Corrigendum: Patterns of cytokine release and association with new onset of post-cardiac surgery atrial fibrillation.

[This corrects the article DOI: 10.3389/fsurg.2023.1205396.].

Cost-effectiveness of intravenous resuscitation fluids in sepsis patients: a patient-level data analysis in Jordan.

AIM: Albumin role as fluid resuscitation in sepsis remains understudied in low- and middle-income countries. This study aimed to evaluate the cost-effectiveness of intravenous (IV) Albumin compared to Crystalloids in sepsis patients using patient-level data in Jordan. METHODS: This was a retrospective cohort study of sepsis patients aged 18 or older admitted to intensive care units (ICU) at two major tertiary hospitals during the period 2018-2019. Patients information, type of IV fluid, and clinical outcomes were retrieved from medical records, and charges were retrieved from the billing system. A 90-day partitioned survival model with two health states (alive and dead) was constructed to estimate the survival of sepsis patients receiving either Albumin or Crystalloids as IV fluids for resuscitation. Overall survival was predicted by fitting a Weibull model on the patient-level data from the current study. To further validate the results, and to support the assessment of uncertainty, time-dependent transition probabilities of death at each cycle were estimated and used to construct a state-transition patient-level simulation model with 10,000 microsimulation trials. Adopting the healthcare system perspective, incremental cost-effectiveness ratios(ICERs) of Albumin versus Crystalloids were calculated in terms of the probability to be discharged alive from the ICU. Uncertainty was explored using probabilistic sensitivity analysis. RESULTS: In the partitioned survival model, Albumin was associated with an incremental cost of $1,007 per incremental1% in the probability of being discharged alive from the ICU. In the state-transition patient-level simulation model, ICER was $1,268 per incremental 1% in the probability of being discharged alive. Probabilistic sensitivity analysis showed that Albumin was favored at thresholds >$800 per incremental 1%in the probability of being discharged alive from the ICU. CONCLUSION: IV Albumin use in sepsis patients might not be cost-effective from the healthcare perspective of Jordan. This has important implications for policymakers to readdress Albumin prescribing practice in sepsis patients.

Sepsis is a life-threatening complication of infection, which usually requires resuscitation with intravenous fluids. Still, no conclusive evidence is available about the best fluid resuscitation to be used in sepsis patients especially in low- and middle-income countries. This study compared the costs and effectiveness of intravenous Albumin versus Crystalloids in sepsis patients. Findings from this study showed that resuscitation with Albumin is much more expensive compared to resuscitation with Crystalloids with no significant difference in mortality but with prolonged length of stay in the hospital and the intensive care unit. Decision makers are advised to change Albumin prescribing practices in a way that mitigates the associated clinical and financial burdens without compromising quality of care or resuscitate with Crystalloids.

New and legacy pesticidal persistent organic pollutants in the agricultural region of the Sultanate of Oman.

Comprehensive air and surface soil monitoring was conducted for new and legacy organochlorine pesticides (OCPs) to fill the knowledge and data gap on the sources and fate of pesticidal persistent organic pollutants (POPs) in the Sultanate of Oman. DDTs in agricultural soil samples ranged from 0.013 to 95.80 ng/g (mean: 8.4 ± 25.06 ng/g), with a median value of 0.07 ng/g. The highest concentration was observed at Shinas, where intensive agricultural practice is prevalent. The dominance of p,p'-DDT in soil and air reflected technical DDT formulation usage in Oman. Among newly enlisted POPs, pentachlorobenzene had the maximum detection frequency in air (47%) and soil (41%). Over 90% of sites reflected extensive past use of hexachlorobenzene. Major OCP isomers and metabolites showed net volatilisation from the agricultural soil, thereby indicating concurrent emission and re-emission processes from the soil of Oman. However, the cleansing effect of oceanic air mass is the possible reason for relatively lower atmospheric OCP levels from a previous study. Although DDT displayed maximum cancer risk, the level is below the permissible limit. DDT primarily stemmed from obsolete stock and inadequate management practices. Hence, we suggest there is a need for DDT regulation in Oman.

