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Oncolytic viruses have emerged as a highly promising modality for cancer treatment due to their ability to replicate specifically within tumors, carry therapeutic genes, and modulate the immunosuppressive tumor microenvironment through various mechanisms. Additionally, they show potential synergy with immune checkpoint inhibitors. A study report indicates that from 2000 to 2020, 49.5% of oncolytic viruses were administered intratumorally and 35% intravenously during clinical trials. However, both administration methods face significant challenges, particularly with intravenous delivery, which encounters issues such as non-specific tissue uptake, neutralizing antibody responses, and antiviral effects mediated by various immune cells. Despite extensive research into the antiviral roles of CD8+ T cells and NK cells in oncolytic virus therapy, neutrophils—constituting approximately 50% to 70% of human peripheral blood leukocytes—have received relatively little attention. Neutrophils are the most abundant leukocyte subset in peripheral circulation, known for their phagocytic activity. Beyond their traditional roles in bacterial and fungal infections, emerging literature suggests that neutrophils also play a critical role in the body's antiviral responses. Given the gaps in understanding the role of neutrophils in oncolytic virus therapy, this article reviews current literature on this topic. It aims to provide a theoretical foundation for developing oncolytic virus-based cancer therapies and enhancing their anti-tumor efficacy in future clinical treatments. [ABSTRACT FROM AUTHOR]

The monitoring of peripheral circulation, as indicated by the capillary refill time, is a sensitive and accurate method of assessing the microcirculatory status of the body. It is a widely used tool for the evaluation of critically ill patients, the guidance of therapeutic interventions, and the assessment of prognosis. In recent years, there has been a growing emphasis on microcirculation monitoring which has led to an increased focus on capillary refill time. The International Sepsis Guidelines, the American Academy of Pediatrics, the World Health Organization, and the American Heart Association all recommend its inclusion in the evaluation of the system in question. Furthermore, the methodology for its measurement has evolved from a traditional manual approach to semiautomatic and fully automatic techniques. This article presents a comprehensive overview of the current research on the measurement of capillary refill time, with a particular focus on its clinical significance. The aim is to provide a valuable reference for clinicians and researchers and further advance the development and application of microcirculation monitoring technology. [ABSTRACT FROM AUTHOR]

Liquid biopsy is an efficient diagnostic/prognostic tool for tumor-derived component detection in peripheral circulation and other body fluids. The rapid assessment of liquid biopsy techniques facilitates early cancer diagnosis and prognosis. Early and precise detection of tumor biomarkers provides crucial information about the tumor that guides clinicians towards effective personalized medicine. Point-of-care-testing remains still a great challenge in cancer diagnostics. Liquid biopsy is a promising alternative to tissue biopsy with the great advantages of less invasion and real-time monitoring of the disease, also providing information about tumor heterogeneity. The field is continuously and rapidly expanding. Numerous sophisticated biosensors have been developed targeting several biomarkers to achieve low detection limits, increased specificity and robustness. Current biosensors include mainly optical sensors, such as colorimetric, fluorescent, SPR, SERS and lateral flow assays. Electrochemical sensors have also been developed, providing very low detection limits. Colorimetric sensors exhibited simplicity in signal interpretation, while fluorescent sensors contributed to low analysis times, and SPR/SERS enabled label-free and rapid analysis. Novel target amplification and signal enhancement techniques have been exploited to increase the detectability of the sensors. In this context, this review is focused on the recent advances in biosensing technology for cutting-edge liquid biopsy applications towards point-of-care testing. [ABSTRACT FROM AUTHOR]

Numerous studies highlight the significant role of exercise therapy in patients with peripheral artery disease (PAD), emphasizing how regular physical exercise enhances vascular endothelial function and promotes metabolic adaptations in skeletal muscles, ultimately improving walking performance. There are currently discussions in the medical world on optimizing noninvasive therapy to prevent the development of lower limb ischemia. This study aimed to assess the impact of a supervised training program combined with whirlpool massage treatment on improving peripheral circulation and physical performance in patients suffering from peripheral artery disease. Methods: One hundred participants (both male and female) aged between 39 and 79 years old (60.0 ± 11.6) were included in the analysis, all diagnosed with peripheral circulation disorders. The participants were assigned to two groups. The study group received 10 whirlpool treatments of the lower limbs and a personalized training program. The control group only participated in the training sessions. Pre- and post-intervention evaluations included impedance plethysmography and the six-minute walk test (6MWT). Results: Assessing the results of local flow parameters, after the procedures, a statistically significant increase in the pulse wave amplitude (PAmpl, p < 0.001) and systolic slope (PSlope, p < 0.001) values was found, as well as a statistically significant decrease in the crest time (CT, p < 0.001) and propagation time (PT, p = 0.007) values in the study group, which indicates an improvement in blood flow in the peripheral circulation. Also, in the 6 min walk test, a statistically significant increase in the walking distance was noted in the study group after the procedures. Conclusions: Physical training, combined with whirlpool massage treatment, has a beneficial effect on improving peripheral blood flow assessed by impedance plethysmography, as well as patients' tolerance to physical exercise. The inclusion of hydrotherapy as part of cardiovascular rehabilitation protocols in patients with peripheral ischemia is a promising form of conservative treatment. [ABSTRACT FROM AUTHOR]

Heart failure is a complex syndrome characterized by cardiac hypertrophy, fibrosis, and diastolic/systolic dysfunction. These changes share many pathological features with significant inflammatory responses in the myocardium. Among the various regulatory systems that impact on these heterogeneous pathological processes, angiotensin II (Ang II)-activated macrophages play a pivotal role in the induction of subcellular defects and cardiac adverse remodeling during the progression of heart failure. Ang II stimulates macrophages via its AT1 receptor to release oxygen-free radicals, cytokines, chemokines, and other inflammatory mediators in the myocardium, and upregulates the expression of integrin adhesion molecules on both monocytes and endothelial cells, leading to monocyte-endothelial cell-cell interactions. The transendothelial migration of monocyte-derived macrophages exerts significant biological effects on the proliferation of fibroblasts, deposition of extracellular matrix proteins, induction of perivascular/interstitial fibrosis, and development of hypertension, cardiac hypertrophy and heart failure. Inhibition of macrophage activation using Ang II AT1 receptor antagonist or depletion of macrophages from the peripheral circulation has shown significant inhibitory effects on Ang II-induced vascular and myocardial injury. The purpose of this review is to discuss the current understanding in Ang II-induced maladaptive cardiac remodeling and dysfunction, particularly focusing on molecular signaling pathways involved in macrophages-mediated hypertension, cardiac hypertrophy, fibrosis, and failure. In addition, the challenges remained in translating these findings to the treatment of heart failure patients are also addressed. [ABSTRACT FROM AUTHOR]

Denileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. A phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 μg/kg, 15 μg/kg, and 25 μg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. The maximum tolerated dose was 15 μg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1–2. One patient treated at the 25 μg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-β, sIL2Ra in ascites or peripheral blood. Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels. Clinical Trial Registration: ClinicalTrials.gov # NCT00357448 • Ovarian cancer has an immunosuppressive tumor microenvironment that has proven resistant to many immunotherapies. • Denileukin diftitox can be safely given intraperitoneally to treatment refractory ovarian cancer patients. • Intraperitoneal denileukin diftitox reduces regulatory T cells both locally, in ascites, and in the peripheral circulation. • Intraperitoneal immunotherapy is feasible and may decrease immunosuppression in the tumor microenvironment. • The effects of local administration should be considered as novel immunotherapies are developed for ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic prompted unprecedented vaccine development efforts against SARS-CoV-2. India, which was one of the countries most impacted by COVID-19, developed its indigenous vaccine in addition to utilizing the ones developed by other countries. While antibody levels and neutralizing antibody titres are considered initial correlates of immune protection, long-term protection from the pathogen relies on memory B and T cells and their recall responses. In this regard, global research has primarily focused on mRNA-based vaccines. The studies on immune memory response, particularly B cell memory response induced by the vaccines given to Indians, remain relatively obscure. Methods: We assessed Receptor Binding Domain-specific memory B cells in the peripheral circulation and their ability to secrete antigen-specific antibodies among Indians vaccinated with Covaxin (BBV152), Covishield (AZD1222), Corbevax (BECOV2D), and Sputnik Light, as well as unvaccinated individuals. Results: Corbevax and Sputnik Light conferred better antibody-secreting cell (ASC) responses over time compared to other groups. Conclusions: These findings contribute to our understanding of vaccine-induced immune memory in the Indian population; providing insights that could inform future vaccine strategies. [ABSTRACT FROM AUTHOR]

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI® (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.S. Food and Drug Administration approval. The impact of CXCR4 antagonism on other aspects of the pathobiology in WHIM syndrome, such as lymphopoiesis and leukocyte trafficking between primary and secondary lymphoid organs, is less understood. Methods: In the current study, the effects of CXCR4 antagonism on leukocyte trafficking and distribution in primary and secondary lymphoid organs were investigated in a mouse model of WHIM syndrome carrying the heterozygous Cxcr41013 mutation. Cxcr4+/1013 and Cxcr4 wild-type mice received the orally bioavailable CXCR4 antagonist X4-185. Blood, spleen and bone marrow samples were collected for numeration, flow cytometry, and functional studies. Results: Cxcr4+/1013 mice exhibited profound peripheral blood leukopenia as seen in patients with WHIM syndrome. CXCR4 antagonism corrected circulating leukopenia and mobilized functional neutrophils without disrupting granulopoiesis in the bone marrow of Cxcr4+/1013 mice. Furthermore, Cxcr4+/1013 displayed aberrant splenic T and B-cell counts and frequency. Treatment with X4-185 normalized splenic T-cell abnormalities, correcting the reduced CD8+ T-cell numbers, restoring the CD4/CD8 T-cell ratio, and ameliorating peripheral blood T-cell lymphopenia. In addition, CXCR4 antagonism was able to correct the abnormal frequencies and numbers of splenic marginal zone and follicular B cells in Cxcr4+/1013 mice, and ultimately normalize B-cell lymphopenia in the peripheral circulation. Conclusions: Our study provides comprehensive evidence that oral dosing with a CXCR4 antagonist can effectively correct WHIM-associated neutrophil and lymphocyte abnormalities in a mouse model of WHIM syndrome. These findings extend our understanding of how targeting the dysregulated CXCR4 signaling pathway can ameliorate the pathogenesis of WHIM syndrome. [ABSTRACT FROM AUTHOR]

