Release Of Biomarkers Research Articles

Low Frequency Ventilation During Cardiopulmonary Bypass to Protect Postoperative Lung Function in Cardiac Valvular Surgery: The PROTECTION Phase II Randomized Trial.

Cardiac surgery with cardiopulmonary bypass (CPB) triggers pulmonary injury. In this trial we assessed the feasibility, safety, and efficacy of low frequency ventilation (LFV) during CPB in patients undergoing valvular surgery. Patients with severe mitral or aortic valve disease were randomized to either LFV or usual care. Primary outcomes included release of generic inflammatory and vascular biomarkers and the lung-specific biomarker sRAGE (soluble receptor for advance glycation end products) up to 24 hours postsurgery. Secondary outcomes included pulmonary function tests and 6-minute walking test up to 8 weeks postdischarge. Sixty-three patients were randomized (33 LFV versus 30 usual care). Mean age was 66.8 years and 30% were female. LFV was associated with changes of sRAGE (soluble receptor for advance glycation end products) levels (geometric mean ratio, 3.05; [95% CI, 1.13-8.24] 10 minutes post CPB, and 1.07 [95% CI, 0.64-1.79], 0.84 [95% CI, 0.55-1.27], 0.67 [95% CI, 0.42-1.07], and 0.62 [95% CI, 0.45-0.85] at 2, 6, 12, and 24 hours post CPB respectively). No changes were observed for any of the generic biomarkers. Respiratory index soon after surgery (mean difference, -0.61 [95% CI, -1.24 to 0.015] 10 minutes post end of CPB), forced expiratory volume after 1 second/forced vital capacity ratio (0.050 [95% CI, 0.007-0.093] at 6 to 8 weeks pos-surgery), Forced vital capacity alone (95% CI, -0.191 L [-0.394 to 0.012]) and 6-minute walking test score at discharge (63.2 m [95% CI, 12.9-113.6]) were better preserved in the LFV group. No other differences were noted. The use of LFV during CPB in patients undergoing valvular surgery was feasible and safe and was associated with changes in sRAGE levels along with better preserved lung function and walking performance. These observations warrant further investigation in larger future studies. URL: https://www.isrctn.com; Unique Identifier: ISRCTN75795633.

Маркеры нарушения почечной функции после перкутанной нефролитотрипсии.

Introduction. Kidney stones (KS) is a common disease and occupies a significant place in urological practice. The incidence of KS is actively growing in industrialized countries. Modern technologies make it possible to carry out mini-cut interventions, reducing the risks of complications of standard techniques. However, an increase in the duration of procedures can lead to perfusion-pressor complications and overheating of the irrigated fluid. Acute kidney injury (AKI) during intraoperative intervention worsens the prognosis of rehabilitation and affects the dynamics of morbidity. For reliable and timely diagnosis of renal dysfunction, research is being conducted to develop new AKI biomarkers. The aim of this study was to study the effect of various percutaneous access methods on the level of acute renal injury in patients with urolithiasis. Materials and methods. The study was conducted on the basis of the Center of Urology, Nephrology and Lithotripsy of the N. A. Semashko from 2022 to 2023. The results of surgical treatment of 21 patients with nephrolithiasis were studied. The patients were divided into two groups depending on the percutaneous access method: standard PNL (28 Ch) and mini-PNL (16 Ch). The work used modern biomarkers of renal damage, such as Cystatin C, NGAL, KIM-1 and IL-18 in the postoperative period. Results. An increase in the concentration of Cystatin C and NGAL after PNL prevailed in group 1, which is associated with the release of biomarkers by tubules from a larger area of damaged renal parenchyma. Changes in KIM-1 levels in the postoperative period were greater in group 2, which is associated with the greatest ischemic damage to renal tissue. A decrease in IL-18 levels in group 2 is associated with less damage to the renal tubules and the absence of inflammatory reactions. It was found out that after 48 hours all AKI biomarkers undergo regression. Conclusions. The results of the study showed that the level of renal damage was higher in patients who underwent standard PNL, compared with those who used mini-PNL. This indicates that the use of mini-PNL may reduce the risk of acute renal injury in patients with urolithiasis.

