Development of segregation and integration of functional connectomes during the first 1,000 days.

The first 1,000 days of human life lay the foundation for brain development and later cognitive growth. However, the developmental rules of the functional connectome during this critical period remain unclear. Using high-resolution, longitudinal, task-free functional magnetic resonance imaging data from 930 scans of 665 infants aged 28 postmenstrual weeks to 3 years, we report the early maturational process of connectome segregation and integration. We show the dominant development of local connections alongside a few global connections, the shift of brain hubs from primary regions to high-order association cortices, the developmental divergence of network segregation and integration along the anterior-posterior axis, the prediction of neurocognitive outcomes, and their associations with gene expression signatures of microstructural development and neuronal metabolic pathways. These findings advance our understanding of the principles of connectome remodeling during early life and its neurobiological underpinnings and have implications for studying typical and atypical development.

Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism.

Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3'-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.

Comprehensive Treatment and Gene Analysis of a Male Patient with Follicular Occlusion Tetrad with Fordyce Granules.

Follicular occlusion tetrad (FOT) is a chronic inflammatory skin disease that seriously affects patients' quality of life. At present, there is no standard treatment plan for FOT. We report the case of a 50-year-old male patient diagnosed as having FOT with Fordyce granules and type 2 diabetes mellitus. During hospitalization, the patient received comprehensive and systematic treatment. The patient healed well after surgery and the 10-month follow-up revealed no recurrence. We found eight gene mutations by whole-exome sequencing (WES) of the patient's peripheral blood.

Foam Cell Targeted Liposomes Co-Encapsulating Superoxide Dismutase and Catalase to Attenuate Atherosclerosis by Inhibiting Oxidative Stress.

BACKGROUND: Oxidative stress, propelled by reactive oxygen species (ROS), serves as a significant catalyst for atherosclerosis (AS), a primary contributor to vascular diseases on a global scale. Antioxidant therapy via nanomedicine has emerged as a pivotal approach in AS treatment. Nonetheless, challenges such as inadequate targeting, subpar biocompatibility, and limited antioxidant effectiveness have restrained the widespread utilization of nanomedicines in AS treatment. This study aimed to synthesize a specialized peptide-modified liposome capable of encapsulating two antioxidant enzymes, intending to enhance targeted antioxidant therapy for AS. METHODS: The film dispersion method was employed for liposome preparation. Fluorescence quantification was conducted to assess the drug encapsulation rate. Characterization of liposome particle size was performed using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Laser confocal microscopy and flow cytometry were utilized to analyze liposome cell uptake and target foam cells. Antioxidant analysis was conducted using 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining, while pro-lipid efflux analysis utilized Oil Red O (ORO) staining. Safety evaluation was performed using Hematoxylin and Eosin (H&E) staining. The level of inflammatory factors was determined through enzyme-linked immunosorbent assay (ELISA). The degree of lipid oxidation at the cellular level was assessed using the malonaldehyde (MDA) assay. In vivo targeting analysis was conducted using small animal live imaging. RESULTS: Our in vitro and in vivo findings substantiated that the modification of Lyp-1 led to increased delivery of antioxidant enzymes into foam cells (p < 0.05), the primary pathological cells within AS plaques. Upon accumulation in foam cells, liposomes loaded with superoxide dismutase (SOD) and catalase (CAT) (LyP-lip@SOD/CAT) effectively mitigated excess ROS and shielded macrophages from ROS-induced damage (p < 0.01). Furthermore, the reduction in ROS levels notably hindered the endocytosis of oxidized low-density lipoprotein (Ox-LDL) by activated macrophages, subsequently alleviating lipid accumulation at atherosclerotic lesion sites, evident from both in vitro and in vivo ORO staining results (p < 0.01). LyP-lip@SOD/CAT significantly curbed the secretion of inflammatory factors at the plaque site (p < 0.001). Additionally, LyP-lip@SOD/CAT demonstrated commendable biological safety. CONCLUSIONS: In this study, we effectively synthesized LyP-lip@SOD/CAT and established its efficacy as a straightforward and promising nano-agent for antioxidant therapy targeting atherosclerosis.

