Search Results (181)

Background/Objectives: Immature platelet fraction (IPF) and reticulated platelets (RPs) are biomarkers reflecting the youngest and most metabolically active platelets in circulation. RPs, a subset of immature platelets, contain residual RNA and have been associated with increased thrombotic potential. Elevated IPF levels indicate enhanced platelet production, commonly observed during elevated platelet turnover, such as in autoimmune reactions, consumption, and thrombotic events. This systematic review aims to evaluate the potential role of IPF and RPs in the context of cerebrovascular events, specifically ischemic and hemorrhagic stroke, as well as transient ischemic attacks (TIAs), and to assess their clinical utility in stroke monitoring and management. Methods: A comprehensive literature search was conducted in PubMed, Scopus, Cochrane Library, and Web of Science for studies published between 2000 and 2024, which focused on IPF and RPs in human subjects with cerebrovascular events. Results: Six studies met the inclusion criteria. Findings suggest that elevated levels of IPF and RP are associated with the acute and chronic phases of ischemic stroke and TIA and may reflect increased platelet turnover and thrombotic activity. Some evidence supports their role in predicting stroke severity, recurrence, and underlying etiology, although results are not yet consistent across all studies. Conclusions: IPF and RPs are emerging biomarkers with potential applications in acute ischemic stroke and risk stratification. While current evidence is promising, further research is needed to standardize measurement techniques and validate their routine use in clinical practice. Full article

The mRNA vaccine has protected humans from the Coronavirus disease 2019 (COVID-19) and has taken the lead in reversing the epidemic efficiently. However, the Centre of Disease Control (CDC) reported and raised the alarm of allergic or acute inflammatory adverse reactions after vaccination with mRNA-LNP vaccines. Meanwhile, the US Food and Drug Administration (FDA) has added four black-box warnings in the instructions for mRNA-LNP vaccines. Numerous studies have proven that the observance of side effects after vaccination is indeed positively correlated to the level of anti-PEG antibodies (IgM or IgG), which are enhanced by PEGylated preparations like LNP vaccine and environmental exposure. After literature research and review in the past two decades, it was found that the many clinical trial failures (BIND-014, RB006 fell in phase II) of PEG modified delivery system or PEGylated drug were related to the high expression of anti-PEG IgM and IgG. In the background of shooting multiple mRNA-LNP vaccines in billions of people around the world in the past three years, the level of anti-PEG antibodies in the population may have significantly increased, which brings potential risks for PEG-modified drug development and clinical safety. This review summarizes the experience of using mRNA-LNP vaccines from the mechanism of the anti-PEG antibodies generation, detection methods, clinical failure cases of PEG-containing products, harm analysis of abuse of PEGylation, and alternatives. In light of the increasing prevalence of anti-PEG antibodies in the population and the need to avoid secondary injuries, this review article holds greater significance by offering insights for drug developers. It suggests avoiding the use of PEG excipients when designing PEGylated drugs or PEG-modified nano-formulations and provides references for strategies such as utilizing PEG-free or alternative excipients. Full article

Ferritin is important for cellular iron storage and metabolism. It consists of 24 ferritin heavy- or light-chain subunits surrounding an iron-containing core, but it is also released as an extracellular molecule that shows increased systemic levels during acute-phase reactions. Furthermore, acute myeloid leukemia (AML) is an aggressive bone marrow malignancy that can be associated with increased ferritin levels both at the time of first diagnosis but also during/following anti-AML treatment due to an iron overload. Such high systemic ferritin levels at diagnosis or later allogeneic stem cell transplantation are associated with decreased long-term survival. Extracellular ferritin binds to several receptors expressed by AML cells (e.g., the transferrin receptor and CXCR4 chemokine receptor) and AML-supporting non-leukemic bone marrow cells (e.g., endothelial, mesenchymal or immunocompetent cells). Ferritin can thereby affect the AML cells directly as well as indirectly via AML-supporting neighboring cells. Finally, ferritin should be regarded as a regulator of the dysfunctional iron metabolism that causes increased iron levels in AML cells, and it is important for cell survival through its function during the initial steps of ferroptosis. Thus, ferritin is not only an adverse prognostic biomarker, but also an important regulator of AML cell proliferation, survival and chemosensitivity and the targeting of iron metabolism/ferroptosis is, therefore, a possible strategy in AML therapy. Full article