The effect of cardioplegic supplementation with sildenafil on cardiac energetics in a piglet model of cardiopulmonary bypass and cardioplegic arrest with warm or cold cardioplegia.

Cardioplegic cardioprotection strategies used during paediatric open-heart surgery remain suboptimal. Sildenafil, a phosphodiesterase 5 (PDE-5) inhibitor, has been shown to be cardioprotective against ischemia/reperfusion injury in a variety of experimental models and this study therefore tested the efficacy of supplementation of cardioplegia with sildenafil in a piglet model of cardiopulmonary bypass and arrest, using both cold and warm cardioplegia protocols. Piglets were anaesthetized and placed on coronary pulmonary bypass (CPB), the aorta cross-clamped and the hearts arrested for 60 min with cardioplegia with or without sildenafil (10 nM). Twenty minutes after removal of cross clamp (reperfusion), attempts were made to wean the pigs from CPB. Termination was carried out after 60 min reperfusion. Throughout the protocol blood and left ventricular tissue samples were taken for analysis of selected metabolites (using HPLC) and troponin I. In both the cold and warm cardioplegia protocols there was evidence that sildenafil supplementation resulted in faster recovery of ATP levels, improved energy charge (a measure of metabolic flux) and altered release of hypoxanthine and inosine, two purine catabolites. There was no effect on troponin release within the studied short timeframe. In conclusion, sildenafil supplementation of cardioplegia resulted in improved cardiac energetics in a translational animal model of paediatric CPB surgery.

Skin Manifestations Among Patients Admitted with COVID-19: A Cross-Sectional Study at a University-Based Tertiary Hospital in Jordan.

Background: COVID-19 pandemic hit the entire world with severe health and economic consequences. Although the infection primarily affected the respiratory system, it was soon recognized that COVID-19 has a multi-systemic component with various manifestations including cutaneous involvement. Objective: The main objective of this study is to assess the incidence and patterns of cutaneous manifestations among moderate-to-severe COVID-19 patients who required hospitalization and whether there was a prognostic indication for cutaneous involvement and the outcome in terms of recovery or death. Methods: This is a cross-sectional observational study that included inpatients who were diagnosed with a moderate or severe COVID-19 infection. The demographic and clinical data of patients were assessed including age, sex, smoking, and comorbidities. All patients were examined clinically for the presence of skin manifestations. Patients were followed for the outcome of COVID-19 infection. Results: A total of 821 patients (356 females and 465 males) aged 4-95 years were included. More than half of patients (54.6%) aged >60 years. A total of 678 patients (82.6%) had at least one comorbid condition, mostly hypertension and diabetes mellitus. Sixty-two patients (7.55%) developed rashes; 5.24% cutaneous and 2.31% oral. The rashes were then grouped into five major types: group A, Exanthema: morbilliform, papulovesicular, varicella-like. Group B, Vascular: Chilblain-like lesions, purpuric/petechial, livedoid lesions. Group C, Reactive erythemas: Urticaria, Erythema multiforme. Group D, other skin rashes including flare-up of pre-existing disease, and O for oral involvement. Most patients (70%) developed rash after admission. The most frequent skin rashes were reactive erythema (23.3%), followed by vascular (20.9%), exanthema (16.3%), and other rashes with flare-ups of pre-existing diseases (39.5%). Smoking and loss of taste were associated with the appearance of various skin rashes. However, no prognostic implications were found between cutaneous manifestations and outcome. Conclusion: COVID-19 infection may present with various skin manifestations including worsening of pre-existing skin diseases.

Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: A protocol for a randomised controlled study (ProMPT2).

INTRODUCTION: Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6 mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection. METHODS AND ANALYSIS: The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12 mcg/ml), low dose of propofol (6 mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48 hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate). ETHICS AND DISSEMINATION: The trial received research ethics approval from South Central - Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters. TRIAL REGISTRATION: ISRCTN15255199. Registered in March 2019.

Correlation between Molar-Incisor Hypomineralization, Stress, and Family Functioning.