Background: The pathological and physiological characteristics between HBsAg-positive HBV infection and occult hepatitis B infection (OBI) are currently unclear. This study aimed to explore the immune microenvironment in the peripheral circulation of OBI patients through integration of proteomic and metabolomic sequencing, and to identify molecular biomarkers for clinical diagnosis of HBsAg-positive HBV and OBI. Methods: This research involved collection of plasma from 20 patients with OBI (negative for HBsAg but positive for HBV DNA, with HBV DNA levels < 200 IU/mL), 20 patients with HBsAg-positive HBV infection, and 10 healthy individuals. Mass spectrometry-based detection was used to analyze the proteome, while nuclear magnetic resonance spectroscopy was employed to study the metabolomic phenotypes. Differential molecule analysis, pathway enrichment and functional annotation, as well as weighted correlation network analysis (WGCNA), were conducted to uncover the characteristics of HBV-related liver disease. Prognostic biomarkers were identified using machine learning algorithms, and their validity was confirmed in a larger cohort using enzyme linked immunosorbent assay (ELISA). Results: HBsAg-positive HBV individuals showed higher ALT levels (p =0.010) when compared to OBI patients. The influence of HBV infection on metabolic functions and inflammation was evident through the analysis of distinct metabolic pathways in HBsAg-positive HBV and OBI groups. Tissue tracing demonstrated a connection between Kupffer cells and HBsAg-positive HBV infection, as well as between hepatocytes and OBI. Immune profiling revealed the correlation between CD4 Tem cells, memory B cells and OBI, enabling a rapid response to infection reactivation through cytokine secretion and antibody production. A machine learning-constructed and significantly expressed molecule-based diagnostic model effectively differentiated HBsAg-positive and OBI groups (AUC values > 0.8). ELISA assay confirmed the elevation of FGB and FGG in OBI samples, suggesting their potential as biomarkers for distinguishing OBI from HBsAg-positive infection. Conclusions: The immune microenvironment and metabolic status of HBsAg-positive HBV patients and OBI patients vary significantly. The machine learning-based diagnostic model described herein displayed impressive classification accuracy, presenting a non-invasive means of differentiating between OBI and HBsAg-positive HBV infections. [ABSTRACT FROM AUTHOR]

Simple Summary: Drug resistance and unwanted side effects in chemotherapies are major causes of therapeutic complications. To monitor cytotoxic drugs on a personalized scale, fast and easy applicable diagnostics should be developed. Chemotherapeutic agents often induce DNA damage, especially in rapidly dividing (cancer) cells, leading to its death. The detection of γH2AX, a protein involved in DNA damage repair, is considered as an efficient marker for drug-specific cell damage. Furthermore, cell-free DNA formation, a result of drug-induced cell death, may serve as a reliable diagnostic marker. Circulating in the bloodstream, cell-free DNA can be extracted in a minimally invasive way and repeatably quantified during chemotherapy. In time-course studies on drug-treated leukemia T-cells and healthy blood cells, both markers confirmed an enhanced drug response in dividing cells. Additionally, we showed formerly unknown drug-specific differences to timely induce DNA and cell damage. Our combined approach can improve personalized biomonitoring in chemotherapies and provides valuable information for patient biosampling. Background: Improving precision medicine in chemotherapy requires highly sensitive and easily applicable diagnostic tools. In addition, non-invasive molecular real-time monitoring of cytotoxic response is highly desirable. Here, we employed the kinetics of DNA double-strand breaks (DSB) and cell-free DNA (cfDNA) in a cell model of topoisomerase II-inhibitors in T cell leukemia (Jurkat cells) compared to normal cells (peripheral blood mononuclear cells, PBMCs). Methods: We applied automated microscopy to quantify immuno-stained phosphorylated H2AX (γH2AX) as a marker for either DNA damage response (DDR) or cell death and quantitative PCR-based analysis of nuclear and mitochondrial cfDNA concentrations. Results: Jurkat cells displayed a DDR to cytotoxic drug treatment significantly earlier than PBMCs, and etoposide (ETP) induced DSB formation faster than doxorubicin (DOX) in both Jurkat and PBMCs. Jurkat cells exhibited an earlier cytotoxic response compared to PBMC, with a significantly increased mitochondrial cfDNA formation after 2 h of DOX application. In PBMCs, increased cell death was detected after 4 h of incubation with ETP, whereas DOX treatment was less effective. Conclusions: Both automated microscopy and mitochondrial cfDNA quantification analysis indicate that (malignant) Jurkat cells are more sensitive to DOX than (healthy) PBMC. Our real-time approach can improve DDR inducing drug selection and adaptation in cancer therapy and aids in decisions for optimal patient biosampling. [ABSTRACT FROM AUTHOR]

Background: Enhancing venous return during cardiopulmonary resuscitation (CPR) can lead to better hemodynamics and improved outcome after cardiac arrest (CA). Peripheral Intravenous Analysis (PIVA) provides feedback on venous flow changes and may indicate an increase in venous return and cardiac output during CPR. We hypothesize PIVA can serve as an early indicator of increased venous return, preceding end-tidal CO2 (etCO2) increase, before the return of spontaneous circulation (ROSC) in a rat model of CA and CPR. Results: Eight male Wistar rats were intubated and ventilated, and etCO2 was measured. Vessels were cannulated in the tail vein, femoral vein, femoral artery, and central venous and connected to pressure transducers. Ventilation was discontinued to achieve asphyxial CA. After 8 min, CPR began with ventilation, epinephrine, and automated chest compressions 200 times per minute until mean arterial pressure increased to 120 mmHg. Waveforms were recorded and analyzed. PIVA was calculated using a Fourier transformation of venous waveforms. Data are mean ± SE. Maximum PIVA values occurred in the tail vein 34.7 ± 2.9 s before ROSC, with subsequent PIVA peaks in femoral vein and centrally at 30.9 ± 5.4 and 25.1 ± 5.0 s, respectively. All PIVA peaks preceded etCO2 increase (21.5 ± 3.2 s before ROSC). Conclusion: PIVA consistently detected venous pressure changes prior to changes in etCO2. This suggests that PIVA has the potential to serve as an important indicator of venous return and cardiac output during CPR, and also as a predictor of ROSC. [ABSTRACT FROM AUTHOR]

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Abstract Background Microcirculation abnormality in septic shock is closely associated with organ dysfunction and mortality rate. It was hypothesized that the arterial blood glucose and interstitial fluid (ISF) glucose difference (GA−I) as a marker for assessing the microcirculation status can effectively evaluate the severity of microcirculation disturbance in patients with septic shock. Methods The present observational study enrolled patients with septic shock admitted to and treated in the intensive care unit (ICU) of a tertiary teaching hospital. The parameters reflecting organ and tissue perfusion, including lactic acid (Lac), skin mottling score, capillary refill time (CRT), venous-to-arterial carbon dioxide difference (Pv-aCO2), urine volume, central venous oxygen saturation (ScvO2) and GA−I of each enrolled patient were recorded at the time of enrollment (H0), H2, H4, H6, and H8. With ICU mortality as the primary outcome measure, the ICU mortality rate at any GA−I interval was analyzed. Results A total of 43 septic shock patients were included, with median sequential organ failure assessment (SOFA) scores of 10.5 (6–16), and median Acute Physiology and Chronic Health Evaluation (APACHAE) II scores of 25.7 (9–40), of whom 18 died during ICU stay. The GA−I levels were negative correlation with CRT (r = 0.369, P

Background: The shaping of the tumor immune microenvironment does not only rely on tumor-infiltrating lymphocytes but on the recruitment of lymphocytes in peripheral blood. Monitoring peripheral blood lymphocyte subsets level (PBLSL) can predict treatment response and prognosis with immune checkpoint inhibitors. This study investigated the heterogeneity of PBLSL in response to chemoradiotherapy (CRT) or combined with immunotherapy (CRIT) in advanced lung cancer patients. Methods: 77 patients with advanced lung cancer receiving CRT or CRIT were divided into treatment-responsive and non-responsive groups based on efficacy. The study analyzed short-term efficacy and progression-free survival (PFS) according to baseline PBLSL and explored the impact under different stratifications, including treatment modality, pathology type, and age. Results: In all patients, higher levels of B cells, higher CD4+/CD8+ T cell ratios, and lower CD8+ T cell levels were associated with better short-term outcomes (P = 0.0035, P = 0.044, P = 0.022). Subgroup analysis revealed that in the CRT group, higher B cell levels correlated with improved efficacy (P = 0.011) and superior PFS (P = 0.048, HR = 0.3886, 95% CI = 0.1696 to 0.8902). In the CRIT group, higher CD4+ T cell levels, lower CD8+ T cell levels, and higher CD4+/CD8+ T cell ratios were linked to better efficacy (P = 0.038, P = 0.047, P = 0.017). For adenocarcinoma patients, higher CD4+/CD8+ T cell ratios and lower CD8+ T cell levels predicted better efficacy (P = 0.0155, P = 0.0119). B cell levels were significant in squamous cell carcinoma (P = 0.0291), while no PBLSL was predictive for small cell lung cancer. Among patients under 65, higher B cell levels were linked to improved efficacy and prolonged PFS (P = 0.0036, P = 0.0332, HR = 0.4111, 95% CI = 0.1973 to 0.8563). For patients over 65, differences in CD4+ T cell levels and CD4+/CD8+ T cell ratios were significant (P = 0.0433, P = 0.0338). Conclusion: PBLSL predicted efficacy and prognosis in various patient stratifications, suggesting PBLSL is a reliable predictor for CRT and CRIT in advanced lung cancer. Detecting different cellular subpopulations helps identify patients with significant treatment responses across different stratifications. [ABSTRACT FROM AUTHOR]

