Levels Of Injury Biomarkers Research Articles

Bezafibrate mitigates cardiac injury against coronary microembolization by preventing activation of p38 MAPK/NF-κB signaling.

Coronary microembolization (CME)-induced inflammatory response and cardiomyocyte apoptosis are the main contributors to CME-associated myocardial dysfunction. Bezafibrate, a peroxisome proliferator-activated receptors (PPARs) agonist, has displayed various benefits in different types of diseases. However, it is unknown whether Bezafibrate possesses a protective effect in myocardial dysfunction against CME. In this study, we aimed to investigate the pharmacological function of Bezafibrate in CME-induced insults in myocardial injury and progressive cardiac dysfunction and explore the underlying mechanism. A CME model was established in rats, and cardiac function was detected. The levels of injury biomarkers in serum including CK-MB, AST, and LDH were determined using commercial kits, and pro-inflammatory mediators including TNF-α and IL-6 were detected using ELISA kits. Our results indicate that Bezafibrate improved cardiac function after CME induction. Bezafibrate reduced the release of myocardial injury indicators such as CK-MB, AST, and LDH in CME rats. We also found that Bezafibrate ameliorated oxidative stress by increasing the levels of the antioxidant GPx and the activity of SOD and reducing the levels of TBARS and the activity of NOX. Bezafibrate inhibited the expression of pro-inflammatory cytokines such as TNF-α and IL-6. Importantly, Bezafibrate was found to mitigate CME-induced myocardial apoptosis by increasing the expression of Bcl-2 and reducing the levels of Bax and cleaved caspase-3. Mechanistically, Bezafibrate could prevent the activation of p38 MAPK/NF-κB signaling. These findings suggest that Bezafibrate may be a candidate therapeutic agent for cardioprotection against CME in clinical applications.

Association of early dexmedetomidine exposure with brain injury biomarker levels following moderate - severe traumatic brain injury: A TRACK-TBI study

BackgroundTraumatic brain injury (TBI) triggers autonomic dysfunction and inflammatory response that can result in secondary brain injuries. Dexmedetomidine is an alpha-2 agonist that may modulate autonomic function and inflammation and has been increasingly used as a sedative agent for critically ill TBI patients. We aimed to investigate the association between early dexmedetomidine exposure and blood-based biomarker levels in moderate-to-severe TBI (msTBI). MethodsWe conducted a retrospective cohort study using data from the Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study (TRACK-TBI), which enrolled acute TBI patients prospectively across 18 United States Level 1 trauma centers between 2014–2018. Our study population focused on adults with msTBI defined by Glasgow Coma Scale score 3–12 after resuscitation, who required mechanical ventilation and sedation within the first 48 h of ICU admission. The study’s exposure was early dexmedetomidine utilization (within the first 48 h of admission). Primary outcome included brain injury biomarker levels measured from circulating blood on day 3 following injury, including glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B) and the inflammatory biomarker C-reactive protein (CRP). Secondary outcomes assessed biomarker levels on days 5 and 14. Linear mixed-effects regression modelling of the log-transformed response variable was used to analyze the association of early dexmedetomidine exposure with brain injury biomarker levels. ResultsAmong the 352 TRACK-TBI subjects that met inclusion criteria, 50 (14.2 %) were exposed to early dexmedetomidine, predominantly male (78 %), white (81 %), and non-Hispanic (81 %), with mean age of 39.8 years. Motor vehicle collisions (27 %) and falls (22 %) were common causes of injury. No significant associations were found between early dexmedetomidine exposure with day 3 brain injury biomarker levels (GFAP, ratio = 1.46, 95 % confidence interval [0.90, 2.34], P = 0.12; UCH-L1; ratio = 1.17 [0.89, 1.53], P = 0.26; NSE, ratio = 1.19 [0.92, 1.53], P = 0.19; S100B, ratio = 1.01 [0.95, 1.06], P = 0.82; hs-CRP, ratio = 1.29 [0.91, 1.83], P = 0.15). The hs-CRP level at day 14 in the dexmedetomidine group was higher than that of the non-exposure group (ratio = 1.62 [1.12, 2.35], P = 0.012). ConclusionsThere were no significant associations between early dexmedetomidine exposure and day 3 brain injury biomarkers in msTBI. Our findings suggest that early dexmedetomidine use is not correlated with either decrease or increase in brain injury biomarkers following msTBI. Further research is necessary to confirm these findings.

Robust Rat and Mouse Models of Bilateral Renal Ischemia Reperfusion Injury.

Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC). We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury. Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model. These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators.

