A dendritic cell-recruiting, antimicrobial blood clot hydrogel for melanoma recurrence prevention and infected wound management.

Surgical resection, the mainstay for melanoma treatment, faces challenges due to high tumor recurrence rates and complex postoperative wound healing. Chronic inflammation from residual disease and the risk of secondary infections impede healing. We introduce an innovative, injectable hydrogel system that integrates a multifaceted therapeutic approach. The hydrogel, crosslinked by calcium ions with sodium alginate, encapsulates a blood clot rich in dendritic cells (DCs) chemoattractants and melanoma cell-derived nanovesicles (NVs), functioning as a potent immunostimulant. This in situ recruitment strategy overcomes the limitations of subcutaneous tumor vaccine injections and more effectively achieves antitumor immunity. Additionally, the hydrogel incorporates Chlorella extracts, enhancing its antimicrobial properties to prevent wound infections and promote healing. One of the key findings of our research is the dual functionality of Chlorella extracts; they not only expedite the healing process of infected wounds but also increase the hydrogel's ability to stimulate an antitumor immune response. Given the patient-specific nature of the blood clot and NVs, our hydrogel system offers customizable solutions for individual postoperative requirements. This personalized approach is highlighted by our study, which demonstrates the synergistic impact of the composite hydrogel on preventing melanoma recurrence and hastening wound healing, potentially transforming postsurgical melanoma management.

Red light-induced localized release of carbon monoxide for alleviating postoperative cognitive dysfunction.

Inflammation within the central nervous system (CNS), which may be triggered by surgical trauma, has been implicated as a significant factor contributing to postoperative cognitive dysfunction (POCD). The relationship between mitigating inflammation at peripheral surgical sites and its potential to attenuate the CNS inflammatory response, thereby easing POCD symptoms, remains uncertain. Notably, carbon monoxide (CO), a gasotransmitter, exhibits pronounced anti-inflammatory effects. Herein, we have developed carbon monoxide-releasing micelles (CORMs), a nanoparticle that safely and locally liberates CO upon exposure to 650 nm light irradiation. In a POCD mouse model, treatment with CORMs activated by light (CORMs + hv) markedly reduced the concentrations of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-alpha (TNF-α) in both the peripheral blood and the hippocampus, alongside a decrease in ionized calcium-binding adapter molecule 1 in the hippocampal CA1 region. Furthermore, CORMs + hv treatment diminished Evans blue extravasation, augmented the expression of tight junction proteins zonula occludens-1 and occludin, enhanced neurocognitive functions, and fostered fracture healing. Bioinformatics analysis and experimental validation has identified Htr1b and Trhr as potential key regulators in the neuroactive ligand-receptor interaction signaling pathway implicated in POCD. This work offers new perspectives on the mechanisms driving POCD and avenues for therapeutic intervention.

Highly BBB-permeable nanomedicine reverses neuroapoptosis and neuroinflammation to treat Alzheimer's disease.

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment.

Night-time blood pressure dipping, but not 24-h blood pressure level, is linked to increased 24-h ocular volume slope

ABSTRACT Purpose: This study investigated the relationship between blood pressure and intraocular pressure in treatmentnaive, non-glaucoma patients with different blood pressure statuses, focusing on the 24-h ocular volume and nocturnal blood pressure decline. Methods: Treatment-naive, non-glaucoma patients undergoing hypertension evaluation were enrolled as study participants. Simultaneous 24-h ambulatory blood pressure measurement and 24-h ocular volume recording with a contact lens sensor. We also compared ocular volume curve parameters between normotensive and hypertensive patients, as well as between those with and without nocturnal blood pressure decline. Results: A total of 21 patients, including 7 normotensive and 14 treatment-naive hypertensive individuals, were included in the study. of them, 11 were dippers and 10 were non-dippers. No significant difference in the 24-h ocular volume slope was observed between the hypertensive and normotensive patients (p=0.284). However, dippers had a significantly higher 24-h ocular volume slope (p=0.004) and nocturnal contact lens sensor output (p=0.041) than non-dippers. Conclusion: Nocturnal blood pressure decline, rather than the blood pressure level, is associated with the increased 24-h ocular volume slope and nocturnal ocular volume. Further studies are required to determine whether the acceleration of glaucoma progression in dippers is primarily due to low blood pressure, high intraocular pressure, or a combination of both.

