Search Results (1,035)

Legg–Calvé–Perthes disease is a juvenile ischemic osteonecrosis (ON) of the femoral head. A disruption of blood supply to the femoral head produces extensive cell death and necrotic debris. Macrophages are innate immune cells recruited to the necrotic bone to orchestrate the repair process. However, the role macrophages play in the ON repair process is still not elucidated. The purpose of this study was to determine the effect of artificial necrotic bone fluid (NBF) on porcine peripheral blood mononuclear cell (PBMC)-derived macrophages. Monocytes were positively selected by CD14 MicroBeads from pig PBMCs. After maturation, cells were treated with no stimulant (Con), LPS + IFNγ (M1), IL4 + IL13 (M2), or NBF. All culture supernatants and cells were harvested for ELISA, Western blot, FACS, RT-qPCR and bulk RNAseq. The Western blot and ELISA showed that only the M1 condition elevated the protein level of pro-inflammatory cytokines. The FACS results indicated that percentage of CD8086+ (M1 marker) cells was significantly lower in the M2 vs. other conditions, whereas the relative median fluorescence intensity of CD8086 was significantly higher in the M1 vs. other conditions. The NBF did not show any significant change compared to the Con. mRNA analysis showed significantly increased IL1β and IL8 expression in the M1 vs. Con scenario. TNFα expression was significantly decreased in the M2 vs. Con scenario. Interestingly, the NBF did not induce pro-inflammatory gene expression. For bulk RNAseq, the Gene Set Enrichment Analyses of the M1-stimulated cells revealed the enrichment of pro-inflammatory gene sets. For the M2, most of the enriched categories were related to the down-regulation of inflammation. For the NBF, the most enriched categories were related to the down-regulation of protein translation and mitochondrial metabolism. We further confirmed the suppressive effects of NBF on macrophage functions using Seahorse Cell Mito Stress Tests, ¹³C-glucose metabolic flux analysis, mitochondrial ROS detection via MitoSOX^TM staining, and phagocytosis assay. Taken together, these results revealed that the artificial NBF down-regulates the overall cellular activity and energy metabolism of macrophages. Full article

The pancreas exhibits a uniquely intricate vascular architecture characterized by frequent and clinically significant morphological variations. These variations—impacting both arterial supply and venous drainage—are critical determinants in surgical planning, radiologic interpretation, and interventional outcomes. This comprehensive review examines the full spectrum of pancreatic vascular anatomy, with particular emphasis on embryological development, imaging manifestations, and surgical relevance. Key arterial structures, including the superior and inferior pancreaticoduodenal arteries (SPDAs and IPDAs) and the dorsal pancreatic artery (DPA)—are explored in detail alongside accessory branches. On the venous side, focus is placed on the gastrocolic trunk (GCT) of Henle, the uncinate and centro-inferior pancreatic veins, and the dorsal pancreatic vein (DPV). The review highlights that arterial aberrations, such as a DPA originating from the superior mesenteric artery (SMA), or duplicated patterns of the IPDA, as well as venous anomalies such as variant drainage of the GCT or the centro-inferior pancreatic vein, have substantial implications during pancreaticoduodenectomy, distal pancreatectomy, and transplantation procedures. With advances in multidetector computed tomography (MDCT), magnetic resonance angiography (MRA), and three-dimensional (3D) modeling, high-risk vascular variants can now be accurately mapped preoperatively, facilitating safer and more effective minimally invasive and robotic-assisted surgeries. In conclusion, the recognition and understanding of pancreatic vascular variations are imperative for optimal surgical and interventional management. This review underscores the importance of multidisciplinary collaboration among surgeons, radiologists, and anatomists, which will allow them to integrate detailed anatomical knowledge into clinical workflows, ultimately improving patient outcomes in pancreatic procedures. Full article