Multi-dimensional evaluation of cardiotoxicity in mice following respiratory exposure to polystyrene nanoplastics

BackgroundNanoplastics (NPs) could be released into environment through the degradation of plastic products, and their content in the air cannot be ignored. To date, no studies have focused on the cardiac injury effects and underlying mechanisms induced by respiratory exposure to NPs.ResultsHere, we systematically investigated the cardiotoxicity of 40 nm polystyrene nanoplastics (PS-NPs) in mice exposed via inhalation. Four exposure concentrations (0 µg/day, 16 µg/day, 40 µg/day and 100 µg/day) and three exposure durations (1 week, 4 weeks, 12 weeks) were set for more comprehensive information and RNA-seq was performed to reveal the potential mechanisms of cardiotoxicity after acute, subacute and subchronic exposure. PS-NPs induced cardiac injury in a dose-dependent and time-dependent manner. Acute, subacute and subchronic exposure increased the levels of injury biomarkers and inflammation and disturbed the equilibrium between oxidase and antioxidase activity. Subacute and subchronic exposure dampened the cardiac systolic function and contributed to structural and ultrastructural damage in heart. Mechanistically, violent inflammatory and immune responses were evoked after acute exposure. Moreover, disturbed energy metabolism, especially the TCA cycle, in the myocardium caused by mitochondria damage may be the latent mechanism of PS-NPs-induced cardiac injury after subacute and subchronic exposure.ConclusionThe present study evaluated the cardiotoxicity induced by respiratory exposure to PS-NPs from multiple dimensions, including the accumulation of PS-NPs, cardiac functional assessment, histology observation, biomarkers detection and transcriptomic study. PS-NPs resulted in cardiac injury structurally and functionally in a dose-dependent and time-dependent manner, and mitochondria damage of myocardium induced by PS-NPs may be the potential mechanism for its cardiotoxicity.Graphical abstract

SNHG1/miR-21 axis mediates the cardioprotective role of aloin in sepsis through modulating cardiac cell viability and inflammatory responses.

Aloin has cardioprotective effects, however, its cardioprotective role in sepsis remains unclear. This study aimed to analyze whether aloin could prevent sepsis-related myocardial damage and explore the underlying mechanisms by examining the expression of long-noncoding RNA (lncRNA) SNHG1 and microRNA-21 (miR-21). The interaction of SNHG1 with miR-21 was identified by dual-luciferase reporter assay. The levels of SNHG1 and miR-21 were measured by real-time quantitative PCR. The cardioprotective function of aloin was assessed in a sepsis animal model, which was induced by cecal ligation and puncture, and in a myocardial injury cell model in H9C2 cells stimulated by lipopolysaccharide. Myocardial injury biomarker levels and hemodynamic indicators in mice model were measured to evaluate cardiac function. The viability of H9C2 cells was assessed by cell counting kit-8 assay. Inflammatory cytokine levels were examined by an ELISA method. Decreased SNHG1 and increased miR-21 were found in sepsis patients with cardiac dysfunction, and they were negatively correlated. Aloin significantly attenuated myocardial damage and inflammatory responses of mice model, and increased the viability and suppressed inflammation in H9C2 cell model. In addition, SNHG1 expression was upregulated and miR-21 expression was downregulated by aloin in both mice and cell models. Moreover, in mice and cell models, SNHG1/miR-21 axis affected sepsis-related myocardial damage, and mediated the cardioprotective effects of aloin. Our findings indicated that aloin exerts protective effects in sepsis-related myocardial damage through regulating cardiac cell viability and inflammatory responses via regulating the SNHG1/miR-21 axis.

Biochemical, coronary angiographic and echocardiographic parameters in inferior acute myocardial infarction with right ventricle injury

