Release Of Biomarkers Research Articles

A study to compare fibrinolytic therapy versus primary percutaneous coronary intervention in ST-segment elevation myocardial infarction in a tertiary care hospital

Background: ST-segment elevation myocardial infarction (STEMI) is the most dramatic manifestation of coronary artery disease, acute STEMI is a clinical syndrome defined by characteristic symptoms of myocardial ischemia in association with persistent electrocardiographic ST elevation and subsequent release of biomarkers of myocardial necrosis. Reperfusion with thrombolysis or PCI (percutaneous coronary intervention) is the current standard of care for STEMI. Aims and Objectives: The aim of the study was to compare the effectiveness of fibrinolytic therapy and primary PCI which are the available reperfusion strategies for STEMI. Materials and Methods: This prospective and observational study was conducted at a tertiary care hospital in Bangalore. Patients presenting with STEMI to emergency department were treated with either fibrinolysis or PCI as per protocol. Patients in each arm were followed up to know the differences in outcome at discharge and 30-day follow-up. Results: Patients admitted with STEMI had overall in hospital mortality of 17 (7.1%) patients, of which 9 (7.6%) patients were from fibrinolysis group and 8 (6.6%) patients from PCI group with no statistically significant difference (P = 0.760). There was significant incidence (P = 0.001) of reinfarct in fibrinolysis group (9.3%) when compared to PCI group (0%). Conclusion: There was no statistically significant mortality difference at discharge and at 30 day between fibrinolysis and primary PCI in patients with STEMI in our study, this may be attributed to use of rescue PCI in failed fibrinolysis patients and early tricuspid valve repair in many patients after fibrinolysis.

Del Nido versus Bretschneider cardioplegic solution in valve replacement for severe aortic stenosis - a case-control pilot study.

IntroductionThe adequate protection provided by the del Nido cardioplegia has already been proven in trials comparing the solution with blood cardioplegia. However, evidence regarding comparison to the Bretschneider HTK solution is limited.AimTo determine the efficacy of the del Nido cardioplegia when compared to Bretschneider HTK solution in patients undergoing aortic valve replacement for severe aortic stenosis.Material and methodsTen patients undergoing isolated aortic valve replacement for severe aortic stenosis using the del Nido solution (group 1) were case-control matched to patients undergoing aortic valve replacement (AVR) using the Bretschneider solution (group 2). The observation included: cardioplegia dosage, time to cardiac arrest, cross-clamp and extracorporeal circulation time, ventricular fibrillation (VF) after removing the cross-clamp, gasometry parameters, creatinine kinase (MB isoenzyme – CK-MB) at 24 and 48 h following the surgery and troponin (highsensitivity troponin T – hsTnT) at 24 and 48 h.ResultsPatients were no different in terms of comorbidities. Higher incidence of VF occurred in group 2 (3 vs. 9, 30% vs. 90%; p = 0.02). Blood sodium measurements after removing the cross-clamp were significantly higher in group 1 (median 137.0 vs. 130.0; p = 0.0004). Biomarker release trended toward lower values in group 1, but not significantly (median troponin at 24 h: 223.1 pg/ml vs. 294.8 pg/ml; p = 0.4 and 48 h: 208.0 pg/ml vs. 242.5 pg/ml; p = 0.7, median CK-MB at 24 h: 16.6 ng/ml vs. 17.3 ng/ml; p = 0.6, and 48 h: 6.7 ng/ml vs. 5.08 ng/ml; p = 0.3). Peak creatinine trended towards lower values in group 2, but not significantly (1.35 mg/dl vs. 1.05 mg/dl; p = 0.09).ConclusionsBoth del Nido and Bretschneider cardioplegia provide satisfactory myocardial protection. However, del Nido cardioplegia reduces the incidence of VF after declamping the aorta. Further studies are required.

A more gradual positive end-expiratory pressure increase reduces lung damage and improves cardiac function in experimental acute respiratory distress syndrome.