Prevalencia y caracterización de la anemia en cirugía electiva en un Hospital Universitario

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Introduction: Anemia is a highly prevalent disorder. Preoperative anemia is associated with higher mortality, more complications, longer hospital stays, and higher healthcare costs. Red blood cell transfusion (RBC) does not improve these outcomes. The World Health Organization recommends implementing Patient Blood Management (PBM) programmes, as they can improve these clinical outcomes, reduce unnecessary RBC transfusions, and save costs. Despite compelling evidence, the implementation of these measures has yet to be effectively achieved. The objective of this study is to conduct a situational analysis to raise awareness about this issue and encourage the implementation of these measures. Methodology: An observational, longitudinal, retrospective cohort study was conducted at a single center. All patients undergoing elective surgery from 01/01/2022 to 01/04/2022 at the Hospital de Clínicas were included. Exclusion criteria: absence of a complete blood count in the three months prior to surgery and refusal to participate in the study. Results: A total of 329 surgeries were analyzed. 52 out of 100 procedures were performed on patients with anemia. A statistically significant association was found between preoperative anemia and receiving RBC transfusion during hospitalization. OR 11.746 (4.518 - 30.540). Anemia and RBC transfusions significantly prolonged hospital stay. Length of hospitalization based on patient condition: No anemia: 10.1 ± 1.1 days, with anemia: 27.2 ± 2.3 days. Value of p < 0.001. Non-transfused: 14.5 ± 1.3 days, transfused: 41.8 ± 4.4 days. Value of p < 0.001. Only 49 (28.6%) of the 171 patients with anemia had iron metabolism assessed before surgery. Among the 140 patients with Hb < 12 g/dL undergoing surgeries with non-insignificant bleeding, only 4 received specific treatment to optimize Hb. A total of 185 units of red blood cells (RBC) were administered during hospitalization. 49 to unstable patients (intraoperative or acute hemorrhage) and 136 to stable patients. From the analysis of the latter group, 42.5% of the patients received 3 or more RBC units. The average pre-transfusion hemoglobin was 7.0 ± 0.1. A statistically significant association was found between receiving RBC units and dying during hospitalization. OR 17.182 (3.360 - 87.872). Conclusiones: A situational analysis was conducted, revealing a high prevalence of preoperative anemia, scarce study and treatment of anemia before surgeries, and an excessive amount of blood transfusions received by some patients. This work establishes the need to implement Patient Blood Management programs to reduce the prevalence of preoperative anemia and improve our transfusion practices. It also sets a comparative framework to evaluate the progress of these measures and indicates possible indicators to assess the benefits of their implementation.

Introdução : A anemia é um distúrbio altamente prevalente. A anemia pré-operatória está associada a maior mortalidade, mais complicações, tempo prolongado de internação e maiores custos de saúde. A transfusão de glóbulos vermelhos (TGV) não melhora esses resultados. A Organização Mundial da Saúde recomenda a implementação de medidas de Gerenciamento de Sangue do Paciente (GSP), pois permitem melhorar esses resultados clínicos, reduzir TGV desnecessárias e economizar custos. Apesar da evidência contundente, a implementação dessas medidas ainda está aquém de ser efetivada. O objetivo deste trabalho é realizar uma análise da situação para conscientizar sobre o problema e incentivar a implementação dessas medidas. Metodologia: Foi realizado um estudo observacional, longitudinal, retrospectivo de coorte histórica, unicêntrico. Foram incluídos todos os pacientes submetidos a cirurgias de coordenação de 01/01/2022 a 01/04/2022 no Hospital de Clínicas. Critérios de exclusão: ausência de hemograma nos três meses anteriores à cirurgia e recusa em participar do estudo. Resultados: Foram analisadas um total de 329 cirurgias. 52 a cada 100 procedimentos foram realizados em pacientes com anemia. Foi encontrada uma associação estatisticamente significativa entre a anemia pré-operatória e a recepção de TGR durante a internação. OR 11,746 (4,518 - 30,540). A anemia e as TGR prolongaram significativamente a internação hospitalar. Dias de internação em função da condição do paciente: Sem anemia: 10,1 ± 1,1 dias, com anemia: 27,2 ± 2,3 dias. Valor p < 0,001. Não transfundidos: 14,5 ± 1,3 dias, transfundidos: 41,8 ± 4,4 dias. Valor p < 0,001. Apenas 49 (28,6%) dos 171 pacientes com anemia tinham metabolismo do ferro antes da cirurgia. Dos 140 pacientes com Hb < 12 mg/dL submetidos a cirurgias com sangramento não insignificante, 4 receberam tratamento específico para otimizar a Hb. Foram administradas um total de 185 unidades de glóbulos vermelhos (UGV) durante a internação. 49 em pacientes instáveis (intraoperatório ou hemorragia aguda) e 136 em pacientes estáveis. Da análise desses últimos, 42,5% dos pacientes receberam 3 ou mais UGV. A hemoglobina pré-transfusional média foi de 7,0 ± 0,1. Foi encontrada uma associação estatisticamente significativa entre receber UGV e falecer durante a internação. OR 17,182 (3,360 - 87,872). Conclusões: Foi realizado uma análise da situação na qual foi observada uma elevada prevalência de anemia pré-operatória, um estudo e tratamento escasso da anemia antes das cirurgias e uma quantidade excessiva de UGV recebidas por alguns pacientes. Este trabalho estabelece a necessidade de implementar programas de Gerenciamento de Sangue do Paciente para reduzir a prevalência de anemia pré-operatória e melhorar nossas práticas transfusionais. Além disso, estabelece um quadro comparativo para avaliar o progresso dessas medidas e aponta possíveis indicadores para avaliar os benefícios de sua implementação.