Background: The involvement of the right ventricular (RV) myocardium in inferior acute myocardial infarction (AMI) increases the risk of complication and death rates, which makes it important to timely identify this type of myocardial infarction.
 Aim: To assess the value of functional, biochemical, coronary angiographic and ultrasound parameters in the patients in their productive age with inferior AMI, in order to identify the RV injury before and after percutaneous coronary intervention (PCI).
 Materials and methods: This cohort prospective study included 141 patients with inferior AMI and ST elevation (26 women aged up to 60 years and 115 men aged up to 65 years), admitted to the emergency of the Medical Unit of Kazan (Volga region) Federal University from 2019 to 2021. The patients past history, clinical, biochemical and ultrasound data were obtained on admission and at discharge from the hospital. The two-dimensional speckle tracking echocardiography was performed at days 5 to 7 after PCI. The results are given as median values and 25% and 75% quartiles (Ме [Q1; Q3]).
 Results: According to electrocardiographic signs, 41.8% (n = 59) patients with inferior AMI comprised the group with the RV injury. There were no differences in the myocardial injury biomarker levels between the groups on admission (р = 0.31 and p = 0.786, respectively). The coronary angiography showed that the index artery was the right coronary artery in 100% (n = 59) cases with the RV injury and in 67.1% (n = 55, р 0.001) of the cases without the RV injury. Proximal involvement was 2.7 more common in biventricular infarction, than in the isolated inferior one (р = 0.013). During PCI, the RV involvement significantly increased the risk of complications (in 28 (47.5%) and 18 (22.0%) of the cases, respectively, р 0.001), among them being the need in a temporary pacemaker placement (8 (13.6%) and 2 (2.4%) patients, р = 0.027). Echocardiography showed worse parameters of global and local contractility of both ventricles in the group with the RV involvement in the inferior AMI. The left ventricular (LV) ejection fraction decreased from 55% [51; 57] to 52% [47; 56] (р = 0.005); global RV deformity from -15.2% [-18.5; -13.4] to -12.3% [-15.6; -10.6] (р 0.001); total number of segments with local contractility abnormalities increased from 2 [1; 3] to 5 [3; 6] (р 0.001).
 Conclusion: The study has confirmed that the involvement of RV into inferior LV AMI in the patients of productive age should be verified by abnormalities of electrocardiographic, biochemical, coronary angiographic and ultrasound parameters. To document the RV injury before PCI, ST elevation in additional right chest leads (V3RV4R) was most informative, whereas after PCI, it was the finding of abnormal local contractility of basal and medial inferior RV segments by two-dimensional echocardiography and decreased longitudinal RV deformation by speckle tracking.

The Urinary Level of Injury Biomarkers Is Not Univocally Reflective of the Extent of Toxic Renal Tubular Injury in Rats.

Nephrotoxicity is a major cause of intrinsic acute kidney injury (AKI). Because renal tissue damage may occur independently of a reduction in glomerular filtration rate and of elevations in plasma creatinine concentration, so-called injury biomarkers have been proposed to form part of diagnostic criteria as reflective of tubular damage independently of renal function status. We studied whether the urinary level of NGAL, KIM-1, GM2AP, t-gelsolin, and REGIIIb informed on the extent of tubular damage in rat models of nephrotoxicity, regardless of the etiology, moment of observation, and underlying pathophysiology. At a time of overt AKI, urinary biomarkers were measured by Western blot or ELISA, and tubular necrosis was scored from histological specimens stained with hematoxylin and eosin. Correlation and regression studies revealed that only weak relations existed between biomarkers and tubular damage. Due to high interindividual variability in the extent of damage for any given biomarker level, urinary injury biomarkers did not necessarily reflect the extent of the underlying tissue injury in individual rats. We contended, in this work, that further pathophysiological contextualization is necessary to understand the diagnostic significance of injury biomarkers before they can be used for renal tubular damage severity stratification in the context of nephrotoxic and, in general, intrinsic AKI.

Ulinastatin Improves Renal Microcirculation by Protecting Endothelial Cells and Inhibiting Autophagy in a Septic Rat Model

Introduction: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. Methods: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 h after the operation. Histological staining was used to evaluate kidney injury scores. Western blot was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors (interleukin-1β, interleukin-6, and tumor necrosis factor-α) in kidney tissue, and enzyme-linked immunosorbent assay detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. Results: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. Conclusion: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

Association of Brain Injury Biomarkers and Circulatory Shock Following Moderate-Severe Traumatic Brain Injury: A TRACK-TBI Study.