Increases in positive end-expiratory pressure (PEEP) or recruitment maneuvers may increase stress in lung parenchyma, extracellular matrix, and lung vessels; however, adaptative responses may occur. We evaluated the effects of PEEP on lung damage and cardiac function when increased abruptly, gradually, or more gradually in experimental mild/moderate acute respiratory distress syndrome (ARDS) induced by Escherichia coli lipopolysaccharide intratracheally. After 24 h, Wistar rats (n = 48) were randomly assigned to four mechanical ventilation strategies according to PEEP levels: 1) 3 cmH2O for 2 h (control); 2) 3 cmH2O for 1 h followed by an abrupt increase to 9 cmH2O for 1 h (no adaptation time); 3) 3 cmH2O for 30 min followed by a gradual increase to 9 cmH2O over 30 min then kept constant for 1 h (shorter adaptation time); and 4) more gradual increase in PEEP from 3 cmH2O to 9 cmH2O over 1 h and kept constant thereafter (longer adaptation time). At the end of the experiment, oxygenation improved in the shorter and longer adaptation time groups compared with the no-adaptation and control groups. Diffuse alveolar damage and expressions of interleukin-6, club cell protein-16, vascular cell adhesion molecule-1, amphiregulin, decorin, and syndecan were higher in no adaptation time compared with other groups. Pulmonary arterial pressure was lower in longer adaptation time than in no adaptation (P = 0.002) and shorter adaptation time (P = 0.025) groups. In this model, gradually increasing PEEP limited lung damage and release of biomarkers associated with lung epithelial/endothelial cell and extracellular matrix damage, as well as the PEEP-associated increase in pulmonary arterial pressure.NEW & NOTEWORTHY In a rat model of Escherichia coli lipopolysaccharide-induced mild/moderate acute respiratory distress syndrome, a gradual PEEP increase (shorter adaptation time) effectively mitigated histological lung injury and biomarker release associated with lung inflammation, damage to epithelial cells, endothelial cells, and the extracellular matrix compared with an abrupt increase in PEEP. A more gradual PEEP increase (longer adaptation time) decreased lung damage, pulmonary vessel compression, and pulmonary arterial pressure.

Self-Assembled Oligo-Urethane Nanoparticles: Their Characterization and Use for the Delivery of Active Biomolecules into Mammalian Cells.

Developing safe and effective strategies to deliver biomolecules such as oligonucleotides and proteins into cells has grown in importance over recent years, with an increasing demand for non-viral methods that enable clinical translation. Here, we investigate uniquely configured oligo-urethane nanoparticles based on synthetic chemistries that minimize the release of pro-inflammatory biomarkers from immune cells, show low cytotoxicity in a broad range of cells, and efficiently deliver oligonucleotides and proteins into mammalian cells. The mechanism of cell uptake for the self-assembled oligo-urethane nanoparticles was shown to be directed by caveolae-dependent endocytosis in murine myoblasts (C2C12) cells. Inhibiting caveolae functions with genistein and methyl-β-cyclodextrin limited nanoparticle internalization. The nanoparticles showed a very high delivery efficiency for the genetic material (a 47-base oligonucleotide) (∼80% incorporation into cells) as well as the purified protein (full length firefly luciferase, 67 kDa) into human embryonic kidney (HEK293T) cells. Luciferase enzyme activity in HEK293T cells demonstrated that intact and functional proteins could be delivered and showed a significant extension of activity retention up to 24 h, well beyond the 2 h half-life of the free enzyme. This study introduces a novel self-assembled oligo-urethane nanoparticle delivery platform with very low associated production costs, enabled by their scalable chemistry (the benchwork cost is $ 0.152/mg vs $ 974.6/mg for typical lipid carriers) that has potential to deliver both oligonucleotides and proteins for biomedical purposes.

Relationship between ablation index and myocardial biomarkers after radiofrequency catheter ablation for atrial fibrillation

