Background: and Purpose Vertebrobasilar fusiform aneurysms (VBFAs) carry substantial morbidity and mortality, but optimal management for unruptured VBFAs remains unclear. We compared the safety and efficacy of conservative management (CM), stent-assisted coiling (SAC), and flow diverters (FDs) in patients with unruptured VBFAs, focusing on long-term prognosis. Methods: This study included data from a nationwide Chinese cohort of patients with vertebrobasilar dissecting aneurysms. Inverse probability of treatment weighting (IPTW) balanced confounders across groups. The primary outcome was poor prognosis (modified Rankin Scale score >2). Secondary outcomes included aneurysm rupture, ischemic stroke, compression symptoms, and VBFA-related deaths. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed. Results: Among 1,115 patients with unruptured VBFAs, 838 (median age, 54 years; 655 men) were included. After IPTW, baseline characteristics were balanced. Median follow-up was 54 months. FD was associated with a lower risk of poor prognosis than CM (OR, 0.48 [95% CI, 0.30 to 0.77]; p=0.002), with no difference between CM and SAC. FD also reduced aneurysm rupture (OR, 0.20 [95% CI, 0.07 to 0.60]; p=0.004) and compression symptoms (OR, 0.30 [95% CI, 0.13 to 0.68]; p=0.004) versus CM. Time-to-event analyses further revealed significant differences in vertebral artery lesions and Type I–II VBFAs, whereas no significant differences were observed in basilar or vertebrobasilar junction lesions or in Type III–IV VBFAs. Conclusions Compared with CM, FD was associated with improved long-term outcomes in unruptured VBFAs, particularly in vertebral artery lesions and Type I–II VBFAs, although residual confounding cannot be excluded.

Cells and exosomes derived from them are extensively used as biological carrier systems. Cells demonstrate superior targeting specificity and prolonged circulation facilitated by their rich array of surface proteins, while exosomes, due to their small size, cross barriers and penetrate tumors efficiently. However, challenges remain, cells' large size restricts tissue penetration, and exosomes have limited targeting accuracy and short circulation times. To address these challenges, we developed a novel concept termed exosomal spheres. This approach involved incorporating platelet-derived exosomes shielded with phosphatidylserine (PS) and linked via pH-sensitive bonds for drug delivery applications. The study demonstrated that, compared with exosomes, the exosomal spheres improved blood circulation through the upregulation of CD47 expression and shielding of phosphatidylserine, thereby minimizing immune clearance. Moreover, the increased expression of P-selectin promoted adhesion to circulating tumor cells, thereby enhancing targeting efficiency. Upon reaching the tumor site, the hydrazone bonds of exosome spheres were protonated in the acidic tumor microenvironment, leading to disintegration into uniform-sized exosomes capable of deeper tumor penetration compared to platelets. These findings suggested that exosome spheres addressed the challenges and offered significant potential for efficient and precise drug delivery.

Rare diseases still lack effective treatments, and the development of drugs for rare diseases (known as orphan drugs) is an urgent medical problem. As natural active ingredients in living organisms, some biomacromolecule drugs have good biocompatibility, low immunogenicity, and high targeting. They have become one of the most promising fields in drug research and development in the 21st century. However, there are still many obstacles in terms of in vivo delivery. In view of the unique advantages of nanocarriers prepared from polymers, lipids, organic biomimetic and inorganic materials in drug delivery, researchers are committed to building an efficient delivery system with versatility and synergy to solve the bottleneck issues in treating rare diseases with biomacromolecule drugs. Therefore, this article reviews the research progress of nanocarrier delivering proteins, peptides and nucleic acids in the field of rare disease treatment in the past ten years, which provides ideas for researches on biomacromolecule drug nanosystems in the field of treatment of rare diseases.

Primary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.
Animals ; Brain Diseases/therapy* ; Xenotropic and Polytropic Retrovirus Receptor ; Brain/pathology*

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2-3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.