THE IMMUNOMODULATORY ROLE OF CYTOKINES IN THE PATHOGENESIS OF PERIODONTAL DISEASE

Background:Inflammatory periodontal diseases are one of the most acute problems of modern dentistry, which is associated with their widespread prevalence in the world. In the structure of periodontal diseases, periodontitis a leading place in the age group of 40-50 years. Many factors play a role in the etiology of periodontitis, the most important of which are the local microbiota and the host immune response. Cytokines play an extremely important role. Cytokines are key modulators of both homeostasis and inflammatory processes, acting in the first wave of responses against pathogens, stimuli at barrier sites and linking tissue cells to lymphocytes and additional cell populations. Objective:The aim of the study was to analyze modern literature on the role of cytokines in the etiology and pathogenesis of inflammatory periodontal diseases. Materials and methods:Data Extraction: A comprehensive electronic literature search was performed in the following databases:PubMed, Scopus,Web of Scienc, Google Scholar, EBSCO host from 2000 to 2024 terms: periodontitis, infection, inflammation, immunity, cytokines, interleukin. 124 articles were found and 50 full-text articles of high methodological quality were selected according to the review method used, the PRISMA. Inclusion criteria:included clinical trials, considered randomized controlled trials, cross-sectional studies, casecontrol studies, and cohort studies in human subjects that evaluated the current literature on the periodontitis, infection, inflammation, immunity, cytokines, interleukin written in English articles.There was no limitation on minimal quality, minimal sample size, or the number of patients. Exclusion criteria were:original primary studies, due to language limitations , abstracts, letters to the editor, book chapters, case reports, conference abstracts, duplicate publications, and in vitro and in vivo animal experimental studies. Result:Many factors of general and local origin are involved in the development and progression of inflammatory periodontal diseases. Microorganisms and their products cause activation of the host immune system, which results in the release of cytokines and other proinflammatory biomarkers that cause tissue damage. The inflammatory process in periodontal tissues progresses through various stages, beginning with the infiltration of immune cells into the gingival tissue. Immune cells secrete proinflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α),which further promote inflammation and tissue destruction. The interaction between bacterial biofilm and the immune response, which is mainly controlled by cytokines, determines the course of periodontal disease. Conclusion:The etiology and pathogenesis of periodontal disease is quite complex, diverse and not yet fully disclosed. Cytokines are control and modulate the immune response in periodontitis

Standard versus High Cardiopulmonary Bypass Flow Rate: A Randomized Controlled Subtrial Comparing Brain Injury Biomarker Release

To compare brain injury biomarker release levels between two different cardiopulmonary bypass (CPB) flow rates in elective cardiac surgery and to explore differences in postoperative delirium between groups and associations between age, sex, CPB time, oxygen levels, and near-infrared spectroscopy, and biomarker levels. A randomized controlled substudy trial SETTING: Sahlgrenska University Hospital, Sweden PARTICIPANTS: Forty patients undergoing elective cardiac surgery with CPB INTERVENTION: Patients were assigned at random to either a standard (2.4 L/min/m2) or a high (2.9 L/min/m2) CPB flow rate. Glial fibrillary acidic protein, neurofilament light chain, total-tau, and phosphorylated-tau217 were sampled in plasma before anesthesia induction, after 60 minutes on CPB, and at 30 minutes, 24 hours, and 72 hours post-CPB. Mixed models for repeated measures were used to analyze differences in biomarker levels between groups and to assess relationships, which showed no differences between the 2 flow rate groups. There also was no difference in the occurrence of delirium between the 2 groups. Associations were found between age and increased neurofilament light chain levels. Female sex, oxygen delivery >330 mL/min/m2, and near-infrared spectroscopy level >60% were associated with lower biomarker levels. An increased flow rate did not have any significant effects on biomarker levels compared to a standard flow rate. Several associations were identified between treatment characteristics and biomarker levels. No difference in delirium was seen.

Sex-Specific Troponin and Creatine Kinase Thresholds After Coronary Bypass Surgery

BackgroundThe impact of sex-differences on the release of cardiac biomarkers after coronary artery bypass grafting (CABG) remains unknown. The aim of our study was to (1) investigate the impact of sex-differences in cardiac biomarker release after CABG and (2) determine sex-specific thresholds for high-sensitivity cardiac troponin (hs-cTn) and creatine kinase-myocardial band (CK-MB) associated with 30-day major adverse cardiovascular events (MACE) and mortality. MethodsA consecutive cohort of 3687 patients, comprising 643 women (17.4%) and 3044 men (82.6%), undergoing CABG from 2008 to 2021 in 2 tertiary university centers with serial postoperative cTn and CK-MB measurement was analyzed. The composite primary outcome was MACE at 30 days. Secondary end points were 30-day mortality and 5-year mortality and MACE. Sex-specific thresholds for cTn and CK-MB were determined. ResultsLower levels of cTn were found in women after CABG (69.18 vs 77.57 times the upper reference limit [URL]; P < .001). The optimal threshold value for cTn was calculated at 94.36 times the URL for female patients and 206.07 times the URL for male patients to predict 30-day MACE. Female patients missed by a general threshold had increased risk for MACE or death within 30 days (cTn: MACE: odds ratio [OR], 3.78; 95% CI, 1.03-13.08; P = .035; death: OR, 4.98; 95% CI, 1.20-20.61; P = .027; CK-MB: MACE: OR, 10.04; 95% CI, 2.07-48.75; P < .001; death: OR 13.59; 95% CI, 2.66-69.47; P = .002). ConclusionsWe provide evidence for sex-specific differences in the outcome and biomarker release after CABG. Sex-specific cutoffs are necessary for the diagnosis of perioperative myocardial injury to improve outcomes of women after CABG.