Background: Postmenopausal osteoporosis (PMO) results from a reduction in bone mass and microarchitectural deterioration in bone tissue due to estrogen deficiency, which may increase the incidence of fragility fractures. In recent years, the "gut-immune response-bone" axis has been proposed as a novel potential approach in the prevention and treatment of PMO. Studies on ovariectomized murine model indicated the reciprocal role of Th17 cells and Treg cells in the aetiology of osteoporosis. However, the relationship among gut microbiota, immune cells and bone metabolic indexes remains unknown in PMO. Methods: A total of 77 postmenopausal women were recruited for the study and divided into control (n = 30), osteopenia (n = 19), and osteoporosis (n = 28) groups based on their T score. The frequency of Treg and Th17 cells in lymphocytes were analyzed by flow cytometry. The serum levels of interleukin (IL)-10, 17 A, 1β, 6, tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) were determined via enzyme-linked immunosorbent assay. Additionally, 16S rRNA gene V3-V4 region sequencing analysis was performed to investigate the gut microbiota of the participants. Results: The results demonstrated decreased bacterial richness and diversed intestinal composition in PMO. In addition, significant differences of relative abundance of the gut microbial community in phylum and genus levels were found, mainly including increased Bacteroidota, Proteobacteria, and Campylobacterota, as well as reduced Firmicutes, Butyricicoccus, and Faecalibacterium. Intriugingly, in the osteoporosis group, the concentration of Treg cells and associated IL-10 in peripheral circulation was negatively regulated, while other chronic systemic proinflammatory cytokines and Th17 cells showed opposite trends. Moreover, significantly elevated plasma lipopolysaccharide (LPS) in patients with osteoporosis indicated that disrupted intestinal integrity and permeability. A correlation analysis showed close relationships between gut bacteria and inflammation. Conclusions: Collectively, these observations will lead to a better understanding of the relationship among bone homeostasis, the microbiota, and circulating immune cells in PMO. The elevated LPS levels of osteoporosis patients which not only indicate a breach in intestinal integrity but also suggest a novel biomarker for assessing osteoporosis risk linked to gut health. [ABSTRACT FROM AUTHOR]

Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in potentiating neo-angiogenesis and vessel stabilization. We show that the endothelium is a major source of TRAIL in the healthy circulation compromised in peripheral artery disease (PAD). EC deletion of TRAIL in vivo or in vitro inhibited neo-angiogenesis, pericyte recruitment, and vessel stabilization, resulting in reduced lower-limb blood perfusion with ischemia. Activation of the TRAIL receptor (TRAIL-R) restored blood perfusion and stable blood vessel networks in mice. Proof-of-concept studies showed that Conatumumab, an agonistic TRAIL-R2 antibody, promoted vascular sprouts from explanted patient arteries. Single-cell RNA sequencing revealed heparin-binding EGF-like growth factor in mediating EC-pericyte communications dependent on TRAIL. These studies highlight unique TRAIL-dependent mechanisms mediating neo-angiogenesis and vessel stabilization and the potential of repurposing TRAIL-R2 agonists to stimulate stable and functional microvessel networks to treat ischemia in PAD. [ABSTRACT FROM AUTHOR]

Arterial carbon dioxide ( Pa CO 2 ) and posture influence the middle (MCAv) and posterior (PCAv) cerebral artery blood velocities, but there is paucity of data about their interaction and need for an integrated model of their effects, including dynamic cerebral autoregulation (dCA). In 22 participants (11 males, age 30.2 ± 14.3 yr), blood pressure (BP, Finometer), dominant MCAv and nondominant PCAv (transcranial Doppler ultrasound), end-tidal CO2 (EtCO2, capnography), and heart rate (HR, ECG) were recorded continuously. Two recordings (R) were taken when the participant was supine (R1, R2), two taken when the participant was sitting (R3, R4), and two taken when the participant was standing (R5, R6). R1, R3, and R5 consisted of 3 min of 5% CO2 through a mask and R2, R4, and R6 consisted of 3 min of paced hyperventilation. The effects of Pa CO 2 were expressed with a logistic curve model (LCM) for each parameter. dCA was expressed by the autoregulation index (ARI), derived by transfer function analysis. Standing shifted LCM to the left for MCAv (P < 0.001), PCAv (P < 0.001), BP (P = 0.03), and ARI (P = 0.001); downward for MCAv and PCAv (both P < 0.001), and upward for HR (P < 0.001). For BP, LCM was shifted downward by sitting and standing (P = 0.024). For ARI, the hypercapnic range of LCM was shifted upward during standing (P < 0.001). A more complete mapping of the combined effects of posture and arterial CO2 on the cerebral circulation and peripheral variables can be obtained with the LCM over a broad physiological range of EtCO2 values. NEW & NOTEWORTHY: Data from supine, sitting, and standing postures were measured. Modeling the data with logistic curves to express the effects of CO2 reactivity on middle cerebral artery blood velocity (MCAv), posterior cerebral artery blood velocity (PCAv), heart rate, blood pressure (BP), and the autoregulation index (ARI), provided a more comprehensive approach to study the interaction of arterial CO2 with posture than in previous studies. Above all, shifts of the logistic curve model with changes in posture have shown interactions with Pa CO 2 that have not been previously demonstrated. [ABSTRACT FROM AUTHOR]

In the pathogenesis and progression of Sjögren's syndrome (SS), hematopoietic cells in the peripheral circulation, tissue-resident immune cells, and parenchymal cells of salivary gland tissues (such as epithelial cells, endothelial cells, fibroblasts, etc.) all play crucial roles. These diverse cells form intricate networks and interact with each other, leading to tissue destruction and persistent chronic inflammation, ultimately causing irreversible damage in glandular function. Among these, salivary gland epithelial cells (SGECs) consistently hold a key position, characterized by their functions in expressing co-stimulatory and antigen-presenting molecules and secreting pro-inflammatory cytokines and chemokines. Moreover, SGECs actively engage in and facilitate the development of specific pathological structures within the salivary gland, such as lymphoepithelial lesions (LELs) and tertiary lymphoid structures (TLSs), thereby substantially elevating the risk of mucosa-associated lymphoid tissue (MALT) lymphoma. Overall, SGECs are recognized for their essential and irreplaceable contributions to the pathogenesis of SS. This review article initially delves into the anatomical composition of salivary gland epithelial cells, subsequently focusing on elucidating the different cytokines derived from SGECs, encompassing chemokines, pro-inflammatory cytokines, anti-inflammatory cytokines, prosurvival cytokines, and damage-associated molecular patterns (DAMPs), to explore their key roles in the pathogenesis of SS. [ABSTRACT FROM AUTHOR]

Introduction: Endometriosis (EMs) and adenomyosis (AD) are common gynecological diseases that impact women's health, and they share symptoms such as dysmenorrhea, chronic pain, and infertility, which adversely affect women's quality of life. Current diagnostic approaches for EMs and AD involve invasive surgical procedures, and thus, methods of noninvasive differentiation between EMs and AD are needed. This retrospective cohort study introduces a novel, noninvasive classification methodology employing a stacked ensemble machine learning (ML) model that utilizes peripheral blood and coagulation markers to distinguish between EMs and AD. Methods: The study included a total of 558 patients (329 with EMs and 229 with AD), in whom key hematological and coagulation markers were analyzed to identify distinctive profiles. Feature selection was conducted through ML (logistic regression, support vector machine, and K-nearest neighbors) to determine significant hematological markers. Results: Red cell distribution width, mean corpuscular hemoglobin concentration, activated partial thromboplastin time, international normalized ratio, and antithrombin III were proved to be the key distinguishing indexes for disease differentiation. Among all the ML classification models developed, the stacked ensemble model demonstrated superior performance (area under the curve = 0.803, 95% credibility interval = 0.701-0.904). Our findings demonstrate the effectiveness of the stacked ensemble ML model for classifying EMs and AD. Discussion: Integrating biomarkers into this multi-algorithm framework offers a novel approach to noninvasive diagnosis. These results advocate for the application of stacked ensemble ML utilizing cost-effective and readily available peripheral blood and coagulation indicators for the early, rapid, and noninvasive differential diagnosis of EMs and AD, offering a potentially transformative approach for clinical decision-making and personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDDs) are a diverse group of neurological disorders characterized by alterations in the structure and function of the central nervous system. Alzheimer's disease (AD), characterized by impaired memory and cognitive abilities, is the most prevalent type of senile dementia. Loss of synapses, intracellular aggregation of hyperphosphorylated tau protein, and extracellular amyloid-β peptide (Aβ) plaques are the hallmarks of AD. MicroRNAs (miRNAs/miRs) are single-stranded ribonucleic acid (RNA) molecules that bind to the 3′ and 5′ untranslated regions of target genes to cause post-transcriptional gene silencing. The brain expresses over 70% of all experimentally detected miRNAs, and these miRNAs are crucial for synaptic function and particular signals during memory formation. Increasing evidence suggests that miRNAs play a role in AD pathogenesis and we provide an overview of the role of miRNAs in synapse formation, Aβ synthesis, tau protein accumulation, and brain-derived neurotrophic factor-associated AD pathogenesis. We further summarize and discuss the role of miRNAs as potential therapeutic targets and biomarkers for AD detection and differentiation between early- and late-stage AD, based on recent research. In conclusion, altered expression of miRNAs in the brain and peripheral circulation demonstrates their potential as biomarkers and therapeutic targets in AD. [ABSTRACT FROM AUTHOR]