The retina is highly sensitive to oxygen and blood supply, and hypoxia plays a key role in retinal diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Müller glial cells, which are essential for retinal homeostasis, respond to injury and hypoxia with reactive gliosis, characterized by the upregulation of the glial fibrillary acidic protein (GFAP) and vimentin, cellular hypertrophy, and extracellular matrix changes, which can impair retinal function and repair. The retinal pigment epithelium (RPE) supports photoreceptors, forms part of the blood–retinal barrier, and protects against oxidative stress; its dysfunction contributes to retinal degenerative diseases such as AMD, retinitis pigmentosa (RP), and Stargardt disease (SD). Extracellular vesicles (EVs) play a crucial role in intercellular communication, protein homeostasis, and immune modulation, and have emerged as promising diagnostic and therapeutic tools. Understanding the role of extracellular vesicles’ (EVs’) signaling machinery of glial cells and the retinal pigment epithelium (RPE) is critical for developing effective treatments for retinal degeneration. In this study, we investigated the bidirectional EV-mediated crosstalk between RPE and Müller cells under hypoxic conditions and its impact on cellular metabolism and retinal cell integrity. Our findings demonstrate that RPE-derived extracellular vesicles (RPE EVs) induce time-dependent metabolic reprogramming in Müller cells. Short-term exposure (24 h) promotes pathways supporting neurotransmitter cycling, calcium and mineral absorption, and glutamate metabolism, while prolonged exposure (72 h) shifts Müller cell metabolism toward enhanced mitochondrial function and ATP production. Conversely, Müller cell-derived EVs under hypoxia influenced RPE metabolic pathways, enhancing fatty acid metabolism, intracellular vesicular trafficking, and the biosynthesis of mitochondrial co-factors such as ubiquinone. Proteomic analysis revealed significant modulation of key regulatory proteins. In Müller cells, hypoxic RPE-EV exposure led to reduced expression of Dyskerin Pseudouridine Synthase 1 (DKc1), Eukaryotic Translation Termination Factor 1 (ETF1), and Protein Ser/Thr phosphatases (PPP2R1B), suggesting alterations in RNA processing, translational fidelity, and signaling. RPE cells exposed to hypoxic Müller cell EVs exhibited elevated Ribosome-binding protein 1 (RRBP1), RAC1/2, and Guanine Nucleotide-Binding Protein G(i) Subunit Alpha-1 (GNAI1), supporting enhanced endoplasmic reticulum (ER) function and cytoskeletal remodeling. Functional assays also revealed the compromised barrier integrity of the outer blood–retinal barrier (oBRB) under hypoxic co-culture conditions. These results underscore the adaptive but time-sensitive nature of retinal cell communication via EVs in response to hypoxia. Targeting this crosstalk may offer novel therapeutic strategies to preserve retinal structure and function in ischemic retinopathies. Full article

This review presents a comprehensive overview of various ultrasound imaging techniques employed in the evaluation of the canine knee joint. It critically analyzes studies conducted on both human and animal subjects, with a focus on the diagnostic accuracy of B-mode ultrasound, Doppler examination, contrast-enhanced ultrasound, and elastography in both normal and pathological conditions. The review underscores the necessity of strict adherence to the protocols of each ultrasound modality and emphasizes the importance of a thorough understanding of the anatomical region to achieve optimal outcomes. The findings suggest that these ultrasound techniques can significantly enhance the diagnostic process, providing valuable insights into anatomy, size, blood supply, and tissue elasticity. Additionally, in cases where advanced imaging modalities such as computed tomography (CT) or magnetic resonance imaging (MRI) are cost-prohibitive or less accessible, ultrasound serves as a reliable alternative, delivering high diagnostic accuracy and critical information regarding mechanical changes in the joint and neovascularization. Full article

Alzheimer’s dementia (AD) is a disease of the ageing brain. It begins in the hippocampal region with the epicentre in the entorhinal cortex, then gradually extends into adjacent brain areas involved in memory and cognition. The events which initiate the damage are unknown and under intense investigation. Localization to the hippocampus can now be explained by anatomical features of the blood vessels supplying this region. Blood supply and hence oxygen delivery to the area are jeopardized by poor flow through narrowed arteries. In genomic and metabolomic studies, the respiratory chain and mitochondrial pathways which generate ATP were leading pathways associated with AD. This review explores the notion that ATP depletion resulting from hippocampal hypoperfusion has a prime role in initiating damage. Sections cover sensing of ATP depletion and protective responses, vulnerable processes with very heavy ATP consumption (the malate shuttle, the glutamate/glutamine/GABA (γ-aminobutyric acid) cycle, and axonal transport), phospholipid disturbances and peroxidation by reactive oxygen species, hippocampal perfusion and the effects of hypertension, chronic hypoxia, and arterial vasospasm, and an overview of recent relevant genomic studies. The findings demonstrate strong scientific arguments for the proposal with increasing supportive evidence. These lines of enquiry should be pursued. Full article