BackgroundFurther in-vivo evidence is needed to support the usefulness of ablation index (AI) in guiding atrial fibrillation (AF) ablation. We aimed at evaluating the relationship between AI and other lesion indicators and the release of myocardial-specific biomarkers following radiofrequency AF ablation. MethodsForty-six patients underwent a first-time radiofrequency AF ablation and were prospectively enrolled in this study. Pulmonary vein isolation was performed by six experienced electrophysiologists with a point-by-point approach, guided by strict Visitag criteria and consistent AI target values. Myocardial-specific biomarkers troponin T and creatine kinase myocardial band were measured after 6 (TnT6 and CKMB6) and 20 h (TnT20 and CKMB20) following sheath removal. Ablation duration, impedance drop (ID), force-time integral (FTI) and AI were registered automatically and analyzed offline. ResultsTnT release was 985 ± 495 ng/L and 1038 ± 461 ng/L (p = ns) while CKMB release was 7.3 ± 2.7 μg/L and 6.5 ± 2.1 μg/L (p < 0.001) at 6 and 20 h respectively. Ablation duration, ID, FTI and AI were all significantly correlated with the release of myocardial-specific biomarkers both at 6 and 20 h. Ablation index showed the highest degree of correlation with TnT6, TnT20, CKMB6 and CKMB20 (Pearson's R 0.69, 0.69, 0.61, 0.64 respectively, p < 0.001). Multiple regression analysis demonstrated that AI had the strongest association with TnT6, TnT20, CKMB6 and CKMB20 (β 0.43, β 0.71, β 0.44 and β 0.43 respectively). ConclusionAblation index appears as the strongest lesion indicator as measured by the release of myocardial-specific biomarkers following radiofrequency catheter ablation for AF.

The value of perioperative biomarker release for the assessment of myocardial injury or infarction in cardiac surgery

Abstract OBJECTIVES Cardiac biomarkers are indicators of irreversible cell damage. Current myocardial infarction (MI) definitions require concomitant clinical characteristics. For perioperative MI, a correlation of biomarker elevations and mortality has been suggested. Definitions emerged relying on cardiac biomarker release only. This approach is questionable as several clinical and experimental scenarios exist where relevant biomarker release can occur apart from MI. METHODS We reviewed the clinical and basic science literature and revealed important aspects regarding the use and interpretation of cardiac biomarker release with special focus on their interpretation in the perioperative setting. RESULTS Ischaemic biomarkers may be released without cell death in multiple conditions, such as after endurance runs in athletes, temporary inotropic stimulation in animal models and flow variations in in vitro cell models. In addition, access through atrial tissue during cannulation or concomitant valve procedures adds sources of enzyme release that may not be related to ventricular ischaemia (i.e. MI). Such non-cell death-related mechanisms may explain the lack of poor correlations of enzyme release and long-term outcomes in recent trials. In addition, the 3 main biomarkers, troponin T, I and creatine kinase myocardial band, differ in their release kinetics, which may differentially trigger MI events in trial patients. CONCLUSIONS The identification of irreversible myocardial injury in cardiac surgery based only on biomarker release is unreliable. Cell death- and non-cell death-related mechanisms create a mix in the perioperative setting that requires additional markers for proper identification of MI. In addition, the 3 most common ischaemic biomarkers display different release kinetics adding to the confusion. We review the topic.

In vivo treatment with varespladib, a phospholipase A2 inhibitor, prevents the peripheral neurotoxicity and systemic disorders induced by Micrurus corallinus (coral snake) venom in rats

In this study, we investigated the action of varespladib (VPL) alone or in combination with a coral snake antivenom (CAV) on the local and systemic effects induced by Micrurus corallinus venom in rats. Adult male Wistar rats were exposed to venom (1.5 mg/kg – i.m.) and immediately treated with CAV (antivenom:venom ratio 1:1.5 ‘v/w’ – i.p.), VPL (0.5 mg/kg – i.p.), or both of these treatments. The animals were monitored for 120 min and then anesthetized to collect blood samples used for haematological and serum biochemical analysis; after euthanasia, skeletal muscle, renal and hepatic tissue samples were collected for histopathological analysis. M. corallinus venom caused local oedema without subcutaneous haemorrhage or apparent necrosis formation, although there was accentuated muscle morphological damage; none of the treatments prevented oedema formation but the combination of CAV and VPL reduced venom-induced myonecrosis. Venom caused neuromuscular paralysis and respiratory impairment in approximately 60 min following envenomation; CAV alone did not prevent the neurotoxic action, whereas VPL alone prevented neurotoxic symptoms developing as did the combination of CAV and VPL. Venom induced significant increase of serum CK and AST release, mostly due to local and systemic myotoxicity, which was partially prevented by the combination of CAV and VPL. The release of hepatotoxic serum biomarkers (LDH and ALP) induced by M. corallinus venom was not prevented by CAV and VPL when individually administered; their combination effectively prevented ALP release. The venom-induced nephrotoxicity (increase in serum creatinine concentration) was prevented by all the treatments. VPL alone or in combination with CAV significantly prevented the venom-induced lymphocytosis. In conclusion, VPL shows to be effective at preventing the neurotoxic, nephrotoxic, and inflammatory activities of M. corallinus venom. In addition, VPL acts synergistically with antivenom to prevent a number of systemic effects caused by M. corallinus venom.