Impaired clearance of amyloid β (Aβ) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aβ clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aβ-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aβ-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aβ levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aβ-binding monocytes may play a role in CNS Aβ clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring. Impaired Aβ clearance in late-onset Alzheimer's disease (AD) affects progression. Here, the authors show that CD14 + CD16+ monocytes carry Aβ in peripheral circulation and CSF in AD, suggesting a role in Aβ clearance. [ABSTRACT FROM AUTHOR]

Background: Microcirculation abnormality in septic shock is closely associated with organ dysfunction and mortality rate. It was hypothesized that the arterial blood glucose and interstitial fluid (ISF) glucose difference (GA−I) as a marker for assessing the microcirculation status can effectively evaluate the severity of microcirculation disturbance in patients with septic shock. Methods: The present observational study enrolled patients with septic shock admitted to and treated in the intensive care unit (ICU) of a tertiary teaching hospital. The parameters reflecting organ and tissue perfusion, including lactic acid (Lac), skin mottling score, capillary refill time (CRT), venous-to-arterial carbon dioxide difference (Pv-aCO2), urine volume, central venous oxygen saturation (ScvO2) and GA−I of each enrolled patient were recorded at the time of enrollment (H0), H2, H4, H6, and H8. With ICU mortality as the primary outcome measure, the ICU mortality rate at any GA−I interval was analyzed. Results: A total of 43 septic shock patients were included, with median sequential organ failure assessment (SOFA) scores of 10.5 (6–16), and median Acute Physiology and Chronic Health Evaluation (APACHAE) II scores of 25.7 (9–40), of whom 18 died during ICU stay. The GA−I levels were negative correlation with CRT (r = 0.369, P < 0.001), Lac (r = -0.269, P < 0.001), skin mottling score (r=-0.223, P < 0.001), and were positively associated with urine volume (r = 0.135, P < 0.05). The ICU mortality rate of patients with septic shock presenting GA−I ≤ 0.30 mmol/L and ≥ 2.14 mmol/L was significantly higher than that of patients with GA−I at 0.30–2.14 mmol/L [65.2% vs. 15.0%, odds ratio (OR) = 10.625, 95% confidence interval (CI): 2.355–47.503]. Conclusion: GA−I was correlated with microcirculation parameters, and with differences in survival. Future studies are needed to further explore the potential impact of GA−I on microcirculation and clinical prognosis of septic shock, and the bedside monitoring of GA−I may be beneficial for clinicians to identify high-risk patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor cells (CTCs) play an important role in the formation of metastases in the body. Various approaches have been proposed to cleanse the blood of these CTCs and thus prevent the formation of metastases. However, the efficiency of non-implantable blood purification devices for CTC removal has not yet been clearly demonstrated. Here, we have attempted to evaluate, with a simple computer simulation, whether the use of a non-implantable device for CTC excision can be effective and lead to a significant reduction in metastases. We show that non-implantable devices for CTC removal are de facto ineffective in terms of reducing metastases due to various factors. The results of this work argue that only implantable devices can successfully deplete metastasis-relevant CTCs and potentially reduce the metastatic burden of cancer patients. Circulating tumor cells (CTCs) are cells that have separated from a solid cancerous lesion and entered the bloodstream. They play a crucial role in driving the metastatic spread to distant organs, which is the leading cause of cancer-related deaths. Various concepts for blood purification devices aiming to remove CTCs from the blood and prevent metastases have been developed. Until now, it is not clear if such devices can indeed reduce new metastasis formation in a significant way. Here, we present a simple theoretical model of CTCs in the bloodstream that can be used to predict a reduction in metastatic burden using an extracorporeal or intracorporeal blood purification device. The model consists of a system of ordinary differential equations that was numerically solved and simulated. Various simulations with different parameter settings of extracorporeal and intracorporeal devices revealed that only devices implanted directly in tumor-draining vessels can reduce the metastatic burden significantly. Even if an extracorporeal device is used permanently, the reduction in metastases is only 82%, while a permanently operating implanted device in the tumor-draining vessel would achieve a reduction of 99.8%. These results are mainly due to the fact that only a small fraction of CTCs reaches peripheral circulation, resulting in a proportionally small amount of purified blood in extracorporeal devices. [ABSTRACT FROM AUTHOR]

Highlights Doppler ultrasound may be used to assess leg blood flow (Q̇leg${{\dot{Q}}_{{\mathrm{leg}}}}$), but the reliability of this method remains unexplored in patients with chronic obstructive pulmonary disease (COPD), where between‐subject variability may be larger than healthy due to peripheral vascular changes. This study aimed to investigate the reliability of Doppler ultrasound in quantifying Q̇leg${{\dot{Q}}_{{\mathrm{leg}}}}$ during single‐leg knee‐extensor exercise (KEE) in COPD patients compared with those obtained from healthy matched controls. In this case–control study, 16 participants with COPD were matched based on sex and age with 16 healthy controls. All participants underwent measurement of Q̇leg${{\dot{Q}}_{{\mathrm{leg}}}}$ using Doppler ultrasound in a KEE set‐up at various intensities on two separate visits. Confounding factors on Q̇leg${{\dot{Q}}_{{\mathrm{leg}}}}$ were controlled for, and the ultrasound scans were consistently performed by the same sonographer. During exercise, smallest real difference (SRD) ranged from 367 mL to 583 mL in COPD and 438 mL to 667 mL in the control group. The coefficient of variation (CV) ranged from 7.9% to 14.3% in COPD and 9.4% to 10.4% in the control group. The intraclass correlation coefficient ranged from 0.75 to 0.92 in COPD and 0.67 to 0.84 in the control group. CV was lower in the control group during exercise at 0 W, but apart from that, reliability was not different between groups during exercise. Doppler ultrasound showed nearly equal reliability when evaluating Q̇leg${{\dot{Q}}_{{\mathrm{leg}}}}$ in COPD patients and healthy individuals with a CV below 15% during exercise for both groups. What is the central question of this study? What is the between‐day reliability of Doppler ultrasound when quantifying leg blood flow during single‐leg knee‐extensor exercise in COPD patients compared to healthy matched controls? What is the main finding and its importance? This study demonstrates a coefficient of variation ranging from 7.9 to 14.3% during single‐leg knee‐extensor exercise for between‐day reliability when applying Doppler ultrasound to assess leg blood flow in patients with COPD. Furthermore, it offers insights into the peripheral circulatory constraints in COPD, as evidenced by diminished leg blood flow. This study is the first of its kind to evaluate the reliability of Doppler ultrasound in the assessment of the peripheral circulation during exercise in COPD. What is the central question of this study?What is the between‐day reliability of Doppler ultrasound when quantifying leg blood flow during single‐leg knee‐extensor exercise in COPD patients compared to healthy matched controls?What is the main finding and its importance?This study demonstrates a coefficient of variation ranging from 7.9 to 14.3% during single‐leg knee‐extensor exercise for between‐day reliability when applying Doppler ultrasound to assess leg blood flow in patients with COPD. Furthermore, it offers insights into the peripheral circulatory constraints in COPD, as evidenced by diminished leg blood flow. This study is the first of its kind to evaluate the reliability of Doppler ultrasound in the assessment of the peripheral circulation during exercise in COPD. [ABSTRACT FROM AUTHOR]

Objective: Neutrophil extracellular traps (NETs) are important factors in initiating and perpetuating inflammation. However, the role of NETs in different subtypes of juvenile idiopathic arthritis (JIA) has been rarely studied. Therefore, we aimed to explore the ability of JIA-derived neutrophils to release NETs and the effect of TNF-α (tumor necrosis factor-alpha) inhibitors on NET formation both in vitro and in vivo, and evaluate the associations of NET-derived products with clinical and immune-related parameters. Methods: The ability of neutrophils to release NETs and the effect of adalimumab on NET formation was assessed via in vitro stimulation and inhibition studies. Plasma NET-derived products were detected to assess the incidence of NET formation in vivo. Furthermore, flow cytometry and western blotting were used to detect NET-associated signaling components in neutrophils. Results: Compared to those derived from HCs, neutrophils derived from patients with oligoarticular-JIA, polyarticular-JIA and enthesitis-related arthritis were more prone to generate NETs spontaneously and in response to TNF-α or PMA in vitro. Excessive NET formation existed in peripheral circulation of JIA patients, and elevated plasma levels of NET-derived products (cell-free DNA and MPO-DNA complexes) could accurately distinguish JIA patients from HCs and were positively correlated with disease activity. Multiple linear regression analysis showed that erythrocyte sedimentation rate and TNF-a levels were independent variables and were positively correlated with cell-free DNA concentration. Notably, TNF-a inhibitors could effectively prevent NET formation both in vitro and in vivo. Moreover, the phosphorylation levels of NET-associated kinases in JIA-derived neutrophils were markedly increased. Conclusion: Our data suggest that NETs might play pathogenic roles and may be involved in TNF-α-mediated inflammation in JIA. Circulating NET-derived products possess potential diagnostic and disease monitoring value. Furthermore, the preliminary results related to the molecular mechanisms of NET formation in JIA patients provide a theoretical basis for NETtargeted therapy. [ABSTRACT FROM AUTHOR]