Zebrafish are model organisms for drug screening owing to their transparent bodies, rapid embryonic development, and genetic similarities with humans. However, using standard polystyrene culture plates can limit the oxygen supply, potentially affecting embryo survival and the reliability of assays conducted in zebrafish. In this study, we evaluated the application of a novel, highly oxygen-permeable culture plate (InnoCell^TM) in zebrafish development and drug screening assays. Under both normal and oxygen-restricted conditions, zebrafish embryos cultured on InnoCell^TM plates exhibited significantly improved developmental parameters, including heart rate and body length, compared with those cultured on conventional polystyrene plates. The InnoCell^TM plate enabled a significant reduction in medium volume without compromising zebrafish embryo viability, thereby demonstrating its advantages, particularly in high-throughput 384-well formats. Drug screening tests using antiangiogenic receptor tyrosine kinase inhibitors (TKIs) revealed enhanced sensitivity and more pronounced biological effects in InnoCell^TM plates, as evidenced by the quantification of intersegmental blood vessels and gene expression analysis of the vascular endothelial growth factor receptor (vegfr, also known as kdrl). These results indicate that the InnoCell^TM highly oxygen-permeable plate markedly improves zebrafish-based drug screening efficiency and assay reliability, highlighting its potential for widespread application in biomedical research. Full article

Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a common condition in hip surgery, which is characterized by the death of bone cells due to disruption of the blood supply and ultimately irreversible destruction of the hip joint. As a result of the COVID-19 pandemic, a significant increase in the incidence of ONFH has been identified. To better understand the pathogenesis of ONFH in the context of COVID-19, our research aimed to determine pathomorphological changes in articular tissues specific to post-COVID-19 ONFH. Methods: Using morphological, morphometric, and statistical methods, the femoral heads after hip arthroplasty were retrospectively studied in patients with post-COVID-19 ONFH (n = 41) compared to a non-COVID-19 group of patients (n = 47). Results: Our results revealed that the key morphofunctional biomarkers of post-COVID-19 ONFH were clusters of mast cells, extensive areas of fibrosis, numerous arterial and venous thrombi, and giant cell granulomas. The potential relationship of those morphological features with the action of the SARS-CoV-2 coronavirus was discussed. Conclusions: Mast cells have been proposed as the leading players that may trigger the main molecular and cellular mechanisms in the development of post-COVID-19 ONFH and can be considered a diagnostic sign of the disease. Full article

Umbilical cord mesenchymal stem cells (UCMSCs)-derived small extracellular vehicles (sEVs) are reported to offer therapeutic effects in regenerative medicine, but they lack safety and biodistribution profiles to support smooth translation at the clinical stage and regulatory requirements. Our study aimed to determine the safety and biodistribution profile in a healthy animal model before application in the metabolic syndrome model. Method: Healthy male Sprague Dawley (SD) rats were given an intravenous (IV) injection of normal saline (control group) or pooled fetal UCMSCs-derived sEVs (treated group) every three weeks for 90 days. Morbidity and mortality observation (daily), physical measurements (weekly), selected serum biochemistry (every three weeks), and hematology (every three weeks) were performed for 90 days. Acute toxicity (on day 14) and sub-chronic toxicity (on day 90) were assessed for gross necropsy, relative organ weight, and histopathological assessment of lungs, liver, spleen, kidney, and lymph nodes. Separately, a biodistribution study was conducted with the sEVs preparations labeled with PKH26 fluorescent dye, given intravenously to the rats. The organs were harvested 24 h post-injection. There were no drastic changes in either group’s morbidity or mortality, physical, hematological, and biochemistry evaluation. The histopathological assessment concluded moderate (focal) inflammation in the treated group’s kidneys and signs of recovery from the inflammation and vascular congestion in the liver. A biodistribution study revealed a higher accumulation of sEVs in the spleen. Multiple IV injections of the pooled fetal UCMSCs-derived sEVs in healthy male SD rats were deemed safe. The sEVs were abundantly distributed in the spleen 24 h post-injection. Full article