Ultrasound-Based Method for the Identification of Novel MicroRNA Biomarkers in Prostate Cancer.

The detection of circulating microRNA (miRNA)-based biomarkers represents an innovative, non-invasive method for the early detection of cancer. However, the low concentration of miRNAs released in body fluids and the difficult identification of the tumor site have limited their clinical use as effective cancer biomarkers. To evaluate if ultrasound treatment could amplify the release of extracellular cancer biomarkers, we treated a panel of prostate cancer (PCa) cell lines with an ultrasound-based prototype and profiled the release of miRNAs in the extracellular space, with the aim of identifying novel miRNA-based biomarkers that could be used for PCa diagnosis and the monitoring of tumor evolution. We provide evidence that US-mediated sonoporation amplifies the release of miRNAs from both androgen-dependent (AD) and -independent (AI) PCa cells. We identified four PCa-related miRNAs, whose levels in LNCaP and DU145 supernatants were significantly increased following ultrasound treatment: mir-629-5p, mir-374-5p, mir-194-5p, and let-7d-5p. We further analyzed a publicly available dataset of PCa, showing that the serum expression of these novel miRNAs was upregulated in PCa patients compared to controls, thus confirming their clinical relevance. Our findings highlight the potential of using ultrasound to identify novel cell-free miRNAs released from cancer cells, with the aim of developing new biomarkers with diagnostic and predictive value.

A novel role of pirfenidone in attenuation acetic acid induced ulcerative colitis by modulation of TGF-β1 / JNK1 pathway

Colon diseases are a major health burden, particularly ulcerative colitis, in both men and women worldwide. Environmental and genetic factors in various colonic pathologies influence the onset and outcome of diseases. As the evidence from recent research is considered, the importance of inflammation in the onset, progression, and outcome is gaining more traction. The goal of this study was to see if pirfenidone could treat ulcerative colitis (UC) and if so, what mechanisms were involved. By intracolonic instillation [2 ml, 3 percent v/v acetic acid (AA)], ulcerative colitis was induced. Pirfenidone was administered to rats in different experimental groups (125 or 250 and 500 mg/kg, orally) for two weeks. Compared to normal group, the AA group showed an increase in colon weight, length, body weight, clinical evaluation, and macroscopic scoring of UC, serum lactate dehydrogenase, C-reactive protein, malondialdehyde, while decreasing serum total antioxidant capacity. Significant increases in colon Jun N terminal kinase1 (JNK1), transforming growth factor-beta (TGF-β1), interleukin 1 beta (IL1β), and Caspase-3 content. Furthermore, immunohistochemical staining revealed increased nuclear factor kappa B (NF-κB) expression along with histopathological changes. Pirfenidone inhibited inflammatory biomarkers release and restored oxidants/antioxidants hemostasis. In a dose-dependent manner, pirfenidone treatment showed a significantly decrease in all of these parameters. In addition, pirfenidone has significantly preserved the histopathological architecture of tissues. Current data demonstrate that Pirfenidone protects against AA-induced UC by modulating the TGF-β1/JNK1 and Caspase-3 pathways. Pirfenidone's antioxidant, anti-inflammatory, and anti-apoptotic properties are thought to be responsible for its therapeutic benefit.