Aim: This study aims to assess the relationship between stress, family functioning, and molar-incisor hypomineralization (MIH). Materials and Methods: A total of 162 children between the ages of 7 and 9 years were included in this retrospective study, as were their respective parents; the children were examined for MIH while questionnaires centering on stress and family functioning were given to the parents. Statistical analysis was performed using the Mann-Whitney U test and independent samples T-test. Results: A significant correlation between stress as a contributing factor and MIH was concluded; children with higher stress scores had higher occurrences of MIH. On the contrary, family functioning quality was not found to have a direct correlation with MIH. Conclusions: Stress is correlated to MIH and is potentially one of the main causal factors that contribute to the development of the defect.

Pathology-related changes in cardiac energy metabolites, inflammatory response and reperfusion injury following cardioplegic arrest in patients undergoing open-heart surgery.

Introduction: Changes in cardiac metabolites in adult patients undergoing open-heart surgery using ischemic cardioplegic arrest have largely been reported for non-ventricular tissue or diseased left ventricular tissue, with few studies attempting to assess such changes in both ventricular chambers. It is also unknown whether such changes are altered in different pathologies or linked to the degree of reperfusion injury and inflammatory response. The aim of the present work was to address these issues by monitoring myocardial metabolites in both ventricles and to establish whether these changes are linked to reperfusion injury and inflammatory/stress response in patients undergoing surgery using cold blood cardioplegia for either coronary artery bypass graft (CABG, n = 25) or aortic valve replacement (AVR, n = 16). Methods: Ventricular biopsies from both left (LV) and right (RV) ventricles were collected before ischemic cardioplegic arrest and 20 min after reperfusion. The biopsies were processed for measuring selected metabolites (adenine nucleotides, purines, and amino acids) using HPLC. Blood markers of cardiac injury (Troponin I, cTnI), inflammation (IL- 6, IL-8, Il-10, and TNFα, measured using Multiplex) and oxidative stress (Myeloperoxidase, MPO) were measured pre- and up to 72 hours post-operatively. Results: The CABG group had a significantly shorter ischemic cardioplegic arrest time (38.6 ± 2.3 min) compared to AVR group (63.0 ± 4.9 min, p = 2 x 10-6). Cardiac injury (cTnI release) was similar for both CABG and AVR groups. The inflammatory markers IL-6 and Il-8 were significantly higher in CABG patients compared to AVR patients. Metabolic markers of cardiac ischemic stress were relatively and significantly more altered in the LV of CABG patients. Comparing diabetic and non-diabetic CABG patients shows that only the RV of diabetic patients sustained major ischemic stress during reperfusion and that diabetic patients had a significantly higher inflammatory response. Discussion: CABG patients sustain relatively more ischemic stress, systemic inflammatory response and similar injury and oxidative stress compared to AVR patients despite having significantly shorter cross-clamp time. The higher inflammatory response in CABG patients appears to be at least partly driven by a higher incidence of diabetes amongst CABG patients. In addition to pathology, the use of cold blood cardioplegic arrest may underlie these differences.

Reducing Detrimental Communication Failure Impacts in Microgrids by Using Deep Learning Techniques.

A Microgrid (MG), like any other smart and interoperable power system, requires device-to-device (D2D) communication structures in order to function effectively. This communication system, however, is not immune to intentional or unintentional failures. This paper discusses the effects of communication link failures on MG control and management and proposes solutions based on enhancing message content to mitigate their detritus impact. In order to achieve this goal, generation and consumption forecasting using deep learning (DL) methods at the next time steps is used. The architecture of an energy management system (EMS) and an energy storage system (ESS) that are able to operate in coordination is introduced and evaluated by simulation tests, which show promising results and illustrate the efficacy of the proposed methods. It is important to mention that, in this paper, three dissimilar topics namely MG control/management, DL-based forecasting, and D2D communication architectures are employed and this combination is proven to be capable of achieving the aforesaid objective.

A review on synthesis, modification method, and challenges of light-driven H2 evolution using g-C3N4-based photocatalyst.

