Targeting Mitochondrial Complex I Deficiency in MPP+/MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

BACKGROUND: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson's disease (PD) in human through its metabolite MPP+ by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP+-treated SH-SY5Y cells and MPTP-treated mice were used as the PD cell culture and mouse models respectively. The recombinant NDI1 lentivirus was transduced into SH-SY5Y cells, or the recombinant NDI1 adeno-associated virus (rAAV5-NDI1) was injected into substantia nigra pars compacta (SNpc) of mice. RESULTS: The study in vitro showed NDI1 prevented MPP+-induced change in cell morphology and decreased cell viability, mitochondrial coupling efficiency, complex I-dependent oxygen consumption, and mitochondria-derived ATP. The study in vivo revealed that rAAV-NDI1 injection significantly improved the motor ability and exploration behavior of MPTP-induced PD mice. Accordingly, NDI1 notably improved dopaminergic neuron survival, reduced the inflammatory response, and significantly increased the dopamine content in striatum and complex I activity in substantia nigra. CONCLUSIONS: NDI1 compensates for the defective complex I in MPP+/MPTP-induced models, and vastly alleviates MPTP-induced toxic effect on dopaminergic neurons. Our study may provide a basis for gene therapy of sporadic PD with defective complex I caused by MPTP-like substance.

Transfer of cGAMP from neuron to microglia activates microglial type I interferon responses after subarachnoid hemorrhage.

Primary subarachnoid hemorrhage (SAH) is a type of acute stroke, accounting for approximately 10% of cases, with high disability and mortality rate. Early brain injury (EBI) is a critical factor in determining SAH mortality; however, there are no effective treatment interventions for EBI. Based on our results, the transmission of cyclic GMP-AMP (cGAMP) from neurons to microglia is a key molecular event that triggers type I interferon response, amplifies neuroinflammation, and leads to neuronal apoptosis. Abnormal intracytoplasmic mitochondrial DNA (mtDNA) is the initiating factor of the cGAS-cGAMP-STING signaling axis. Overall, the cGAS-cGAMP-STING signaling axis is closely associated with neuroinflammation after subarachnoid hemorrhage. Targeting cGAS triggered by cytoplasmic mtDNA may be useful for comprehensive clinical treatment of patients after SAH. Further studies targeting cGAS-specific antagonists for treating SAH are warranted. Video Abstract.

Application of Nanoparticles as Novel Adsorbents in Blood Purification Strategies.

BACKGROUND: Blood purification therapy for patients overloaded with metabolic toxins or drugs still needs improvement. Blood purification therapies, such as in hemodialysis or peritoneal dialysis can profit from a combined application with nanoparticles. SUMMARY: In this review, the published literature is analyzed with respect to nanomaterials that have been customized and functionalized as nano-adsorbents during blood purification therapy. Liposomes possess a distinct combined structure composed of a hydrophobic lipid bilayer and a hydrophilic core. The liposomes which have enzymes in their aqueous core or obtain specific surface modifications of the lipid bilayer can offer appreciated advantages. Preclinical and clinical experiments with such modified liposomes show that they are highly efficient and generally safe. They may serve as indirect and direct adsorption materials both in hemodialysis and peritoneal dialysis treatment for patients with renal or hepatic failure. Apart from dialysis, nanoparticles made of specially designed metal and activated carbon have also been utilized to enhance the removal of solutes during hemoadsorption. Results are a superior adsorption capacity and good hemocompatibility shown during the treatment of patients with toxication or end-stage renal disease. In summary, nanomaterials are promising tools for improving the treatment efficacy of organ failure or toxication. KEY MESSAGES: (i) The pH-transmembrane liposomes and enzyme-loaded liposomes are two representatives of liposomes with modified aqueous inner core which have been put into practice in dialysis. (ii) Unmodified or physiochemically modified liposomal bilayers are ideal binders for lipophilic protein-bound uremic toxins or cholestatic solutes, thus liposome-supported dialysis could become the next-generation hemodialysis treatment of artificial liver support system. (iii) Novel nano-based sorbents featuring large surface area, high adsorption capacity and decent biocompatibility have shown promise in the treatment of uremia, hyperbilirubinemia, intoxication, and sepsis. (vi) A major challenge of production lies in avoiding changes in physical and chemical properties induced by manufacturing and sterilizing procedures.