Maternal KLF17 controls zygotic genome activation by acting as a messenger for RNA Pol II recruitment in mouse embryos.

Initiation of timely and sufficient zygotic genome activation (ZGA) is crucial for the beginning of life, yet our knowledge of transcription factors (TFs) contributing to ZGA remains limited. Here, we screened the proteome of early mouse embryos after cycloheximide (CHX) treatment and identified maternally derived KLF17 as a potential TF for ZGA genes. Using a conditional knockout (cKO) mouse model, we further investigated the role of maternal KLF17 and found that it promotes embryonic development and full fertility. Mechanistically, KLF17 preferentially binds to promoters and recruits RNA polymerase II (RNA Pol II) in early 2-cell embryos, facilitating the expression of major ZGA genes. Maternal Klf17 knockout resulted in a downregulation of 9% of ZGA genes and aberrant RNA Pol II pre-configuration, which could be partially rescued by introducing exogenous KLF17. Overall, our study provides a strategy for screening essential ZGA factors and identifies KLF17 as a crucial TF in this process.

Cardiac monoamine oxidase-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control.

AIMS: A mechanistic link between depression and risk of arrhythmias could be attributed to altered catecholamine metabolism in the heart. Monoamine oxidase-A (MAO-A), a key enzyme involved in catecholamine metabolism and longstanding antidepressant target, is highly expressed in the myocardium. The present study aimed to elucidate the functional significance and underlying mechanisms of cardiac MAO-A in arrhythmogenesis. METHODS AND RESULTS: Analysis of the TriNetX database revealed that depressed patients treated with MAO inhibitors had a lower risk of arrhythmias compared with those treated with selective serotonin reuptake inhibitors. This effect was phenocopied in mice with cardiomyocyte-specific MAO-A deficiency (cMAO-Adef), which showed a significant reduction in both incidence and duration of catecholamine stress-induced ventricular tachycardia compared with wild-type mice. Additionally, cMAO-Adef cardiomyocytes exhibited altered Ca2+ handling under catecholamine stimulation, with increased diastolic Ca2+ reuptake, reduced diastolic Ca2+ leak, and diminished systolic Ca2+ release. Mechanistically, cMAO-Adef hearts had reduced catecholamine levels under sympathetic stress, along with reduced levels of reactive oxygen species and protein carbonylation, leading to decreased oxidation of Type II PKA and CaMKII. These changes potentiated phospholamban (PLB) phosphorylation, thereby enhancing diastolic Ca2+ reuptake, while reducing ryanodine receptor 2 (RyR2) phosphorylation to decrease diastolic Ca2+ leak. Consequently, cMAO-Adef hearts exhibited lower diastolic Ca2+ levels and fewer arrhythmogenic Ca2+ waves during sympathetic overstimulation. CONCLUSION: Cardiac MAO-A inhibition exerts an anti-arrhythmic effect by enhancing diastolic Ca2+ handling under catecholamine stress.

Successful repair of an encephalocele wound in a child following a car accident: A case report.

Repair of large cranial complex traumas in children is difficult. Notably, children have poorer underlying conditions than adults and are frailer under trauma. In addition, children have more limited treatment options, leading to the need to consider long-term functional and aesthetic outcomes. The present report describes the case of a 2-year-old child weighing 9 kg who experienced a skull fracture with encephalocele after a car accident and had a poor underlying condition. An artificial dura mater combined with bone cement was used to repair the skull, and then a free latissimus dorsi muscle flap (LDMF) combined with a split-thickness skin graft (STSG) was used to cover the wound, allowing the child to overcome the life-threatening situation as soon as possible with a satisfactory outcome. LDMF combined with STSG is an ideal option in repairing head wounds in children. Preoperative imaging and postoperative care also serve an important role in the success of the operation. When the situation is critical, multidisciplinary team treatment can guarantee the safety of the child.

Sensitive and Extraction-Free Detection of Methicillin-Resistant Staphylococcus aureus through Ag+ Aptamer-Based Color Reaction.