The energy scarcity is exacerbating and needs an urgent solution. The most plausible solution to address the forthcoming energy scarcity is to diversify the energy sources. Developing the water-splitting process (WSP) efficiency depends on solar energy representing "21st-century dream technology". We present a comprehensive review of related papers employing graphitic carbon nitride (g-C3N4) as pure, doped, or composite nanostructure in the evolution of hydrogen from water dissociation under simulated sunlight irradiation, mainly in the last ten years. Herein, after a concise introduction to the main principle of the water-splitting process, the methods to synthesize, modify and upgrade the photocatalytic performance of g-C3N4 were reviewed in detail. Moreover, the main challenges of using g-C3N4-based photocatalytic material in WSP have been mentioned. The report mainly targets the g-C3N4 character, synthesis method, photocatalytic activity, and strategies toward enhancing photoreactivity under visible light, along with the reusability of the fabricated nanohybrid catalysts. Above and over, this review suggests the potential of g-C3N4 to produce green H2 from water at a competitive price, which can contribute to satisfying the global energy sector demand and suppressing global warming.

Response of upstream migrating juvenile European eel (Anguilla anguilla) to electric fields: Application of the marginal gains concept to fish screening.

The decline in European eel (Anguilla anguilla) recruitment over the past half-century is partly due to river infrastructure that delays or blocks upstream migration to rearing habitat. Stimuli, such as electricity, can be used to modify the behaviour of downstream moving fish and guide them to preferred routes of passage at river infrastructure; but research on upstream migrating juvenile eel remains limited. The response of upstream migrating juvenile eel exposed to pulsed direct current (PDC) electric fields was investigated using a recirculatory flume. Eel were presented a choice of two routes upstream under either: (1) a treatment condition, in which the selection of one route resulted in exposure to High Electric Field (HEF) strength that was between 1.5-2 times stronger than the Low Electric Field (LEF) strength encountered in the alternative route; or (2) a control in which the electric field was absent in both routes. Under the treatment, five different mean HEF strengths (0.53, 0.77, 1.22, 2.17 and 3.74 Vcm-1) were tested at one of two frequencies (2 and 10 Hz). Route choice, distance downstream of the first set of electrodes at which an initial response was observed and avoidance behaviours (acceleration, retraction, switching and rejection) were compared among treatments. For the 1.22, 2.17 and 3.74 Vcm-1 and under 2 Hz, eel preferred to pass the LEF route. Avoidance was greater in the HEF route and positively related to field strength. The distance of the initial response did not differ between routes, field strengths or frequency. Upstream migrating eel avoided electric fields indicating potential to develop this approach for fish guidance. Further work is needed to test prototypes in field settings, particularly in combination with traditional physical screens to water intakes as part of a process of applying the concept of marginal gains to advance environmental impact mitigation technology.

Next-Generation and Single-Cell Sequencing Approaches to Study Atherosclerosis and Vascular Inflammation Pathophysiology: A Systematic Review.

Background and Aims: Atherosclerosis is a chronic inflammatory disease that remains the leading cause of morbidity and mortality worldwide. Despite decades of research into the development and progression of this disease, current management and treatment approaches remain unsatisfactory and further studies are required to understand the exact pathophysiology. This review aims to provide a comprehensive assessment of currently published data utilizing single-cell and next-generation sequencing techniques to identify key cellular and molecular contributions to atherosclerosis and vascular inflammation. Methods: Electronic searches of Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases were undertaken from inception until February 2022. A narrative synthesis of all included studies was performed for all included studies. Quality assessment and risk of bias analysis was evaluated using the ARRIVE and SYRCLE checklist tools. Results: Thirty-four studies were eligible for narrative synthesis, with 16 articles utilizing single-cell exclusively, 10 utilizing next-generation sequencing and 8 using a combination of these approaches. Studies investigated numerous targets, ranging from exploratory tissue and plaque analysis, cell phenotype investigation and physiological/hemodynamic contributions to disease progression at both the single-cell and whole genome level. A significant area of focus was placed on smooth muscle cell, macrophage, and stem/progenitor contributions to disease, with little focus placed on contributions of other cell types including lymphocytes and endothelial cells. A significant level of heterogeneity exists in the outcomes from single-cell sequencing of similar samples, leading to inter-sample and inter-study variation. Conclusions: Single-cell and next-generation sequencing methodologies offer novel means of elucidating atherosclerosis with significantly higher resolution than previous methodologies. These approaches also show significant potential for translatability into other vascular disease states, by facilitating cell-specific gene expression profiles between disease states. Implementation of these technologies may offer novel approaches to understanding the disease pathophysiology and improving disease prevention, management, and treatment.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021229960, identifier: CRD42021229960.