A cross-sectional survey of first-aid kit equipment in a family in Sichuan, China.

PURPOSE: To examine residents' first-aid kit preparation and its influencing factors. DESIGN: Cross-sectional survey. METHODS: A questionnaire survey was conducted among 449 permanent residents in Sichuan Province using convenience sampling. We examined participants' demographic characteristics, self-efficacy, health literacy, and personality. FINDINGS: Of the participants, 111 (24.7%) stocked a home first-aid kit. The most frequent supplies were disinfection supplies (91.9%), common medicines (86.5%), and dressing supplies (76.6%). Family per capita monthly income, medical expenses payment method, chronic diseases, general self-efficacy, and health literacy were influencing factors of family first-aid kit preparedness. CONCLUSION: A multilevel and interactive emergency literacy education system should be established to improve residents' abilities to prevent emergencies.

Brain tissue oxygen partial pressure monitoring and prognosis of patients with traumatic brain injury: a meta-analysis.

To assess whether monitoring brain tissue oxygen partial pressure (PbtO2) or employing intracranial pressure (ICP)/cerebral perfusion pressure (CCP)-guided management improves patient outcomes, including mortality, hospital length of stay (LOS), mean daily ICP and mean daily CCP during the intensive care unit(ICU)stay. We searched the Web of Science, EMBASE, PubMed, Cochrane Library, and MEDLINE databases until December 12, 2023. Prospective randomized controlled and cohort studies were included. A meta-analysis was performed for the primary outcome measure, mortality, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Eleven studies with a total of 37,492 patients were included. The mortality in the group with PbtO2 was 29.0% (odds ratio: 0.73;95% confidence interval [CI]:0.56-0.96; P = 0.03; I = 55%), demonstrating a significant benefit. The overall hospital LOS was longer in the PbtO2 group than that in the ICP/CPP group (mean difference:2.03; 95% CI:1.03-3.02; P<0.0001; I = 39%). The mean daily ICP in the PbtO2 monitoring group was lower than that in the ICP/CPP group (mean difference:-1.93; 95% CI: -3.61 to -0.24; P = 0.03; I = 41%). Moreover, PbtO2 monitoring did not improve the mean daily CPP (mean difference:2.43; 95%CI: -1.39 to 6.25;P = 0.21; I = 56%).Compared with ICP/CPP monitoring, PbtO2 monitoring reduced the mortality and the mean daily ICP in patients with severe traumatic brain injury; however, no significant effect was noted on the mean daily CPP. In contrast, ICP/CPP monitoring alone was associated with a short hospital stay.

Association of gut microbiome with risk of intracranial aneurysm: a mendelian randomization study.

