Curcumin/TGF-ß1 siRNA loaded solid lipid nanoparticles alleviate cerebral injury after intracerebral hemorrhage by transnasal brain targeting.

Intracerebral hemorrhage (ICH) is a prevalent cerebrovascular disorder. The inflammation induced by cerebral hemorrhage plays a crucial role in the secondary injury of ICH and often accompanied by a poor prognosis, leading to disease exacerbation. However, blood-brain barrier (BBB) limiting the penetration of therapeutic drugs to the brain. In this paper, our primary objective is to develop an innovative, non-invasive, safe, and targeted formulation. This novel approach aims to synergistically harness the combined therapeutic effects of drugs to intervene in inflammation via a non-injectable route, thereby significantly mitigating the secondary damage precipitated by inflammation following ICH. Thus, a novel "anti-inflammatory" cationic solid lipid nanoparticles (SLN) with targeting ability were constructed, which can enhance the stability of curcumin(CUR) and siRNA. We successfully developed SLN loaded with TGF-ß1 siRNA and CUR (siRNA/CUR@SLN) that adhere to the requirements of drug delivery system by transnasal brain targeting. Through the characterization of nanoparticle properties, cytotoxicity assessment, in vitro pharmacological evaluation, and brain-targeting evaluation after nasal administration, siRNA/CUR@SLN exhibited a nearly spherical structure with a particle size of 125.0±1.93 nm, low cytotoxicity, high drug loading capacity, good sustained release function and good stability. In vitro anti-inflammatory results showcasing its remarkable anti-inflammatory activity. Moreover, in vivo pharmacological studies revealed that siRNA/CUR@SLN can be successfully delivered to brain tissue. Furthermore, it also elicited an effective anti-inflammatory response, alleviating brain inflammation. These results indicated that favorable brain-targeting ability and anti-inflammatory effects of siRNA/CUR@SLN in ICH model mice. In conclusion, our designed siRNA/CUR@SLN showed good brain targeting and anti-inflammatory effect ability after nasal administration, which lays the foundation for the treatment of inflammation caused by ICH and offers a novel approach for brain-targeted drug delivery and brings new hope.

The Venous Occlusion Image Score: A Novel Quantitative Scoring Instrument for Cerebral Venous Sinus Thrombosis.

PURPOSE: This study aims to test the validity of a new quantitative scoring instrument-the Venous Occlusion Image Score (VOIS), and assess the diagnostic and prognostic value of VOIS for cerebral venous sinus thrombosis (CVST). METHODS: The VOIS divided the major cerebral venous sinuses and internal jugular veins into nine parts of interest. CT venography and DSA source images and reconstruction were extracted from the database, then interpreted and scored independently according to VOIS by a panel of three reviewers. Inter-observer and intra-observer reliability were determined using the intraclass correlation coefficient (ICC) and the kappa coefficient (κ). The primary outcome was the 3-month functional outcome and evaluated by modified Rankin Scale (mRS). The sensitivity and specificity of VOIS for the primary outcomes were computed. Logistic regression was applied to evaluate the association between the score on VOIS and the primary outcomes. RESULTS: Fifty-six patients with CVST were included in the study. For 16 patients underwent cerebral CTV and DSA, excellent interobserver agreement was observed for DSA (ICC=0.90, 95%CI = 0.87 - 0.92, P < 0.001), and CTV (ICC = 0.92, 95%CI = 0.84 - 0.93, P < 0.001). The κ coefficient of agreement for the two radiology measures was 0.88 (95%CI = 0.79-0.92), indicating good inter-method agreement. For 56 patients followed up by CTV, baseline VOIS value correlated inversely with the severity of stroke on the National Institutes of Health Stroke Scale (r = -0·53, P < 0·001), and modified Rankin Scale (r = -0·59, P < 0·001). Baseline CTV-VOIS value predicted functional outcome (P < 0·05). CONCLUSION: VOIS may serve as a convenient and reliable method in the treatment guidance and outcome prediction of patients with CVST.

Effects of Apolipoprotein E Polymorphism on Cerebral Oxygen Saturation After Traumatic Brain Injury.

Objective: To investigate the effects of the apolipoprotein E gene (APOE) on the cerebral oxygen saturation of patients after traumatic brain injury (TBI). Methods: Clinical data of 114 patients with TBI and 54 normal people were collected. The APOE genotypes of all subjects were determined by quantitative fluorescent polymerase chain reaction (QF-PCR). The regional cerebral oxygen saturation (rScO2) of TBI patients and normal people were monitored by near-infrared spectroscopy (NIRS). Results: The mean rScO2 of patients was (55.06 ± 7.60)% in the early stage of TBI, which was significantly lower than that of normal people (67.21 ± 7.80)% (P < 0.05). Single-factor and multifactor logistic regression analyses showed APOEε4 was an independent risk factor that caused the early decline of rScO2 in TBI patients. Furthermore, in the TBI group, the rScO2 of APOEε4 carriers (52.23 ± 8.02)% was significantly lower than that of non-ε4 carriers (60.33 ± 7.12)% (P < 0.05). But in the normal group, no significant differences in rScO2 were found between APOEε4 carriers and non-carriers. Conclusion: The rScO2 may be significantly decreased after TBI, and APOEε4 may be a risk factor for decreased rScO2 in the early stage of TBI.

CP-CRE/non-CP-CRE Stratification And CRE Resistance Mechanism Determination Help In Better Managing CRE Bacteremia Using Ceftazidime-Avibactam And Aztreonam-Avibactam.

PURPOSE: This observational study aimed to identify the independent risk factors for both the acquisition and mortality of carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) bacteremia and further assess the in vitro antimicrobial activities of ceftazidime-avibactam (CAZ/AVI) and aztreonam-avibactam (ATM/AVI) against recent CRE bacteremic isolates. PATIENTS AND METHODS: This observational study was conducted to reveal the risk factors and mortality rate for CP-CRE bacteremia between 2012 and 2018 and also evaluate the in vitro antimicrobial activities of CAZ/AVI and ATM/AVI against recent CRE bacteremic isolates from 2016 to 2018. RESULTS: A total of 81 non-repetitive isolates were collected from 2012 to 2018, with 67.90% (55/81) being CP-CRE. Old age (P = 0.01), transfusion [odds ratio (OR): 17.19; 95% CI: 3.15-93.72; P = 0.001], longer ICU stay (P = 0.02), cancer (OR: 15.91; 95% CI: 3.56-71.37; P < 0.001), and previous carbapenem exposure (OR: 27.86; 95% CI: 5.03-154.19; P = 0.001) were identified as independent risk factors for the acquisition of CP-CRE bacteremia compared with the ESBL bacteremia. The in vitro antimicrobial activities of CAZ/AVI and ATM/AVI against the CRE bacteremic isolates from 2016 to 2018 showed a respective susceptibility rate of 70.68% (41/58) and 100.00% (58/58). CONCLUSION: The findings indicated that both CP-CRE/non-CP-CRE stratification and CRE resistance mechanism determination were necessary for better guiding the clinical management of CRE bacteremia: ATM/AVI probably works with both non-CP-CRE and CP-CRE bacteremia, even the most notorious double-carbapenemase producer with porin loss/deficiency, whereas CAZ/AVI works with most of the non-CP-CRE and KPC-producers in the region.