Enhanced Venous Thrombosis and Hypercoagulability in Murine and Human Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND: Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events (VTE), including deep vein thrombosis (DVT). To date, the study of DVT in MASH has been hampered by the lack of reliable models that mimic the pathological aspects of human disease. OBJECTIVES: To evaluate DVT severity and hypercoagulability in murine and human MASH. METHODS: Transcriptional changes in the liver, plasma markers of coagulation, and DVT severity were evaluated in mice fed a chow diet or a high-fructose, high-fat, and high-cholesterol, MASH diet for 24 weeks. Plasma analyses of coagulations markers and thrombin generation assay were performed in a well-characterized cohort of patients with or without MASH. RESULTS: Mice fed the MASH diet developed steatohepatitis and fibrosis, mimicking human MASH. Liver RNA-sequencing revealed a significant upregulation of pathways related to inflammation and coagulation concomitant with increased plasma coagulation markers including increased prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor-1 levels, and endothelin 1. MASH exacerbated DVT severity in mice, as evidenced by increased thrombus weight and higher thrombosis incidence (15/15 vs. 11/15 in controls, p=0.0317). Higher endothelin 1 release and increased apoptosis were found in endothelial cells stimulated with supernatants of palmitate-stimulated HepG2 cells. Patients with MASH exhibited increased plasma coagulation markers and delayed thrombin generation. CONCLUSION: We report enhanced DVT severity and hypercoagulability, both in murine and human MASH. Our model of MASH-DVT can facilitate a better understanding of the fundamental mechanisms leading to increased VTE in patients with MASH.

Stool and blood metabolomics in the metabolic syndrome: a cross-sectional study.

INTRODUCTION/OBJECTIVES: Changes in the stool metabolome have been poorly studied in the metabolic syndrome (MetS). Moreover, few studies have explored the relationship of stool metabolites with circulating metabolites. Here, we investigated the associations between stool and blood metabolites, the MetS and systemic inflammation. METHODS: We analyzed data from 1,370 participants of the KORA FF4 study (Germany). Metabolites were measured by Metabolon, Inc. (untargeted) in stool, and using the AbsoluteIDQ® p180 kit (targeted) in blood. Multiple linear regression models, adjusted for dietary pattern, age, sex, physical activity, smoking status and alcohol intake, were used to estimate the associations of metabolites with the MetS, its components and high-sensitivity C-reactive protein (hsCRP) levels. Partial correlation and Multi-Omics Factor Analysis (MOFA) were used to investigate the relationship between stool and blood metabolites. RESULTS: The MetS was significantly associated with 170 stool and 82 blood metabolites. The MetS components with the highest number of associations were triglyceride levels (stool) and HDL levels (blood). Additionally, 107 and 27 MetS-associated metabolites (in stool and blood, respectively) showed significant associations with hsCRP levels. We found low partial correlation coefficients between stool and blood metabolites. MOFA did not detect shared variation across the two datasets. CONCLUSIONS: The MetS, particularly dyslipidemia, is associated with multiple stool and blood metabolites that are also associated with systemic inflammation. Further studies are necessary to validate our findings and to characterize metabolic alterations in the MetS. Although our analyses point to weak correlations between stool and blood metabolites, additional studies using integrative approaches are warranted.