OBJECTIVE: To investigate the potential causal link between genetic variants associated with gut microbiome and risk of intracranial aneurysm (IA) using two-sample mendelian randomization (MR). METHODS: We performed two sets of MR analyses. At first, we selected the genome-wide statistical significant(P < 5 × 10-8) single nucleotide polymorphisms (SNPs) as instrumental variables (IVs). Then, we selected the locus-wide significant (P < 1 × 10-5) SNPs as IVs for the other set of analyses to obtain more comprehensive conclusions. Gut microbiome genetic association estimates were derived from a genome-wide association study (GWAS) of 18,473 individuals. Summary-level statistics for IA were obtained from 79,429 individuals, which included 7,495 cases and 71,934 controls. RESULTS: On the basis of locus-wide significance level, inverse variance weighted(IVW) showed that Clostridia [(odds ratio (OR): 2.60; 95% confidence interval (CI): 1.00-6.72, P = 0.049)], Adlercreutzia (OR: 1.81; 95% CI: 1.10-2.99, P = 0.021) and Victivallis (OR: 1.38; 95% CI: 1.01-1.88, P = 0.044) were positively related with the risk of unruptured intracranial aneurysm(UIA); Weighted median results of MR showed Oscillospira (OR: 0.37; 95% CI: 0.17-0.84, P = 0.018) was negatively with the risk of UIA and Sutterella (OR: 1.84; 95% CI: 1.04-3.23, P = 0.035) was positively related with the risk of UIA; MR-Egger method analysis indicated that Paraprevotella (OR: 0.32; 95% CI: 0.13-0.80, P = 0.035) was negatively with the risk of UIA and Rhodospirillaceae (OR: 13.39; 95% CI: 1.44-124.47, P = 0.048) was positively related with the risk of UIA. The results suggest that Streptococcus (OR: 5.19; 95% CI: 1.25-21.56; P = 0.024) and Peptostreptococcaceae (OR: 4.92; 95% CI: 1.32-18.32; P = 0.018) may increase the risk of UIA according to genome-wide statistical significance thresholds. CONCLUSION: This MR analysis indicates that there exists a beneficial or detrimental causal effect of gut microbiota composition on IAs.

Gene therapy of yeast NDI1 on mitochondrial complex I dysfunction in rotenone-induced Parkinson's disease models in vitro and vivo.

PURPOSE: Parkinson's disease (PD) is the second most common neurodegenerative disease without cure or effective treatment. This study explores whether the yeast internal NADH-quinone oxidoreductase (NDI1) can functionally replace the defective mammalian mitochondrial complex I, which may provide a gene therapy strategy for treating sporadic PD caused by mitochondrial complex I dysfunction. METHOD: Recombinant lentivirus expressing NDI1 was transduced into SH-SY5Y cells, or recombinant adeno-associated virus type 5 expressing NDI1 was transduced into the right substantia nigra pars compacta (SNpc) of mouse. PD cell and mouse models were established by rotenone treatment. The therapeutic effects of NDI1 on rotenone-induced PD models in vitro and vivo were assessed in neurobehavior, neuropathology, and mitochondrial functions, by using the apomorphine-induced rotation test, immunohistochemistry, immunofluorescence, western blot, complex I enzyme activity determination, oxygen consumption detection, ATP content determination and ROS measurement. RESULTS: NDI1 was expressed and localized in mitochondria in SH-SY5Y cells. NDI1 resisted rotenone-induced changes in cell morphology, loss of cell viability, accumulation of α-synuclein and pS129 α-synuclein, mitochondrial ROS production and mitochondria-mediated apoptosis. The basal and maximal oxygen consumption, mitochondrial coupling efficiency, basal and oligomycin-sensitive ATP and complex I activity in cell model were significantly increased in rotenone + NDI1 group compared to rotenone + vector group. NDI1 was efficiently expressed in dopaminergic neurons in the right SNpc without obvious adverse effects. The rotation number to the right side (NDI1-treated side) was significantly increased compared to that to the left side (untreated side) in mouse model. The number of viable dopaminergic neurons, the expression of tyrosine hydroxylase, total and maximal oxygen consumption, mitochondrial coupling efficiency and complex I enzyme activity in right substantia nigra, and the content of dopamine in right striatum were significantly increased in rotenone + NDI1 group compared to rotenone + vector group. CONCLUSION: Yeast NDI1 can rescue the defect of oxidative phosphorylation in rotenone-induced PD cell and mouse models, and ameliorate neurobehavioral and neuropathological damages. The results may provide a basis for the yeast NDI1 gene therapy of sporadic PD caused by mitochondrial complex I dysfunction.

A regulatory role for CD72 expression on B cells and increased soluble CD72 in primary Sjogren's syndrome.

