Study of vascular sclerosing agent based on the dual mechanism of vascular endothelial cell damage-plasmin system inhibition.

Venous malformations are a vascular disorder. Currently, the use of chemical sclerosing agents is a common clinical approach for the treatment of venous malformations. However, the effectiveness of existing sclerosing agents is unsatisfactory and often accompanied by severe side effects. In this study, we have developed a novel cationic surfactant-based sclerosing agent (POL-TA) by conjugating the plasmin inhibitor tranexamic acid (TA) with a nonionic surfactant polidocanol (POL) through an ester bond. POL-TA induces endothelial cell damage, triggering the coagulation cascade and thrombus formation. Moreover, it releases TA in vivo, which inhibits plasmin activity and the activation of matrix metalloproteinase (MMPs), thereby stabilizing the fibrin network of the thrombus and promoting vascular fibrosis. We have established a cell model using venous malformation endothelial cells and assessed the cellular damage and underlying mechanisms of POL-TA. The inhibitory effects of POL-TA on the plasmin-MMPs system were evaluated using MMP-9 activity assay kit. Additionally, the mice tail vein model was employed to investigate the vascular sclerosing effects and mechanisms of POL-TA.

A survey study on early detection of young children with disabilities in urban and rural areas of China.

AIM: This study aimed to understand how children and families access early intervention in China. BACKGROUND: Timely identification and high-quality intervention is expected to prevent and reduce the occurrence and severity of chronic functional impairment for children with disability and is of great significance to individuals and the society. The current study recruited 1129 caregivers of children with disabilities from rural and urban areas of China were recruited to participate in a survey. RESULTS: (a) The first concern about development was raised, usually by the parents, when a child with disabilities was 26 months of age, (b) developmental screening took place 4 months after the first concern and diagnostic evaluation happened 7 months after, (c) the types of early intervention programme varied across urban and rural areas and (d) child and family factors were found associating with age of detection. CONCLUSIONS: Findings highlight the concerningly late age of children being identified for early intervention and disparities in services between urban and rural areas in China. Implications are provided for practitioners, policy makers and future research.

Erythrocyte Membrane-Coated Invisible Acoustic-Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

ADAPTING A PARENT-COMPLETED, SOCIOEMOTIONAL QUESTIONNAIRE IN CHINA: THE AGES & STAGES QUESTIONNAIRES: SOCIAL-EMOTIONAL.

The Ages & Stages Questionnaire: Social-Emotional (ASQ:SE; Squires, Bricker, & Twombly, 2002a), developed in the United States, was translated and adapted for use in China. Lack of valid and reliable instruments for identifying social and emotional delays in young children is a worldwide issue. Professionals in China have recently focused efforts on developing methods for early identification of social, emotional, and behavioral issues in the birth-to-5 population. Following the guidelines of the International Test Commission, the ASQ:SE was translated into Simplified Chinese (ASQ:SE-C) to collect a normative sample of 2,528 children across China. Data were analyzed to evaluate the psychometric properties of the ASQ:SE-C, using both classical test theory and item response theory, including generating cutoff points appropriate for the Chinese sample. A panel of Chinese experts was surveyed to assess face validity and estimated utility of the newly adapted tool. Discussions of research findings and implications for future studies are provided.

RETRACTED: Chen et al. A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy. Pharmaceutics 2022, 14, 343.

The Pharmaceutics Editorial Office retracts the article, "A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy" [...].

Concurrent validity of the ages and stages questionnaires with Bayley Scales of Infant Development-III at 2 years - Singapore cohort study.