Effect of cardioplegic arrest and reperfusion on left and right ventricular proteome/phosphoproteome in patients undergoing surgery for coronary or aortic valve disease.

Our earlier work has shown inter­disease and intra­disease differences in the cardiac proteome between right (RV) and left (LV) ventricles of patients with aortic valve stenosis (AVS) or coronary artery disease (CAD). Whether disease remodeling also affects acute changes occuring in the proteome during surgical intervention is unknown. This study investigated the effects of cardioplegic arrest on cardiac proteins/phosphoproteins in LV and RV of CAD (n=6) and AVS (n=6) patients undergoing cardiac surgery. LV and RV biopsies were collected during surgery before ischemic cold blood cardioplegic arrest (pre) and 20 min after reperfusion (post). Tissues were snap frozen, proteins extracted, and the extracts were used for proteomic and phosphoproteomic analysis using Tandem Mass Tag (TMT) analysis. The results were analysed using QuickGO and Ingenuity Pathway Analysis softwares. For each comparision, our proteomic analysis identified more than 3,000 proteins which could be detected in both the pre and Post samples. Cardioplegic arrest and reperfusion were associated with significant differential expression of 24 (LV) and 120 (RV) proteins in the CAD patients, which were linked to mitochondrial function, inflammation and cardiac contraction. By contrast, AVS patients showed differential expression of only 3 LV proteins and 2 RV proteins, despite a significantly longer duration of ischaemic cardioplegic arrest. The relative expression of 41 phosphoproteins was significantly altered in CAD patients, with 18 phosphoproteins showing altered expression in AVS patients. Inflammatory pathways were implicated in the changes in phosphoprotein expression in both groups. Inter­disease comparison for the same ventricular chamber at both timepoints revealed differences relating to inflammation and adrenergic and calcium signalling. In conclusion, the present study found that ischemic arrest and reperfusion trigger different changes in the proteomes and phosphoproteomes of LV and RV of CAD and AVS patients undergoing surgery, with markedly more changes in CAD patients despite a significantly shorter ischaemic period.

Determination of Agrin and Related Proteins Levels as a Function of Age in Human Hearts.

Background: Mature cardiomyocytes are unable to proliferate, preventing the injured adult heart from repairing itself. Studies in rodents have suggested that the extracellular matrix protein agrin promotes cardiomyocyte proliferation in the developing heart and that agrin expression is downregulated shortly after birth, resulting in the cessation of proliferation. Agrin based therapies have proven successful at inducing repair in animal models of cardiac injury, however whether similar pathways exist in the human heart is unknown. Methods: Right ventricular (RV) biopsies were collected from 40 patients undergoing surgery for congenital heart disease and the expression of agrin and associated proteins was investigated. Results: Agrin transcripts were found in all samples and their levels were significantly negatively correlated to age (p = 0.026), as were laminin transcripts (p = 0.023), whereas no such correlation was found for the other proteins analyzed. No significant correlations for any of the proteins were found when grouping patients by their gender or pathology. Immunohistochemistry and western blots to detect and localize agrin and the other proteins under analysis in RV tissue, confirmed their presence in patients of all ages. Conclusions: We show that agrin is progressively downregulated with age in human RV tissue but not as dramatically as has been demonstrated in mice; highlighting both similarities and differences to findings in rodents. Our results lay the groundwork for future studies exploring the potential of agrin-based therapies in the repair of damaged human hearts.

Endothelial glycocalyx is damaged in diabetic cardiomyopathy: angiopoietin 1 restores glycocalyx and improves diastolic function in mice.