Leg fidgeting alleviates reduced oxygen extraction in the gastrocnemius muscle caused by prolonged sitting: a randomized crossover trial.

PURPOSE: Oxygen extraction in skeletal muscle is an important determinant of exercise tolerance. Prolonged sitting decreases oxygen extraction in the gastrocnemius muscle. However, the underlying mechanism remains unknown, and preventive measures are yet to be established. Therefore, we aimed to elucidate the mechanism by which prolonged sitting decreased muscle oxygen extraction and investigate preventive measures. METHODS: Ten healthy young males (age 21.2 ± 0.4 years; body mass index, 20.5 ± 1.3 kg/m2) were randomly assigned to each of the following conditions: 3-h supine (CON), 3-h sitting (SIT), and 3-h fidgeting of one lower leg during sitting (FID). Oxygen extraction from the gastrocnemius muscle was measured using near-infrared spectroscopy and the vascular occlusion test under each condition. The rate of change in total Hb + Mb (THb) was measured as an indicator of venous stasis and interstitial fluid accumulation in the lower leg. RESULTS: Muscle oxygen extraction was significantly lower at 180 min for SIT and FID than for CON (4384.2 ± 1426.8; 5281.5 ± 1823.7; 6517.4 ± 1390.8 a.u., respectively) and significantly higher for FID than for SIT (5281.5 ± 1823.7 vs. 4384.2 ± 1426.8 a.u., respectively). The rate of THb change was significantly higher at 180 min for SIT than for CON and FID (12.9 ± 15.1; -2.3 ± 5.7; 2.2 ± 11.6%, respectively). However, no significant difference was observed between CON and FID. CONCLUSION: We found that 3-h prolonged sitting reduced oxygen extraction in the gastrocnemius muscles due to reduced oxygen supply to capillaries and increased distance between capillaries and myocytes. However, leg fidgeting alleviated this effect in healthy young males. TRIAL REGISTRATION NUMBER: UMIN000050531 (March 8, 2023).

Death due to unrecognized intoxication of nifedipine in an adult.

PURPOSE: Diagnosis of drug intoxication in the medico-legal autopsy is challenging due to many factors such as non-specific clinical features and non-specific, inconclusive autopsy findings, etc. Thus, deaths due to drug intoxication can be misclassified in a low-resource setting where post-mortem toxicology testing is selective. The paper presents a fatal case of unrecognized nifedipine intoxication in an adult where the manner of death was undetermined after extensive investigation. METHOD: The liquid-liquid extraction using chloroform was carried out on a blood sample spiked with nifedipine. Subsequently, the post-mortem blood sample was analyzed and quantified using gas chromatography-mass spectrometry with electron ionization technique. RESULTS: The patient before death had symptoms, such as trismus, vomiting, and dizziness. The initial blood pressure and pulse rate were 94/56 mm Hg and 110 beats per minute, respectively. The respiratory rate was 20 breaths per minute. The post-mortem examination revealed no pathological changes or injuries in any organs. Upon histopathological examination, no significant findings that could have led to death were observed in any of the organs. The level of nifedipine in the peripheral blood, 0.645 µg/ml was determined to be either  close to or exceeding the reported fatal dose. The cause of death was ascertained as acute nifedipine intoxication. CONCLUSION: It is crucial to accurately determine the cause of death in cases that pose a significant threat to public health. This case highlights the challenges faced by forensic pathologists in scientifically ascertaining the cause of death accurately, especially in intoxication deaths, and the importance of comprehensive toxicology testing services including analytical toxicology for the integrity of the medico-legal death investigation system.

Blood immune profiles reveal a CXCR3/CCR5 axis of dysregulation in early sepsis.

We report on a pilot study exploring whether blood immune signatures can reveal early specific indicator profiles for patients meeting sepsis criteria upon hospital admission. We analysed samples of sepsis-suspected patients (N=20) and age-spanning healthy controls (N=12), using flow cytometry-based assays. We measured inflammatory markers from plasma fractions, and immunophenotyped freshly isolated unfixed PBMCs for leukocytes subsets representation and expression of activation markers, including chemokine receptors. We found that beside IL-6 and sCD14, CXCR3 ligands (CXCL9 and CXCL10) separated sepsis-suspected patients from healthy controls. The abundance of CD4+ T cells was significantly reduced in patients, while they displayed substantial losses of CCR5-expressing monocytes and CXCR3/CCR5 double positive T cells. Post-hoc subgrouping of patients according to their sepsis diagnosis on discharge, identified CXCR3/CCR5 double expression on T cells as a separating characteristic for confirmed cases. This work suggests a potential novel axis of dysregulation affecting CXCR3 and CCR5 in early sepsis.