BACKGROUND: With increasing acceptance of universal developmental screening in primary care, it is essential to evaluate the local validity and psychometric properties of commonly used questionnaires like the parent-completed Ages and Stages Questionnaires, 3rd Edition (ASQ-3) in identifying developmental delays. The aim of this study is to assess the convergent validity of the ASQ-3 with the Bayley Scales of Infant Development-3rd edition (Bayley-III) in identifying developmental delay in a low-risk term cohort in Singapore. METHODS: ASQ-3 and Bayley-III data was collected prospectively with generation of ASQ-3 cut-off scores using three different criteria: 1-standard deviation (SD) (Criterion-I) or 2-SD (Criterion-II) below the mean, and using a Receiver Operator Curve (ROC) (Criterion-III). Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated. Correlations between the ASQ-3 and Bayley-III domains were evaluated using Pearson coefficients. RESULTS: With all three criteria across different domains ASQ-3 showed high specificity (72-99%) and NPV (69-98%), but lower sensitivity (19-74%) and PPV (11-59%). Criterion-I identified 11-21% of children as "at-risk of developmental delay," and was the most promising criterion measure, with high specificity (82-91%), NPV (69-74%) and overall agreement of 64-71%. Moderate-strong correlations were seen between ASQ-3 Communication and Bayley-III Language scales (r = 0.44-0.59, p < 0.01). The lowest sensitivities were seen in the motor domains. CONCLUSIONS: ASQ-3 is reliable in low-risk settings in identifying typically developing children not at risk of developmental delay, but it has modest sensitivity. Moderate-strong correlations seen in the communication domain are clinically important for early identification of language delay, which is one of the most prevalent areas of early childhood developmental delay.

Gastrointestinal syndrome encountered during a train voyage to high altitudes: A 14-day survey of 69 passengers in China.

BACKGROUND: The diagnosis and evaluation of the severity of acute mountain sickness (AMS) continue to be problematic due to a lack of consensus on the inclusion of symptoms in a scoring system. Recent investigations highlight the significance of gastrointestinal symptoms in identifying this condition. However, the specific gastrointestinal symptoms associated with AMS have not been thoroughly elucidated in previous studies, and the underlying risk factors remain inadequately comprehended. METHODS: This study aimed to investigate the characteristics, trends, and risk factors related to gastrointestinal symptoms encountered during train travel to high altitude. A total of 69 passengers, specifically all with medical backgrounds, were surveyed 6 times over a period of 14 days. RESULTS: The daily incidence of abdominal discomfort was higher than non-gastrointestinal symptoms within 14 days. Gastrointestinal symptoms demonstrated a greater prevalence, longer duration, and increased risk compared to non-gastrointestinal symptoms, such as headaches. The symptoms of abdominal distension and bowel sound hyperaction were found to be prevalent and persistent among patients diagnosed with AMS, exhibiting a high incidence rate. Gender, age, body mass index (BMI), smoking habits, and alcohol consumption were identified as risk factors associated with the occurrence and duration of gastrointestinal symptoms. CONCLUSION: This study suggests that gastrointestinal symptoms are more common and persistent when traveling to the plateau by train. These symptoms should be taken into consideration in the further diagnosis and prevention of AMS. Therefore, this study provides a significant theoretical foundation for the prevention and treatment of AMS.

Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy.

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvß3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

Exploring the validity of the ASQ-SE for socio-emotional competency screening of a low-risk Asian cohort at 2 years of age.

AIMS: To assess the Ages & Stages Questionnaire: Social-Emotional (ASQ-SE)'s concurrent validity in a low-risk Singapore cohort and study its association with maternal mental health status. METHODS: Concurrent validity of the parent-filled ASQ-SE with Child Behavior Checklist (CBCL1.5-5) was evaluated in 341 children at age 24 months. Data on maternal anxiety and depression were collected using the State-Trait Anxiety Inventory (STAI) and Beck Depression Inventory-Second Version (BDI-II). ASQ-SE cut-off scores based on receiver operating characteristic curve were compared to CBCL scores to derive a local ASQ-SE "at risk" cut-off score. Correlations of ASQ-SE with CBCL scores and with maternal STAI and BDI scores were evaluated using Pearson coefficients. RESULTS: Using a cut-off score of 51 at 24 months, ASQ-SE had acceptable concurrent validity, with an AUC of 0.819(0.765-0.872), 70 % sensitivity and 79 % specificity. Mothers of children with "at-risk" ASQ-SE scores had significantly higher STAI and BDI-II scores. ASQ-SE had moderate- high correlations (r = 0.32-0.53) (p < .01) with CBCL scores at 24 and 48 months and with maternal mental health status(r = 0.32). INTERPRETATION: ASQ-SE can be a useful tool for screening child's socio-emotional competence for primary health care use in Singapore Dyadic mental health screening would be helpful in identifying families at risk.

Measuring family outcomes for young autistic children receiving interventions in China: The structure of the Family Outcomes Survey and predicting variables.