AIMS/HYPOTHESIS: Diabetic cardiomyopathy (DCM) is a serious and under-recognised complication of diabetes. The first sign is diastolic dysfunction, which progresses to heart failure. The pathophysiology of DCM is incompletely understood but microcirculatory changes are important. Endothelial glycocalyx (eGlx) plays multiple vital roles in the microcirculation, including in the regulation of vascular permeability, and is compromised in diabetes but has not previously been studied in the coronary microcirculation in diabetes. We hypothesised that eGlx damage in the coronary microcirculation contributes to increased microvascular permeability and hence to cardiac dysfunction. METHODS: We investigated eGlx damage and cardiomyopathy in mouse models of type 1 (streptozotocin-induced) and type 2 (db/db) diabetes. Cardiac dysfunction was determined by echocardiography. We obtained eGlx depth and coverage by transmission electron microscopy (TEM) on mouse hearts perfusion-fixed with glutaraldehyde and Alcian Blue. Perivascular oedema was assessed from TEM images by measuring the perivascular space area. Lectin-based fluorescence was developed to study eGlx in paraformaldehyde-fixed mouse and human tissues. The eGlx of human conditionally immortalised coronary microvascular endothelial cells (CMVECs) in culture was removed with eGlx-degrading enzymes before measurement of protein passage across the cell monolayer. The mechanism of eGlx damage in the diabetic heart was investigated by quantitative reverse transcription-PCR array and matrix metalloproteinase (MMP) activity assay. To directly demonstrate that eGlx damage disturbs cardiac function, isolated rat hearts were treated with enzymes in a Langendorff preparation. Angiopoietin 1 (Ang1) is known to restore eGlx and so was used to investigate whether eGlx restoration reverses diastolic dysfunction in mice with type 1 diabetes. RESULTS: In a mouse model of type 1 diabetes, diastolic dysfunction (confirmed by echocardiography) was associated with loss of eGlx from CMVECs and the development of perivascular oedema, suggesting increased microvascular permeability. We confirmed in vitro that eGlx removal increases CMVEC monolayer permeability. We identified increased MMP activity as a potential mechanism of eGlx damage and we observed loss of syndecan 4 consistent with MMP activity. In a mouse model of type 2 diabetes we found a similar loss of eGlx preceding the development of diastolic dysfunction. We used isolated rat hearts to demonstrate that eGlx damage (induced by enzymes) is sufficient to disturb cardiac function. Ang1 restored eGlx and this was associated with reduced perivascular oedema and amelioration of the diastolic dysfunction seen in mice with type 1 diabetes. CONCLUSIONS/INTERPRETATION: The association of CMVEC glycocalyx damage with diastolic dysfunction in two diabetes models suggests that it may play a pathophysiological role and the enzyme studies confirm that eGlx damage is sufficient to impair cardiac function. Ang1 rapidly restores the CMVEC glycocalyx and improves diastolic function. Our work identifies CMVEC glycocalyx damage as a potential contributor to the development of DCM and therefore as a therapeutic target.

Cardioprotection of Immature Heart by Simultaneous Activation of PKA and Epac: A Role for the Mitochondrial Permeability Transition Pore.

Metabolic and ionic changes during ischaemia predispose the heart to the damaging effects of reperfusion. Such changes and the resulting injury differ between immature and adult hearts. Therefore, cardioprotective strategies for adults must be tested in immature hearts. We have recently shown that the simultaneous activation of protein kinase A (PKA) and exchange protein activated by cAMP (Epac) confers marked cardioprotection in adult hearts. The aim of this study is to investigate the efficacy of this intervention in immature hearts and determine whether the mitochondrial permeability transition pore (MPTP) is involved. Isolated perfused Langendorff hearts from both adult and immature rats were exposed to global ischaemia and reperfusion injury (I/R) following control perfusion or perfusion after an equilibration period with activators of PKA and/or Epac. Functional outcome and reperfusion injury were measured and in parallel, mitochondria were isolated following 5 min of reperfusion to determine whether cardioprotective interventions involved changes in MPTP opening behaviour. Perfusion for 5 min preceding ischaemia of injury-matched adult and immature hearts with 5 µM 8-Br (8-Br-cAMP-AM), an activator of both PKA and Epac, led to significant reduction in post-reperfusion CK release and infarct size. Perfusion with this agent also led to a reduction in MPTP opening propensity in both adult and immature hearts. These data show that immature hearts are innately more resistant to I/R injury than adults, and that this is due to a reduced tendency of MPTP opening following reperfusion. Furthermore, simultaneous stimulation of PKA and Epac causes cardioprotection, which is additive to the innate resistance.