Inflammatory biomarkers and state of the tibiofemoral joint in the osteoarthritic knee: a narrative review.

The healing process is initiated by injurious stimuli in response to cellular damage. Upon recruiting proinflammatory biomarkers to the tissue site of injury, the release of additional biomarkers occurs, including the likes of cytokines, matrix molecules, macrophages, neutrophils, and others. This influx of immune system mediators can occur for chronic periods, and though its intention is for healing the original injurious stimuli, it is also suspected of causing long term cartilage impairment following internal structure damage. The objective of this narrative review is to identify which inflammatory factors have the leading roles in the progression of osteoarthritis (OA) following knee injuries and how they fluctuate throughout the healing process, both acutely and chronically. This narrative review was performed following a computerized search of the electronic database on PubMed in May 2023. Abstracts related to the inflammatory biomarkers of the post-traumatic knee were included for review. The chronic low-level inflammation that leads to OA leads to the destruction of the cartilage extracellular matrix, which new and developing orthopedic research is still attempting to find resolve for. Some of this damage is attributed to the biomechanical alterations that occurs following injury, though with most procedures capable of joint biomechanical restoration, focus has rather been shifted toward the environment of inflammatory biomarkers. Future studies will be aiming to improve the diagnostics of OA, focusing on a consistent correlation of inflammatory biomarkers with imaging. Additionally, biochemical treatments will need to focus on validating reproducible modulation of signaling molecules, in attempts to lessen the chronic elevations of destructive biomarkers.

Electrospun fibrillary scaffold for electrochemical cell biomarkers detection

A novel scaffold for in situ electrochemical detection of cell biomarkers was developed using electrospun nanofibers and commercial adhesive polymeric membranes. The electrochemical sensing of cell biomarkers requires the cultivation of the cells on/near the (bio)sensor surface in a manner to preserve an appropriate electroactive available surface and to avoid the surface passivation and sensor damage. This can be achieved by employing biocompatible nanofiber meshes that allow the cells to have a normal behavior and do not alter the electrochemical detection. For a better mechanical stability and ease of handling, nylon 6/6 nanofibers were collected on commercial polymeric membranes, at an optimal fiber density, obtaining a double-layered platform. To demonstrate the functionality of the fabricated scaffold, the screening of cellular stress has been achieved integrating melanoma B16-F10 cells and the (bio)sensor components on the transducer whereas the melanin exocytosis was successfully quantified using a commercial electrode. Either directly on the surface of the (bio)sensor or spatially detached from it, the integration of cell cultures in biosensing platforms based on electrospun nanofibers represents a powerful bioanalytical tool able to provide real-time information about the biomarker release, enzyme activity or inhibition, and monitoring of various cellular events.Graphical

Oxidative Stress as a Target for Non-Pharmacological Intervention in MAFLD: Could There Be a Role for EVOO?

Oxidative stress plays a central role in most chronic liver diseases and, in particular, in metabolic dysfunction-associated fatty liver disease (MAFLD), the new definition of an old condition known as non-alcoholic fatty liver disease (NAFLD). The mechanisms leading to hepatocellular fat accumulation in genetically predisposed individuals who adopt a sedentary lifestyle and consume an obesogenic diet progress through mitochondrial and endoplasmic reticulum dysfunction, which amplifies reactive oxygen species (ROS) production, lipid peroxidation, malondialdehyde (MDA) formation, and influence the release of chronic inflammation and liver damage biomarkers, such as pro-inflammatory cytokines. This close pathogenetic link has been a key stimulus in the search for therapeutic approaches targeting oxidative stress to treat steatosis, and a number of clinical trials have been conducted to date on subjects with NAFLD using drugs as well as supplements or nutraceutical products. Vitamin E, Vitamin D, and Silybin are the most studied substances, but several non-pharmacological approaches have also been explored, especially lifestyle and diet modifications. Among the dietary approaches, the Mediterranean Diet (MD) seems to be the most reliable for affecting liver steatosis, probably with the added value of the presence of extra virgin olive oil (EVOO), a healthy food with a high content of monounsaturated fatty acids, especially oleic acid, and variable concentrations of phenols (oleocanthal) and phenolic alcohols, such as hydroxytyrosol (HT) and tyrosol (Tyr). In this review, we focus on non-pharmacological interventions in MAFLD treatment that target oxidative stress and, in particular, on the role of EVOO as one of the main antioxidant components of the MD.