LAY ABSTRACT: Efforts to measure, document, and monitor family outcomes can be helpful to practitioners in developing and delivering effective and sustainable interventions. Researchers have developed the Family Outcomes Survey, Form A, for measuring the outcomes experienced by families of children in the early intervention/early childhood special education system. Little has been reported on how well the five outcomes on the Family Outcomes Survey, Form A describe the experiences and expectations of families of autistic children in China. We conducted a survey using the Family Outcomes Survey, Form A, Chinese version with 467 caregivers of young autistic children in China. First, the five-outcome structure of the Family Outcomes Survey, Form A seemed to be appropriate for measuring family outcomes of autistic children in China. We also found that the Chinese caregivers of autistic children seemed to give general lower ratings on all five outcomes on the Family Outcomes Survey, Form A as compared to caregivers of children in early intervention/early childhood special education in Western countries like the United States and Australia. Furthermore, caregivers' ratings on the five Family Outcomes Survey, Form A outcomes seemed to be related to their educational attainment, employment status, family income level, and how much time caregivers spent with their autistic child. This study supported the use of the Family Outcomes Survey, Form A, Chinese version with families of autistic children in China. We also discussed how the coronavirus disease 2019 pandemic could have impacted the family outcomes as reported by the Chinese caregivers.

Erythrocyte-Cancer Hybrid Membrane-Camouflaged Prussian Blue Nanoparticles with Enhanced Photothermal Therapy in Tumors.

Prussian blue (PB) nanoparticles have been widely used in photothermal therapy research due to the efficient photothermal conversion ability. In this study, PB was modified with a bionic coating using a hybrid membrane of red blood cell membranes and tumor cell membranes to prepare bionic photothermal nanoparticles (PB/RHM), which can further improve the blood circulation ability and tumor targeting of the nanoparticles to achieve efficient photothermal therapy for tumor treatment. In vitro formulation characterization showed that PB/RHM was a monodisperse spherical core-shell structured nanoparticle with a diameter of 207.2 nm and effectively retained the cell membrane proteins. The in vivo biological evaluation results showed that PB/RHM could effectively accumulate into the tumor tissue, inducing a rapid temperature increase in the tumor site to 50.9 °C within 10 min, inhibiting tumor growth efficiently with a tumor inhibition rate of 93.56% and with good therapeutic safety. In summary, this paper provided a hybrid film-modified Prussian blue nanoparticle with efficient photothermal anti-tumor capacity and safety.

Dissecting the effect of ileal faecal diversion on the intestine using single-cell sequencing.

BACKGROUND: Although ileal faecal diversion is commonly used in clinical settings, complications accompany it. Elucidating the intestinal changes caused by ileal faecal diversion will help resolve postoperative complications and elucidate the pathogenic mechanisms of associated intestinal disorders, such as Crohn's disease (CD). Therefore, our study aimed to provide new insights into the effects of ileal faecal diversion on the intestine and the potential mechanisms. METHODS: Single-cell RNA sequencing was performed on proximal functional and paired distal defunctioned intestinal mucosae from three patients with ileal faecal diversion. We also performed in vitro cellular and animal experiments, tissue staining and analysed public datasets to validate our findings. RESULTS: We found that the epithelium in the defunctioned intestine tended to be immature, with defective mechanical and mucous barriers. However, the innate immune barrier in the defunctioned intestine was enhanced. Focusing on the changes in goblet cells, we demonstrated that mechanical stimulation promotes the differentiation and maturation of goblet cells through the TRPA1-ERK pathway, indicating that the absence of mechanical stimulation may be the main cause of defects in the goblet cells of the defunctioned intestine. Furthermore, we found obvious fibrosis with a pro-fibrotic microenvironment in the defunctioned intestine and identified that monocytes may be important targets for faecal diversion to alleviate CD. CONCLUSIONS: This study revealed the different transcription landscapes of various cell subsets and the potential underlying mechanisms within the defunctioned intestine, when compared to the functional intestine, based on the background of ileal faecal diversion. These findings provide novel insights for understanding the physiological and pathological roles of the faecal stream in the intestine.

Enteric fungi protect against intestinal ischemia-reperfusion injury via inhibiting the SAA1-GSDMD pathway.