Interplay of Oxidative Stress and Necrosis-like Cell Death in Cardiac Ischemia/Reperfusion Injury: A Focus on Necroptosis.

Extensive research work has been carried out to define the exact significance and contribution of regulated necrosis-like cell death program, such as necroptosis to cardiac ischemic injury. This cell damaging process plays a critical role in the pathomechanisms of myocardial infarction (MI) and post-infarction heart failure (HF). Accordingly, it has been documented that the modulation of key molecules of the canonical signaling pathway of necroptosis, involving receptor-interacting protein kinases (RIP1 and RIP3) as well as mixed lineage kinase domain-like pseudokinase (MLKL), elicit cardioprotective effects. This is evidenced by the reduction of the MI-induced infarct size, alleviation of myocardial dysfunction, and adverse cardiac remodeling. In addition to this molecular signaling of necroptosis, the non-canonical pathway, involving Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated regulation of mitochondrial permeability transition pore (mPTP) opening, and phosphoglycerate mutase 5 (PGAM5)-dynamin-related protein 1 (Drp-1)-induced mitochondrial fission, has recently been linked to ischemic heart injury. Since MI and HF are characterized by an imbalance between reactive oxygen species production and degradation as well as the occurrence of necroptosis in the heart, it is likely that oxidative stress (OS) may be involved in the mechanisms of this cell death program for inducing cardiac damage. In this review, therefore, several observations from different studies are presented to support this paradigm linking cardiac OS, the canonical and non-canonical pathways of necroptosis, and ischemia-induced injury. It is concluded that a multiple therapeutic approach targeting some specific changes in OS and necroptosis may be beneficial in improving the treatment of ischemic heart disease.

Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells.

Vascular endothelial cell stimulation is associated with the activation of different signalling pathways and transcription factors. Acute shear stress is known to induce different pro-inflammatory mediators such as IL-8. Nrf2 is activated by prolonged high shear stress promoting an antiinflammatory and athero-protective environment. However, little is known about the impact of acute shear stress on Nrf2 and Keap1 function and its role in IL-8 regulation. We aimed to examine Nrf2-Keap1 complex activation in-vitro and its role in regulating IL-8 transcripts under acute arterial shear stress (12 dyn/cm2) in venous endothelial cells (ECs). We note that acute high shear stress caused a significant upregulation of Nrf2 target genes, HO-1 and GCLM and an increased IL-8 upregulation at 90 and 120 minutes. Mechanistically, acute high shear did not affect Nrf2 nuclear translocation but resulted in reduced nuclear Keap1, suggesting that the reduction in nuclear Keap1 may result in increased free nuclear nrf2 to induce transcription. Consistently, the suppression of Keap1 using shRNA (shKeap1) resulted in significant upregulation of IL-8 transcripts in response to acute shear stress. Interestingly; the over expression of Nrf2 using Nrf2-Ad-WT or Sulforaphane was also associated with significant upregulation of IL-8 compared to controls. This study highlights the role of Keap1 in Nrf2 activation under shear stress and indicates that activation of Nrf2 may be deleterious in ECs in the context of acute haemodynamic injury.

Simultaneous removal of Cu (II) and Cr (VI) ions from petroleum refinery wastewater using ZnO/Fe3O4 nanocomposite.