Comparison of the Impact of VRP-034 and Polymyxin B upon Markers of Kidney Injury in Human Proximal Tubule Monolayers In Vitro.

In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximateTM. Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin-cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 μM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 μM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximateTM model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.

Vernodalin Alleviates Cardiotoxicity and Inflammation in Isoproterenol-Mediated Myocardial Infarction through NF-κB/AMPK Signaling Pathways in Rats.

Myocardial infarction (MI) is the foremost cause of mortality in cardiovascular diseases. MI ultimately exacerbates cardiotoxicity due to the release of toxicity biomarkers and inflammatory infiltration. Vernodalin (VN) is a renowned cytotoxic sesquiterpene lactone that possesses antioxidant, anticancer, and anti-inflammatory properties. The cardioprotective mechanism of VN remains concealed. Hence, we explored the cardioprotective efficacy of VN on isoproterenol (ISO)- mediated MI and analyzed its underlying mechanism. Wistar albino rats were injected ISO (85 mg/kg bw) subcutaneously to induce MI to evaluate the cardioprotective potential of VN (10 mg/kg bw) by assessing heart weight/ body weight index, hemodynamic, toxicity enzymes, histopathology, inflammatory mediators, and signaling pathway. ISO enhanced heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammation, and histopathological changes while reducing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways. Treatment with VN could significantly (p<0.05) mitigate the heart weight/body weight index, cardiotoxicity enzymes, biomarkers, inflammatory cytokines, and histopathological changes while enhancing hemodynamic parameters and VEGF-B, AMPK, and eNOS signaling pathways. Collectively, our findings revealed that the VN ameliorated defensive action against MI and averted myocardial injury by reducing the NF-κB-mediated inflammatory pathways in rats. These findings established that VN expressively preserves the myocardium and employs anti-inflammatory actions by regulating NF-κB, VEGF-B, AMPK, and eNOS signaling pathways.

Pulsed-field vs. cryo-balloon based pulmonary vein isolation: does reduced autonomic modulation effect freedom of atrial fibrillation?

Abstract Background Pulsed-field ablation (PFA) is a new energy source integrated into single-shot devices enabling pulmonary vein isolation (PVI) during atrial fibrillation (AF) ablation. It has been demonstrated that PFA is noninferior to conventional thermal ablation. Conceptually, PFA preferentially damages cardiomyocytes and our prior data show that PFA causes less damage to neuronal tissue and reduced autonomic dysfunction than CBA. Here, we analyzed heart rate variability (HRV) as an additional parameter of intracardiac nervous system and whether the damage to neuronal tissue quantified by biomarker release and functional parameters might influence the recurrence rate of atrial fibrillation in PFA and CBA treated patients. Methods We prospectively included consecutive patients with paroxysmal AF undergoing index PVI applying PFA (n=65) or CBA (n=112). We quantified the ablation-dependent effect on intracardiac autonomic nervous system by comparing resting heart rate (HR), HRV and circulating concentrations of the neuronal biomarker S100B. Recurrent AF was detected using Holter ECGs, wearables and telephone interviews. Results Baseline characteristics did not differ between PFA and CBA (age 66 vs. 68 years, female 33% vs. 39%, CHADS-VASc Score 2.1 vs. 2.2, indexed LA volume 32 vs. 31 ml/m², BMI 27.3 vs. 27.4 kg/m²). After CBA-based PVI, HR increased (pre 63 vs. post 70 bpm, p&amp;lt;0.001) and HRV decreased (SDNN pre 54 vs. post 26 ms, p=0.007). After PFA-based PVI, HR and HRV remained stable (HR pre 63 vs. 64 bpm, p=0.591; HRV SDNN pre 37 vs. post 36 ms, p=0.890). In a direct comparison, the HR-increase and HRV-decrease observed after CBA-based PVI was significant compared to PFA (0.8 vs. 7.3 bpm, p&amp;lt;0.001 and SDNN -1 vs. 29 ms, p=0.003). We reported previously that PFA induced less S100B release (28 ng/dl) than CBA (68 ng/dl, p&amp;lt;0.001) and that PV reconnection rates in ReDo procedure were similar between PFA (40%) and CBA (40%). 1 year follow-up revealed freedom of AF in 79% after PFA and 73% after CBA (p=0.230). Dividing patients in upper and lower half of HR increase and S100B release after PVI, patients showed no difference in recurrence rates after CBA. Conclusion These data suggest that neurocardiac damage near the pulmonary veins seems not to contribute to freedom of AF recurrences after PVI.