BACKGROUND: CD72, a co-receptor of B cell receptor (BCR), has been reported to have both positive and negative effects on B cell functions in several immunological diseases. The B cell plays an important role in the pathogenesis of primary Sjogren's syndrome (pSS). However, whether CD72 is involved in the process remains unknown. This study aimed to observe the possible role of CD72 in the pathogenesis of pSS. RESULTS: A total of 60 cases who fulfilled the American-European Consensus Group (AECG) criteria for the diagnosis of pSS and 61 gender and age-matched healthy controls were recruited in this study. The percentage of CD72+ B cells was 85.31 ± 8.37% in pSS patients and 76.91 ± 8.50% in healthy controls(p < 0.001). The percentage of CD72+ B cells was correlated to serum IgG levels in patients [ß = 0.018(0.001-0.036), p = 0.034]. The level of serum soluble CD72 was significantly higher in pSS patients than the one in healthy controls (0.41 (0.29) vs 0.07 (0.08) ng/mL, p < 0.001). CONCLUSIONS: The percentage of CD72+ B cells was upregulated in pSS patients and was correlated to the serum IgG level, which revealed the hyperactivity of B cells in this disease. The serum soluble CD72 level was also increased in pSS patients. These results indicated a potential role of CD72 in the pathogenesis of pSS.

Model-based Evaluation of the Clinical and Microbiological Efficacy of Vancomycin: A Prospective Study of Chinese Adult In-house Patients.

Background: Our aims in this prospective study were to evaluate the correlations between pharmacokinetic/pharmacodynamic (PK/PD) indices and the clinical/microbiological efficacy of vancomycin and to identify an appropriate PK/PD target in the Chinese population to guide vancomycin treatment in the clinic. Methods: Adult patients from 11 hospitals in China with gram-positive infections who received vancomycin therapy for ≥5 days and who were under therapeutic drug monitoring (TDM) were enrolled in this study. A 1-compartment population PK model was established and validated. The correlations between PK/PD indices (Cmin, Cmax, 0-24 hour area under the curve (AUC0-24), and AUC0-24/minimum inhibitory concentration (MIC) and clinical outcomes (clinical efficacy and bacterial eradication) were evaluated. Results: In total, 402 adult Chinese patients were enrolled. Among them, 380 patients were evaluable for PK analysis, and 334 were evaluable for PK/PD analysis. In the final population PK model, creatinine clearance (CLCR) was the significant covariate on CL (typical value, 3.87 L/hour; between-subject variability (BSV), 12.5%), and age was the significant covariate on volume of distribution (V) (typical value, 45.1 L; BSV, 24.8%). The univariate analysis showed that Cmax, AUC0-24, and AUC0-24/MIC were significantly different or marginally significantly different (P values were 0.009, 0.0385, and 0.0509, respectively) between microbiological outcome groups with coagulase-negative Staphylococcus infections. However, there were no significant differences (P > .05) in the above PK parameters by multivariate logistic regression analysis, indicating there was no independently associated factor. Conclusions: No significant correlations were identified between PK/PD indices and the clinical or microbiological efficacy of vancomycin in Chinese patients. The necessity of vancomycin TDM based on trough concentration and the current treatment target of AUC0-24/MIC ≥400 need to be further evaluated and confirmed in additional prospective studies.

[Screening of LDLR gene mutations in nine patients with familial hypercholesterolemia].

OBJECTIVE: To screen for LDLR gene mutations in 9 patients with familial hypercholesterolemia (FH). METHODS: All exons of the LDLR gene and flanking intronic sequences were amplified by PCR and subjected to automatic DNA sequencing. For patients with homozygous or compound heterozygous mutations, parental DNA sequencing or T cloning sequencing was carried out to determine the parental origin of the mutant alleles. RESULTS: Direct sequencing of PCR products revealed 8 LDLR variants in 7 patients, which included c.259T>G, c.513delC, c.530C>T, c.682G>T, c.763C>T, c.1187-10G>A, c.1948delG, and c.1730G>A, among which c.1948delG was novel. Four patients have carried heterozygous mutations, two carried homozygous mutations, and one carried compound heterozygous mutations. The patients with biallelic mutations presented with a more severe phenotype compared those carrying heterozygous mutations. CONCLUSION: LDLR mutations were identified in 7 out of 9 patients with FH. Among the 8 identified LDLR mutations, c.1948delG was firstly reported. Above findings have expanded the mutation spectrum of LDLR gene.