Background: Hormonal fluctuations across the menstrual cycle can significantly impair physical performance, neuromuscular function, and cognitive processing in female athletes, particularly during the premenstrual phase. Emerging evidence suggests that dark chocolate (DC), rich in flavonoids, polyphenols, magnesium, and theobromine, may exert anti-inflammatory, analgesic, and neuroprotective effects. This study investigated the acute effects of 85% DC supplementation on cognitive and physical performance, as well as delayed-onset muscle soreness (DOMS), in female CrossFit^® athletes across four distinct hormonal phases. Methods: In this randomized, double-blind, placebo-controlled, crossover study, fifteen trained eumenorrheic female CrossFit^® athletes completed three intervention conditions: dark chocolate (DC), placebo (PLA), and control (CON). Participants were evaluated during four distinct menstrual phases—menstrual, follicular, luteal, and premenstrual syndrome (PMS)—over three consecutive menstrual cycles. In each phase, participants consumed 30 g/day of either DC or PLA for three days, followed by performance testing on day four. Functional and cognitive performance were assessed via the CINDY WOD, handgrip strength (HGS), and Stroop tests (reaction time and correct answer percentage, CAP). DOMS was measured using a 100 mm visual analog scale at baseline and at 0, 12, 24, 48, and 72 h post-exercise. Results: DC supplementation significantly improved functional performance (CINDY WOD) across all menstrual phases, with the greatest enhancement during PMS (p < 0.01). Reaction time significantly improved during PMS (p = 0.010 vs. control; p = 0.002 vs. placebo). Additionally, DOMS was notably reduced in the luteal phase at 12 h, 24 h, and 72 h post-exercise in the DC condition compared to the control and placebo (p < 0.05). No significant differences were observed in HGS across conditions or phases (p > 0.05). Conclusions: Short-term DC supplementation may selectively enhance high-intensity functional performance and cognitive accuracy in trained female athletes, particularly during hormonally sensitive phases such as PMS. Its anti-inflammatory and neuromodulatory properties make DC a promising, non-pharmacological strategy to support female-centric recovery and performance in CrossFit^® and similar sports. Future research should explore chronic intake, mechanistic biomarkers, and individual variability across menstrual cycles. Full article

Coaches manipulate training variables to optimize and improve them, with intensity being crucial. Velocity-based training, measuring intensity by the movement speed, is advantageous over traditional methods. Flywheel training, offering concentric and eccentric loads, allows for supramaximal loading during the eccentric phase, enhancing muscle hypertrophy and performance and reducing injury risk. This study examines the specific effects of flywheel training on post-activation potentiation (PAP). Forty-one high-level male athletes performed flywheel half squats at fast (0.95–1.05 m/s), medium (0.65–0.75 m/s), and slow (0.35–0.45 m/s) speeds. Their drop jump performance was assessed at 30 s and 4, 8, and 12 min post-induction. Lower-limb kinematic data and ground reaction forces were recorded using infrared motion capture and force plates. Measures included peak collision force, peak extension force, knee joint extension moment, knee joint power, average power output, and vertical jump height. High-speed intensity significantly increased peak impact force, peak vertical ground reaction force, knee joint eccentric power, concentric power, and extension torque at 4, 8, and 12 min post-induction (p < 0.05). Fast- (0.95–1.05 m/s) and medium-speed (0.65–0.75 m/s) flywheel squats acutely improved lower-limb performance, especially vertical jump height, within 4–12 min post-stimulation. Fast-speed loading showed greater benefits for reactive strength and power output, while a medium speed also yielded meaningful gains. These findings support using movement velocity to guide flywheel training intensity. Full article