Effect of revascularization on exercise-induced changes in cardiac and pro-thrombotic biomarkers in patients with coronary artery disease

Abstract Introduction Exercise-induced increase in cardiac and pro-thrombotic biomarkers have previously been shown in patients with coronary artery disease (CAD) before revascularization, which may be due to myocardial ischemia. Purpose We aimed to examine whether resting levels and exercise-induced changes of high sensitive cardiac Troponin T (cTnT), NT-proBNP, pro-thrombin fragment (F) 1+2, D-dimer, tissue factor pathway inhibitor (TFPI) and endogenous thrombin potential (ETP) were affected by revascularization in patients with CAD. We hypothesized that resting and exercise-induced levels of the biomarkers would be reduced after revascularization. Methods Patients presenting with symptoms of CAD were included. A maximal exercise ECG stress test (EST) (EST1) was performed, and venous blood samples were drawn at rest and within five min after termination. All patients underwent coronary angiography. Patients (n=20) with confirmed CAD, fully revascularized with percutaneous coronary intervention (PCI) and without symptoms of angina, were invited to perform a second EST (EST2), at the same workload (median 145W), at a median of 66 days after revascularization. Mean exercise duration at both time points were 11:30 min:sec. Of the total population 15 patients were treated with PCI on stenosis located on LAD and 5 patients with stenosis on RCA. Results Significant increase in cTnT and NT-proBNP from resting to post exercise levels at EST1 was found as expected (p&amp;lt;0.001, both). Also at EST2, increased levels were observed (p&amp;lt;0.01, both), however, not significantly different from the changes at EST1. Resting levels of cTnT at EST2 compared to EST1 were significantly higher (median 8.1 vs 7.1 ng/L, p=0.02). At both visits significant increase in D-dimer (p=0.008 and &amp;lt;0.001), F1+2 (p=0.009 and 0.001) and TFPI (p&amp;lt;0.001 and 0.001) during exercise were demonstrated, with no difference in these changes. There were no significant changes in ETP during exercise at any visit, but resting levels were reduced at EST2 vs EST1 (p&amp;lt;0.01). Also resting levels of TFPI were reduced at EST2 (p&amp;lt;0.01). Conclusion After revascularization there was still significant increase in exercise-induced release of cardiac and pro-thrombotic biomarkers, thus revascularization does not affect the ability to release these biomarkers. Also, the higher resting levels of cTnT after revascularization indicate that revascularization per se does not affect secretion of cardiac biomarkers, probably due to the disease state. The lower resting levels of ETP and TFPI after revascularization may, however, be indicative of reduced thrombin generation potential and endothelial activation. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Stein Erik Hagens Foundation for Clinical Heart Research, Oslo, Norway

Influence of UV-irradiation intensity and exposure duration on the hemobiocompatibility enhancement of a novel synthesized phosphobetaine zwitterions polyethersulfone clinical hemodialysis membranes.

To improve the biocompatibility of polyethersulfone (PES) membranes utilized for biomedical hemodialysis (HD) applications, surface grafting with hydrophilic polymers has become a reliable modification strategy. Like most photochemical catalyzed reactions, UV-assisted grafting is distinctly advantageous for inducing permanent surface chemistry, enhancing hydrophilicity, improving morphology, and surface charge of membranes. PES membranes may be hydrophilic and chemically stable; however, they also have low protein-binding capacity and very susceptible to fouling and target analyte binding. In this study, novel zwitterionic polymers (PVP-ZW) have been synthesized by UV-assisted grafting PVP to a phosphobetaine monomer in a reaction involving dimethylamino and dioxaphospholane-2-oxide terminal groups in an NVP monomer solution at varying UV exposure conditions. The highlight of the present study is the investigation of the hemocompatibility of coated PES HD membranes at varying UV exposure conditions with respect to membrane chemistry and morphology and its influence on human serum protein adsorption. A clinical investigation of inflammatory biomarker release from incubated coated membranes within uremic blood samples of HD patients reveals they are weak complement and coagulation activators compared to bare PES membrane. The trend of fibrinogen adsorption on coated PES membranes was observed to increase with reducing UV intensity and exposure duration. Fibrinogen adhesion only increased with roughened membrane surfaces, and this also led to the formation of biological activation pathways hindering biocompatibility. Resistance against fibrinogen absorption on zwitterionic modified PES membrane could be linked with the creation of electrostatically induced neutral zwitterionic PVP-phosphobetaine hydration layer with hydrophilic character. Experimental results are accompanied by spectroscopic and morphological imaging evidence. Zwitterion coated PES membranes (PES-PVP-ZW) fabricated from higher UV intensities through longer exposure durations showed significant presence of surface deformations in the forms of inherent exfoliations due to harsh UV reaction conditions. The zeta potential and surface roughness of coated membranes also played significant role in the fibrinogen adsorption on PES membranes during ultrafiltration.