Maternal obesity during pregnancy is associated with adverse pregnancy outcomes. This might be due to undesired obesity-induced changes in the maternal gut microbiota and related changes in the maternal immune adaptations during pregnancy. The current study examines how obesity affects gut microbiota and immunity in pregnant obese and lean mice during mid-pregnancy (gestational day 12 (GD12)). C57BL/6 mice were fed a high-fat diet or low-fat diet from 8 weeks before mating and during pregnancy. At GD12, we analyzed the gut microbiota composition in the feces and immune responses in the intestine (Peyer's patches, mesenteric lymph nodes) and the peripheral circulation (spleen and peripheral blood). Maternal obesity reduced beneficial bacteria (e.g., Bifidobacterium and Akkermansia) and changed intestinal and peripheral immune responses (e.g., dendritic cells, Th1/Th2/Th17/Treg axis, monocytes). Numerous correlations were found between obesity-associated bacterial genera and intestinal/peripheral immune anomalies. This study shows that maternal obesity impacts the abundance of specific bacterial gut genera as compared to lean mice and deranges maternal intestinal immune responses that subsequently change peripheral maternal immune responses in mid-pregnancy. Our findings underscore the opportunities for early intervention strategies targeting maternal obesity, ideally starting in the periconceptional period, to mitigate these obesity-related pregnancy effects. [ABSTRACT FROM AUTHOR]

Objective To explore the value of peripheral blood circulating DNA in predicting the efficacy and prognosis of immunotherapy for advanced non-small cell lung cancer. Method A retrospective study was conducted on 78 NSCLC patients who were admitted to the Respiratory and Critical Care Medicine Department of the First Affiliated Hospital of Hebei North University and were treated with tirelizumab for advanced driver gene negativity from January 2021 to December 2021. After 2 cycles of immunotherapy, the efficacy was evaluated according to the Solid Tumor Efficacy Evaluation Criteria (RECIST 1.1), including complete remission, partial remission, disease stability, and disease progression. CR and PR patients were defined as the experimental group (n = 48) Other patients were defined as the control group (n = 30), and the ctDNA levels in peripheral blood were measured before and after treatment in both groups. ROC curves were used to analyze the predictive value of periph eral blood ctDNA levels for achieving objective remission after immunotherapy.All patients were followed up and their progression free survival were calcutated.Using univariate and multivariate regression analysis identified the factors affecting the prognosis of patients after immunotherapy. Using Spearman correlation coefficient analyzed the correlation between ctDNA levels and PFS. Kalplan Meier survival curve were used for survival analysis. Result The peripheral blood ctDNA levels before and after treatment in the experimental group were (4.47 ± 1.21)ng/μL and (2.65 ± 1.14) ng/μL, respectively (t = 7.559,P < 0.001), while those in the control group were (4.54 ± 1.15)ng/mL and (4.29 ± 1.57) ng/μL, respectively (t = 0.699,P = 0.487). There was no statistically significant difference in peripheral blood ctDNA levels between the two groups before treatment (t = -0.25,P = 0.801). The peripheral blood ctDNA levels in the experimental group decreased compared to the control group after treatment (t = -5.35,P < 0.001). The ROC curve analysis showed that the area under the curve for predicting objective remission after immunotherapy based on peripheral blood ctDNA levels was 0.819, with a sensitivity of 81.3% and specificity of 80%. Peripheral blood ctDNA levels were negatively correlated with progression free survival (r = -0.784,P = 0.000). Single factor COX regression was used to analyze the clinical and pathological characteristics and ctDNA levels of enrolled patients, and the results showed that the maximum tumor diameter was greater than 5 cm (HR = 0.501, 95% CI: 6.731 ~ 35.567) Tumor stage IV (HR = 0.392,95% CI: 0.227 ~ 0.677), treatment approach (HR = 15.473,95% CI: 6.731 ~ 35.567), and ctDNA levels (HR = 4.657,95% CI: 3.182 ~ 6.555) are all influencing factors for PFS in advanced NSCLC patients after immunotherapy. Multiple factor analysis was conducted on the appeal indicators with statistical differences, and the results showed that treatment approach (HR = 2.981,95% CI:1.019 ~ 8.722) and peripheral blood ctDNA levels (HR = 3.918,95% CI: 2.619 ~ 5.861) It is an independent influencing factor of PFS in advanced NSCLC patients. The Kalplan Meier survival curve was used for analysis, and the results showed that the median PFS of the treatment effective group was 8.4 months, while the median PFS of the control group was 5.4 months. (χ² = 49.277, P = 0.000). Conclusion Immunotherapy combined with chemotherapy can enhance the ability to kill tumor cells, and peripheral blood ctDNA levels can evaluate the efficacy and prognosis of immunotherapy, which can be used to guide immunotherapy in advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Introduction: Filariasis, a parasitic infection caused by several types of nematode worms, is a matter of great concern for public health in India, The disease is caused by microfilaria, which are released into the peripheral blood circulation with periodicity during the night. However, identifying microfilaria in routine peripheral blood smears, Fine Needle Aspiration (FNAC) smears, and body fluids is challenging due to their scarce nature. Our study aimed to underscore the significance of having a heightened suspicion of filarial infection in patients with swelling, particularly those from endemic regions. Furthermore, the study emphasised the importance of using FNAC as an economical and effective diagnostic tool for detecting microfilaria. Materials and Methods: This retrospective study was conducted in the Pathology Department of ESIC Medical College and Hospital Gulbarga over a period of ten years (2013-2023). A 22-23 gauze needle made aspiration smears were stained by Papanicolaou and May-Grünwald Giemsa stain. Results: In this study, 24 cases showed the presence of microfilaria, a type of parasitic worm, despite the lack of clinical suspicion. Of these cases, eight involved breast lumps, eight involved thyroid swelling, and eight involved lymph nodes. In fifteen of these cases, fragments of adult worms were also reported, indicating a potentially more severe infection. These findings suggest the need for more diligent screening and testing to detect and treat parasitic infections before they can cause further harm. Conclusion: Filariasis is a rare disease that requires thorough screening of FNA smears, particularly in asymptomatic patients from endemic regions, to avoid missing incidental findings. Moreover, the study emphasises the cost-effectiveness and efficacy of FNAC in diagnosing microfilaria. [ABSTRACT FROM AUTHOR]