Investigation of the effect of ABO blood types on the prognosis of endometrioid-type endometrial cancer.

Objective: The aim of this study was to examine how the ABO blood type affects endometrioid-type, EC prognosis. Method: A total of 522 patients diagnosed with EC between February 2010 and December 2021 were assessed, retrospectively. ABO blood types were used to divide the patients into four groups as A, B, O, and AB. Demographic data, menopause, prognostic variables, FIGO stage, and survival were evaluated. A in 217 patients, B in 84 patients, O in 181 patients, and AB blood type in 40 patients were analyzed. Results: Age, gravida, parity, body mass index, menopause, comorbidity, prognostic variables, FIGO stage, and survival according to the groups were similar (p > 0.012). Group A differed from other groups statistically in peritoneal fluid cytology (p = 0.004). B blood type had the best chance of cumulative overall survival, followed by AB, A, and O blood types, in that order (p = 0.170). Conclusion: In light of blood types sensitivity to endometrioid-type EC, O blood type has been identified as blood type with the highest risk of endometrioid EC.

Objetivo: Examinar cómo los tipos de sangre ABO afectan el pronóstico del cáncer de endometrio de tipo endometrioide. Método: Se evaluaron retrospectivamente 522 pacientes diagnosticadas con CE entre 2010 y 2021. Se utilizaron los tipos de sangre ABO para dividir a las pacientes cuatro grupos: A, B, O, y AB. Se evaluaron la edad, la menopausia, las variables pronósticas, la etapa FIGO y la supervivencia. Se determinó el tipo de sangre A en 217 pacientes, el B en 84 pacientes, el O en 181 pacientes y el AB en 40 pacientes. Resultados: La edad, la menopausia, las variables pronósticas, la etapa FIGO y la supervivencia según grupos fueron similares (p > 0.012). El grupo A difirió estadísticamente de los otros grupos en la citología del líquido peritoneal (p = 0.004). El tipo de sangre B tuvo mejor probabilidad de una supervivencia global acumulativa, seguido por los tipos AB, A, y 0, en este orden (p = 0.170). Conclusión: A la luz de la sensibilidad de los tipos de sangre al cáncer de endometrio tipo endometrioide, el O ha sido identificado como el de mayor riesgo de cáncer endometrial tipo endometrioide.

[Active components and mechanism of Wuhu Decoction in intervening RSV-induced asthma based on network pharmacology and in vivo experiment].

This study aims to explore the active components and mechanism of Wuhu Decoction in treating respiratory syncytial virus(RSV)-induced asthma. Ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry was used to determine the components of Wuhu Decoction in the blood. By utilizing databases, Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis and Gene Ontology(GO) functional analysis were conducted to investigate the targets of the components of Wuhu Decoction in asthma. Furthermore, the information on target proteins, and metabolite-target-pathway was imported into the STRING database to construct a network interaction diagram to identify the core components and key pathways of Wuhu Decoction. In the in vivo experiment, an asthma model was established using RSV combined with ovalbumin(OVA) in mice. The intervention effect of Wuhu Decoction on RSV-induced asthma in mice was validated through lung function tests, hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay(ELISA), Western blot, and immunohistochemistry. The results showed that the main components of Wuhu Decoction in the blood were flavonoids, phenylpropanoids, lignans, and terpenoids. The core components of Wuhu Decoction in treating pediatric asthma included(-)-epigallocatechin, kaempferol, isoliquiritigenin, diosmetin, betulinic acid, ursolic acid, daphnetin, aescin. The main pathways targeted by Wuhu Decoction were calcium signaling pathway, neuroactive ligand-receptor interaction, NOD-like receptor signaling pathway, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. The results of in vivo experiments demonstrated that Wuhu Decoction could improve lung function indicators, down-regulate levels of interleukin-6(IL-6), interleukin-17(IL-17), and tumor necrosis factor-alpha(TNF-α), and reduce the expression of proteins such as NOD-like receptor pyrin domain-containing 3(NLRP3), mitogen-activated protein kinase 1(MAPK1), mitogen-activated protein kinase 14(MAPK14), and nuclear factor kappaB subunit 1(NFKB1) in lung tissue, thereby alleviating neutrophilic inflammation and pulmonary congestion. These findings indicate that Wuhu Decoction intervenes in virus-induced asthma through a synergistic effect on multiple components, targets, and pathways, and it can inhibit the activation of the NOD-like receptor signaling pathway, thereby alleviating airway inflammation and injury in asthmatic mice.