INTRODUCTION: Prophylactic antifungal therapy has been widely used for critical patients, but it has failed to improve patient prognosis and has become a hot topic. This may be related to disruption of fungal homeostasis, but the mechanism of fungi action is not clear. As a common pathway in critical patients, intestinal ischemia-reperfusion (IIR) injury is fatal and regulated by gut microbiota. However, the exact role of enteric fungi in IIR injury remains unclear. OBJECTIVES: This is a clinical study that aims to provide new perspectives in clarifying the underlying mechanism of IIR injury and propose potential strategies that could be relevant for the prevention and treatment of IIR injury in the near future. METHODS: ITS sequencing was performed to detect the changes in fungi before and after IIR injury. The composition of enteric fungi was altered by pretreatment with single-fungal strains, fluconazole and mannan, respectively. Intestinal morphology and function impairment were evaluated in the IIR injury mouse model. Intestinal epithelial MODE-K cells and macrophage RAW264.7 cells were cultured for in vitro tests. RESULTS: Fecal fungi diversity revealed the obvious alteration in IIR patients and mice, accompanied by intestinal epithelial barrier dysfunction. Fungal colonization and mannan supplementation could reverse intestinal morphology and function impairment that were exacerbated by fluconazole via inhibiting the expression of SAA1 from macrophages and decreasing pyroptosis of intestinal epithelial cells. Clodronate liposomes were used to deplete the number of macrophages, and it was demonstrated that the protective effect of mannan was dependent on macrophage involvement. CONCLUSION: This finding firstly validates that enteric fungi play a crucial role in IIR injury. Preventive antifungal treatment should consider damaging fungal balance. This study provides a novel clue to clarify the role of enteric fungi in maintaining intestinal homeostasis.

Enteric glial cells aggravate the intestinal epithelial barrier damage by secreting S100ß under high-altitude conditions.

Damage to the intestinal epithelial barrier (IEB) has been reported under high-altitude (HA) conditions and may be responsible for HA-associated gastrointestinal (GI) disorders. However, this pathogenetic mechanism does not fully explain the GI stress symptoms, such as flatulence and motility diarrhea, which accompany the IEB damage under HA conditions, especially for the people exposed to HA acutely. In the present study, we collected the blood samples from the people who lived at HA and found the concentration of enteric glial cells (EGCs)-associated biomarkers increased significantly. HA mouse model was then established and the results revealed that EGCs were involved in IEB damage. Zona occludens (ZO)-1, occludin, and claudin-1 expression was negatively correlated with that of glial fibrillary acidic protein (GFAP) and S100ß under HA conditions. In order to learn more about how EGCs influence IEB, the in vitro EGC and MODE-K hypoxia experiments that used hypoxic stimulation for simulating in vivo exposure to HA was performed. We found that hypoxia increased S100ß secretion in EGCs. And MODE-K cells cultured in medium conditioned by hypoxic EGCs showed low ZO-1, occludin, and claudin-1 levels of expression. Furthermore, treatment of MODE-K cells with recombinant mouse S100ß resulted in diminished levels of ZO-1, occludin, and claudin-1 expression. Thus, HA exposure induces greater S100ß secretion by EGCs, which aggravates the damage to the IEB. This study has revealed a novel mechanism of IEB damage under HA conditions, and suggest that EGCs may constitute a fresh avenue for the avoidance of GI disorders at HA.

A Novel Drug Self-Delivery System from Fatty Alcohol Esters of Tranexamic Acid for Venous Malformation Sclerotherapy.