The pathophysiology of a stroke is a complex process involving oxidative stress and inflammation. As a result of the actions of reactive oxygen species (ROS), not only does vascular damage occur, but the brain tissue is also damaged. It is a dynamic process, induced by a cellular–molecular immune response, focused on the development of an immediate reaction. During ischemia, inflammatory mediators are released, among which IL-6 plays a particularly important role in the acute phase of a stroke. Recently, a lot of attention has been devoted to this pleiotropic pro-inflammatory cytokine, which enhances the migration of leukocytes and is controlled by chemokines and the expression of adhesion handlers. The impact of IL-6 on the severity of neurological treatment and on patient prognosis in AIS is of interest to many researchers. More and more data indicate that it may be a reliable prognostic factor in strokes. Full article

Background/Objectives: Blast-induced traumatic ocular injuries (bTOI) pose a significant risk to military and civilian populations, often leading to visual impairment or blindness. Retina, the innermost layer of ocular tissue consisting of photoreceptor and glial cells, is highly susceptible to blast injuries. Despite its prevalence, the molecular mechanisms underlying retinal damage following bTOI remain poorly understood, hindering the development of targeted therapies. Melatonin, a neuroprotective indoleamine with antioxidant, anti-inflammatory, and circadian regulatory properties, is synthesized in the retina and plays a crucial role in retinal health. Similarly, retina-specific genes, such as Rhodopsin, Melanopsin, and RPE65, are essential for photoreceptor function, visual signaling, and the visual cycle. However, their responses to blast exposure have not been thoroughly investigated. Methods: In this study, we utilized a ferret model of bTOI to evaluate the temporal expression of melatonin-synthesizing enzymes, such as tryptophan hydroxylase 1 and 2 (TPH1 and TPH2), Aralkylamine N-acetyltransferase (AANAT), and Acetylserotonin-O-methyltransferase (ASMT), and retina-specific genes (Rhodopsin, Melanopsin) and retinal pigment epithelium-specific 65 kDa protein (RPE65) at 4 h, 24 h, 7 days, and 28 days post-blast. Ferrets were exposed to tightly coupled blast overpressure waves using an advanced blast simulator, and retinal tissues were collected for quantitative polymerase chain reaction (qPCR) analysis. Results: The results revealed dynamic and multiphasic transcriptional responses. TPH1 and TPH2 exhibited significant upregulation at 24 h, followed by downregulation at 28 days, indicating blast-induced dysregulation of tryptophan metabolism, including melatonin synthesis. Similarly, AANAT and ASMT showed acute downregulation post-blast, with late-phase disruptions. Rhodopsin expression increased at 24 h but declined at 28 days, while Melanopsin and RPE65 demonstrated early upregulation followed by downregulation, reflecting potential disruptions in circadian regulation and the visual cycle. Conclusions: These findings highlight the complex regulatory mechanisms underlying retinal responses to bTOI, involving neuroinflammation, oxidative stress, and disruptions in melatonin synthesis and photoreceptor cell functions. The results emphasize the therapeutic potential of melatonin in mitigating retinal damage and preserving visual function. Full article

The acute phase response is a hallmark of all inflammatory reactions and acute phase reactants, such as C-reactive protein (CRP) and serum amyloid A (SAA) proteins, are among the most useful plasma and serum markers of inflammation in clinical medicine. Although it is well established that inflammatory cytokines, mainly interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) induce SAA in the liver, the biological functions of elicited SAA remain an enigma. By the classical multi-step protein purification studies of chemotactic factors present in plasma or serum, we discovered novel chemokines and SAA1 fragments, which are induced during inflammatory reactions. In contrast to earlier literature, pure SAA1 fails to induce chemokines, an ascribed function that most probably originates from contaminating lipopolysaccharide (LPS). However, intact SAA1 and fragments thereof synergize with CXC and CC chemokines to enhance chemotaxis. Natural SAA1 fragments are generated by inflammatory proteinases such as matrix metalloproteinase-9 (MMP-9). They mediate synergy with chemokines by the interaction with cognate G protein-coupled receptors (GPCRs), formyl peptide receptor 2 (FPR2) and (CC and CXC) chemokine receptors. In conclusion, SAA1 enforces the action of many chemokines and assists in local leukocyte recruitment, in particular, when the concentrations of specifically-induced chemokines are still low. Full article