#91 Ultrafiltration rate induced cardiac strain (ULRICA) – study. Preliminary results of a prospective multicentre study in Sweden

Abstract Background and Aims Cardiovascular disease is the principal cause of mortality in the haemodialysis population, attributable not only to traditional risk factors but also to those specific to dialysis treatment such as fluid overload and ultrafiltration. These are modifiable risk factors. The cardiac biomarkers N-terminal pro-B-type natriuretic peptide (proBNP) and hs-Troponin T (TnT) increase during dialysis (Laveborn et al. 2012). Previous studies (Goto et al. 2023) hypothesize that this increase was related to ultrafiltration rate. The aim of the study was to determine if modifying ultrafiltration rate could reduce the elevation of these cardiac biomarkers. Method ULRICA is a multicentre study registered at ClinicalTrials.gov (NCT06153888), conducted in six centres across Sweden. It investigated the effect of ultrafiltration rate in adult, stable haemodialysis patients with a) interdialytic weight gain (IDWG) of more than 2.5% of dry body weight and b) an ultrafiltration rate of over 0.72 IDWG/h (standard UF rate). In a crossover setting each patient underwent one treatment according to standard prescription and, after one week, a second treatment with prolonged UF time to achieve an ultrafiltration rate of less than 0.6 IDWG/h or a reduction of ultrafiltration rate of at least 20% compared to standard treatment. All treatments were performed using low flux dialysers. Blood samples were collected before, after 180 min and after treatment. Levels of proBNP and TnT were then adjusted for haemoconcentration after the formula of Schneditz et al. (2012). Echocardiographic measurements were derived from echocardiographs performed within one year from study start under stable conditions. Due to the small sample size and non-normally distributed values, data were analysed using Wilcoxon signed-rank test for comparisons between treatments and Spearman's rank correlation coefficient for correlations. Results This preliminary one-centre report included 12 patients (four women, eight men) with a median age of 68.5 (range 32-86 years). There was a significant increase in TnT (p=0.008) and proBNP (p= 0.002) during dialysis with standard UF rate. The median levels of cardiac markers before treatment did not differ between the two treatments, TnT 61.5 ng/l (IQR 33.3-87.2) resp. 59.5 ng/l (IQR 35.5-90.0) and proBNP 12177.5 ng/l (IQR 3112.5-34773.0) resp. 9105 ng/l (IQR 2555.3-36803.0); (p=0.906 for TnT and p=0.638 for proBNP). The median increase of TnT was 4.1 ng/l (IQR 1.2-8.4) during standard treatment and 5.8 ng/l (IQR 0.1-10.3) during the prolonged treatment (p= 0.158). The median increase in proBNP was 3257.5 ng/l (IQR 855.0- 15074.7) during standard treatment and 2996.9 ng/l (IQR 724.1-13338.4) during the prolonged treatment (p=0.814). The changes at 180 min were also non-significant (p=0.182 for TnT and p=0.875 for proBNP). There was a positive correlation between the change in proBNP during treatment and age (R=0.85, p&amp;lt;0.001) and left ventricular mass index (LVMI) (R=0.89, p=0.019). There was also a correlation between age and LVMI (R=0.83, p=0.042). Conclusion Preliminary data of a small group of patients confirm an increase of TnT and proBNP during dialysis. Age and LVMI are strongly associated with increase of proBNP. To show whether a reduction of ultrafiltration rate per se might reduce the release of cardiac biomarkers during haemodialysis treatment, further inclusion of patients is in progress.

Neutrophil reduction attenuates the severity of lung injury in the early phase of pneumococcal pneumonia in mice.