Venous malformation (VM), which causes severe damage to patients' appearance and organ function, is one of the most common vascular malformations. At present, many drugs in clinical treatment cause various adverse reactions. Herein, we synthesized cationic amphiphilic gelators (TA6, TA8, and TA9) by introducing saturated carbon chains of different lengths to tranexamic acid (TA), which could self-assemble into low-molecular-weight gels (LMWGs) as drug delivery carriers by hydrogen bonds, van der Waals forces, and hydrophobic interactions. The rheological properties, gelation driving force and drug release profiles of TA6, TA8, and TA9 hydrogels were characterized, and the results indicated that the hydrogels prepared in this study possessed the typical characteristics of a gel and could release drugs slowly. More importantly, the TA9 gelator showed significant pharmacological activity, in that it served as both an active drug compound and a drug carrier. The in vitro experiments demonstrated that TA9 induced HUVECs death and hemolysis by destroying cell membranes in a dose-dependent manner, and caused cell death and hemolysis at a concentration of 0.09 µM/mL. Meanwhile, we found TA9 could interact not only with fibrinogen, but also with other endogenous molecules in the blood. After the administration of TA9 hydrogel for 15 days, macroscopic imaging and histological evaluation in mice and rabbits displayed obvious thrombi, inflammatory reactions, and venous embolization, indicating that the mechanism of the TA9 hydrogel in treating VM was involved in two processes. Firstly, the TA9 hydrogel relied on its mechanical strength to physically block veins and continuously release TA9, in situ, for targeted therapy. Then, TA9 destroyed endothelial cells and damaged venous walls critically, causing thrombi. Most excitingly, TA9 was hydrolyzed to TA by enzymes that inhibited the degradation of thrombi by plasmin to prolong the embolization time and to promote venous fibrosis. Compared with other clinically available sclerosants, the degradation of TA9 also empowered a better biocompatibility and biodegradability for the TA9 hydrogel. In conclusion, we synthesized a potentially safe and effective derivative of TA and developed a low-molecular-weight gel as a self-delivery system for TA in treating VM.

Cell-free protein synthesis of influenza virus hemagglutinin HA2-integrated virosomes for siRNA delivery.

It is well known that the difficulty of siRNA therapeutic application is the lack of safe and effective delivery vector. Virosome is a nano vesicle composed of lipid membrane and membrane protein. It retains fusion protein without virus genetic material, and therefore has the reduced immunogenicity compared with viral vector. Virosomes have the potential to deliver protein and nucleic acid drugs, but the traditional preparation method of virosomes is quite limited. In this study, we firstly proposed to synthesize influenza virus hemagglutinin HA2 virosomes by cell-free protein synthesis. In this study, liposomes provided the hydrophobic lipid bilayer environment for the formation of HA2 protein multimer, which inhibited the aggregation of hydrophobic HA2 and improved HA2 protein expression. Chitosan as a rigid core adsorbed siRNA and improved the encapsulation efficiency of siRNA. In conclusion, the cell-free protein synthesis was used to prepare HA2 virosomes, which paves the way for constructing a novel nano vector with high delivery efficiency and biosafety for the delivery of siRNA.

Parental involvement in developmental disabilities across three cultures: A systematic review.

BACKGROUND: Parents play a critical role in the early intervention/early childhood special education (EI/ECSE) services provided to young children (birth-6 years) with developmental disabilities. AIM: The aim of this systematic review was to explore parental involvement in developmental disabilities across three cultures: Mainland China, Taiwan, and Turkey. METHOD: According to PRISMA guidelines, we searched for articles indexed in EBSCOhost, PsycINFO, and PubMed published within the last decade for one culture (i.e., Mainland China, Taiwan, and Turkey), using the following keywords: family/parent involvement/engagement, developmental disability/disabilities, young child/children, EI/ECSE, and culture. RESULTS: Twenty-four empirical studies were identified as relevant to our research. A majority of articles reported maternal involvement in EI/ECSE, and only a few studies included parents as intervention agents. CONCLUSIONS: This review highlights the need for future research to investigate effects of culture on parental involvement and develop culturally responsive methodical approaches to underpin meaningful parental involvement in EI/ECSE.

Construct validity of the Family Outcomes Survey - Revised expanded helpfulness scale.

BACKGROUND: With family centred practice as one of the tenets in early childhood intervention (ECI), it is important to understand family outcomes as a means of assessing the effectiveness of ECI services. AIMS: The present paper investigates the psychometric properties of an expanded measure of caregivers' perceptions of helpfulness of ECI services, the Family Outcomes Survey - Revised, Expanded Part B (FOS-RE B). METHODS AND PROCEDURES: Two-hundred and forty-six caregivers of children enrolled in an ECI programme in Singapore completed the FOS-RE B, as well as convergent validity measures (FOS-R Part A, Depression, Stress and Anxiety Scale and questions addressing perceptions of family situation and optimism for the child's future). Confirmatory factor analysis was used to examine the factor structure of the FOS-RE B and correlations were used to examine convergent validity. OUTCOMES AND RESULTS: The factor structure of the FOS-RE B was found to mirror the structure of the FOS-R A, as hypothesized. Evidence for convergent validity, in the form of correlations with family well-being measures was found, as well as evidence for good internal consistency reliability. CONCLUSIONS AND IMPLICATIONS: It is concluded that the FOS-RE B presents a promising measure of perceived helpfulness of ECI services.