Early circulatory shock following traumatic brain injury (TBI) is a multifactorial process; however, the impact of brain injury biomarkers on the risk of shock has not been evaluated. We examined the association between neuronal injury biomarker levels and the development of circulatory shock following moderate-severe TBI. In this retrospective cohort study, we examined adults with moderate-severe TBI (Glasgow Coma Scale score <13) enrolled in the TRACK-TBI study, an 18-center prospective TBI cohort study. The exposures were day-1 levels of neuronal injury biomarkers (glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], neuron-specific enolase), and of an inflammatory biomarker (high-sensitivity C-reactive protein). The primary outcome was the development of circulatory shock, defined as cardiovascular Sequential Organ Failure Assessment Score ≥2 within 72 hours of admission. Association between day-1 biomarker levels and the development of circulatory shock was assessed with regression analysis. The study included 392 subjects, with a mean age of 40 years; 314 (80%) were male and 165 (42%) developed circulatory shock. Median (interquartile range) day-1 levels of UCH-L1 (994.8 [518.7 to 1988.2] pg/mL vs. 548.1 [280.2 to 1151.9] pg/mL; P <0.0001) and S100B (0.47 μg/mL [0.25 to 0.88] vs. 0.27 [0.16 to 0.46] μg/mL; P <0.0001) were elevated in those who developed early circulatory shock compared with those who did not. In multivariable regression, there were associations between levels of both UCH-L1 (odds ratio, 1.63 [95% confidence interval, 1.25-2.12]; P <0.0005) and S100B (odds ratio, 1.73 [95% confidence interval 1.27-2.36]; P <0.0005) with the development of circulatory shock. Neuronal injury biomarkers may provide the improved mechanistic understanding and possibly early identification of patients at risk for early circulatory shock following moderate-severe TBI.

Attenuation of Cardiomyopathy Induced in Sub-Chronic Exposure of Acrolein by Sulforaphane via Indirect PPARy Expression Promoter

Abstract: Sulforaphane (SPN) is reported to activate the Nrf2/Keap1 complex responsible for protein and gene expression promotion of various antioxidant enzymes. The present study examined the role of Nrf2 in modulating other signaling pathways involved in SPN’s attenuation of acrolein (ACL)-induced cardiomyopathy in rats. Forty-two rat was categorized into seven 4-week treatment groups: control, SPN, losartan (LTN), ACL, ACL+SPN, ACL+LTN, and ACL+SPN+LTN. Heart samples were harvested for analysis; cardiac oxidative and injury biomarker levels and histopathological examination were undertaken. PPARγ, Nrf2, NF-κB, COX-2, and CYP2E1 protein expressions were examined. Results show that SPN and SPN+LTN reduced GSH, catalase, and lipid peroxidation compared to the ACL-treated group. Also, levels of creatine kinase-MB, cardiac troponin, and caspase 3 induced by ACL were all attenuated. Altered cardiac tissue pathophysiology by ACL was alleviated. SPN+LTN significantly increased Nrf2 expression via PPARγ action but decreased NF-κB and COX-2 expressions. Also, ACLincreased CYP2E1 expression was significantly attenuated by the SPN+LTN combination. For the first time, it suggests that SPN+LTN might offer a better therapeutic alternative to ACL-induced cardiomyopathy by activating Nrf2 via PPARγ and reducing NF-κB/COX- 2/CYP2E1 expressions. Key words: Sulforaphane, Losartan, Acrolein, Cardiomyopathy, Oxidative Stress, PPARγ; Nrf2.

Intraoperative Methylprednisolone and Neurodevelopmental Outcomes in Infants After Cardiac Surgery

BackgroundNeurodevelopmental impairment is an important consequence for survivors of surgery for critical congenital heart disease. This study sought to determine whether intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes. MethodsWe performed a planned secondary analysis of a 2-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery. A brain injury biomarker was measured during surgery. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two-sample t tests and generalized linear models were used. ResultsThere were 129 participants (n = 61 methylprednisolone; n = 68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between treatment groups. Participants who underwent a palliative (versus corrective) procedure had lower mean BSID-III cognitive (101 ± 15 versus 106 ± 14; P = .03) and motor scores (85 ± 18 versus 94 ± 16; P < .01). Longer ventilation time was associated with lower motor scores. Longer cardiac intensive care unit stay was associated with lower cognitive, language, and motor scores. Cardiopulmonary bypass time, aortic cross-clamp time, and deep hypothermic circulatory arrest were not associated with BSID-III scores. ConclusionsNeurodevelopmental outcomes were not associated with intraoperative methylprednisolone or intraoperative variables. Participants who underwent a neonatal palliative (versus corrective) procedure had longer cardiac intensive care unit stays and worse neurodevelopmental outcomes at 1 year. This work suggests that interventions focused solely on the operative period may not be associated with a long-term neurodevelopmental benefit.

Kidney Function, Self-Reported Symptoms, and Urine Findings in Nicaraguan Sugarcane Workers.