Combination Cyclophosphamide/Glucocorticoids Provide Better Tolerability and Outcomes versus Glucocorticoids Alone in Patients with Sjogren's Associated Chronic Interstitial Nephritis.

BACKGROUND: Steroid therapy has become an effective option for patients with primary Sjogren's syndrome with tubulointerstitial nephritis (TIN), while the use of cytotoxic agents is still debated. Our study aimed to compare the clinical outcomes of patients treated with cyclophosphamide (CTX) combined with glucocorticoids with those of patients treated with glucocorticoids alone. METHODS: All patients with primary Sjogren's syndrome with chronic TIN admitted to the Division of Nephrology, Ruijin Hospital, from January 1, 2002, to April 30, 2016, and treated with steroids alone or combined with CTX were included. The immunological prognosis, improvements of renal function, and acquired tubular defects of the patients were retrospectively compared between the 2 therapeutic groups. RESULTS: A total of 70 cases were included. Of these, 36 were diagnosed by renal biopsy. A total of 56 patients were treated with glucocorticoids alone, while 14 patients received glucocorticoids combined with CTX. There were no significant differences in clinical characteristics and laboratory parameters between the 2 therapeutic groups at baseline. Compared with patients in the steroid group, patients in the CTX group showed better estimated glomerular filtration rate (eGFR) improvement (21.35 ± 19.63 vs. 2.72 ± 19.11 mL/min/1.73 m2, p = 0.006) but a similar decline in immunoglobulin G (IgG; 450 [interquartile range, IQR 910] vs.176 [IQR 1,910] mg/dL, p = 0.93) at 12 months of follow-up. CTX therapy was associated with better eGFR improvement (ß = 12.96 [2.95-22.97]) even after adjusting for dry mouth, anti-Sjögren's-syndrome-related antigen A and anti-Sjögren's-syndrome-related antigen B positivity, hemoglobin, initial steroid dose, and baseline eGFR by linear regression analyses. Subgroup analyses revealed that the beneficial effects of CTX therapy on renal function were only observed in patients with baseline IgG ≥1,560 mg/dL or eGFR <90 mL/min/1.73 m2. The urine α1-microglobulin improvement was better in the CTX group than in the steroid group at 12 months of follow-up (ß = 1.29, 95% CI 0.56-2.02, p = 0.001). CONCLUSIONS: CTX therapy is suggested for primary Sjogren's syndrome patients with chronic TIN, especially those with higher IgG levels and abnormal renal function at baseline.

An autoregressive integrated moving average and long short-term memory (ARIM-LSTM) hybrid model for multi-source epidemic data prediction.

The COVID-19 pandemic has far-reaching impacts on the global economy and public health. To prevent the recurrence of pandemic outbreaks, the development of short-term prediction models is of paramount importance. We propose an ARIMA-LSTM (autoregressive integrated moving average and long short-term memory) model for predicting future cases and utilize multi-source data to enhance prediction performance. Firstly, we employ the ARIMA-LSTM model to forecast the developmental trends of multi-source data separately. Subsequently, we introduce a Bayes-Attention mechanism to integrate the prediction outcomes from auxiliary data sources into the case data. Finally, experiments are conducted based on real datasets. The results demonstrate a close correlation between predicted and actual case numbers, with superior prediction performance of this model compared to baseline and other state-of-the-art methods.

Generating human bone marrow organoids for disease modeling and drug discovery.