The treatment of patients diagnosed with hematologic malignancies typically includes hematopoietic stem cell transplantation (HSCT) as part of a therapeutic standard of care. The primary graft source of hematopoietic stem and progenitor cells (HSPCs) for HSCT is mobilized from the bone marrow into the peripheral blood of allogeneic donors or patients. More recently, these mobilized HSPCs have also been the source for gene editing strategies to treat diseases such as sickle-cell anemia. For a HSCT to be successful, it requires the infusion of a sufficient number of HSPCs that are capable of adequate homing to the bone marrow niche and the subsequent regeneration of stable trilineage hematopoiesis in a timely manner. Granulocyte-colony-stimulating factor (G-CSF) is currently the most frequently used agent for HSPC mobilization. However, it requires five or more daily infusions to produce an adequate number of HSPCs and the use of G-CSF alone often results in suboptimal stem cell yields in a significant number of patients. Furthermore, there are several undesirable side effects associated with G-CSF, and it is contraindicated for use in sickle-cell anemia patients, where it has been linked to serious vaso-occlusive and thrombotic events. The chemokine receptor CXCR4 and the cell surface integrin α4β1 (very late antigen 4 (VLA4)) are both involved in the homing and retention of HSPCs within the bone marrow microenvironment. Preclinical and/or clinical studies have shown that targeted disruption of the interaction of the CXCR4 or VLA4 receptors with their endogenous ligands within the bone marrow niche results in the rapid and reversible mobilization of HSPCs into the peripheral circulation and is synergistic when combined with G-CSF. In this review, we discuss the roles CXCR4 and VLA4 play in bone marrow homing and retention and will summarize more recent development of small-molecule CXCR4 and VLA4 inhibitors that, when combined, can synergistically improve the magnitude, quality and convenience of HSPC mobilization for stem cell transplantation and ex vivo gene therapy after the administration of just a single dose. This optimized regimen has the potential to afford a superior alternative to G-CSF for HSPC mobilization. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) have regenerative and immunomodulatory potential and may be used to treat injured tissues. Pregnancy has been associated with increased MSCs in the peripheral circulation in multiple species, but to date, there are no reports on this matter in horses. This study aimed to evaluate the effect of pregnancy on isolation efficiency and proliferation capacity of equine MSCs derived from the peripheral blood (PB) of mares. Venous blood samples were collected at the 11th month of gestation and 1 month after delivery from clinically healthy Arabian mares that presented normal pregnancies. Blood samples were processed for in vitro cellular culture and hormonal and metabolic profiles. MSCs were isolated and characterized by trilineage differentiation potential, immunophenotyping, analyzed by gene sequencing and proliferation assays. The isolation of peripheral blood mononuclear cells (PBMCs) of pregnant mares were associated with higher isolation efficiency and proliferative capacity of MSCs derived from peripheral blood (PB-MSCs) recovered pre-partum than those isolated post-partum. Although fetal gender, parity, 5α-reduced pregnanes, insulin, and cortisol were shown to affect cellular proliferation, individual factors and the small population studied must be considered. This study suggests that PB-MSCs from pregnant mares could be a valuable alternative source of MSCs for therapeutic purposes. • Lack of reports onthe isolation of mesenchymal stromal cells (MSCs) from peripheral blood (PB-MSCs) in pregnant mares. • Pregnancy in Arabian mares was associated with higher isolation efficiency and proliferative capacity of PB-MSCs. • Fetal gender, parity, and levels of 5α-reduced pregnanes, insulin and cortisol were shown to affect cellular proliferation. • Pregnant mares could be a valuable, readily available source of MSCs for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Skin tissue-resident memory T (Trm) cells are produced by antigenic stimulation and remain in the skin for a long time without entering the peripheral circulation. In the healthy state Trm cells can play a patrolling and surveillance role, but in the disease state Trm cells differentiate into various phenotypes associated with different diseases, exhibit different localizations, and consequently have local protective or pathogenic roles, such as disease recurrence in vitiligo and maintenance of immune homeostasis in melanoma. The most common surface marker of Trm cells is CD69/CD103. However, the plasticity of tissueresident memory T cells after colonization remains somewhat uncertain. This ambiguity is largely due to the variation in the functionality and ultimate destination of Trm cells produced from memory cells differentiated from diverse precursors. Notably, the presence of Trm cells is not stationary across numerous non-lymphoid tissues, most notably in the skin. These cells may reenter the blood and distant tissue sites during the recall response, revealing the recycling and migration potential of the Trm cell progeny. This review focuses on the origin and function of skin Trm cells, and provides new insights into the role of skin Trm cells in the treatment of autoimmune skin diseases, infectious skin diseases, and tumors. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB) is an extensive capillary network that protects the brain from environmental and metabolic toxins while limiting drug delivery to the central nervous system (CNS). The ATP-binding cassette transporter breast cancer resistance protein (Bcrp) reduces drug delivery across the BBB by actively transporting its clinical substrates back into peripheral circulation before their entry into the CNS compartment. 17β-Estradiol (E2)-elicited changes in Bcrp transport activity and expression have been documented previously. We report a novel signaling mechanism by which E2 decreases Bcrp transport activity in mouse brain capillaries via rapid nongenomic signaling through estrogen receptor α. We extended this finding to investigate the effects of different endocrine-disrupting compounds (EDCs) and selective estrogen receptor modulators (SERMs) on Bcrp transport function. We also demonstrate sex-dependent expression of Bcrp and E2-sensitive Bcrp transport activity at the BBB ex vivo. This work establishes an explanted tissue-based model by which to interrogate EDCs and SERMs as modulators of nongenomic estrogenic signaling with implications for sex and hormonal regulation of therapeutic delivery into the CNS. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus, a chronic metabolic disease, can lead to serious complications, including impaired blood circulation in the extremities, termed diabetic foot, leading to peripheral neuropathy and poor perfusion. Objectives: This study aimed to assess the impact of diabetic foot exercise on improving blood circulation among diabetic patients. Design: This case study utilized a descriptive method on two diabetic patients in Teratai Room, RSU Wonolangan Probolinggo. Foot exercise intervention was implemented three times weekly for 15–20 minutes. Results: Both patients showed improvement in peripheral blood circulation, indicated by Ankle Brachial Index (ABI) scores within the mild obstruction range after consistent foot exercise. Conclusion: Regular diabetic foot exercises may enhance blood circulation and prevent complications among diabetes mellitus patients.

The editorial discusses the importance of the blood-brain barrier (BBB) in regulating the transport of molecules between the brain and blood circulation, protecting the brain from pathogens and toxins. Disruption of the BBB is associated with neuroinflammatory and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. The research topic presented in the article explores various aspects of BBB dysfunction in brain diseases and potential therapeutic interventions. Understanding these mechanisms is crucial for assessing disease severity and developing effective treatments for brain disorders. [Extracted from the article]

Purpose: We aimed to evaluate the ability of the peripheral perfusion index (PPI) to predict reintubation of critically ill surgical patients. Methods: This prospective observational study included mechanically ventilated adults who were extubated after a successful spontaneous breathing trial (SBT). The patients were followed up for the next 48 h for the need for reintubation. The heart rate, systolic blood pressure, respiratory rate, peripheral arterial oxygen saturation (SpO2), and PPI were measured before-, at the end of SBT, 1 and 2 h postextubation. The primary outcome was the ability of PPI 1 h postextubation to predict reintubation using area under the receiver operating characteristic curve (AUC) analysis. Univariate and multivariate analyses were performed to identify predictors for reintubation. Results: Data from 62 patients were analysed. Reintubation occurred in 12/62 (19%) of the patients. Reintubated patients had higher heart rate and respiratory rate; and lower SpO2 and PPI than successfully weaned patients. The AUC (95%confidence interval) for the ability of PPI at 1 h postextubation to predict reintubation was 0.82 (0.71–0.91) with a negative predictive value of 97%, at a cutoff value of ≤ 2.5. Low PPI and high respiratory rate were the independent predictors for reintubation. Conclusion: PPI early after extubation is a useful tool for prediction of reintubation. Low PPI is an independent risk factor for reintubation. A PPI > 2.5, one hour after extubation can confirm successful extubation. [ABSTRACT FROM AUTHOR]

In eukaryotic RNA, N6‐methyladenosine (m6A) is a prevalent form of methylation modification. The m6A modification process is reversible and dynamic, written by m6A methyltransferase complex, erased by m6A demethylase, and recognized by m6A binding proteins. Through mediating RNA stability, decay, alternative splicing, and translation processes, m6A modification regulates gene expression at the post‐transcriptional level. Erythropoiesis is the process of hematopoietic stem cells undergoing proliferation, a series of differentiation and maturation to form red blood cells (RBCs). Thalassemia is a common monogenic disease characterized by excessive production of ineffective RBCs in the peripheral circulation, resulting in hemolytic anemia. Increasing evidence suggests that m6A modification plays a crucial role in erythropoiesis. In this review, we comprehensively summarize the function of m6A modification in erythropoiesis and further generalize the mechanism of m6A modification regulating ineffective erythropoiesis and fetal hemoglobin expression. The purpose is to improve the understanding of the pathogenesis of erythroid dysplasia and offer new perspectives for the diagnosis and treatment of thalassemia. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light chain (NfL) is released into the peripheral circulation by damaged axons. Objective s : To evaluate the diagnostic value of serum NfL concentration in dogs with intracranial diseases. Animals: Study included 37 healthy dogs, 31 dogs with idiopathic epilepsy (IE), 45 dogs with meningoencephalitis of unknown etiology (MUE), 20 dogs with hydrocephalus, and 19 dogs with brain tumors. Methods: Cohort study. Serum NfL concentrations were measured in all dogs using single‐molecule array technology. Results: Serum NfL concentration in dogs with each structural disease was significantly higher than in healthy dogs and dogs with IE (P =.01). The area under the receiver operating characteristic curve of NfL for differentiating between dogs with structural diseases and IE was 0.868. An optimal cutoff value of the NfL 27.10 pg/mL had a sensitivity of 86.67% and a specificity of 74.19% to differentiate the dogs with IE from those with structural brain diseases. There were significant correlations between NfL concentrations and lesion size: (1) MUE, P =.01, r = 0.429; (2) hydrocephalus, P =.01, r = 0.563. Conclusions and Clinical Importance: Serum NfL could be a useful biomarker for distinguishing IE from structural diseases in dogs and predicting the lesion sizes of MUE and hydrocephalus. [ABSTRACT FROM AUTHOR]

Gut microbiome dysbiosis is a major contributing factor to several pathological conditions. However, the mechanistic understanding of the communication between gut microbiota and extra‐intestinal organs remains largely elusive. Extracellular vesicles (EVs), secreted by almost every form of life, including bacteria, could play a critical role in this inter‐kingdom crosstalk and are the focus of present study. Here, we present a novel approach for isolating lipopolysaccharide (LPS)+ bacterial extracellular vesicles (bEVLPS) from complex biological samples, including faeces, plasma and the liver from lean and diet‐induced obese (DIO) mice. bEVLPS were extensively characterised using nanoparticle tracking analyses, immunogold labelling coupled with transmission electron microscopy, flow cytometry, super‐resolution microscopy and 16S sequencing. In liver tissues, the protein expressions of TLR4 and a few macrophage‐specific biomarkers were assessed by immunohistochemistry, and the gene expressions of inflammation‐related cytokines and their receptors (n = 89 genes) were measured using a PCR array. Faecal samples from DIO mice revealed a remarkably lower concentration of total EVs but a significantly higher percentage of LPS+ EVs. Interestingly, DIO faecal bEVLPS showed a higher abundance of Proteobacteria by 16S sequencing. Importantly, in DIO mice, a higher number of total EVs and bEVLPS consistently entered the hepatic portal vein and subsequently reached the liver, associated with increased expression of TLR4, macrophage markers (F4/80, CD86 and CD206), cytokines and receptors (Il1rn, Ccr1, Cxcl10, Il2rg and Ccr2). Furthermore, a portion of bEVLPS escaped liver and entered the peripheral circulation. In conclusion, bEV could be the key mediator orchestrating various well‐established biological effects induced by gut bacteria on distant organs. [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines mediate the course of rosacea, anxiety, and depression through various means such as immunity and inflammation. This study aims to further explore the relationship between rosacea, anxiety, and depression through changes in the levels of pro-inflammatory cytokines. Methods: 280 rosacea patients were included in the rosacea group, divided into: rosacea without mental disorders, rosacea with anxiety, rosacea with depression, and rosacea with combined anxiety and depression. The mental control group included 210 anxiety and depression patients, divided into: anxiety, depression, and combined anxiety and depression. The healthy control group consisted of 70 healthy individuals. Serum specimens were collected and ELISA was used to detect major pro-inflammatory cytokines. CEA, IGA, GFSS, RosaQoL, HAMA, and HAMD-24 were used for the diagnosis and severity assessment of rosacea and anxiety and depression. Results: This study primarily used the Chi-Square test, Kruskal–Wallis H-test, generalized linear model, and binary logistic regression to evaluate the data. IL-1β, IL-17, and IL-8 levels in rosacea patients and anxiety/depression patients were higher than those in the healthy population (P< 0.001), and TNF-α levels in rosacea patients were higher than those in the healthy population (P< 0.001). There was an interaction between rosacea, anxiety, and depression in terms of IL-1β, IL-17, and IL-8 levels (P< 0.001). Elevated levels of IL-1β, IL-17, and IL-8 are positively correlated with anxiety and depression in rosacea (all P<=0.05). Conclusion: It was confirmed that the elevated levels of IL-1β, IL-17, and IL-8 are positively correlated with the onset of anxiety and depression in rosacea. The interaction of the above inflammatory factors suggests a possible common inflammatory mechanism in the coexistence of rosacea and mental disorders. TNF-α only increased in patients with rosacea, combined with the skin-to-mental irreversible phenomenon, indicating that this cytokine may be a key and potential therapeutic target for the onset of rosacea. [ABSTRACT FROM AUTHOR]