An epidemic of CKD in Central America predominantly affects males working in certain industries, including sugarcane. Urinary tract infections are commonly diagnosed among men in Nicaragua, who often receive antibiotics and nonsteroidal anti-inflammatory drugs for urinary symptoms. We followed 251 male Nicaraguan sugarcane workers in seven job tasks over one harvest and measured urine dipstick parameters, kidney injury biomarkers, and eGFR. We administered a questionnaire about urinary symptoms, health-related behaviors, and medication history. We cultured urine in a subset of workers. The study population was composed of factory workers (23%), cane cutters (20%), irrigators (20%), drivers (16%), agrichemical applicators (12%), seeders/reseeders (6%), and seed cutters (4%). The mean age of participants was 33.9 years, and mean employment duration was 10.1 years. Cane cutters reported higher proportions of urinary-related symptoms compared with agrichemical applicators, irrigators, and seeders/reseeders. Seed cutters were more likely to take antibiotics (22%), whereas drivers and seeders/reseeders were more likely to take pain medications (27% and 27%, respectively). Proteinuria was uncommon, whereas dipstick leukocyte esterase was relatively common, especially among cane cutters, seed cutters, and seeders/reseeders (33%, 22%, and 21% at late harvest, respectively). Dipstick leukocyte esterase at late harvest was associated with a 12.9 ml/min per 1.73 m2 (95% CI, -18.7 to -7.0) lower mean eGFR and 2.8 times (95% CI, 1.8 to 4.3) higher mean neutrophil gelatinase-associated lipocalin. In general, workers who reported urinary-related symptoms had higher mean kidney injury biomarker levels at late harvest. None of the workers had positive urine cultures, including those reporting urinary symptoms and/or with positive leukocyte esterase results. Amoxicillin, ibuprofen, and acetaminophen were the most commonly used medications. Job task is associated with urinary symptoms and dipstick leukocyte esterase. Urinary tract infection is misdiagnosed based on leukocyte esterase, which may be an important predictor of kidney outcomes.

Non-clinical safety study of a sugarcane bacterial cellulose hydrogel

A hydrogel of bacterial cellulose of 0.8%, biopolymer produced from sugarcane molasses and synthesized from a bacteria called Zoogloea sp., was analyzed for its composition and tested by two routes of administration, subcutaneous and intraperitoneal, to clarify the local and systemic adverse effects after skin implantation in Wistar rats (24 males, 24 females, 55 days old). Analysis of two samples of BC films indicates carbon (42.94%; 43.43%), hydrogen (6.73%; 6.76%), nitrogen (0.28%, 0.23%) and oxygen (50.05%, 49.58%). No abnormal behavior, clinical signs of chronic toxicity or inflammation were observed. There was no change in liver injury biomarker levels (ALT, AST and ALP), as well as in renal histology, where it was evaluated to signs of tubular cell injury, glomerular or vascular damage, and renal morphometry, in which it was quantified the number of renal corpuscles, the number of cells per glomerulus and the capsular space area. Thus, the absence of signs and symptoms of toxicity suggests that subcutaneous or intraperitoneal injections of these polymers may be used in clinical situations.

Stim1 Polymorphism Disrupts Immune Signaling and Creates Renal Injury in Hypertension.

BackgroundSpontaneously hypertensive rats of the stroke‐prone line (SHR‐A3) develop hypertensive renal disease as a result of naturally occurring genetic variation. Our prior work identified a single‐nucleotide polymorphism unique to SHR‐A3 that results in truncation of the carboxy terminus of STIM1. The SHR‐B2 line, which is also hypertensive but resists hypertensive renal injury, expresses the wild‐type STIM1. STIM1 plays a central role in lymphocyte calcium signaling that directs immune effector responses. Here we show that major defects in lymphocyte function affecting calcium signaling, nuclear factor of activated T cells activation, cytokine production, proliferation, apoptosis, and regulatory T‐cell development are present in SHR‐A3 and attributable to STIM1.Methods and ResultsTo assess the role of Stim1 variation in susceptibility to hypertensive renal injury, we created a Stim1 congenic line, SHR‐A3(Stim1‐B2), and STIM1 function was rescued in SHR‐A3. We found that Stim1 gene rescue restores disturbed lymphocyte function in SHR‐A3. Hypertensive renal injury was compared in SHR‐A3 and the SHR‐A3(Stim1‐B2) congenic line. Histologically assessed renal injury was markedly reduced in SHR‐A3(Stim1‐B2), as were renal injury biomarker levels measured in urine. Stim1 deficiency has been linked to the emergence of antibody‐mediated autoimmunity. Renal glomerular immunoglobulin deposition was greater in SHR‐A3 than SHR‐B2 and was reduced by Stim1 congenic substitution. Serum anti–double‐stranded DNA antibody titers in SHR‐A3 were elevated compared with SHR‐B2 and were reduced in SHR‐A3(Stim1‐B2).Conclusions Stim1 deficiency in lymphocyte function originating from Stim1 truncation in SHR‐A3 combines with hypertension to create end organ disease and may do so as a result of antibody formation.