Nasal spray treatments that inhibit the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) entry into nose and nasopharynx at early stages can be an appropriate approach to stop or delay the progression of the disease. We performed a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicentric, phase II clinical trial comparing the rate of hospitalization due to COVID-19 infection between azelastine 0.1% nasal spray and placebo nasal spray treatment groups. The study furthermore assessed the reduction in virus load in SARS-CoV-2-infected subjects estimated via quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using nasopharyngeal swabs in both groups during the treatment period. A total of 294 subjects with mild COVID-19 infection were screened and randomized in a 1:1 ratio. There was no incidence of COVID-19-related hospitalization in either treatment group. Mean virus load was significantly reduced in both groups during the 11 treatment days as compared with baseline viral load values. The reduction in virus load in the azelastine 0.1% nasal spray group was significantly higher than the reduction in the placebo group at day 11 (log₁₀ 5.93 vs. log₁₀ 5.85 copies/mL, respectively, p = 0.0041). A total of 39 (32.0%) subjects in the azelastine 0.1% treatment group and 40 (31.0%) subjects in the placebo group reported 48 and 51 adverse events, respectively. It is therefore concluded that azelastine 0.1% nasal spray is an efficacious, safe, and well-tolerated treatment of mild COVID-19 infection. Full article

Hematological emergencies are critical medical conditions that require immediate attention due to their rapid progression and life-threatening nature. As various examples, hypercalcemia, often associated with cancers such as multiple myeloma, can lead to severe neurological and cardiac dysfunction. Hyperleukocytosis, common in acute myeloid leukemias, increases the risk of leukostasis and multiorgan failure. Sickle cell crisis, a common complication in sickle cell disease, results from vaso-occlusion, leading to acute pain and tissue ischemia. Tumor lysis syndrome, reported in cases of rapid destruction of cancer cells, causes electrolyte imbalances and acute kidney injury. Acute transfusion reactions, fundamental in hematological conditions, can range from mild allergic responses to severe hemolysis and shock, requiring prompt management. Disseminated intravascular coagulation, involving excessive coagulation and bleeding, is commonly triggered by hematological malignancies, common in the first phases of acute promyelocytic leukemia. Recently, in the era of bispecific antibodies and chimeric antigen receptor T cells, cytokine release syndrome is a manifestation that must be recognized and promptly treated. Understanding the pathophysiology, recognizing the clinical manifestations, and ensuring adequate diagnostic strategies and management approaches for each condition are central to early intervention in improving patient outcomes and reducing mortality. Full article

Severe fever with thrombocytopenia syndrome (SFTS) is an acute febrile illness caused by the SFTS virus (SFTSV). We conducted this study to propose a scientific evidence-based treatment that can improve prognosis through changes in viral load and inflammatory cytokines according to the specific treatment of SFTS patients. This prospective and observational study was conducted at 14 tertiary referral hospitals, which are located in SFTS endemic areas in Korea, from 1 May 2018 to 31 October 2020. Patients of any age were eligible for inclusion if they were polymerase chain reaction positive against SFTSV, or showed a four-fold or higher increase in IgG antibody titers between two serum samples collected during the acute and convalescent phases. On the other hand, patients with other tick-borne infections were excluded. In total, 79 patients were included in the study. The viral load of the group treated with steroids was 3.39, 3.21, and 1.36 log₁₀ RNA copies/reaction at each week since the onset of symptoms, and the viral load in patients treated with plasma exchange was 4.47, 2.60, and 2.00 log₁₀ RNA copies/reaction at each week after symptom onset. The inflammatory cytokines were not reduced effectively by any specific treatment except IVIG for the entire treatment period. Secondary infections according to pathogens revealed four bacterial (26.7%) and one fungal (6.7%) infection in the steroid group. The viral load of SFTSV and inflammatory cytokines cannot be decreased by steroid and plasma exchange treatments. Secondary bacterial infections can occur when steroids are administered for the treatment of SFTS. Therefore, caution should be exercised when choosing treatment strategies for SFTS. Full article