Background/Objectives: A growing body of evidence is amassing in the literature suggesting a correlation between Alzheimer’s disease (AD) and thrombotic vascular complications, which led to the suggestive hypothesis that thrombosis may contribute to AD onset and progression by damaging the neurovasculature and reducing the cerebral blood flow. In turn, low cerebral blood flow is likely to contribute to neurodegeneration by reducing nutrient and oxygen supply and impairing toxic metabolite removal from the brain tissue. Methods: We searched the literature for studies in animal models of AD or patients diagnosed with the disease that reported circulating markers of platelet hyperactivity or hypercoagulation, or histological evidence of brain vascular thrombosis. Results: Platelet hyperactivity and hypercoagulability have been described in multiple animal models of AD, and histological evidence of neurovascular thrombosis has also been reported. Similarly, clinical studies on patients with AD showed circulating markers of platelet hyperactivity and hypercoagulation, or histological evidence of neurovascular thrombosis collected from post-mortem brain tissue samples. Conclusions: Taken together, a convincing picture is emerging that suggests a strong correlation between systemic or neurovascular thrombosis and AD. Nonetheless, a mechanistic role for haemostasis dysregulation and neurovascular damage in the onset or the progression of AD remains to be proven. Future research should focus on this important question in order to clarify the mechanisms underlying AD and identify a treatment for this disease. Full article

In the context of the relentless pursuit of precision, intelligence, and personalization within the realm of medical technology, the real-time monitoring of human physiological signals has assumed heightened significance. Implantable wireless sensor devices have exhibited extraordinary capabilities in tracking internal physiological parameters, including intraocular pressure, blood glucose levels, electrocardiographic activity, and arterial blood pressure. These devices are characterized by elevated temporal continuity and exceptional measurement accuracy. This paper undertakes an in-depth investigation into the key technologies underlying biodegradable implantable sensing devices. Initially, it expounds on diverse sensing mechanisms employed in implantable devices. Additionally, it presents common data transmission and power supply strategies for wireless sensing systems. Finally, it introduces biodegradable materials suitable for human implantation and their respective application domains and enumerates several implantable devices that are either under development or have already been commercialized. Through an in-depth and comprehensive discourse on the current state of development and extant challenges in this domain, the development trajectory of biodegradable devices is put forward. Moreover, this paper also serves as a valuable reference for the design and selection of implantable medical devices. Full article

Characterized by insufficient blood supply leading to tissue hypoxia and damage, ischemia is the underlying cause of major conditions such as ischemic stroke, myocardial infarction, and peripheral artery disease. Stem cell therapy, as a regenerative strategy, demonstrates significant potential in restoring tissue blood flow and organ function in ischemic environments. This review systematically explores the latest advances in stem cell therapy for ischemic diseases, focusing on different cell types and their mechanisms of action, including direct differentiation, paracrine signaling, immunomodulation, and microenvironment regulation. Furthermore, it highlights innovations in gene editing and bioengineering technologies that enhance cell delivery, targeting, and therapeutic efficacy. Simultaneously, this article discusses the challenges faced, advances in cell tracking and delivery, and future research directions, aiming to provide insights for the development of more effective and personalized treatment strategies Full article

Background: PP-007 (SANGUINATE^®, PEGylated carboxyhemoglobin, bovine) is under development to treat conditions of ischemia/hypoxia. Hemorrhagic/hypovolemic shock (H/HVS) becomes a life-threatening comorbidity due in part to hypotension and hypoxia. Blood transfusions are indicated, but supply and compatibility issues may limit subject access or when blood is not an option due to religious restriction or concern for clinical complications. PP-007 is universally compatible with an effective hydrodynamic radius and colloidal osmotic pressure facilitating perfusion without promoting extravasation. Methods: A review of previous clinical trials was performed and revealed an Open-Label Phase 1 safety study of acute severe anemia (hemoglobin ≤ 5 g/dL) in adult (≥18 y) patients unable to receive red blood cell transfusion (NCT02754999). Primary outcomes included safety events with secondary efficacy measures of organ function and survival at 1, 14, and 28 days. Additionally, a retrospective review of published, peer-reviewed case reports was performed, evaluating the administration of Sanguinate for Expanded Access in those patient populations where blood was not an option over the past 12 years. Results: A total of 103 subjects were enrolled in the Phase I safety study with significant co-morbidities that most commonly included hypertension (n = 43), acute and chronic kidney disease (n = 38), diabetes mellitus (n = 29), gastrointestinal bleeds (n = 18), and sickle cell disease (n = 13). Enrollment characteristics included decreased hemoglobin and severe anemia (mean baseline hemoglobin of 4.2 g/dL). Treatments included an average of three infusions [range 1–17]. Secondary efficacy measures were mean Hb levels, respiratory support, and vasopressor requirements, all demonstrating clinically relevant improvements. Fourteen additional cases were identified in the literature. Though one patient died due to pre-treatment conditions, all patients but one were discharged home in stable condition. Conclusion: Collectively, these observations are encouraging and provide support for the continued evaluation of PP-007 in advanced clinical trials in severe anemia including H/HVS. The review of published case reports underscored the potential of Sanguinate to reduce early mortality. Adverse effects included transient hypertension, lethargy, dizziness, and troponin elevation. These findings highlight the need for continued research and funding of blood alternatives to improve outcomes when standard blood transfusions are unavailable or contraindicated. Full article