[Traditional Chinese medicine theoretical mechanism of blood-activating and stasis-resolving therapy combined with thrombolysis/thrombectomy in improving clinical efficacy].

Thrombolysis/thrombectomy treatment is an emergency medical intervention for patients with acute ischemic stroke. Its core purpose is to reduce brain tissue damage and improve patient prognosis by restoring blood flow to the brain, which is significantly advantageous in timely restoring blood flow to the brain and reducing post-stroke sequelae. However, research shows that even with successful thrombolysis/thrombectomy treatment, some patients may still experience re-occlusion of the target vessel, leading to secondary damage and worsening of the condition. This study retrospectively examined clinical, experimental, and theoretical aspects of thrombolysis/thrombectomy in both traditional Chinese medicine(TCM) and western medicine, and analyzed the characteristics of blood-activating and stasis-resolving therapy in different stages of thrombolysis/thrombectomy and the synergistic mechanism of different types of blood-activating and stasis-resolving drugs with thrombolysis/thrombectomy in combination of previous clinical studies by the research team. Furthermore, the "vessel hyperactivity" characteristics embodied by Yang vessel irritability and Yin vessel stagnation was explained, revealing the TCM mechanism by which blood-activating TCM drugs reduce the incidence of vessel re-occlusion after thrombolysis/thrombectomy through multiple targets and pathways from a theoretical perspective. It also explored how blood-activating and stasis-resolving drugs promoted the excretion of pathological products such as phlegm, fluid, stasis, and toxins from damaged brain tissue, enhanced self-repair of damaged brain tissue, and accelerated the reconstruction of the brain by facilitating the transformation of Qi, blood, and essence within the body. This study aims to deeply elucidate the TCM theoretical mechanism of blood-activating and stasis-resolving therapy in reducing the occurrence of "cerebral infarction and vascular re-occlusion" during thrombolysis/thrombectomy, which holds significant theoretical and practical significance.

Latest Perspectives on Alzheimer's Disease Treatment: The Role of Blood-Brain Barrier and Antioxidant-Based Drug Delivery Systems.

There has been a growing interest recently in exploring the role of the blood-brain barrier (BBB) in the treatment of Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline and memory loss that affects millions of people worldwide. Research has shown that the BBB plays a crucial role in regulating the entry of therapeutics into the brain. Also, the potential benefits of using antioxidant molecules for drug delivery were highlighted in Alzheimer's treatment to enhance the therapeutic efficacy and reduce oxidative stress in affected patients. Antioxidant-based nanomedicine shows promise for treating AD by effectively crossing the BBB and targeting neuroinflammation, potentially slowing disease progression and improving cognitive function. Therefore, new drug delivery systems are being developed to overcome the BBB and improve the delivery of therapeutics to the brain, ultimately improving treatment outcomes for AD patients. In this context, the present review provides an in-depth analysis of recent advancements in AD treatment strategies, such as silica nanoparticles loaded with curcumin, selenium nanoparticles loaded with resveratrol, and many others, focusing on the critical role of the BBB and the use of antioxidant-based drug delivery systems.

Monitoring SARS-CoV-2 IgA, IgM and IgG antibodies in dried blood and saliva samples using antibody proximity extension assays (AbPEA).

Using a modified proximity extension assay, total and immunoglobulin (Ig) class-specific anti-SARS-CoV-2 antibodies were sensitively and conveniently detected directly from ø1.2 mm discs cut from dried blood and saliva spots (DBS and DSS) without the need for elution. For total Ig detection, antigen probes were prepared by conjugating recombinant spike protein subunit 1 (S1-RBD) to a pair of oligonucleotides. To detect isotype-specific antibody reactivity, one antigen probe was replaced with oligonucleotide-conjugated antibodies specific for antibody isotypes. Binding of pairs of oligonucleotide-conjugated probes to antibodies in patient samples brings oligonucleotides in proximity. An added DNA polymerase uses a transient hybridization between the oligonucleotides to prime synthesis of a DNA strand, which serves as a DNA amplicon that is quantified by real-time PCR. The S1-RBD-specific IgG, IgM, and IgA antibodies in DBS samples collected over the course of a first and second vaccination exhibited kinetics consistent with previous reports. Both DBS and DSS collected from 42 individuals in the autumn of 2023 showed significant level of total S1-RBD antibodies with a correlation of R = 0.70. However, levels in DSS were generally 10 to 100-fold lower than in DBS. Anti-S1-RBD IgG and IgA in DSS demonstrated a correlation of R = 0.6.