Refractory infections, such as hospital-acquired pneumonia, can be better diagnosed with the assistance of precise methicillin-resistant Staphylococcus aureus (MRSA) testing. However, traditional methods necessitate high-tech tools, rigorous temperature cycling, and the extraction of genetic material from MRSA cells. Herein, we propose a sensitive, specific, and extraction-free strategy for MRSA detection by integrating allosteric probe-based target recognition and exonuclease-III (Exo-III)-enhanced color reaction. The penicillin-binding protein 2a (PBP2a) aptamer in the allosteric probe binds with MRSA to convert protein signals to nucleic acid signals. This is followed by the DNA polymerase-assisted target recycle and the production of numerous single-strand DNA (ssDNA) chains which bind with silver ion (Ag+) aptamer to form a blunt terminus that can be identified by Exo-III. As a result, the Ag+ aptamer pre-coupled to magnetic nanoparticles is digested. After magnetic separation, the Ag+ in liquid supernatant catalyzes 3,3',5,5'-tetramethylbenzidine (TMB) for a color reaction. In addition, a concentration of 54 cfu/mL is predicted to be the lowest detectable value. Based on this, our assay has a wide linear detection range, covering 5 orders of magnitude and demonstrating a high specificity, which allows it to accurately distinguish the target MRSA from other microorganisms.

Zabramski classification in predicting the occurrence of symptomatic intracerebral hemorrhage in sporadic cerebral cavernous malformations.

OBJECTIVE: The authors aimed to investigate the evolutionary characteristics of the Zabramski classification of cerebral cavernous malformations (CCMs) and the value of the Zabramski classification in predicting clinical outcome in patients with sporadic CCM. METHODS: This retrospective study consecutively included cases of sporadic CCM that had been untreated from January 2001 through December 2021. Baseline and follow-up patient information was recorded. The evolution of the Zabramski classification of a sporadic CCM was defined as the initial lesion type changing into another type for the first time on MRI follow-up. The primary outcome was the occurrence of a hemorrhage event, which was defined as a symptomatic event with radiological evidence of overt intracerebral hemorrhage. RESULTS: Among the 255 included cases, 55 (21.6%) were classified as type I CCM, 129 (50.6%) as type II CCM, and 71 (27.8%) as type III CCM, based on initial MRI. During a mean follow-up of 58.8 ± 33.6 months, 51 (20.0%) patients had lesion classification transformation, whereas 204 (80.0%) patients maintained their initial type. Among the 51 transformed lesions, 29 (56.9%) were type I, 11 (21.6%) were type II, and 11 (21.6%) were type III. Based on all follow-up imaging, of the initial 55 type I lesions, 26 (47.3%) remained type I and 27 (49.1%) regressed to type III because of hematoma absorption; 91.5% of type II and 84.5% of type III lesions maintained their initial type during MRI follow-up. The classification change rate of type I lesions was statistically significantly higher than those of type II and III lesions. After a total follow-up of 1157.7 patient-years, new clinical hemorrhage events occurred in 40 (15.7%) patients. The annual cumulative incidence rate for symptomatic hemorrhage in all patients was 3.4 (95% CI 2.5-4.7) per 100 person-years. Kaplan-Meier survival analysis showed that the annual cumulative incidence rate for symptomatic hemorrhage of type I CCM (15.3 per 100 patient-years) was significantly higher than those of type II (0.6 per 100 patient-years) and type III (2.3 per 100 patient-years). CONCLUSIONS: This study suggests that the Zabramski classification is helpful in estimating clinical outcome and can assist with surgical decision-making in patients with sporadic CCM.

Exploration of the optimal time to discontinue propranolol treatment in infantile hemangiomas: A prospective study.