The bone marrow supports and regulates hematopoiesis, responding to physiological requirements for blood cell production over ontogeny and during pathological challenges. Interactions between hematopoietic cells and niche components are challenging to study mechanistically in the human context, but are important to delineate in order to explore the pathobiology of blood and bone marrow disorders. Organoids are proving transformative in many research settings, but an accurate human bone marrow model incorporating multiple hematopoietic and stromal elements has been lacking. This protocol describes a method to generate three-dimensional, multilineage bone marrow organoids from human induced pluripotent stem cells (hiPSCs), detailing the steps for the directed differentiation of hiPSCs using a series of cytokine cocktails and hydrogel embedding. Over 18 days of differentiation, hiPSCs yield the key lineages that are present in central myelopoietic bone marrow, organized in a well-vascularized architecture that resembles native hematopoietic tissues. This presents a robust, in vitro system that can model healthy and perturbed hematopoiesis in a scalable three-dimensional microenvironment. Bone marrow organoids also support the growth of immortalized cell lines and primary cells from healthy donors and patients with myeloid and lymphoid cancers, including cell types that are poorly viable in standard culture systems. Moreover, we discuss assays for the characterization of organoids, including interrogation of pathogenic remodeling using recombinant TGF-ß treatment, and methods for organoid engraftment with exogenous cells. This protocol can be readily adapted to specific experimental requirements, can be easily implemented by users with tissue culture experience and does not require access to specialist equipment.

Acyloxyacyl Hydrolase Protects against Kidney Injury via Inhibition of Tubular CD74-Macrophage Crosstalk.

Renal fibrosis is the common pathway in the progression of chronic kidney disease (CKD). Acyloxyacyl hydrolase (AOAH) is expressed in various phagocytes and is highly expressed in proximal tubular epithelial cells (PTECs). Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases, although its role in kidney injury is unknown. Here, we found that AOAH deletion led to exacerbated kidney injury and fibrosis after folic acid (FA) administration, which was reversed by overexpression of Aoah in kidneys. ScRNA-seq revealed that Aoah-/- mice exhibited increased subpopulation of CD74+ PTECs, though the percentage of total PTECs were decreased compared to WT mice after FA treatment. Additionally, exacerbated kidney injury and fibrosis seen in Aoah-/- mice was attenuated via administration of methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1), an inhibitor of macrophage inhibition factor (MIF) and CD74 binding. Finally, AOAH expression was found positively correlated with estimated glomerular filtration rate while negatively correlated with the degree of renal fibrosis in kidneys of CKD patients. Thus, our work indicates that AOAH protects against kidney injury and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.

Galectin-3 modulates microglial activation and neuroinflammation in early brain injury after subarachnoid hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (SAH) is a devastating acute cerebrovascular event with high mortality and permanent disability rates. Higher galectin-3 levels on days 1-3 have been shown to predict the development of delayed cerebral infarction or adverse outcomes after SAH. Recent single-cell analysis of microglial transcriptomic diversity in SAH revealed that galectin could influence the development and course of neuroinflammation after SAH. METHODS: This study aimed to investigate the role and mechanism of galectin-3 in SAH and to determine whether galectin-3 inhibition prevents early brain injury by reducing microglia polarization using a mouse model of SAH and oxyhemoglobin-treated activation of mouse BV2 cells in vitro. RESULTS: We found that the expression of galectin-3 began to increase 12 h after SAH and continued to increase up to 72 h. Importantly, TD139-inhibited galectin-3 expression reduced the release of inflammatory factors in microglial cells. In the experimental SAH model, TD139 treatment alleviated neuroinflammatory damage after SAH and improved defects in neurological functions. Furthermore, we demonstrated that galectin-3 inhibition affected the activation and M1 polarization of microglial cells after SAH. TD139 treatment inhibited the expression of TLR4, p-NF-κB p65, and NF-κB p65 in microglia activated by oxyhemoglobin as well as eliminated the increased expression and phosphorylation of JAK2 and STAT3. CONCLUSION: These findings suggest that regulating microglia polarization by galectin-3 after SAH to improve neuroinflammation may be a potential therapeutic target.