Truncated mini LRP1 transports cargo from luminal to basolateral side across the blood brain barrier.

BACKGROUND: The most crucial area to focus on when thinking of novel pathways for drug delivery into the CNS is the blood brain barrier (BBB). A number of nanoparticulate formulations have been shown in earlier research to target receptors at the BBB and transport therapeutics into the CNS. However, no mechanism for CNS entrance and movement throughout the CNS parenchyma has been proposed yet. Here, the truncated mini low-density lipoprotein receptor-related protein 1 mLRP1_DIV* was presented as blood to brain transport carrier, exemplified by antibodies and immunoliposomes using a systematic approach to screen the receptor and its ligands' route across endothelial cells in vitro. METHODS: The use of mLRP1_DIV* as liposomal carrier into the CNS was validated based on internalization and transport assays across an in vitro model of the BBB using hcMEC/D3 and bEnd.3 cells. Trafficking routes of mLRP1_DIV* and corresponding cargo across endothelial cells were analyzed using immunofluorescence. Modulation of γ-secretase activity by immunoliposomes loaded with the γ-secretase modulator BB25 was investigated in co-cultures of bEnd.3 mLRP1_DIV* cells and CHO cells overexpressing human amyloid precursor protein (APP) and presenilin 1 (PSEN1). RESULTS: We showed that while expressed in vitro, mLRP1_DIV* transports both, antibodies and functionalized immunoliposomes from luminal to basolateral side across an in vitro model of the BBB, followed by their mLRP1_DIV* dependent release of the cargo. Importantly, functionalized liposomes loaded with the γ-secretase modulator BB25 were demonstrated to effectively reduce toxic Aß42 peptide levels after mLRP1_DIV* mediated transport across a co-cultured endothelial monolayer. CONCLUSION: Together, the data strongly suggest mLRP1_DIV* as a promising tool for drug delivery into the CNS, as it allows a straight transport of cargo from luminal to abluminal side across an endothelial monolayer and it's release into brain parenchyma in vitro, where it exhibits its intended therapeutic effect.

An evaluation of the quality care for type 2 diabetes patients in the primary healthcare using the lot quality assurance sampling technique.

BACKGROUND: Diabetes is the most prevalent metabolic disease globally. Correct and effective healthcare management requires up-to-date and accurate information at the local level. This level of information allows managers to determine whether the health system has achieved its desired goals in this area. This study aimed to evaluate the adequacy and quality of care for Type 2 diabetes mellitus (T2DM) patients using the Lot quality assurance sampling (LQAS) technique to provide evidence for decision-making at the local level, prioritizing and allocating resources. METHODS: A descriptive-analytical study was conducted in 12 supervision areas (SAs)/health facilities in northwestern Iran involving 240 patients with T2DM in primary health care. The selection of patients and determination of SAs were done randomly using the LQAS technique. Glycated Hemoglobin (HbA1c) was used to evaluate patients' blood sugar control in each SA. Multiple linear regression analysis was used to estimate predictors of HbA1c in T2DM. RESULTS: The overall average of HbA1c value was 7.84%. The HbA1c level was > 7% in 148 (61.6%) of the patients. Among the 12 SAs, the LQAS identified unacceptable quality of care in 5 SAs. In the final analysis, each unit increase in fasting blood sugar (FBS), High-density lipoprotein (HDL), Low-density lipoprotein (LDL), and Thyroglobulin (TG) values resulted in an increased in HbA1c levels by 0.43, 0.183, 0.124, and 0.182 times, respectively. However, with a one-unit increase in the care of a family physician and nutritionist, along with regular physical activity, HbA1c levels decreased by - 0.162, -0.74, and - 0.11 times, respectively. CONCLUSIONS: The quality of care for diabetic patients needs improvement in some SAs. Findings indicated that the LQAS technique effectively identifies centers/areas with substandard diabetes care quality and efficiently allocates resources to those in need. It is recommended to implement corrective measures in areas with inadequate care quality.

Prognostic and diagnostic utility of pancreatic stone protein in pediatric sepsis and mortality.