BACKGROUND: Relapse of infantile hemangiomas after withdrawal from propranolol treatment is common. Early withdrawal is believed to increase the risk of relapse. OBJECTIVE: The objective of this study was to determine the optimal time to discontinue propranolol treatment for infantile hemangiomas. METHODS: A prospective study conducted at a tertiary referral center. RESULTS: Compared to withdrawal after 1-month maintenance treatment, withdrawal after 3-month maintenance, corresponding achieving maximum regression of infantile hemangiomas, was associated with a lower major relapse rate (P = .041). The relapse (P = .055) and adverse event rates (P = .154) between the 2 withdrawal modes were not statistically significant. Compared with direct withdrawal, the relapse (P = .396), major relapse (P = .963), and adverse event rates (P = .458) of gradual withdrawal were not statistically different. Patients with/without relapse could be best distinguished according to whether withdrawal followed a 3-month maintenance and age >13 months (area under the receiver operating characteristic curve = 0.603). Patients with/without major relapse could be best distinguished according to whether withdrawal was accompanied by 3-month maintenance (area under the receiver operating characteristic curve = 0.610). LIMITATIONS: The limitations of this study are nonrandomization and single-center design. CONCLUSIONS: The optimal propranolol withdrawal time to avoid relapse is when the patient is aged >13 months and the lesion has maintained for 3 months after reaching maximum regression, while the optimal time to prevent major relapse is after 3 months of maintenance.

Tough gel adhesive is an effective method for meniscal repair in a bovine cadaveric study.

PURPOSE: To test tough gel adhesives to repair meniscus tears under relevant loading conditions and determine if they have adequate biomechanical properties to repair meniscus tears in a bovine cadaveric study. METHODS: Cyclic compression tests on 24 dissected bovine knees were performed. The tough gel adhesive was used either as an adhesive patch or as a coating bonded onto commercially available surgical sutures. Forty-eight menisci were tested in this study; 24 complete radial tears and 24 bucket-handle tears. After preconditioning, the specimens underwent 100 cycles of compression, (800 N/0.5 Hz) on an Instron© machine and the size of the gaps measured. One third of the menisci were repaired with pristine sutures, one third with adhesive patches, and one third with sutures coated in adhesive gel. The size of the gaps was compared after 100 and 500 cycles of compression. RESULTS: The mean gap measured at the tear site without treatment was 6.46 mm (± 1.41 mm) for radial tears and 1.92 mm (± 0.65 mm) for bucket-handle tears. After treatment and 500 cycles of compression, the mean gap was 1.63 mm (± 1.41 mm) for pristine sutures, 1.50 mm (± 1.16 mm) for adhesive sutures and 2.06 mm (± 1.53 mm) for adhesive gel patches. There was no significant difference between treatments regardless of the type of tear. Also, the gaps for radial tears increased significantly with the number of compression cycles applied (p > 0.001). CONCLUSION: From a biomechanical standpoint, the tough adhesive gel patch is as effective as suturing. In addition, it would allow the repair of non-suturable tears and thus broaden the indications for meniscus repair. LEVEL OF EVIDENCE: Controlled laboratory study.

Follicular fluid C3a-peptide promotes oocyte maturation through F-actin aggregation.

BACKGROUND: Immature cumulus-oocyte complexes are retrieved to obtain mature oocytes by in vitro maturation (IVM), a laboratory tool in reproductive medicine to obtain mature oocytes. Unfortunately, the efficiency of IVM is not satisfactory. To circumvent this problem, we therefore intended to commence with the composition of ovarian follicular fluid (FF), an important microenvironment influencing oocyte growth. It is well known that FF has a critical role in oocyte development and maturation. However, the components in human FF remain largely unknown, particularly with regard to small molecular peptides. RESULTS: In current study, the follicular fluid derived from human mature and immature follicles were harvested. The peptide profiles of FF were further investigated by using combined ultrafiltration and LC-MS/MS. The differential peptides were preliminary determined by performing differentially expressed analysis. Human and mouse oocyte culture were used to verify the influence of differential peptides on oocyte development. Constructing plasmids, cell transfecting, Co-IP, PLA etc. were used to reveal the detail molecular mechanism. The results from differentially expressed peptide as well as cultured human and mouse oocytes analyses showed that highly conserved C3a-peptide, a cleavage product of complement C3a, definitely affected oocytes development. Intriguingly, C3a-peptide possessed a novel function that promoted F-actin aggregation and spindle migration, raised the percentage of oocytes at the MII stage, without increasing the chromosome aneuploidy ratio, especially in poor-quality oocytes. These effects of C3a-peptide were attenuated by C3aR morpholino inhibition, suggesting that C3a-peptide affected oocytes development by collaborating with its classical receptor, C3aR. Specially, we found that C3aR co-localized to the spindle with ß-tubulin to recruit F-actin toward the spindle and subcortical region of the oocytes through specific binding to MYO10, a key regulator for actin organization, spindle morphogenesis and positioning in oocytes. CONCLUSIONS: Our results provide a new perspective for improving IVM culture systems by applying FF components and also provide molecular insights into the physiological function of C3a-peptide, its interaction with C3aR, and their roles in enabling meiotic division of oocytes.