Resolvin D1 Improves Post-Resuscitation Cardiac and Cerebral Outcomes in A Porcine Model of Cardiac Arrest.

Following global ischemia reperfusion injury triggered by cardiac arrest (CA) and resuscitation, the ensuing cardiac and cerebral damage would result in high mortality and morbidity. Recently, resolvin D1 has been proven to have a protective effect on regional cardiac and cerebral ischemia reperfusion injury. In this study, we investigated the effects of resolvin D1 on cardiac and cerebral outcomes after cardiopulmonary resuscitation (CPR) in a porcine model.Twenty-eight male domestic pigs weighing between 33 and 41 kg were randomly divided into one of the four groups: sham, CPR, low-dose resolvin D1 (LRD), and high-dose resolvin D1 (HRD). Sham animals underwent the surgical preparation only. Other animals were subjected to 8 min of untreated ventricular fibrillation and then 5 min of CPR. At 5 min after resuscitation, resolvin D1 was intravenously administered with the doses of 0.3 and 0.6 μg/kg in the LRD and HRD groups, respectively. The resuscitated animals were monitored for 6 h and observed for an additional 18 h.After resuscitation, myocardial and neurological function were significantly impaired, and their serum levels of injury biomarkers were markedly increased in the CPR, LRD, and HRD groups compared with the sham group. In addition, tissue inflammation and oxidative stress in the heart and brain were observed in the three groups. However, myocardial function was significantly improved and its injury biomarker was significantly decreased starting 3 h after resuscitation in the LRD and HRD groups compared with the CPR group. Similarly, neurological function was significantly better at 24 h post-resuscitation and its injury biomarkers were significantly lower at 6 and 24 h post-resuscitation in the LRD and HRD groups than in the CPR group. In addition, myocardial, cerebral inflammation, and oxidative stress were significantly milder in the two resolvin D1-treated groups. Especially, HRD produced significantly greater post-resuscitation cardiac and cerebral protection compared with the LRD group.In conclusion, resolvin D1 significantly improved post-resuscitation cardiac and cerebral outcomes in a porcine model of CA, in which the protective effects may be in a dose-dependent manner.

Physiological and Biochemical Effects of Intrinsically High and Low Exercise Capacities Through Multiomics Approaches.

Regular exercise prevents lipid abnormalities and conditions such as diabetes mellitus, hypertension, and obesity; it considerably benefits sedentary individuals. However, individuals exhibit highly variable responses to exercise, probably due to genetic variations. Animal models are typically used to investigate the relationship of intrinsic exercise capacity with physiological, pathological, psychological, behavioral, and metabolic disorders. In the present study, we investigated differential physiological adaptations caused by intrinsic exercise capacity and explored the regulatory molecules or mechanisms through multiomics approaches. Outbred ICR mice (n = 100) performed an exhaustive swimming test and were ranked based on the exhaustive swimming time to distinguish intrinsically high- and low-capacity groups. Exercise performance, exercise fatigue indexes, glucose tolerance, and body compositions were assessed during the experimental processes. Furthermore, the gut microbiota, transcriptome, and proteome of soleus muscle with intrinsically high exercise capacity (HEC) and low exercise capacity (LEC) were further analyzed to reveal the most influential factors associated with differential exercise capacities. HEC mice outperformed LEC mice in physical activities (exhaustive swimming and forelimb grip strength tests) and exhibited higher glucose tolerance than LEC mice. Exercise-induced peripheral fatigue and the level of injury biomarkers (lactate, ammonia, creatine kinase, and aspartate aminotransferase) were also significantly lower in HEC mice than in LEC mice. Furthermore, the gut of the HEC mice contained significantly more Butyricicoccus than that of the LEC mice. In addition, transcriptome data of the soleus muscle revealed that the expression of microRNAs that are strongly associated with exercise performance-related physiological and metabolic functions (i.e., miR-383, miR-107, miR-30b, miR-669m, miR-191, miR-218, and miR-224) was higher in HEC mice than in LEC mice. The functional proteome data of soleus muscle indicated that the levels of key proteins related to muscle function and carbohydrate metabolism were also significantly higher in HEC mice than in LEC mice. Our study demonstrated that the mice with various intrinsic exercise capacities have different gut microbiome as well as transcriptome and proteome of soleus muscle by using multiomics approaches. The specific bacteria and regulatory factors, including miRNA and functional proteins, may be highly correlated with the adaptation of physiological functions and exercise capacity.