Dirofilaria immitis is a mosquito-borne parasitic nematode that causes fatal heartworm disease in canids. The microfilariae are essential for research, including drug screening and mosquito-parasite interactions. However, no reliable methods for maintaining microfilaria long-term are currently available. Therefore, we used severe combined immunodeficiency (SCID) mice to develop a reliable method for maintaining D. immitis microfilaria. SCID mice were injected intravenously with microfilariae isolated from a D. immitis-infected dog. Microfilariae were detected in blood collected from the tail vein 218 days post-inoculation (dpi) and via cardiac puncture 296 dpi. Microfilariae maintained in and extracted from SCID mice showed infectivity and matured into third-stage larvae (L3s) in the vector mosquito Aedes aegypti. L3s can develop into the fourth stage larvae in vitro. Microfilariae from SCID mice respond normally to ivermectin in vitro. The microfilariae in SCID mice displayed periodicity in the peripheral circulation. The SCID mouse model aided in the separation of microfilariae from cryopreserved specimens. The use of SCID mice enabled the isolation and sustained cultivation of microfilariae from clinical samples. These findings highlight the usefulness of the SCID mouse model for studying D. immitis microfilaremia in canine heartworm research. [ABSTRACT FROM AUTHOR]

Introduction: This study assesses the accuracy of neutrophil activation markers, including neutrophil extracellular traps (NETs) and calprotectin, as biomarkers of disease activity in patients with established rheumatoid arthritis (RA). We also analyse the relationship between NETs and various types of therapies as well as their association with autoimmunity. Methods: Observational cross-sectional study of patients with RA receiving treatment with biological disease-modifying antirheumatic drugs or Janus kinase inhibitors (JAK-inhibitors) for at least 3 months. Plasma calprotectin levels were measured using an enzyme-linked immunosorbent assay test kit and NETs by measuring their remnants in plasma (neutrophil elastase-DNA and histone-DNA complexes). We also assessed clinical disease activity, joint ultrasound findings and autoantibody status [reumatoid factor (RF), anti-citrullinated peptide/protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP)]. Associations between neutrophilic biomarkers and clinical or ultrasound scores were sought using correlation analysis. The discriminatory capacity of both neutrophilic biomarkers to detect ultrasound synovitis was analysed through receiver-operating characteristic (ROC) curves. Results: One hundred fourteen patients were included. Two control groups were included to compare NET levels. The active control group consisted of 15 patients. The second control group consisted of 30 healthy subjects. Plasma NET levels did not correlate with clinical disease status, regardless of the clinic index analysed or the biological therapy administered. No significant correlation was observed between NET remnants and ultrasound synovitis. There was no correlation between plasma NET and autoantibodies. In contrast, plasma calprotectin positively correlated with clinical parameters (swollen joint count [SJC] rho = 0.49; P < 0.001, Clinical Disease Activity Index [CDAI] rho = 0.30; P < 0.001) and ultrasound parameters (rho > 0.50; P < 0.001). Notably, this correlation was stronger than that observed with acute phase reactants. Conclusion: While NET formation induced by neutrophils may play a role in RA pathogenesis, our study raises questions about the utility of NET remnants in peripheral circulation as a biomarker for inflammatory activity. In contrast, this study strongly supports the usefulness of calprotectin as a biomarker of inflammatory activity in patients with RA. [ABSTRACT FROM AUTHOR]

Background: Autonomic dysfunction precedes endothelial dysfunction in Parkinson's disease (PD) and causes blood pressure and circulation abnormalities that are highly disruptive to one's quality of life. While exercise interventions have proven helpful for motor symptoms of PD, improving associated non-motor symptoms is limited. Low-intensity resistance training with blood flow restriction (LIRT-BFR) improves autonomic dysfunction in non-PD patients and high-intensity resistance training (HIRT) is recommended for motor symptom improvements for people with PD (PwPD). Objective: To determine the effects of LIRT-BFR and HIRT on homocysteine and autonomic and endothelial function in PwPD and to determine the hemodynamic loads during LIRT-BFR and HIRT in PwPD using a novel exercise protocol. Methods: Thirty-eight PwPD were assigned LIRT-BFR, HIRT or to a control (CNTRL) group. The LIRT-BFR and HIRT groups exercised three days per week for four weeks. The LIRT-BFR protocol used 60% limb occlusion pressure (LOP) and performed three sets of 20 repetitions at 20% of the one-repetition maximum (1RM). The HIRT group performed three sets of eight repetitions at 80% 1RM. The CNTRL group was asked to continue their normal daily routines. Results: LIRT-BFR significantly improved orthostatic hypotension (p = 0.026), homocysteine levels (p < 0.001), peripheral circulation (p = 0.003), supine blood pressure (p = 0.028) and heart rate variability (p = 0.041); LIRT-BFR improved homocysteine levels (p < 0.018), peripheral circulation (p = 0.005), supine blood pressure (p = 0.007) and heart rate variability (p = 0.047) more than HIRT; and hemodynamic loads for LIRT-BFR and HIRT were similar. Conclusions: LIRT-BFR may be more effective than HIRT for autonomic and endothelial function improvements in PwPD and hemodynamic loads may be lessened in LIRT-BFR protocols using single-joint exercises with intermittent blood flow restriction. Further research is needed to determine if non-motor symptoms improve over time and if results are sustainable. [ABSTRACT FROM AUTHOR]

This study examined the impact of continuous blood flow restriction (BFR) during repeated‐sprint exercise (RSE) on acute performance, peripheral, systemic physiological, and perceptual responses. In a randomized crossover design, 26 adult male semi‐professional and amateur team‐sport players completed two RSE sessions (3 sets of 5 × 5‐s sprints with 25 s of passive recovery and 3 min of rest) with continuous BFR (45% arterial occlusion; excluding during between‐set rest periods) or without (non‐BFR). Mean and peak power output were significantly lower (p < 0.001) during BFR compared to non‐BFR (dz = 0.85 and 0.77, respectively). Minimum tissue saturation index during the sprints and rest periods was significantly reduced (p < 0.001) for BFR (dz = 1.26 and 1.21, respectively). Electromyography root mean square was significantly decreased (p < 0.01) for biceps femoris and lateral gastrocnemius muscles during BFR (dz = 0.35 and 0.79, respectively), but remained unchanged for the vastus lateralis muscle in both conditions. Oxygen consumption and minute ventilation were significantly reduced (both p < 0.01) for BFR (dz = 1.46 and 0.43, respectively). Perceived limb discomfort was significantly higher (p < 0.001) for BFR (dz = 0.78). No differences (p > 0.05) in blood lactate concentration or rating of perceived exertion were observed between conditions. Blood flow‐restricted RSE reduced performance and likely increased the physiological and perceptual stimulus for the periphery with greater reliance on anaerobic glycolysis, despite comparable or decreased systemic demands. Highlights: Continuous cuff inflation reduces external loads during repeated sprints which is suitable for athletes undertaking demanding training blocks or rehabilitating an injury.Blood flow‐restricted repeated sprints likely increase anaerobic energy contribution from further muscle deoxygenation.Inflatable cuffs likely reduce antagonistic muscle activation during cycling repeated sprints to maintain efficient inter‐muscle coordination given the deteriorated contractility of prime mover muscles with metabolic stress. [ABSTRACT FROM AUTHOR]