A simplified machine learning model utilizing platelet-related genes for predicting poor prognosis in sepsis.

Background: Thrombocytopenia is a known prognostic factor in sepsis, yet the relationship between platelet-related genes and sepsis outcomes remains elusive. We developed a machine learning (ML) model based on platelet-related genes to predict poor prognosis in sepsis. The model underwent rigorous evaluation on six diverse platforms, ensuring reliable and versatile findings. Methods: A retrospective analysis of platelet data from 365 sepsis patients confirmed the predictive role of platelet count in prognosis. We employed COX analysis, Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) techniques to identify platelet-related genes from the GSE65682 dataset. Subsequently, these genes were trained and validated on six distinct platforms comprising 719 patients, and compared against the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ-Failure Assessment (SOFA) score. Results: A PLT count <100×109/L independently increased the risk of death in sepsis patients (OR = 2.523; 95% CI: 1.084-5.872). The ML model, based on five platelet-related genes, demonstrated impressive area under the curve (AUC) values ranging from 0.5 to 0.795 across various validation platforms. On the GPL6947 platform, our ML model outperformed the APACHE II score with an AUC of 0.795 compared to 0.761. Additionally, by incorporating age, the model's performance was further improved to an AUC of 0.812. On the GPL4133 platform, the initial AUC of the machine learning model based on five platelet-related genes was 0.5. However, after including age, the AUC increased to 0.583. In comparison, the AUC of the APACHE II score was 0.604, and the AUC of the SOFA score was 0.542. Conclusion: Our findings highlight the broad applicability of this ML model, based on platelet-related genes, in facilitating early treatment decisions for sepsis patients with poor outcomes. Our study paves the way for advancements in personalized medicine and improved patient care.

A Rare Case Report of Neonatal Neurofibromatosis Type 1 Presented with Giant Faciocervical Mass and Complicated with HIE.

A newborn with giant faciocervical mass and presented with asphyxia during birth was admitted to the hospital. After stabilizing her vital sign, we provided the patient with image examinations and whole-exome sequencing, which revealed a heterozygous variation of neurofibromatosis type 1 (NF1). The final diagnosis of the patient was NF1 complicated with neonatal hypoxic-ischemic encephalopathy (NHIE). During hospitalization, the patient received comprehensive and systematic care. There was no reports of similar cases in the literature. So, this report aimed to elucidate the special clinical manifestations, diagnosis, treatment and prognosis of NF1 complicated with NHIE by analyzing the clinical data of the patient and her family and reviewing relevant literature.

Carotid artery perivascular adipose tissue on magnetic resonance imaging: a potential indicator for carotid vulnerable atherosclerotic plaque.