Hypertonic Mannitol for the Prevention of Intradialytic Hypotension: A Randomized Controlled Trial

Intradialytic hypotension (IDH) is a common complication at the initiation of hemodialysis (HD) therapy, is associated with greater mortality, and may be related to relatively rapid shifts in plasma osmolality. This study sought to evaluate the effect of an intervention to minimize intradialytic changes in plasma osmolality on the occurrence of IDH. Double-blind, single-center, randomized, controlled trial. Individuals requiring initiation of HD for acute or chronic kidney disease. Mannitol, 0.25g/kg/h, versus a similar volume of 0.9% saline solution during the first 3 HD sessions. The primary end point was average decline in systolic blood pressure (SBP). The secondary end point was the proportion of total sessions complicated by IDH (defined as a decrease≥ 20mm Hg from the pre-HD SBP). Exploratory end points included biomarkers of cardiac and kidney injury. 52 patients were randomly assigned and contributed to 156 study visits. There were no significant differences in average SBP decline between the mannitol and placebo groups (15±11 vs 19±16mm Hg; P= 0.3). The proportion of total sessions complicated by IDH was lower in the mannitol group compared to placebo (25% vs 43%), with a nominally lower risk for developing an episode of IDH (OR, 0.38; 95% CI, 0.14-1.00), though this finding was of borderline statistical significance (P= 0.05). There were no consistent differences in cardiac and kidney injury biomarker levels between treatment groups. Modest sample size and number of events. In this pilot randomized controlled trial studying patients requiring initiation of HD, we found no difference in absolute SBP decline between those who received mannitol and those who received saline solution. However, there were fewer overall IDH events and a nominally lower risk for dialysis sessions being complicated by IDH in the mannitol group. A larger multicenter randomized controlled trial is warranted. Government funding to an author (Dr Mc Causland is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant K23DK102511). Registered at ClinicalTrials.gov with study number NCT01520207.

Association of intraoperative circulating-brain injury biomarker and neurodevelopmental outcomes at 1 year among neonates who have undergone cardiac surgery

BackgroundNeurodevelopmental disability is the most significant complication for survivors of infant surgery for congenital heart disease. In this study we sought to determine if perioperative circulating brain injury biomarker levels are associated with neurodevelopmental outcomes at 12 months. MethodsA secondary analysis of a randomized controlled trial of neonates who underwent cardiac surgery was performed. Glial fibrillary acidic protein (GFAP) was measured: (1) before skin incision; (2) immediately after bypass; (3) 4 and (4) 24 hours postoperatively. Linear regression models were used to determine an association with the highest levels of GFAP and Bayley Scales of Infant and Toddler Development third edition (BSID) composite scores. ResultsThere were 97 subjects who had cardiac surgery at a mean age of 9 ± 6 days and completed a BSID at 12.5 ± 0.6 months of age. Median (25th-75th percentile) levels of GFAP were 0.01 (0.01-0.02), 0.85 (0.40-1.55), 0.07 (0.05-0.11), and 0.03 (0.02-0.04) ng/mL at the 4 time points, respectively. In univariate analysis GFAP was negatively associated with cognitive, language, and motor composite scores. GFAP levels immediately after bypass differed between institutions; 1.57 (0.92-2.48) versus 0.77 (0.36-1.21) ng/mL (P = .01). After adjusting for center and potential confounders, GFAP was independently associated with BSID motor score (P = .04). ConclusionsHigher GFAP levels at the time of neonatal cardiac operations were independently associated with decreased BSID motor scores at 12 months. GFAP might serve as a diagnostic means to acutely identify perioperative brain-specific injury and serve as a benchmark of therapeutic efficacy for investigational treatments, discriminate center-specific effects, and provide early prognostic information for intervention.

Increased susceptibility to hypertensive renal disease in spontaneously hypertensive rats due to a mutation in Stim1