Background: The hypothalamus plays a crucial role in the health and productivity of dairy cows, yet studies on its functionality and its impact on peripheral circulation in these animals are relatively scarce, particularly regarding dietary interventions. Therefore, our study undertook a comprehensive analysis, incorporating both metabolomics and transcriptomics, to explore the effects of a grain-based diet on the functionality of the hypothalamus, as well as on blood and milk in dairy cows. Results: The hypothalamic metabolome analysis revealed a significant reduction in prostaglandin E2 (PGE2) level as a prominent response to the grain-based diet introduction. Furthermore, the hypothalamic transcriptome profiling showed a notable upregulation in amino acid metabolism due to the grain-based diet. Conversely, the grain-based diet led to the downregulation of genes involved in the metabolic pathway from lecithin to PGE2, including phospholipase A2 (PLA2G4E, PLA2G2A, and PLA2G12B), cyclooxygenase-2 (COX2), and prostaglandin E synthase (PTGES). Additionally, the plasma metabolome analysis indicated a substantial decrease in the level of PGE2, along with a decline in adrenal steroid hormones (tetrahydrocortisol and pregnenolone) following the grain-based diet introduction. Analysis of the milk metabolome showed that the grain-based diet significantly increased uric acid level while notably decreasing PGE2 level. Importantly, PGE2 was identified as a critical metabolic marker in the hypothalamus, blood, and milk in response to grain intervention. Correlation analysis demonstrated a significant correlation among metabolic alterations in the hypothalamus, blood, and milk following the grain-based diet. Conclusions: Our findings suggest a potential link between hypothalamic changes and alterations in peripheral circulation resulting from the introduction of a grain-based diet. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a key role in brain damage because of the sensitivity of brain tissue to oxidative damage. Biomarkers with easy measurement can be a candidate for reflecting the oxidative stress issue in humans. For this reason, we need to focus on specific metabolic products of the brain. End products of free radical reactions such as malondialdehydes form fluorescent products known as lipophilic fluorescent products (LFPs). The distinctive feature of LFPs is their autofluorescent properties. LFPs are detectable in the brain and cerebrospinal fluid. Furthermore, because of the diffusion into the bloodstream, these lipophilic molecules can be detected in the blood. Accumulations of these compounds produce more reactive oxygen species and increase the sensitivity of cells to oxidative damage. Hence, LFPs can be considered a danger signal for neurons and can be introduced as a strong index of oxidative damage both in the central and in the peripheral. [ABSTRACT FROM AUTHOR]

Mast cells (MCs) are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, MCs act as tissue sentinels, able to detect the presence of bacteria and parasites and to respond to different environmental stimuli. MCs originate from bone marrow (BM) progenitors that enter the circulation and mature in peripheral organs under the influence of microenvironment factors, thus differentiating into heterogeneous tissue-specific subsets. Even though MC activation has been traditionally linked to IgE-mediated allergic reactions, a role for these cells in other pathological conditions including tumor progression has recently emerged. However, several aspects of MC biology remain to be clarified. The advent of single-cell RNA sequencing platforms has provided the opportunity to understand MCs' origin and differentiation as well as their phenotype and functions within different tissues, including the gut. This review recapitulates how single-cell transcriptomic studies provided insight into MC development as well as into the functional role of intestinal MC subsets in health and disease. [ABSTRACT FROM AUTHOR]

Context.--In 2018 the College of American Pathologists Diagnostic Immunology and Flow Cytometry Committee designed and implemented a new plasma cell neoplasia flow cytometry proficiency testing program--PCNEO--to allow clinical flow cytometry laboratories to monitor and assess their performance compared with a peer group. Objective.--To report the results from the first 4 years of the PCNEO program. Design.--Program participants were sent 2 sets of challenges per year, each including 1 wet challenge and 2 dry challenges, with associated clinical and laboratory findings. The wet challenges were composed of myeloma cell line specimens (with or without dilution in preserved whole blood) for flow cytometric analysis. The dry (paper) challenges were composed of clinical case summaries and images of flow cytometric test results from various flow cytometry laboratories of committee members. Results.--A total of 116 to 145 laboratories from 17 countries enrolled in the proficiency testing program. For the wet challenges, almost all participants (97%--100%; cumulative, 98.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of undiluted myeloma cell lines. Slightly fewer participants (89.0%--97.4%; cumulative, 95.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of diluted myeloma cell lines (10% or 50% dilutions into peripheral blood) intended to better represent a typical clinical sample. There was generally agreement among 80% or more of participants for positive or negative staining for CD38, CD138, CD19, CD20, and surface and cytoplasmic K and λ light chains. Similarly, 84% to 100% of participants were able to correctly identify the presence of neoplastic plasma cell populations in paper challenges, including the presence of small, neoplastic plasma cell populations (0.01%--5.0% clonal plasma cells) and the presence of nonneoplastic plasma cell populations (correctly identified by 91%--96% of participants). Conclusions.--Participant performance in the new proficiency testing program was excellent overall, with the vast majority of participants able to perform flow cytometric analysis and identify neoplastic plasma cell populations and to identify small plasma cell clones or expanded populations of reactive plasma cells in dry challenge flow cytometry results. This program will allow laboratories to verify the accuracy of their testing program and test interpretations for the assessment of patients suspected of having a plasma cell neoplasm. [ABSTRACT FROM AUTHOR]

Introduction: Nowadays, some aspects of neuroendocrine and immune systems intercalation are already known. Accordingly, it has been shown that certain immune cells, such as monocytes, can produce and store dopamine in their secretory vesicles. This study was conducted to investigate the effects of dopamine on some immunological functions of the rat peripheral blood monocytes. Material & Methods: In this experimental study, peripheral blood mononuclear cells of rats were isolated by a ficoll-hypaque gradient. Afterward, the plastic adherent fractions were used as monocytes. Monocytes in the treatment group cocultured for 24 h with 5×10-7 M dopamine, and then their phagocytosis performance, respiratory burst, killing ability, nitric oxide production, neutral red harvest, vital ability, and NFκB gene expression were investigated. Results: The results of this study showed that both control or treatment monocytes showed no significant difference in phagocytosis after the challenge with opsonized yeast. Nevertheless, the neutral red uptake, respiratory burst, and nitric oxide production after the challenge with opsonized yeast, and also the expression of NFκB, were decreased in dopamine-treated monocytes compared to monocytes in the control group (P<0.05). The monocyte vitality of the treatment group did not show any significant effects compared to the monocytes of the control group. Discussion & Conclusion: It seems that dopamine dynamically creates an antiinflammatory phenotype in the monocyte. Therefore, alongside a decrease in the lysosomal compartment activity, the monocytes produce lower levels of free oxygen and nitrogen radicals. [ABSTRACT FROM AUTHOR]

Aging population has led to an increased prevalence of chronic and degenerative pathologies. A manifestation of unhealthy aging is frailty, a geriatric syndrome that implies a non-specific state of greater vulnerability. Currently, methods for frailty diagnosis are based exclusively on clinical observation. The aim of this study is to determine whether the bioenergetic capacity defined as mitochondrial oxygen consumption rate (OCR) of peripheral circulation mononuclear cells (PBMC) associates with the frailty phenotype in older adults and with their nutritional status. This is a cross-sectional analytic study of 58 participants 70 years and older, 18 frail and 40 non-frail adults, from the ALEXANDROS cohort study, previously described. Participants were characterized through sociodemographic and anthropometric assessments. Frail individuals displayed a higher frequency of osteoporosis and depression. Themean age of the participants was 80.2 ± 5.2 years, similar in both groups of men andwomen. Regarding the nutritional status defined as the bodymass index, most non-frail individuals were normal or overweight,while frail participants were mostly overweight or obese. We observed that OCR was significantly decreased in frail men (p < 0.01). Age was also associated with significant differences in oxygen consumption in frail patients, with lower oxygen consumption being observed in those over 80 years of age. Therefore, the use of PBMC can result in an accessible fingerprint thatmay identify initial stages of frailty in a minimally invasive way. [ABSTRACT FROM AUTHOR]

Passive whole‐body hyperthermia increases limb blood flow and cardiac output (Q̇$\dot Q$), but the interplay between peripheral and central thermo‐haemodynamic mechanisms remains unclear. Here we tested the hypothesis that local hyperthermia‐induced alterations in peripheral blood flow and blood kinetic energy modulate flow to the heart and Q̇$\dot Q$. Body temperatures, regional (leg, arm, head) and systemic haemodynamics, and left ventricular (LV) volumes and functions were assessed in eight healthy males during: (1) 3 h control (normothermic condition); (2) 3 h of single‐leg heating; (3) 3 h of two‐leg heating; and (4) 2.5 h of whole‐body heating. Leg, forearm, and extracranial blood flow increased in close association with local rises in temperature while brain perfusion remained unchanged. Increases in blood velocity with small to no changes in the conduit artery diameter underpinned the augmented limb and extracranial perfusion. In all heating conditions, Q̇$\dot Q$ increased in association with proportional elevations in systemic vascular conductance, related to enhanced blood flow, blood velocity, vascular conductance and kinetic energy in the limbs and head (all R2 ≥ 0.803; P < 0.001), but not in the brain. LV systolic (end‐systolic elastance and twist) and diastolic functional profiles (untwisting rate), pulmonary ventilation and systemic aerobic metabolism were only altered in whole‐body heating. These findings substantiate the idea that local hyperthermia‐induced selective alterations in peripheral blood flow modulate the magnitude of flow to the heart and Q̇$\dot Q$ through changes in blood velocity and kinetic energy. Localised heat‐activated events in the peripheral circulation therefore affect the human heart's output. Key points: Local and whole‐body hyperthermia increases limb and systemic perfusion, but the underlying peripheral and central heat‐sensitive mechanisms are not fully established.Here we investigated the regional (leg, arm and head) and systemic haemodynamics (cardiac output: Q̇$\dot Q$) during passive single‐leg, two‐leg and whole‐body hyperthermia to determine the contribution of peripheral and central thermosensitive factors in the control of human circulation.Single‐leg, two‐leg, and whole‐body hyperthermia induced graded increases in leg blood flow and Q̇$\dot Q$. Brain blood flow, however, remained unchanged in all conditions. Ventilation, extracranial blood flow and cardiac systolic and diastolic functions only increased during whole‐body hyperthermia.The augmented Q̇$\dot Q$ with hyperthermia was tightly related to increased limb and head blood velocity, flow and kinetic energy.The findings indicate that local thermosensitive mechanisms modulate regional blood velocity, flow and kinetic energy, thereby controlling the magnitude of flow to the heart and thus the coupling of peripheral and central circulation during hyperthermia. [ABSTRACT FROM AUTHOR]