circulation, and removing blood stasis. Lonicera japonica flos (LJF) has long been known as an excellent antipyretic and antidote. Luteoloside (Lut) is one of the main components of LJF and exhibits antioxidant, anti-inflammatory, and cytoprotective properties. However, the protection of Lut against iron overload injury and its underlying mechanisms remain unclear. Therefore, HUVECs were exposed to 50 μmol·L-1 iron dextran for 48 h to establish an iron overload damage model and the effects of Lut were assessed. Our results showed that 20 μmol·L-1 Lut not only increased cell viability and weakened LDH activity, but also significantly up-regulated DDAHⅡ expression and activity, increased p-eNOS/eNOS ratio and NO content, and reduced ADMA content in HUVECs exposed to iron overload. Furthermore, Lut significantly attenuated intracellular/mitochondrial ROS generation, improved SOD, CAT, and GSH-Px activities, reduced MDA content, maintained MMP, inhibited mPTP opening, prevented cyt c from mitochondria released into cytoplasm, reduced cleaved-caspase3 expression, and ultimately decreased cell apoptosis induced by iron overload. The effects of Lut were similar to those of L-arginine (an ADMA competitive substrate), cyclosporin A (a mPTP blocker agent), and edaravone (a free radical scavenger) as positive controls. However, addition of pAD/DDAH II-shRNA adenovirus reversed the above beneficial effects of Lut. In conclusion, Lut can protect HUVECs against iron overload injury via the ROS/ADMA/DDAH II/eNOS/NO pathway. The mitochondria are the target organelles of Lut's protective effects.

The Impact of Revised Definitions for TACO and TRALI on Hemovigilance Reporting

IntroductionTransfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are serious adverse transfusion reactions. Standardized surveillance definitions are important to ensure consistent and accurate reporting of cases. Recently, revised definitions have been developed for both TACO and TRALI, the latter which have not yet been widely implemented. The primary aim of this study is to assess the impact of the new TACO and TRALI definitions on hemovigilance reporting. The secondary aim is to collate a TRALI case series to describe the epidemiological and laboratory features of this uncommon condition.MethodsThe Australian Red Cross Lifeblood Adverse Transfusion Reaction database, a passive reporting system, was accessed to identify all cases of suspected or confirmed TACO and TRALI referred from 1 July 2015 to 30 June 2019. Cases were assessed against both the former and new definitions of TACO and TRALI and results compared. For confirmed cases of TRALI the following information was collected: patient demographics, antibody investigation results, type and age of products implicated, donor gender and donor outcomes. Statistical analysis was performed using Fisher's exact test.ResultsIn total 99 cases were identified, of which 12 cases were excluded from analysis due to insufficient clinical details. A further 14 cases were excluded as they were deemed not to be transfusion related. The final number of cases assessed was 73.There were 48 TACO cases identified. Only 26 cases strictly met the former 2011 International Society of Blood Transfusion (ISBT) definition of TACO; 6 cases did not meet the definition and 16 cases lacked sufficient clinical details due to the passive nature of the reporting system. In comparison, 46 cases met the revised 2018 ISBT definition, with only 2 cases having insufficient details.There were 24 cases of TRALI according to the 2004 Canadian Consensus Conference (CCC) definition compared with 25 cases according to the proposed 2019 revised definition. Of the 24 cases of TRALI, 15 were classified as TRALI and 9 as possible TRALI. One case was excluded from having TRALI or possible TRALI under the 2004 CCC definition as the patient had pre-existing acute respiratory distress syndrome from influenza A pneumonia, but could be diagnosed as a TRALI Type II under the revised definition as their respiratory status had been stable for more than 12 hours. A total of 62 components from 81 donors were associated with the 24 TRALI cases. Forty-nine (60%) of these donors were male, 31 (38%) female and 1 (1%) unknown (cadaveric liver). Thirty-three (41%) of these donors were deferred due to the presence of HLA antibodies or being the only donor associated with a case. Sixteen cases (67%) were associated with donor antibodies, most commonly HLA class I and HLA class II antibodies that were non-recipient specific. HNA antibodies were present in 3 cases. There were 8 cases in which an HLA or HNA antibody was not implicated. There was no difference in antibody detection rates between low plasma volume components (red cells, pooled platelets and cryoprecipitate) and high plasma volume components (fresh frozen plasma and apheresis platelets) (45% versus 34%, p=0.44). There was a trend towards higher antibody detection rates in female donors (46%) compared with male donors (29%), however this was not statistically significant (p=0.10).ConclusionsThe revised TACO definition appears to capture more cases than the former definition. There appears to be no significant difference in the number of TRALI cases under the proposed new definition compared to the definition currently in use. This is the first study to provide validation data for the revised TRALI definition. TRALI is a rare condition and further studies such as these are required to improve our understanding of its pathophysiology and laboratory findings. DisclosuresNo relevant conflicts of interest to declare.