Emerging evidence implicates CD4+ T cells in the pathogenesis of hypertensive renal injury, though the underlying mechanisms that drive T cell dysfunction are not well understood. We identified a novel truncating mutation in the renal injury‐prone spontaneously hypertensive rat (SHR‐A3/SHRSP) line affecting the C‐terminus of STIM1, a protein involved in the store‐operated Ca2+ entry (SOCE) pathway. SOCE is required by T cells to activate the transcription factor NFAT and regulate T cell proliferation and cytokine production and regulatory T cell (Treg) development. In humans with loss‐of‐function mutations in Stim1, defective SOCE leads to a complex phenotype of immunodeficiency coupled with autoimmunity and uncontrolled lymphoproliferation. Our prior work identified defects in CD4+ T cell effector as well as regulatory function in SHR‐A3 rats as a result of impaired SOCE. We hypothesized that aberrant Stim1‐mediated SOCE leads to susceptibility to progressive renal injury in hypertension, potentially as a result of defective regulation of the immune response by T cells. Here, we test whether the emergence or renal injury in SHR‐A3 is affected by gene rescue of Stim1. A Stim1 congenic line (SHR‐A3(Stim1‐SHR‐B2)), in which the functional ‘wild type’ Stim1 allele was transferred from the SHR‐B2 line, which resists renal injury, into the injury‐susceptible SHR‐A3 genome. SOCE was restored to SHR‐B2 levels in the congenic SHR‐A3(Stim1‐SHR‐B2) line. This resulted in adequate NFAT activation (% cells with nuclear NFAT: 67±4.8 vs 8±3.8, p&lt;0.001) in SHR‐A3(Stim1‐SHR‐B2) rats compared to SHR‐A3 rats. TCR‐induced lymphokine production was markedly higher in CD4+ T cells from SHR‐A3(Stim1‐SHR‐B2) compared with SHR‐A3 rats (IL‐2: 2074±367.1 vs 168±83.4 pg/mL, p&lt;0.001; IFNγ: 2069±307.7 vs 235±69.5 pg/mL, p=0.002). Flow cytometric analysis of circulating T cell subsets revealed normalized CD4+CD25+FoxP3+ Treg frequencies in SHR‐A3(Stim1‐SHR‐B2) compared to SHR‐A3 (8.44±0.59 vs 4.34±0.59%, p=0.01). Restoration in SOCE in the congenic line was also associated with reduced renal T cell infiltration and decreased susceptibility to renal injury (uACR: 7.3±1.5 vs 13.4±2.9 p&lt;0.05) at 40 weeks of age. Urinary renal injury biomarker levels were also lower in the congenic line than in SHR‐A3 rats at 30 weeks of age (KIM1: 0.7±0.07 vs 2.9±0.29 ng/mL, p&lt;0.001; OPN: 6.9±1.4 vs 32.3±8.1 ng/mL, p&lt;0.01; NGAL: 201.9±42.7 vs 1701±264.4 pg/mL, p&lt;0.01). This correlated with lower renal injury scores assessed histologically. BP at 18 weeks, prior to the emergence of renal injury, was comparable between the SHR‐A3(Stim1‐SHR‐B2) and SHR‐A3 lines. Based on our findings, we conclude that defects in SOCE in SHR‐A3 attributable to the Stim1 mutation alter T cell function, reduce Treg numbers and may disturb regulatory interactions between T cells and other immune cells involved in hypertensive renal injury.Support or Funding InformationSupported by NIH‐NIDDK DK069632 and DK114235 to PAD and AHA 17POST33660779 to ISDThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Utility of Applying Quality Assessment Tools for Kidneys With KDPI ≥80.

Kidneys with "high" Kidney Donor Profile Index (KDPI) are often biopsied and pumped, yet frequently discarded. In this multicenter study, we describe the characteristics and outcomes of kidneys with KDPI of 80 or greater that were procured from 338 deceased donors. We excluded donors with anatomical kidney abnormalities. Donors were categorized by the number of kidneys discarded: (1) none (n = 154, 46%), (2) 1 discarded and 1 transplanted (n = 48, 14%), (3) both discarded (n = 136, 40%). Donors in group 3 were older, more often white, and had higher terminal creatinine and KDPI than group 1 (all P < 0.05). Biopsy was performed in 92% of all kidneys, and 47% were pumped. Discard was associated with biopsy findings and first hour renal resistance. Kidney injury biomarker levels (neutrophil gelatinase-associated lipocalin, IL-18, and kidney injury molecule-1 measured from donor urine at procurement and from perfusate soon after pump perfusion) were not different between groups. There was no significant difference in 1-year estimated glomerular filtration rate or graft failure between groups 1 and 2 (41.5 ± 18 vs 41.4 ± 22 mL/min per 1.73 m; P = 0.97 and 9% vs 10%; P = 0.76). Kidneys with KDPI of 80 or greater comprise the most resource consuming fraction of our donor kidney pool and have the highest rates of discard. Our data suggest that some discarded kidneys with KDPI of 80 or greater are viable; however, current tools and urine and perfusate biomarkers to identify these viable kidneys are not satisfactory. We need better methods to assess viability of kidneys with high KDPI.