Neutrophils are the first leukocytes to be recruited to sites of inflammation in response to chemotactic factors released by activated macrophages and pulmonary epithelial and endothelial cells in bacterial pneumonia, a common cause of acute respiratory distress syndrome (ARDS). Although neutrophilic inflammation facilitates the elimination of pathogens, neutrophils also may cause bystander tissue injury. Even though the presence of neutrophils in alveolar spaces is a key feature of acute lung injury and ARDS especially from pneumonia, their contribution to the pathogenesis of lung injury is uncertain. The goal of this study was to elucidate the role of neutrophils in a clinically relevant model of bacterial pneumonia. We investigated the effect of reducing neutrophils in a mouse model of pneumococcal pneumonia treated with antibiotics. Neutrophils were reduced with anti-lymphocyte antigen 6 complex locus G6D (Ly6G) monoclonal antibody 24 h before and immediately preceding infection. Mice were inoculated intranasally with Streptococcus pneumoniae and received ceftriaxone 12 h after bacterial inoculation. Neutrophil reduction in mice treated with ceftriaxone attenuated hypoxemia, alveolar permeability, epithelial injury, pulmonary edema, and inflammatory biomarker release induced by bacterial pneumonia, even though bacterial loads in the distal air spaces of the lung were modestly increased as compared with antibiotic treatment alone. Thus, when appropriate antibiotics are administered, lung injury in the early phase of bacterial pneumonia is mediated in part by neutrophils. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.NEW & NOTEWORTHY Neutrophil accumulation is a key feature of ARDS, but their contribution to the pathogenesis is still uncertain. We investigated the effect of reducing neutrophils in a clinically relevant mouse model of pneumococcal pneumonia treated with antibiotics. When appropriate antibiotics were administered, neutrophil reduction with Ly6G antibody markedly attenuated lung injury and improved oxygenation. In the early phase of bacterial pneumonia, neutrophils contribute to the severity of lung injury, although they also participate in host defense.

Susceptibility to innate immune activation in genetically-mediated myocarditis.

Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment for myocarditis is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis with biomarkers and pathological features indistinguishable from other forms of myocarditis. DSP-associated myocarditis can progress to dilated cardiomyopathy with heightened arrhythmia risk. To model the cardiomyocyte aspects of DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients and gene-edited healthy control hiPSC lines. Homozygous and heterozygous DSP disrupted EHTs were generated to contain 90% hiPSC-CMs and 10% healthy control human cardiac fibroblasts. We measured innate immune activation and function at baseline and in response to Toll-like receptor (TLR) stimulation in EHTs. At baseline, DSP-/- EHTs displayed a transcriptomic signature of immune activation which was mirrored by EHT cytokine release. Importantly, DSP-/- EHTs were hypersensitive to TLR stimulation demonstrating greater contractile function impairment compared to isogenic controls. Compared to homozygous DSP-/- EHTs, heterozygous DSP patient-derived EHTs had less functionally impairment but also displayed heightened sensitivity to TLR stimulation. When subjected to strain, heterozygous DSP EHTs developed greater functional deficit indicating reduced contractile reserve compared to healthy control. Colchicine or NFΚB inhibitors improved baseline force production and strain-induced force deficits in DSP EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Genetic reduction of DSP renders cardiomyocytes susceptible to innate immune activation and strain-dependent contractile deficits. EHTs replicate electrical and contractile phenotypes seen in human myocarditis implicating cytokine release as a key part of the myogenic susceptibility to inflammation. This heightened innate immune activation and sensitivity is a target for clinical intervention.

Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion.

The pulmonary endothelium is the primary target of lung ischemia-reperfusion injury leading to primary graft dysfunction after lung transplantation. We hypothesized that treating damaged rat lungs by a transient heat stress during ex-vivo lung perfusion (EVLP) to elicit a pulmonary heat shock response could protect the endothelium from severe reperfusion injury. Rat lungs damaged by 1h warm ischemia were reperfused on an EVLP platform for up to 6h at a constant temperature (T°) of 37°C (EVLP37°C group), or following a transient heat stress (HS) at 41.5°C from 1 to 1.5h of EVLP (EVLPHS group). A group of lungs exposed to 1h EVLP only (pre-heating conditions) was added as control (Baseline group). In a first protocol, we measured lung heat sock protein expression (HSP70, HSP27 and Hsc70) at selected time-points (n=5/group at each time). In a second protocol, we determined (n=5/group) lung weight gain (edema), pulmonary compliance, oxygenation capacity, pulmonary artery pressure (PAP) and vascular resistance (PVR), the expression of PECAM-1 (CD31) and phosphorylation status of Src-kinase and VE-cadherin in lung tissue, as well as the release in perfusate of cytokines (TNFα, IL-1β) and endothelial biomarkers (sPECAM, von Willebrand Factor -vWF-, sE-selectin and sICAM-1). Histological and immunofluorescent studies assessed perivascular edema and formation of 3-nitrotyrosine (a marker of peroxinitrite) in CD31 lung endothelium. HS induced an early (3h) and persisting expression of HSP70 and HSP27, without influencing Hsc70. Lungs from the EVLP37°C group developed massive edema, low compliance and oxygenation, elevated PAP and PVR, substantial release of TNFα, IL-1β, s-PECAM, vWF, E-selectin and s-ICAM, as well as significant Src-kinase activation, VE-cadherin phosphorylation, endothelial 3-NT formation and reduced CD31 expression. In marked contrast, all these alterations were either abrogated or significantly attenuated by HS treatment. The therapeutic application of a transient heat stress during EVLP of damaged rat lungs reduces endothelial permeability, attenuates pulmonary vasoconstriction, prevents src-kinase activation and VE-cadherin phosphorylation, while reducing endothelial peroxinitrite generation and the release of cytokines and endothelial biomarkers. Collectively, these data demonstrate that therapeutic heat stress may represent a promising strategy to protect the lung endothelium from severe reperfusion injury.