Primary Studies on Construction and Evaluation of Ion-Sensitive in situ Gel Loaded with Paeonol-Solid Lipid Nanoparticles for Intranasal Drug Delivery.

BACKGROUND: Paeonol (PAE) is a potential central neuroprotective agent with poor water solubility and rapid metabolism in vivo. The key to improve the clinical application of PAE in the treatment of neurodegenerative diseases is to improve the brain delivery of it. The purpose of this study was to construct a paeonol-solid lipid nanoparticles-in situ gel (PAE-SLNs-ISG) drug delivery system based on nose-brain transport pathway. MATERIALS AND METHODS: In this study, the stability of PAE in simulated biological samples was studied firstly in order to clarify the reasons for low oral bioavailability. Paeonol-solid lipid nanoparticles (PAE-SLNs) were prepared by high-temperature emulsification-low-temperature curing combined with ultrasound. The PAE-SLNs-ISG drug delivery system was constructed, and related formulation optimization, preparation characterization, cell evaluation and in vivo evaluation were performed. RESULTS: The metabolic mechanism of PAE incubated in the liver microsomes metabolic system was in accordance with the first-order kinetics, and the half-life was 0.23 h. PAE-SLNs were polyhedral or spherical particles with good dispersion and the particle size was 166.79 nm ± 2.92 nm. PAE-SLNs-ISG solution was a Newtonian fluid with a viscosity of 44.36 mPa · S ± 2.89 mPa · S. The viscosity of PAE-SLNs-ISG gel was 1542.19 mPa · S ± 19.30 mPa · S, and the rheological evaluation showed that the gel was a non-Newtonian pseudoplastic fluid with shear thinning, thixotropy and yield value. The release mechanism of PAE from PAE-SLNs was drug diffusion; the release mechanism of PAE from PAE-SLNs-ISG was a synergistic effect of skeleton erosion and drug diffusion. The cell viabilities of PAE-SLNs and PAE-SLNs-ISG in the concentration range of 0.001 µg/mL to 10 µg/mL were higher than 90%, showing a low level of cytotoxicity. The geometric mean fluorescent intensities of RPMI 2650 cells incubated with fluorescein isothiocyanate-solid lipid nanoparticles (FITC-SLNs) for 1 h, 4 h and 6 h were 1841 ± 24, 2261 ± 27 and 2757 ± 22, respectively. Cyanine7 NHS ester-solid lipid nanoparticles-in situ gel (Cy7-SLNs-ISG) accumulated effectively in the brain area after administration through the olfactory area, and the fluorescence response was observed in olfactory bulb, cerebellum and striatum. CONCLUSION: SLNs-ISG nose-brain drug delivery system can effectively deliver SLNs to brain regions, and it is a potentially effective strategy to realize the brain region delivery of PAE.

Evaluation of the Ages and Stages Questionnaire (ASQ 3) as a developmental screener at 9, 18, and 24 months.

BACKGROUND: Without the use of standardized screening tools, only 30% of the estimated 5-15% of children with developmental delay can be identified, potentially delaying intervention. AIM: 1)To evaluate the ASQ-3's reliability and validity at 9, 18, and 24 months and to compare the results with normative USA data. 2)To determine the risk factors for a screen positive result, which requires further evaluation. METHODS: Study of 649 low-risk children was part of a larger longitudinal cohort study, the GUSTO project. Socio-demographic and ASQ3 data were analyzed to estimate reliability, validity, mean ASQ scores, and cut-off scores. RESULTS: ASQ-3 showed an acceptable to good internal consistency (0.49-0.83) and a medium level of correlations (0.22-0.59) between the five domains but differed significantly compared to normative USA data. Using local cut-off scores, 12.6-13.6% of the cohort had a positive screen in ≥ 1 domain at 9, 18, or 24 months. ASQ-3 screening categorization was consistent, with only 3-11% of children showing change in categorization longitudinally. On regression, lower family income (OR 3.3-9.42) and maternal education (OR2.65-3.03) were predictive of a positive screen across domains and age intervals. INTERPRETATION: ASQ-3 is a useful, valid screening tool in Singapore. Further research is needed to investigate item functioning and to assess its concurrent validity with a criterion standard tool for culturally sensitive developmental screening.