Background/aim: Early detection and prognosis of sepsis in critically ill children is crucial. The aim of this research was to investigate the prognostic ability of pancreatic stone protein (PSP) in validating sepsis and predicting mortality in a prospective observational study. Materials and methods: In a single-center study, pediatric intensive care unit patients were divided into cohorts of confirmed and suspected sepsis, as well as survivors and nonsurvivors. Patients with positive blood culture growth were considered to have confirmed sepsis, while their negative counterparts were considered to have suspected sepsis. Comparisons were made between complete blood counts, laboratory parameters, mortality indices, and C-reactive protein (CRP), procalcitonin (PCT), and PSP levels. The correlations between PSP and alternative inflammatory markers and mortality indices were then analyzed. The diagnostic and prognostic applicability of PSP for sepsis confirmation and mortality prediction was assessed using receiver operating characteristic curve analysis. Results: PSP levels were significantly elevated in patients with confirmed sepsis and within the nonsurvivor segment. In confirming sepsis and predicting mortality, PSP outperformed CRP and PCT in terms of sensitivity. It had sensitivity of 95% in diagnosing sepsis at a cut-off level of 50 ng/L, with an area under the curve (AUC) of 0.67 (95% CI: 0.52-0.81), and sensitivity of 92% in predicting mortality, with an AUC of 0.71 (95% CI: 0.56-0.83). In addition, PSP showed significant correlations with CRP, PCT, and mortality scores. Conclusion: PSP is emerging as a highly sensitive marker for confirming sepsis and predicting mortality in critically ill pediatric patients. Incorporating the PSP biomarker into routine clinical practice could potentially improve the management of pediatric sepsis.

Reduced B cell frequencies in cord blood of HIV-exposed uninfected infants: an immunological and transcriptomic analysis.

Introduction: In the course of immune development, HIV-exposed uninfected (HEU) infants exhibit abnormal immune function and increased infectious morbidity compared to HIV-unexposed uninfected (HUU) infants. Yet the specific functional phenotypes and regulatory mechanisms associated with in-utero HIV and/or ART exposure remain largely obscure. Methods: We utilized flow cytometry and RNA-seq technologies to conduct the immunological and transcriptomic profiling in cord blood from 9 HEU mother-infant pairs and 24 HUU pairs. On top of that, we compared the cord blood dataset with the maternal venous blood dataset to characterize unique effects induced by in-utero HIV and/or ART exposure. Results: Flow cytometry immunophenotyping revealed that the level of B lymphocyte subsets was significantly decreased in HEU cord blood as compared to HUU (P < 0.001). Expression profiling-based cell abundance assessment, includes CIBERSORT and ssGSEA algorithm, showed a significantly reduced abundance of naive B cells in HEU cord blood (both P < 0.05), supporting the altered composition of B lymphocyte subsets in HEU. Functional enrichment analysis demonstrated suppressed innate immune responses and impaired immune regulatory function of B cells in HEU cord blood. Furthermore, through differential expression analysis, co-expression network analysis using WGCNA, and feature selection analysis using LASSO, we identified a 4-gene signature associated with HEU status. This signature effectively assesses B cell levels in cord blood, enabling discrimination between HEU and HUU infants. Discussion: Our study provides the first comprehensive immunological and transcriptomic characterization of HEU cord blood. Additionally, we establish a 4-gene-based classifier that holds potential for predict immunological abnormalities in HEU infants.

A biomimetic targeted nanosystem delivering synergistic inhibitors for glioblastoma immune microenvironment reprogramming and treatment.

Efficient drug delivery across the blood-brain barrier is imperative for treating glioblastoma (GBM). This study utilized the GBM cell membrane to construct a biomimetic targeted nanosystem (GMNPs@AMD/RAPA) that hierarchically releases the CXCR4 antagonist AMD3100 and the mTOR pathway inhibitor rapamycin (RAPA) for reprogramming the tumor immune microenvironment and suppressing the progression of GBM. By initially inhibiting the CXCL12/CXCR4 axis, the tumor microenvironment (TME) was reprogrammed to enhance the infiltration of cytotoxic T lymphocytes (CTLs) into the TME while suppressing tumor cell survival, proliferation, and angiogenesis. Subsequently, through further cellular uptake and degradation of the nanoparticles, the mTOR pathway inhibitor RAPA was released, further suppressing the tumor progression. This study successfully combined chemotherapy and immunotherapy, achieving effective synergistic therapeutic effects, and suppressing the progression of GBM.