Focused Ultrasound-Enhanced Liquid Biopsy: A Promising Diagnostic Tool for Brain Tumor Patients.

The performance of minimally invasive molecular diagnostic tools in brain tumors, such as liquid biopsy, has so far been limited by the blood-brain barrier (BBB). The BBB hinders the release of brain tumor biomarkers into the bloodstream. The use of focused ultrasound in conjunction with microbubbles has been shown to temporarily open the BBB (FUS-BBBO). This may enhance blood-based tumor biomarker levels. This systematic review provides an overview of the data regarding FUS-BBBO-enhanced liquid biopsy for primary brain tumors. A systematic search was conducted in PubMed and Embase databases with key terms "brain tumors", "liquid biopsy", "FUS" and their synonyms, in accordance with PRISMA statement guidelines. Five preclinical and two clinical studies were included. Preclinical studies utilized mouse, rat and porcine glioma models. Biomarker levels were found to be higher in sonicated groups compared to control groups. Both stable and inertial microbubble cavitation increased biomarker levels, whereas only inertial cavitation induced microhemorrhages. In clinical studies involving 14 patients with high-grade brain tumors, biomarker levels were increased after FUS-BBBO with stable cavitation. In conclusion, FUS-BBBO-enhanced liquid biopsy using stable cavitation shows diagnostic potential for primary brain tumors. Further research is imperative before integrating FUS-BBBO for liquid biopsy enhancement into clinical practice.

Cardiac biomarker responses following high-intensity interval and continuous exercise: the influence of ACE-I/D gene polymorphism and training status in men.

This study aimed to investigate the relationship between pre- and postexercise cardiac biomarker release according to athletic status (trained vs. untrained) and to establish whether the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene had an influence on cardiac biomarkers release with specific regard on the influence of the training state. We determined cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in 29 trained and 27 untrained male soccer players before and after moderate-intensity continuous exercise (MICE) and high-intensity interval exercise (HIIE) running tests. Trained soccer players had higher pre (trained: 0.014 ± 0.007 ng/mL; untrained: 0.010 ± 0.005 ng/mL) and post HIIE (trained: 0.031 ± 0.008 ng/mL; untrained: 0.0179 ± 0.007) and MICE (trained: 0.030 ± 0.007 ng/mL; untrained: 0.018 ± 0.007) cTnI values than untrained subjects, but the change with exercise (ΔcTnI) was similar between groups. There was no significant difference in baseline and postexercise NT-proBNP between groups. NT-proBNP levels were elevated after both HIIE and MICE. Considering three ACE genotypes, the mean pre exercise cTnI values of the trained group (DD: 0.015 ± 0.008 ng/mL, ID: 0.015 ± 0.007 ng/mL, and II: 0.014 ± 0.008 ng/mL) and their untrained counterparts (DD: 0.010 ± 0.004 ng/mL, ID: 0.011 ± 0.004 ng/mL, and II: 0.010 ± 0.006 ng/mL) did not show any significant difference. To sum up, noticeable difference in baseline cTnI was observed, which was related to athletic status but not ACE genotypes. Neither athletic status nor ACE genotypes seemed to affect the changes in cardiac biomarkers in response to HIIE and MICE, indicating that the ACE gene does not play a significant role in the release of exercise-induced cardiac biomarkers indicative of cardiac damage in Iranian soccer players.NEW & NOTEWORTHY Our study investigated the impact of athletic status and angiotensin-converting enzyme (ACE) gene I/D polymorphism on cardiac biomarkers in soccer players. Trained players showed higher baseline cardiac troponin I (cTnI) levels, whereas postexercise ΔcTnI remained consistent across groups. N-terminal pro-brain natriuretic peptide increased after exercise in both groups, staying within normal limits. ACE genotypes did not significantly affect pre-exercise cTnI. Overall, athletic status influences baseline cTnI, but neither it nor ACE genotypes significantly impact exercise-induced cardiac biomarker responses in this population.