Insomnia severity and its correlates among English as a second language (ESL) college students.

OBJECTIVE: Little is known about insomnia characteristics among the English as a second language (ESL) student population. This study compared insomnia severity between ESL students and English native-speaking students and identified correlates of insomnia in the ESL population. PARTICIPANTS: College students (N = 352) from a private university in the Northeastern United States, including 22.4% (N = 79) ESL students. METHODS: For this cross-sectional study, participants completed the Insomnia Severity Index and indices of common risk factors of insomnia along with acculturation and language anxiety. RESULTS: ESL students reported higher insomnia severity than their US counterparts after controlling for depression, anxiety, and demographics. General anxiety, language anxiety, and cognitive pre-sleep arousal were selected as the strongest predictors of insomnia among the ESL population. CONCLUSIONS: Findings suggest that ESL college group is vulnerable to greater insomnia, and language anxiety is unique and important correlate of insomnia in this population.

Endovascular treatment of multiple intracranial aneurysms in patients with subarachnoid hemorrhage: one or multiple sessions?

Objective: This study aimed to compare the safety and efficacy of single- and multiple-stage endovascular treatment in aneurysmal subarachnoid hemorrhage (SAH) patients with multiple intracranial aneurysms. Methods: We retrospectively analyzed the clinical and imaging data of 61 patients who harbored multiple aneurysms and presented to our institution with aneurysmal subarachnoid hemorrhage. Patients were grouped according to endovascular treatment strategy: one-stage or multiple-stage. Result: The 61 study patients harbored 136 aneurysms. One aneurysm in each patient had ruptured. In the one-stage treatment group, all 66 aneurysms in 31 patients were treated in one session. The mean follow-up was 25.8 months (range, 12-47). At the last follow-up, the modified Rankin scale was ≤2 in 27 patients. In total, 10 complications occurred (cerebral vasospasm, six patients; cerebral hemorrhage, two patients; and thromboembolism, two patients). In the multiple-stage treatment group, only the ruptured aneurysm (30 in total) was treated at the time of presentation, and the remaining aneurysms (40 in total) were treated later. The mean follow-up was 26.3 months (range, 7-49). At the last follow-up, the modified Rankin scale score was ≤2 in 28 patients. In total, five complications occurred (cerebral vasospasm, four patients; and subarachnoid hemorrhage, one patient). During the follow-up period, there was one recurrence of aneurysm with subarachnoid hemorrhage in the single-stage treatment group and four recurrences in the multiple-stage treatment group. Conclusion: Both single- and multiple-stage endovascular treatment is safe and effective in aneurysmal subarachnoid hemorrhage patients who harbor multiple aneurysms. However, multiple-stage treatment is associated with a lower rate of hemorrhagic and ischemic complications.

Lycopene attenuates D-galactose-induced cognitive decline by enhancing mitochondrial function and improving insulin signaling in the brains of female CD-1 mice.

The incidence of neurodegenerative diseases is severely increasing with ageing. Lycopene (LYC), a carotenoid pigment, has been reported to have antioxidant, anti-inflammatory and neuroprotective properties. In the present study, we aimed to investigate the ameliorative effect of LYC on D-galactose (D-gal) induced cognitive defects and the underlying mechanisms. Forty-five female CD-1 mice (2 months old) were separated into three groups to be fed with either a normal diet or a LYC diet (0.03%, w/w, mixed into normal diet). Meanwhile, the mice were treated by intraperitoneal injection of normal saline or D-gal 150 mg/kg/day for 8 weeks. The behavioral test results indicated that LYC alleviated D-gal induced cognitive impairments. LYC ameliorated brain ageing by decreasing the number of SA-ß-gal- stained neurons, downregulating the protein expression of the cellular senescence associated genes P19/P21/P53, increasing the activities of the antioxidant enzymes GSH and SOD, downregulating the level of ROS, inhibiting the activation of MAPKs signaling and downregulating the levels of the inflammatory cytokines IL-1ß and TNFɑ in mouse brains. LYC ameliorated synaptic dysfunction by increasing the expression of the neurotrophic factor BDNF and synaptic proteins. Moreover, LYC attenuated D-gal-induced mitochondrial morphological damage, and promoted the expression of mitochondrial functional proteins. LYC also promoted insulin signal transduction in mouse brains through the regulation of IRS-1/AKT/GSK3ß signaling.