Background/Objectives: Measles, mumps, and rubella (MMR) continue to pose a significant public health challenge due to insufficient immunization coverage. This study aimed to provide the first seroprevalence data against MMR and to explore self-reported immunity among future healthcare workers (HCWs) in Serbia, including women of childbearing age. Methods: We included 1296 future health care workers (HCWs) aged 19 to 29, born in Serbia. All HCWs supplied a blood sample for serology and filled in a questionnaire. Antibodies were measured using an enzyme immunoassay against measles, mumps, and rubella (MMR). Results: Anti-measles, -mumps, and -rubella seronegativity rates were 25.6%, 26.5%, and 4.4%, respectively, among future HCWs in Serbia. The mumps seronegativity rate was significantly higher in the oldest (27–29-year) age group, accompanied by significantly lower anti-mumps IgG GMCs in the same age group compared to younger participants (p = 0.035 and p < 0.001, respectively). Anti-mumps seronegativity also increased significantly across birth cohorts, from the youngest to the oldest (p = 0.004). Furthermore, anti-mumps IgG antibody GMCs were significantly higher among females, those who attended nursery/kindergarten, and unvaccinated individuals (p = 0.050, p = 0.020, and p = 0.005, respectively). Finally, older age and unvaccinated status were identified as independent factors associated with anti-measles and anti-mumps seronegativity among future HCWs in Serbia. Conclusions: The cross-sectional seroprevalence data revealed insufficient seroprotection in this population of particular importance, i.e., future HCWs, and women of childbearing age. These results strongly support the national recommendations for the mandatory vaccination of these populations. Identified immunity gaps should be closed promptly by strategic, targeted serologic screening, followed by vaccination of those lacking MMR antibodies. Full article

Background: Superomedial pedicle breast reduction is a widely performed procedure in plastic surgery. However, in cases of massive ptosis and excessively large breasts, achieving adequate pedicle reduction can be challenging. Direct excision of the tissue bulk may compromise blood supply while insufficient reduction can hinder proper pedicle positioning or result in strangulation when forcefully placed in the keyhole area. This study investigates the application of power-assisted liposuction (PAL) to the superomedial pedicle, aiming to achieve volume reduction while preserving its vascular integrity. Methods: Patients who underwent reduction mammaplasty with concomitant PAL were retrospectively reviewed. Parenchymal resection was performed first, followed by PAL, which was selectively applied to the pedicle. Eligibility for liposuction was made intraoperatively based on breast morphology and the ease of pedicle insetting. Results: The mean lipoaspirate per breast was 243.0 mL (SD 131.3) following a mean resection weight of 1261.7 g (SD 356.9). In 76.7% of cases, more than 150 mL was aspirated. The smallest volume per breast was 50 mL, while the highest reached 500 mL. A strong correlation was observed between the aspirated volume and resection weight. The overall complication rate was 3.3%, with one patient requiring hematoma evacuation. No cases of NAC necrosis occurred. All patients reported satisfactory breast shape and size. Conclusions: Power-assisted liposuction of the superomedial pedicle is a reliable and efficient technique for reshaping and reducing the pedicle while maintaining a low risk of complications. Full article

Platelet transfusions are a cornerstone of hemorrhage management in patients with thrombocytopenia or platelet dysfunction, yet their indications and dosing are largely based on expert opinion and low-quality evidence. This review offers a timely and comprehensive analysis of platelet transfusion practices in the United States (U.S.), uniquely integrating clinical evidence, such as the pivotal PLADO trial, with emerging technological advancements. Using a holistic approach, this manuscript addresses not only conventional practices (such as dosing standards and storage methods), but also cutting-edge alternatives like cold-stored and freeze-dried platelets, pathogen reduction technologies, and synthetic platelet substitutes. By juxtaposing U.S. practices with international standards, it highlights inefficiencies in dosing and supply management, proposing actionable solutions like lower-dose transfusions and diversified platelet inventories. Furthermore, the manuscript’s exploration of whole blood-derived platelets and the ethical debate surrounding paid donors adds a forward-looking perspective. By examining these innovations alongside strategies to optimize supply, this work aims to provide a comprehensive overview of how transfusion medicine is adapting to meet clinical and logistical demands. Full article