Background: Magnetic resonance imaging (MRI) has the potential in assessing the inflammation of perivascular adipose tissue (PVAT) due to its excellent soft tissue contrast. However, evidence is lacking for the association between carotid PVAT measured by MRI and carotid vulnerable atherosclerotic plaques. This study aimed to investigate the association between signal intensity of PVAT and vulnerable plaques in carotid arteries using multi-contrast magnetic resonance (MR) vessel wall imaging. Methods: In this cross-sectional study, a total of 104 patients (mean age, 64.9±7.0 years; 86 men) with unilateral moderate-to-severe atherosclerotic stenosis referred to carotid endarterectomy (CEA) were recruited from April 2018 to December 2020 at Department of Neurosurgery of Peking University Third Hospital. All patients underwent multi-contrast MR vessel wall imaging including time-of-flight (ToF) MR angiography, black-blood T1-weighted (T1w) and T2-weighted (T2w) and simultaneous non-contrast angiography and intraplaque hemorrhage (IPH) imaging sequences. Patients with contraindications to endarterectomy or MRI examinations were excluded. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of PVAT were measured on ToF images and vulnerable plaque characteristics including IPH, large lipid-rich necrotic core (LRNC), and fibrous cap rupture (FCR) were identified. The SNR and CNR of PVAT were compared between slices with and without vulnerable plaque features using Mann-Whitney U test and their associations were analyzed using the generalized linear mixed model (GLMM). Results: Carotid artery slices with IPH (30.93±14.56 vs. 27.34±10.02; P<0.001), FCR (30.35±13.82 vs. 27.53±10.37; P=0.006), and vulnerable plaque (29.15±12.52 vs. 27.32±10.05; P=0.016) had significantly higher value of SNR of PVAT compared to those without. After adjusting for clinical confounders, the SNR of PVAT was significantly associated with presence of IPH [odds ratio (OR) =0.627, 95% confidence interval (CI): 0.465-0.847, Puncorr=0.002, PFDR=0.016] and vulnerable plaque (OR =0.762, 95% CI: 0.629-0.924, Puncorr=0.006, PFDR=0.020). However, no significant association was found between the CNR of PVAT and presence of vulnerable plaque features (all P>0.05). Conclusions: The SNR of carotid artery PVAT measured by ToF MR angiography is independently associated with vulnerable atherosclerotic plaque features, suggesting that the signal intensity of PVAT might be an effective indicator for vulnerable plaque.

Complication rates and safety of pulsed dye laser treatment for port-wine stain: a systematic review and meta-analysis.

Pulsed dye laser (PDL) is the most commonly used method for port-wine stain (PWS); however, no studies have reported the safety of PDL. This review aimed to collect and summarize complications reported in relevant literature, assess complication rates in treating PWS with PDL, and explore the relevant influencing factors. A systematic review and meta-analysis were conducted to search for related studies in PubMed, Embase, and the Cochrane Library until August 2022. Two reviewers independently evaluated the risk of bias of included studies. Stata Software version 17.0 was used for the analysis. All complications reported in the literature are divided into acute phase complications and long-term complications. Overall pooled purpura, edema, crusting, blistering, hyperpigmentation, hypopigmentation, and scarring rates were 98.3%, 97.6%, 21.5%, 8.7%, 12.8%, 0.9%, and 0.2%, respectively. Although the acute adverse reactions were found to be common, the long-term permanent complications clearly have a lower frequency, and the occurrence of scarring is much lower than that initially thought. This indicates that effective protective measures after treatment are very important for preventing scar formation. Overall, PDL treatment for PWS shows a high level of safety and low chances of causing long-term complications.

Multifunctional liposomes Co-encapsulating epigallocatechin-3-gallate (EGCG) and miRNA for atherosclerosis lesion elimination.

Atherosclerosis (AS) is a chronic inflammatory disease, characterized by a lipid accumulated plaque. Anti-oxidative and anti-inflammation and lipid metabolism promoting therapeutic strategies have been applied for atherosclerosis treatment. However, the therapeutic effect of a single therapeutic method is limited. It is suggested that a combination of these two strategies could help prevent lipid accumulation caused by inflammation and oxidative stress, and also promote lipid efflux from atherosclerotic plaque, to normalize arteries to the maximum extent. Hence, a strategy involving a multifunctional liposome co-encapsulating an antioxidant and anti-inflammatory drug epigallocatechin-3-gallate (EGCG) and a lipid-efflux-promoting gene miR-223 was established. The system (lip@EGCG/miR-223) could encapsulate miR-223 in core areas of the liposomes to provide a protective effect for gene drugs. Moreover, lip@EGCG/miR-223 was smaller in size (91.28 ± 2.28 nm characterized by DLS), making it easier to target AS lesions, which have smaller vascular endothelial spaces. After being efficiently internalized into the cells, lip@EGCG/miR-223 exhibited excellent antioxidant and anti-inflammatory effects in vitro by eliminating overproduced ROS and decreasing the level of inflammatory cytokines (TNF-α, IL-1ß, and MCP-1), which was due to the effect of EGCG. Besides, the lipid-efflux-promoting protein ABCA1 was upregulated when treated with lip@EGCG/miR-223. Through the two therapies mentioned, lip@EGCG/miR-223 could effectively inhibit the formation of foam cells, which are a main component of atherosclerotic plaques. In AS model mice, after intravenous (i.v.) administration, lip@EGCG/miR-223 was effectively accumulated in atherosclerotic plaques, and the distribution of drugs in the heart and aorta compared to that in the kidney was significantly increased when compared with free drugs (the ratio was 6.27% for the free miR-223-treated group, which increased to 66.10% for the lip@EGCG/miR-223-treated group). By decreasing the inflammation level and lipid accumulation, the arterial vessels in AS were normalized, with less macrophages and micro-angiogenesis, when treated with lip@EGCG/miR-223. Overall, this study demonstrated that lip@EGCG/miR-223 could be developed as a potential system for atherosclerosis treatment by a combined treatment of antioxidant, anti-inflammatory, and lipid-efflux-promoting effects, which provides a novel strategy for the safe and efficient management of atherosclerosis.