Objective: To investigate the role of inflammatory biomarkers in the relationship between blood lead levels and blood pressure changes. Methods: A total of 9 910 people aged 18-79 years who participated in the China National Human Biomonitoring in 2017-2018 were included in this study. A self-made questionnaire was used to collect demographic characteristics, lifestyle and other information, and the data including height, weight and blood pressure were determined through physical examination. Blood and urinary samples were collected for the detection of blood lead and cadmium levels, urinary arsenic levels, white blood cells, neutrophils, lymphocytes, and hypersensitive C-reactive protein (hs-CRP). Weighted linear regression models were used to evaluate the associations between blood lead, inflammatory biomarkers and blood pressure. Mediation analysis was performed to investigate the role of inflammation in the relationship between blood lead levels and blood pressure changes. Results: The median (Q₁, Q₃) age of all participants was 45.4 (33.8, 58.4)years, including 4 984 males accounting for 50.3%. Multivariate logistic regression model analysis showed that after adjusting for age, gender, residence area, BMI, education level, smoking and drinking status, family history of hypertension, consumption frequency of rice, vegetables, and red meat, fasting blood glucose, total cholesterol, triglycerides, blood cadmium and urinary arsenic levels, there was a positive association between blood lead levels, inflammatory biomarkers and blood pressure (P<0.05). Each 2.71 μg/L (log-transformed) increase of the lead was associated with a 2.05 (95%CI: 0.58, 3.53) mmHg elevation in systolic blood pressure (SBP), 2.24 (95%CI: 1.34, 3.14) mmHg elevation in diastolic blood pressure (DBP), 0.25 (95%CI: 0.05, 0.46) mg/L elevation in hs-CRP, 0.16 (95%CI: 0.03, 0.29)×10⁹/L elevation in white blood cells, and 0.11 (95%CI: 0.02, 0.21)×10⁹/L elevation in lymphocytes, respectively. Mediation analysis showed that the levels of hs-CRP significantly mediated the association of blood lead with SBP, with a proportion about 3.88% (95%CI: 0.45%, 7.32%). The analysis also found that the levels of hs-CRP and neutrophils significantly mediated the association of blood lead with SBP, with a proportion about 4.10% (95%CI: 1.11%, 7.10%) and 2.42% (95%CI: 0.07%, 4.76%), respectively. Conclusion: This study suggests that inflammatory biomarkers could significantly mediate the association of blood lead levels and blood pressure changes.
Adult ; Male ; Humans ; Blood Pressure/physiology* ; C-Reactive Protein/analysis* ; Lead ; Arsenic/analysis* ; Cadmium ; Biomarkers ; Hypertension/epidemiology* ; China/epidemiology*

【Objective】 To compare the volumes of brain regions and the white matter hyperintensities(WMH) in Alzheimer's disease(AD) and vascular dementia(VaD) patients, and discuss values of magnetic resonance imaging (MRI) in the differential diagnosis of AD and VaD. 【Methods】 The clinical data and MRI images of 35 patients with VaD and 74 patients with AD were retrospectively analyzed. Volumes of different brain regions and WMH were measured by using AccuBrain^TM system and visual rating scale was used to assess WMH. We then compared the volumes of brain regions and the WMH between AD and VaD. The principal component analysis(PCA) and logistic regression analysis were adopted for differential diagnosis. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic efficiency of the indexes. 【Results】 ①Compared with VaD patients, AD patients showed statistically smaller volumes of total intracranial volume, brain parenchyma, gray matter, white matter, hippocampus, amygdala, hypothalamus, frontal lobe(left, right), occipital lobe(left, right), temporal lobe(left, right), parietal lobe(left, right), hippocampus (left, right), amygdala(left, right), hypothalamus(left, right) (P<0.05). ②There was statistically significant difference in the visual scores for deep WMH(DWMH) between AD and VaD patients(P=0.015). The absolute and relative volumes of WMH in VaDpatients were statistically larger than those in AD patients(P<0.05). ③PCA revealed eight important parameters including brain parenchyma, hippocampus, amygdala, hypothalamus, frontal lobe(left), occipital lobe(left), temporal lobe(left) and parietal lobe(left) .The identification model consisting of amygdala, occipital lobe (left) and absolute volume of WMH was established based on logistic regression analysis. ④Among all the indexes, the identification model had the best diagnostic performance to differentiate AD from VaD and its sensitivity and specificity were 81.1% and 74.3%, respectively. 【Conclusions】 There are significant differences in both volumes of certain brain regions and severity of WMH between VaD and AD patients. The cranial MRI is of great value for the differential diagnosis of VaD and AD.

Objectives: To explore the clinical experience for a bridge therapy of percutaneous balloon aortic valvuloplasty (PBAV) in treating the patients with severe aortic stenosis (AS). Methods: A total of 37 patients with severe AS who were not suitable for surgical valvular replacement received PBAV in our hospital from 2011-03 to 2017-03 were retrospectively studied. The patient's mean age was (74±12) years, their clinical and anatomical features, efficacy and safety of operation were observed and the outcomes were evaluated by follow-up study. Results: Patients presented the high surgical risk and worse cardiac function, 50% of them had bicuspid leaflet morphology with severe calcification [HU850=(856.0±658.2) mm3]. Balloon size was chosen by the intra-operative supra-annular diameters; at 7 days after operation, aortic valve orifice area (AVOA) was increased from (0.37±0.10) cm2to (0.87±1.10) cm2, the mean trans-aortic valve gradient pressure decreased form (55.1±22.9) mmHg to (44.8±17.8) mmHg, P<0.001 and LVEF elevated form(35.8±14.3)% to(41.0±12.2)%,P<0.001.There were 4 patients died in hospital,1 received permanent pacemaker and 1 developed severe aortic valve regurgitation. The patients were followed-up for (16.5±11.1)months after operation, 13/37 (35.1%) patients were in transition to surgical or transcatheter aortic valve replacement (TAVR). Conclusions: PBAV may have good early clinical efficacy in severe AS patients who were not suitable for surgical valvular replacement and TAVR; PBAV could be expected to become a bridge therapy, smaller supra-annular diameter was safe and effective for patients having bicuspid leaflet with severe calcification.