Association of soluble ST2 and infarct location within 12–24 h in STEMI: A cross-sectional study

BackgroundST-Segment Elevation Myocardial Infarction (STEMI) causes the release of soluble ST2 biomarkers at high level on acute phase. However, sST2 has never been used as adjunct biomarker in ESC/AHA guideline for STEMI. Furthermore, the specific onset that sST2 may have role in acute phase of STEMI related with infarct location has not been established. This study aimed to prove the association between serum ST2 levels and infarct location in STEMI. Material and methodsThis study was cross-sectional. STEMI patients with onset of anginal pain 12–24 h were included in study. The exclusion criterias were patients with AMI aside from STEMI and other potential confounders affecting the sST2 level. Serum sST2 was collected on first medical contact when admitted to emergency unit. The patients were grouped into anterior STEMI and non-anterior STEMI. sST2 levels were compared with demographics data, clinical and laboratory variables using Student's t-test. Correlation of sST2 levels was analyzed using Spearman's correlation coefficient. Results19 subjects were included in the anterior STEMI and 20 subjects were included in the non-anterior STEMI. We found no difference in sST2 levels between anterior STEMI and non-anterior STEMI (mean ± SD; 729.97 pg/mL ± 147.78 pg/mL vs 606.87 pg/mL ± 147.78 pg/mL, p = 0.119). Onset was correlated with serum sST2 levels in male subjects (r = −0.459, p = 0.012). We found significant difference of mean sST2 between 2 onset groups divided at median (12–18 h vs 19–24 h, Δ mean = 107.75 pg/mL, p-value = 0.021). ConclusionsST2 was not associated with infarct location within 12–24 h onset of STEMI. This results suggest that infarct location might not responsible for the elevation of serum sST2 levels in acute phase of STEMI.

Superimposed secondary alteration of oil reservoirs. Part II: The characteristics of biomarkers under the superimposed influences of biodegradation and thermal alteration

Petroleum biomarkers could be altered to varying extents under the influence of biodegradation and thermal alteration in reservoir, and their respective influence has been well documented. However, the superimposed influence of successive biodegradation and thermal alteration has not been systematically studied so far. In this study, a sequence of crude oils and oil sands that are of identical origin but at different biodegradation levels from the Liaohe Basin of China were artificially matured via closed-system pyrolysis. The distributions of biomarkers such as steranes and hopanes in the variably biodegraded oil samples and in their pyrolyzates at varying artificial thermal maturities were compared. The results showed that the presence of normal (n-) alkanes in crude oil does not necessarily excludes the possibility of previous moderate–severe biodegradation as n-alkanes can be further generated under advanced thermal stress. Besides, biomarkers in the oils that have suffered superimposed alterations could be derived not only from the modifications of free biomarkers in the oils, but also from the release of biomarkers bound in the asphaltenes. The mix of these two sources complicated the biomarker profiles in this type of oils. Most source related parameters based on steranes and tri-, tetra- and penta-cyclic terpanes seem to be reliable only when the oil reservoir has suffered biodegradation not beyond moderate level and the maturity of the crude oil is below 0.91 Easy%Ro. The TT23/(TT23 + TT24) ratio, however, was found to remain constant even after severe biodegradation and thermal alteration, making it applicable in oil-source correlation in superimposed oil reservoirs. In addition, isomerization-based maturity parameters such as methylphenanthrene index of crude oils are reliable if subsequent thermal alteration reached above 0.91 Easy%Ro despite prior moderate–severe biodegradation, because the related isomerization reactions would approach the same level observed for the non-biodegraded oil after subsequent thermal alteration.

Evaluation of chronic drug-induced effects of oncologic compounds on cardiac function and cardiac biomarkers release in human induced pluripotent stem cell-derived cardiomyocytes

Evaluation of chronic drug-induced effects of oncologic compounds on cardiac function and cardiac biomarkers release in human induced pluripotent stem cell-derived cardiomyocytes

From Oxidative Stress to Inflammation in the Posterior Ocular Diseases: Diagnosis and Treatment.