Background/Objectives: Clinical studies show that SARS-CoV-2 vaccination sometimes entails a severe and disabling chronic syndrome termed post-acute-COVID-19-vaccination syndrome (PACVS). PACVS shares similarities with long COVID. Today, PACVS is still not officially recognised as a disease. In contrast, long COVID was registered by health authorities in December 2021. Here, we address possible reasons for that discrepancy. Methods: We analyse whether common symptoms of PACVS have been registered by European pharmacovigilance as adverse vaccination reactions and which consequences have been drawn thereof. Results: (i) PACVS is distinguished from normal vaccination reactions solely by prolonged duration. (ii) Symptom duration is poorly monitored by post-authorisation pharmacovigilance. (iii) PACVS-specific signals were faithfully recorded by pharmacovigilance systems but have not prompted appropriate reactions of health authorities. (iv) The most widely applied SARS-CoV-2 mRNA-vaccine has been modified after roll-out without renewed phase III evaluation; the modification has increased DNA contaminations suspected to extend the spectrum of adverse events. (v) Crossing of pharmacovigilance data with corresponding estimates of applied vaccine doses suggest a PACVS prevalence of 0.003% in the general population. In contrast, occupational surveillance studies suggest a PACVS prevalence of 0.9% in young and middle-aged persons. Conclusions: (a) Denial of official recognition of PACVS is unjustified. (b) PACVS seems to target preferentially young and middle-aged persons. (c) Without official disease recognition, access to public healthcare and welfare services is made difficult for PACVS-affected persons, which creates considerable socio-economic problems. (d) Without official disease recognition, development and evaluation of PACVS therapies is impaired. Full article

Background and Objectives: The use of temporary left ventricular assist devices (tLVADs) for patients suffering from cardiogenic shock (CS) is becoming more common. This study examines the indications and outcomes of microaxial flow pumps (Impella^®, Abiomed Inc., Danvers, MA, USA) when cannulated through the axillary artery in patients with severe CS, with a particular focus on acute phase reactions and hemolytic responses. Materials and Methods: This single-center, retrospective cohort involved patients who received microaxial Impella implantation via the axillary artery from 2020 to 2022 (n = 47). Results: Among the patients, 66% (N = 31 cases) were treated with the Impella 5.5, 25.5% (N = 12 cases) with the Impella 5.0, and 8.5% (N = 4 cases) with the Impella CP. Additionally, 28% were managed using the ECMELLA concept. The mean length of time for Impella support was 8 days. The overall 30-day survival rate was 78%, with no significant differences observed between the ECMELLA group and the various Impella types. At 30 days post-therapy, 47% of survivors no longer required mechanical support, while 26% were upgraded to a durable LVAD. Interleukin-6 (IL-6) levels were significantly lower in patients receiving Impella 5.5 (n = 17 vs. 12) immediately following implantation (p = 0.03) compared with those with smaller devices. Haptoglobin levels were significantly higher in the Impella 5.5 group (n = 17 vs. 11, p = 0.02), with overall lower rates of hemolysis (45.1%, p < 0.01). Conclusions: The mortality rate in critical CS appears reduced with axillary artery implantation of Impella devices relative to existing literature. A full-flow microaxial pump (Impella 5.5) seems advantageous regarding systemic inflammatory response syndrome (SIRS) and acute hemolysis, indicated by lower IL-6 and higher haptoglobin levels, compared with smaller Impella devices. A tailored escalation/de-escalation concept using axillary access for different mAFP types appears feasible and safe. Full article