BACKGROUND: Bone marrow mesenchymal stem cells (BMSCs) and BMSCs-derived exosomes have similar functions, but the regulatory mechanism underlying the release of exosomes is still unclear. OBJECTIVE: To investigate the role of GW4869, an inhibition of neutral sphingomyelinase 2, in the release of exosomes in BMSCs and the influence of GW4869 on BMSCs proliferation. METHODS: Rat BMSCs were divided into three groups: normal control group, 24-hour GW4869 treatment group and withdrawal of GW4869 for 24 hours group (24-hour GW4869 treatment followed by 24-hour successive culture with drug withdrawal). Cultured cells were collected to extract exosomes by ultracentrifugation. Western blot was used to detect exosome-associated proteins CD63 and tumor susceptibility gene 101 (TSG101). The concentration and size distribution of exosomes were measured using nanoparticle tracking analysis. BCA was used to test the level of total proteins in exosomes. Live cell imaging system was used to observe the influence of GW4869 on BMSCs proliferation. RESULTS AND CONCLUSION: (1) Western blot results showed that exosomes expressed marker proteins such as CD63, TSG101. (2) Findings from the nanoparticle tracking analysis confirmed that the size of released exosomes was about 114 nm. (3) Significantly reduced release of exosomes was found in the two treatment groups compared with the normal control group (P < 0.01), but there was no significant difference between 24-hour GW4869 treatment group and withdrawal of GW4869 for 24 hours group (P > 0.05). (4) No significant difference in the proliferation of BMSCs was found among the three groups (P > 0.05). To conclude, 24-hour W4869 can inhibit the release of exosomes by BMSCs and this inhibitory effect is still sustained within 24 hours after drug withdrawal. However, GW4869 has no influence on the proliferation of BMSCs.

OBJECTIVETo evaluate the clinical value of three-dimensional pseudo-continuous arterial spin labeling (3D pCASL) perfusion magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC) enhanced perfusion MRI in the diagnosis of transient ischemic attack (TIA).

METHODSThirty-nine consecutive patients with suspected TIA underwent multi-modal MRI scans including DSC, magnetic resonance angiography (MRA), diffusion-weighted imaging (DWI) and 3D pCASL (post-labeling delay, PLD=1.5 s and 2.5 s) within 24 h of symptom onset. Cerebral blood flow (CBF) from ASL and the time to the maximum of tissue residual function (Tmax) map from DSC were calculated using AW workstation. DWI and MRA were applied to detect acute cerebral infarction and intracranial artery stenosis. Two neuroradilogists who were blinded to the patients' clinical data assessed the presence of perfusion deficit, ischemic lesion and the lesion sites both from 1.5 s, 2.5 s PLD ASL-CBF and DSC-Tmax independently, and then graded them. The differences in the ranking grades between 1.5 s, 2.5 s PLD ASL and DSC were analyzed, and the frequency of lesion detection was compared between ASL-CBF, Tmax and MRA combining DWI method.

RESULTSNo significant differences was found in hypoperfusion grades detected by 3D pCASL (including PLD1.5 s and 2.5 s) CBF and Tmax maps, while significant differences were detected between 1.5 s PLD ASL-CBF and MRA combining DWI method; ASL with PLD 1.5 s CBF detected ischemic lesions and lesion site significantly more frequently than MRA combining DWI method.

CONCLUSIONs Three dimensional pCASL is a non-invasive perfusion method free of radiation exposure, and short PLD ASL is more sensitive than long PLD ASL for detecting ischemic lesions and lesion sites.

Arteries ; physiopathology ; Brain ; physiopathology ; Brain Infarction ; diagnosis ; Brain Ischemia ; diagnosis ; Cerebrovascular Circulation ; Diffusion Magnetic Resonance Imaging ; Humans ; Magnetic Resonance Angiography ; Perfusion ; Perfusion Imaging ; Spin Labels