Most irreversible blindness observed with glaucoma and retina-related ocular diseases, including age-related macular degeneration and diabetic retinopathy, have their origin in the posterior segment of the eye, making their physiopathology both complex and interconnected. In addition to the age factor, these diseases share the same mechanism disorder based essentially on oxidative stress. In this context, the imbalance between the production of reactive oxygen species (ROS) mainly by mitochondria and their elimination by protective mechanisms leads to chronic inflammation. Oxidative stress and inflammation share a close pathophysiological process, appearing simultaneously and suggesting a relationship between both mechanisms. The biochemical end point of these two biological alarming systems is the release of different biomarkers that can be used in the diagnosis. Furthermore, oxidative stress, initiating in the vulnerable tissue of the posterior segment, is closely related to mitochondrial dysfunction, apoptosis, autophagy dysfunction, and inflammation, which are involved in each disease progression. In this review, we have analyzed (1) the oxidative stress and inflammatory processes in the back of the eye, (2) the importance of biomarkers, detected in systemic or ocular fluids, for the diagnosis of eye diseases based on recent studies, and (3) the treatment of posterior ocular diseases, based on long-term clinical studies.

Concept Design of Transdermal Microneedles for Diagnosis and Drug Delivery: A Review

Microneedles (MNs) are one of intriguing approach for efficient transdermal drug delivery that penetrates the protective skin barrier in a painless and less invasive way. In recent years, multidisciplinary studies have been conducted to improve their properties to meet stringent requirements and obtain market release approval. This review aims to summarize the latest concept design with unique properties in the advancement of transdermal MNs for diagnosis and therapeutic application. Numerous significant innovation strategies in improving MNs in aspects of adhesion ability, dosing capacity, drug‐controlled release, diffusion control ability, site‐targeted and on‐demand drug delivery, and biomarker or drug release monitoring are presented. Given that the majority of technologies used in such design are exclusively laboratory‐based, striving toward commercialization is a critical aspect of the revolution. Key challenges and future perspectives in industrial and economic aspects are identified with the intention of translating the reviewed technologies into marketable products.

A novel platform for drug testing: Biomimetic three-dimensional hyaluronic acid-based scaffold seeded with human hepatocarcinoma cells

Hepatic cancer is one of the most widespread maladies worldwide that requires urgent therapies and thus reliable means for testing anti-cancer drugs. The switch from two-dimensional (2D) to three-dimensional (3D) cell cultures produced an improvement in the in vitro outcomes for testing anti-cancer drugs. We aimed to develop a novel hyaluronic acid (HA)-based 3D cell model of human hepatocellular carcinoma (HepG2 cells) for drug testing and to assess comparatively in 3D vs. 2D, the cytotoxicity and the apoptotic response to the anti-tumor agent, cisplatin. The 3D model was developed by seeding HepG2 cells in a HA/poly(methylvinylether-alt-maleic acid) (HA3P50)-based scaffold. Compared to 2D, the cells grown in the HA3P50 scaffold proliferate into larger-cellular aggregates that exhibit liver-like functions by controlling the release of hepatocyte-specific biomarkers (albumin, urea, bile acids, transaminases) and the synthesis of cytochrome-P450 (CYP)7A1 enzyme. Also, growing the cells in the scaffold sensitize the hepatocytes to the anti-tumor effect of cisplatin, by a mechanism involving the activation of ERK/p38α-MAPK and dysregulation of NF-kB/STAT3/Bcl-2 pathways. In conclusion, the newly developed HA-based 3D model is suitable for chemotherapeutic drug testing on hepatocellular carcinoma. Moreover, the system can be adapted and employed as experimental platform functioning as a proper tissue/tumor surrogate.

Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy.

Ischemic stroke is a damaging cerebral vascular disease associated with high disability and mortality rates worldwide. In spite of the continuous development of new diagnostic and prognostic methods, early detection and outcome prediction are often very difficult. The neurovascular unit (NVU) is a complex multicellular entity linking the interactions between neurons, glial cells, and brain vessels. Novel research has revealed that exosome-mediated transfer of microRNAs plays an important role in cell-to-cell communication and, thus, is integral in the multicellular crosstalk within the NVU. After a stroke, NVU homeostasis is altered, which induces the release of several potential biomarkers into the blood vessels. The addition of biological data representing all constituents of the NVU to clinical and neuroradiological findings can significantly advance stroke evaluation and prognosis. In this review, we present the current literature regarding the possible beneficial roles of exosomes derived from the components of the NVU and multipotent mesenchymal stem cells in preclinical studies of ischemic stroke. We also discuss the most relevant clinical trials on the diagnostic and prognostic roles of exosomes in stroke patients.