Background and Objectives: Revumenib (SNDX-5613) is a powerful and specific inhibitor of the menin–KMT2A binding interaction. It is a small molecule that is currently being researched to treat KMT2A-rearranged (KMT2Ar) acute leukemias. Revumenib (RVB) has received Orphan Drug Designation from the US FDA for treating patients with AML. It has also been granted Fast Track designation by the FDA for treating pediatric and adult patients with R/R acute leukemias that have a KMT2Ar or NPM1 mutation. Materials and Methods: The target of this research was to create a fast, precise, green, and extremely sensitive UPLC-MS/MS technique for the estimation of the RVB level in human liver microsomes (HLMs), employing an ESI source. The validation procedures were carried out in accordance with the bioanalytical technique validation requirements established by the US Food and Drug Administration that involve linearity, selectivity, precision, accuracy, stability, matrix effect, and extraction recovery. The outcome data of the validation features of the UPLC-MS/MS approach were acceptable according to FDA guidelines. RVB parent ions were formed in the positive ESI source and its two fragment ions were estimated employing multiple reaction monitoring (MRM) mode. The separation of RVB and encorafenib was achieved using a C8 column (2.1 mm, 50 mm, and 3.5 µm) and isocratic mobile phase. Results: The RVB calibration curve linearity ranged from 1 to 3000 ng/mL (y = 0.6515x − 0.5459 and R² = 0.9945). The inter-day precision and accuracy spanned from −0.23% to 11.33%, while the intra-day precision and accuracy spanned from −0.88% to 11.67%, verifying the reproducibility of the UPLC-MS/MS analytical technique. The sensitivity of the developed methodology demonstrated its capability to quantify RVB levels at an LOQ of 0.96 ng/mL. The AGREE score was 0.77, confirming the greenness of the current method. The low in vitro t_1/2 (14.93 min) and high intrinsic clearance (54.31 mL/min/kg) of RVB revealed that RVB shares similarities with medications that have a high extraction ratio. Conclusions: The present LC-MS/MS approach is considered the first analytical approach with the application of metabolic stability assessment for RVB estimation in HLMs. These methods are essential for advancing the development of new pharmaceuticals, particularly in enhancing metabolic stability. Full article

Schistosomiasis is a parasitic disease that poses a serious threat to human health. However, the pathogenic mechanism during the progression of Schistosoma japonicum infection remains unclear. In order to elucidate this mechanism, we used single-cell RNA sequencing (scRNA-seq) to investigate the transcriptome characteristics of the cellular (single-cell) landscape in the livers of mice infected with Schistosoma japonicum, which were divided into three groups: uninfected mice (0 week (w)), infected mice at 6 w post-infection (the acute phase), and infected mice at 10 w post-infection (the chronic phase). A total of 31,847 liver cells were included and clustered into 21 groups. The cells and T-cells had high heterogeneity in the liver during the progression of schistosome infection. The number and intensity of the intercellular interactions significantly increased at 6 w after infection but decreased at 10 w. The inflammatory signaling pathways chemoattractant cytokine ligand (CCL)5-chemokine C-C-motif receptor (CCR)5 between macrophages and T-cells were predominant at 6 w post-infection; the CCL6-CCR2 signaling pathway between macrophages was predominant at 10 w. The CD80 signaling pathway related to T-cell activation was increased at 6 w after infection, and increased expression of its receptor CD28 on the surfaces of CD4⁺ and CD8⁺ T-cells was confirmed by flow cytometry, suggesting an increase in their activation. In addition, scRNA-seq and quantitative reverse transcription polymerase chain reaction (qRT-PCR) confirmed that the intercellular communication between secretory phosphoprotein 1 (SPP1)-cluster of differentiation (CD44), insulin-like growth factor (IGF)-1-IGF1r and visfatin-insulin receptor (Insr) associated with bone metabolism and insulin metabolism was increased and enhanced in the liver at 6 w post-infection. Overall, we provide the comprehensive single-cell transcriptome landscape of the liver in mice during the progression of schistosome infection and delineate the key cellular and molecular events involved in schistosome infection-induced liver injury and fibrosis. The elevated CCL5-CCR5 and CCL6-CCR2 signaling pathways in the liver may be a drug target for liver injury and fibrosis caused by schistosome infection, respectively. Full article