Endovascular treatment strategy and clinical outcome of tentorial dural arteriovenous fistula.

Introduction: To evaluate treatment strategies and clinical outcomes following endovascular embolization of tentorial dural arteriovenous fistulas. Methods: We retrospectively analyzed 19 patients with tentorial dural arteriovenous fistulas admitted to the Department of Neurosurgery at Jiangsu Provincial People's Hospital between October 2015 and May 2022, all treated with endovascular therapy. To collect and analyze patients' clinical presentation, imaging data, postoperative complications, and prognosis and to analyze the safety and clinical outcomes of endovascular treatment of tentorial dural arteriovenous fistulas. Results: Imaging cure was achieved in 18 patients, with the arterial route chosen for embolization in 17 patients and the venous route in one patient; one patient received partial embolization. Staged embolization was performed in four patients. At postoperative follow-up of 9-83 months (37.8 ± 21.2), all 19 patients had recovered well (mRS score ≤ 2). Three patients experienced perioperative complications: intraoperative Onyx reflux into the middle cerebral artery in one patient; postoperative permanent limited left visual field loss and deafness in the left ear in one patient; and transient diplopia, vertigo, and decreased pain and temperature sensation of the left limb in one patient, with no abnormalities on post-procedure magnetic resonance examinations. A total of 17 patients completed a postoperative digital subtraction angiography review during follow-up, and one patient had a recurrence of an arteriovenous fistula. Conclusion: Endovascular treatment of tentorial dural arteriovenous fistulas is safe and effective. Reduction of the Borden or Cognard classification via eliminating cortical venous reflux through multi-staged embolization or combined open surgery is a reasonable goal of treatment where complete obliteration of the fistula is not achievable.

Modulation of methamphetamine memory reconsolidation by neural projection from basolateral amygdala to nucleus accumbens.

Drug-associated conditioned cues promote subjects to recall drug reward memory, resulting in drug-seeking and reinstatement. A consolidated memory becomes unstable after recall, such that the amnestic agent can disrupt the memory during the reconsolidation stage, which implicates a potential therapeutic strategy for weakening maladaptive memories. The basolateral amygdala (BLA) involves the association of conditioned cues with reward and aversive valences and projects the information to the nucleus accumbens (NAc) that mediates reward-seeking. However, whether the BLA-NAc projection plays a role in drug-associated memory reactivation and reconsolidation is unknown. We used methamphetamine (MeAM) conditioned place preference (CPP) to investigate the role of BLA-NAc neural projection in the memory reconsolidation. Two weeks before CPP training, we infused adeno-associated virus (AAV) carrying the designer receptor exclusively activated by designer drugs (DREADD) or control constructs. We infused clozapine-N-oxide (CNO) after the recall test to manipulate the neural activity of BLA-NAc projections in mice. We found that after recall, DREADD-mediated inhibition of BLA neurons projecting to the NAc core blunted consolidated MeAM-associated memory. Inhibition of BLA glutamatergic nerve terminals in the NAc core 1 h after recall disrupted consolidated MeAM-associated memory. However, inhibiting this pathway after the time window of reconsolidation failed to affect memory. Furthermore, under the condition without memory retrieval, DREADD-mediated activation of BLA-NAc core projection was required for amnesic agents to disrupt consolidated MeAM-associated memory. Our findings provide evidence that the BLA-NAc pathway activity is involved in the post-retrieval processing of MeAM-associated memory in CPP.