Association of vitamin D and inflammatory biomarkers with newly diagnosed cases of hypothyroidism- A case-control study

Background: Deranged thyroid hormones and TSH induces the release of inflammatory biomarkers and recent evidence has demonstrated an association between low vitamin D status and autoimmune thyroid diseases, but there is little documented evidence available about the association of vitamin D and inflammatory biomarkers. So, this study was planned to investigate the relationship between vitamin D and inflammatory biomarkers. Materials and Methods: This case-control study was carried out among 60 study participants (30 cases and 30 controls) in the Department of Biochemistry, F.H Medical College, its associated Hospital from January 2023 to June 2023 The samples were divided in to two groups, cases (hypothyroid patients) and healthy control group. Serum was separated by centrifuging blood at 3000 rpm for 10 mi. Estimation of CRP was done turbidimetric immune assay method. Statistical analysis was done by using the (SPSS) version 20.0. Pearson correlation and Student’s t-test was applied, p-value &lt;0.0001 was taken as significance. Results: The (mean ±SD) CRP values in the subjects having hypothyroid disorder (cases) were 3.12± 0.79 mg/L and in control was 2.01±0.75 mg/L (p-value &lt;0.0001). The weight was found to be higher in cases. The CRP and IL-6 had an insignificant correlation with the BMI (r=0.06, p=0.74) and (r=0.64, p=0.35) and also insignificant correlation was found in between the CRP and the blood pressure. Conclusion: This study concludes that CRP and IL-6 levels were significantly higher in hypothyroid patients and insignificant correlation was found between anthropometric measurements of hypothyroid patients and inflammatory biomarkers. Keywords: vitamin D; CRP; IL-6; hypothyroidism; hypothyroid patients

Releasing genetic biomarkers from cells and tissues with ultrasound

Ultrasound sonoporation has long been investigated as a means of enhancing therapeutic delivery into cells. More recently, however, ultrasound has been explored as means to liberate biomarkers out of cells. I will discuss our past efforts to enhance ultrasound biomarker release using microbubbles and nanodroplets both in vivo and ex vivo. Our recent in vivo work has demonstrated that ultrasound and nanodroplets can enhance extracellular vesicles and tumor DNA/RNA in the blood by 100-1000-fold. Because we can compare post- sonication blood biomarker levels to a pre-sonication blood draw baseline, and because any increase in biomarkers must be due to ultrasound treatment, this approach is a powerful alternative to biopies with much less tissue damage. In a different paradigm, we are exploring contrast-agent-free ablative acoustic mechanisms on a micro-scale to enhance biomarker release even further. Our group is further exploring novel avenues to detect circulating tumor cells in blood samples, where ultrasound treatment is applied to a separated blood fraction. By detecting biomarkers released from circulating tumor cells but primarily absent in blood cells, our approach is sensitive to single cells. Ongoing work in prostate cancer patients suggest promise for sensitive and specific detection of clinically significant prostate cancer. Ultrasound for biomarker release is a promising avenue of research which could lead to many important clinical applications given additional work and validation.

Capillaries, cancer, and cavitation: An introduction to the Biomedical Acoustics Technical Committee

Biomedical acoustics is a growing field comprised of individuals who study the interaction of sound with biological materials. While ultrasound in medicine is most associated with fetal imaging, researchers and clinicians continue to push the boundaries of ultrasound to improve the diagnosis and treatment of disease. As such, this conference features special sessions on imaging the microvasculature in the brain and beamforming to improve the speed and quality of the ultrasound image. But ultrasound can also be used as a therapeutic due to absorption of the acoustic wave, radiation forces, and cavitation. On the therapy side, special sessions have been organized on: phase-change contrast agents, which can improve imaging contrast or locally deliver medications to cells; sonodynamic therapy, which involves killing cancer cells with ultrasound; sonobiopsy, which uses ultrasound to enhance the release of biomarkers for noninvasive disease diagnosis; and wave propagation in complex media, which helps us to understand our acoustic field for imaging and therapy. BATC has also organized a session on training students in technical writing. Ultrasound is an important diagnostic and treatment modality that continues to advance as researchers and physicians work to improve patient outcomes.