Investigating the Association of Carotid Atherosclerotic Plaque MRI Features and Silent Stroke After Carotid Endarterectomy.

BACKGROUND: The predictive value of carotid plaque characteristics for silent stroke (SS) after carotid endarterectomy (CEA) is unclear. OBJECTIVE: To investigate the associations between carotid plaque characteristics and postoperative SS in patients undergoing CEA. STUDY TYPE: Prospective. POPULATION: One hundred fifty-three patients (mean age: 65.4 ± 7.9 years; 126 males) with unilateral moderate-to-severe carotid stenosis (evaluated by CT angiography) referred for CEA. FIELD STRENGTH/SEQUENCE: 3 T, brain-MRI:T2-PROPELLER, T1-/T2-FLAIR, diffusion weighted imaging (DWI) and T2*, carotid-MRI:black-blood T1-/T2W, 3D TOF, Simultaneous Non-contrast Angiography intraplaque hemorrhage. ASSESSMENT: Patients underwent carotid-MRI within 1-week before CEA, and brain-MRI within 48-hours pre-/post-CEA. The presence and size (volume, maximum-area-percentage) of carotid lipid-rich necrotic core (LRNC), intraplaque hemorrhage (Type-I/Type-II IPH) and calcification were evaluated on carotid-MR images. Postoperative SS was assessed from pre-/post-CEA brain DWI. Patients were divided into moderate-carotid-stenosis (50%-69%) and severe-carotid-stenosis (70%-99%) groups and the associations between carotid plaque characteristics and SS were analyzed. STATISTICAL TESTS: Independent t test, Mann-Whitney U-test, chi-square test and logistic regressions (OR: odds ratio, CI: confidence interval). P value <0.05 was considered statistically significant. RESULTS: SS was found in 8 (16.3%) of the 49 patients with moderate-carotid-stenosis and 21 (20.2%) of the 104 patients with severe-carotid-stenosis. In patients with severe-carotid-stenosis, those with SS had significantly higher IPH (66.7% vs. 39.8%) and Type-I IPH (66.7% vs. 38.6%) than those without. The presence of IPH (OR 3.030, 95% CI 1.106-8.305) and Type-I IPH (OR 3.187, 95% CI 1.162-8.745) was significantly associated with SS. After adjustment, the associations of SS with presence of IPH (OR 3.294, 95% CI 1.122-9.669) and Type-I IPH (OR 3.633, 95% CI 1.216-10.859) remained significant. Moreover, the volume of Type-II IPH (OR 1.014, 95% CI 1.001-1.028), and maximum-area-percentage of Type-II IPH (OR 1.070, 95% CI 1.002-1.142) and LRNC (OR 1.030, 95% CI 1.000-1.061) were significantly associated with SS after adjustment. No significant (P range: 0.203-0.980) associations were found between carotid plaque characteristics and SS in patients with moderate-carotid-stenosis. DATA CONCLUSIONS: In patients with unilateral severe-carotid-stenosis, carotid vulnerable plaque MR features, particularly presence and size of IPH, might be effective predictors for SS after CEA. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.