Association between ablation index and myocardial injury following radiofrequency catheter ablation for atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background Unpredictable lesion formation is a major limiting factor for radiofrequency catheter ablation for atrial fibrillation (AF). Ablation index (AI) emerged as a novel parameter to monitor lesion development and potentially improve clinical outcomes. Additional evidence is needed to support its use. Purpose We aimed at evaluating the relationship between AI and other lesion indicators and the release of myocardial-specific biomarkers following AF ablation. Methods Forty-six patients with similar baseline characteristics underwent a first-time radiofrequency ablation for AF and were prospectively enrolled in this study. Pulmonary vein isolation was performed by six experienced electrophysiologists with a point-by-point approach, guided by strict Visitag criteria and consistent AI target values. Myocardial-specific biomarkers troponin T and creatine kinase myocardial band were measured after 6 (TnT6 and CKMB6) and 20 hours (TnT20 and CKMB20) following sheath removal. Ablation duration, impedance drop (ID), force-time integral (FTI) and AI were registered automatically and analyzed off-line. Since biomarkers release reflect the total amount of myocardial injury, our independent variables consisted of total ablation duration, total ID, total FTI and total AI. Results 97% of total ablation duration fulfilled pre-specified Visitag criteria. Mean application duration was 20.0 ± 3.5 s, mean contact force was 15.9 ± 4.2 g, mean maximum power was 35.3 ± 1.5 W. Troponin T release was 985 ± 495 ng/L and 1038 ± 461 ng/L (p = ns) while CKMB release was 7.3 ± 2.7 mcg/L and 6.5 ± 2.1 mcg/L (p &amp;lt; 0.001) at 6 and 20 hours, respectively. Ablation duration, ID, FTI and AI were all significantly correlated with the release of myocardial-specific biomarkers both at 6 and 20 hours (all correlations significant at p &amp;lt; 0.01 level, Fig. 1). Ablation index showed the highest degree of correlation with TnT6, TnT20, CKMB6 and CKMB20 (Pearson`s R 0.69, 0.69, 0.58, 0.64 respectively, p &amp;lt; 0.001). Multiple regression analysis demonstrated that AI had the strongest association with TnT6, TnT20, CKMB6 and CKMB20 (beta 0.43, 0.71, 0.41 and 0.43, respectively). Conclusion Ablation index appears as the strongest lesion size indicator as measured by the release of myocardial-specific biomarkers following radiofrequency catheter ablation for AF. Abstract Figure. Scatter plots and correlations

The IC-D score for predicting prophylactic cardioverter-defibrillator implantation following acute myocardial infarction.

A reduced left ventricular ejection fraction (LVEF) ≤35% ≥6weeks following an acute myocardial infarction (MI) may indicate prophylactic implantation of a cardioverter-defibrillator (ICD). We sought to find predictors of absence of significant left ventricular (LV) remodeling post-MI. All consecutive patients hospitalized for acute MI with an LVEF ≤35% at discharge in our institution from 2010 were retrospectively included. Patients were assigned to two groups according to the persistence of an LVEF ≤35% (ICD+) or a recovery>35% (ICD-). Logistic regression was performed to build a predictive score, which was then externally validated. Among a total of 1533 consecutive MI patients, 150 met inclusion criteria, 53 (35%) in the ICD+ group and 97 in the ICD group. After multivariable analyses, an LVEF ≤25% at discharge (adjusted OR 6.23 [2.47 to 17.0], p<.0001) and a CPK peak at the MI acute phase>4600 UI/L (adjusted OR 9.99 [4.27 to 25.3], p<.0001) both independently predicted non-recovery at 6weeks. The IC-D (Increased Cpk-LV Dysfunction) score predicted persistent LVEF ≤35% with areas under curve of 0.83 and 0.73, in the study population and in a multicenter validation cohort of 150 patients, respectively (p<.0001). The association of a severely reduced LVEF and a major release of myocardial necrosis biomarkers at the acute phase of MI predict unfavorable remodeling, and prophylactic ICD implantation.