The presence and removal of heavy metals such as Cu(II) as well as Cr(VI) in petroleum refinery wastewater calls for concerted efforts due to their mobility, toxicity, bioaccumulation, and non-biodegradability in the environment. In this present work, zinc oxide (ZnO), iron oxide (Fe3O4) nanoparticles and ZnO/Fe3O4 nanocomposites were synthesized via simple sol-gel and chemical reduction methods; characterized using different analytical tools and then applied as nanoadsorbent to sequester Cu(II) and Cr(VI) ions from Petroleum Refinery wastewater via batch adsorption process. Cu(II) and Cr(VI) adsorption processes were examined with respect to contact time (kinetic effect), nanoadsorbent dosage, isotherm equilibrium, and thermodynamic parameters. ZnO/Fe3O4 nanocomposites with higher surface area (39.450 m2/g) have a mixture of rod-like and spherical shapes as compared to ZnO and Fe3O4 nanoparticles with spherical shape only and surface areas of 8.62 m2/g and 7.86 m2/g) according to the high-resolution scanning electron microscopy (HRSEM) and Brunauer-Emmett-Teller (BET) analysis. The X-ray diffractometer (XRD) results revealed the formation of hexagonal wurtzite structure of ZnO and the face-centered cubic structure phase of Fe3O4 nanoparticles, after the formation of the ZnO/Fe3O4 nanocomposites the phases of the nanoparticles were not affected but the diffraction peaks shifted to higher 2θ degree. The average crystallite size of ZnO and Fe3O4 nanoparticles and ZnO/Fe3O4 nanocomposites were 20.12, 26.36 and 14.50 nm respectively. The maximum removal efficiency of Cu (II) (92.99%) and Cr (VI) (77.60%) by ZnO/Fe3O4 nanocomposites was higher than 85.83%; 65.19% for Cu (II) and 80.57%; 62.53 for Cr (VI) using ZnO and Fe3O4 nanoadsorbents individually under the following conditions: contact time (15), dosage (0.08 g) and temperature (30 °C). The experimental data for Cu (II) and Cr (VI) ion removal fitted well to the pseudo-second-order kinetic and Langmuir isotherm models. The thermodynamic study suggested that the removal of the two metal ions from petroleum wastewater was endothermic. The reusability study after the fourth adsorption-desorption cycle indicated the stability of ZnO/Fe3O4 nanocomposites with 85.51% and 69.42% removal efficiency of Cu (II) and Cr (VI). The results showed that ZnO/Fe3O4 nanocomposite achieves higher performance than ZnO and Fe3O4 alone in the removal of Cu (II) and Cr (VI) ions from the petroleum refinery wastewater.

Anticoccidial efficacy of Garcinia kola (Heckel H.) against experimental Eimeria tenella infection in chicks.

There is a need to advance commercial poultry production to cater to the essential protein needs of an ever-increasing population, however, the rampant occurrence of coccidiosis infection poses a threat to this achievement. This study evaluated the in vivo anticoccidial activities of the extracts and fractions of Garcinia kola against experimental Eimeria tenella infection using broiler chickens as experimental subjects. A total of 40 broiler chicks were experimentally infected with E. tenella and assigned randomly into five groups consisting of eight chicks each. Three days post experimental infection groups I and II were administered orally with tween 80 (0.8%) and Amprolium (30 mg/kg) and served as untreated and treated control groups, respectively whereas Groups III, IV, and V were administered orally with crude methanol extract (CME) at doses of 200, 400 and 600 mg/kg, respectively, for five consecutive days. Daily weight gains were recorded and faecal oocysts per gram (OPG) counts were made by the McMaster Egg counting technique. Blood samples from each experimental group were collected on days 0, 3, 6, and 8 for haematological examination. In the acute toxicity studies, the CME of G. kola did not produce any toxic effect or mortality at doses between 10 and 5000 mg/kg. The CME G. kola was then considered safe and the LD50 was assumed to be > 5000 mg/kg. Graded doses of CME of G. kola considerably (P < 0.05) improved body weight gain and decreased OPG in a dose-depended manner. There was also significant improvement in the Packed Cell Volume (PCV), Red Blood Cell (RBC) and White Blood Cell (WBC) counts upon treatment with the graded doses of CME of G. kola. Besides, G. kola significantly decreased histopathological lesions in the caecum. The results of this study indicates that G. kola may provide beneficial effects against E. tenella-induced coccidiosis in broiler chickens.