Transcriptome Analysis Reveals Dynamic Microglial-Induced A1 Astrocyte Reactivity via C3/C3aR/NF-κB Signaling After Ischemic Stroke.

Microglia and astrocytes are key players in neuroinflammation and ischemic stroke. A1 astrocytes are a subtype of astrocytes that are extremely neurotoxic and quickly kill neurons. Although the detrimental A1 astrocytes are present in many neurodegenerative diseases and are considered to accelerate neurodegeneration, their role in the pathophysiology of ischemic stroke is poorly understood. Here, we combined RNA-seq, molecular and immunological techniques, and behavioral tests to investigate the role of A1 astrocytes in the pathophysiology of ischemic stroke. We found that astrocyte phenotypes change from a beneficial A2 type in the acute phase to a detrimental A1 type in the chronic phase following ischemic stroke. The activated microglial IL1α, TNF, and C1q prompt commitment of A1 astrocytes. Inhibition of A1 astrocytes induction attenuates reactive gliosis and ameliorates morphological and functional defects following ischemic stroke. The crosstalk between astrocytic C3 and microglial C3aR contributes to the formation of A1 astrocytes and morphological and functional defects. In addition, NF-κB is activated following ischemic stroke and governs the formation of A1 astrocytes via direct targeting of inflammatory cytokines and chemokines. Taken together, we discovered that A2 astrocytes and A1 astrocytes are enriched in the acute and chronic phases of ischemic stroke respectively, and that the C3/C3aR/NF-κB signaling leads to A1 astrocytes induction. Therefore, the C3/C3aR/NF-κB signaling is a novel therapeutic target for ischemic stroke treatment.

Recent advances in light energy biotherapeutic strategies with photobiomodulation on central nervous system disorders.

Transcranial photobiomodulation refers to irradiation of the brain through the skull using low-intensity red or near-infrared light, which is the most commonly studied method of light energy biotherapy for central nervous system disorders. The absorption of photons by specific chromophores within the cell elevates ATP synthesis, reduces oxidative stress damage, alleviates inflammation or mediates the activation of transcription factors and signaling mediators through secondary mediators, which in turn trigger downstream signaling pathways to cause a series of photobiological effects including upregulation of neurotrophic factors. Multiple mechanisms are simultaneously involved in the pathological process of central nervous system disorders. The pleiotropic treatment of transcranial photobiomodulation towards multiple targets plays a beneficial role in improving hemodynamics, neural repair and improving behaviors in central nervous system disorders such as ischemic stroke, traumatic brain injury, neurodegenerative diseases, epilepsy and depression. This review mainly introduces the mechanism and recent preclinical and clinical advances of transcranial photobiomodulation for central nervous system disorders, which will provide a reference for clinicians to understand and engage in related studies, and calls for more and larger studies to validate and develop a wider application of transcranial photobiomodulation in central nervous system.

Clinical Practice Guidelines for the Management of Behavioral and Psychological Symptoms of Dementia: A Systematic Review With AGREE II.

Background: High-quality clinical practice guidelines (CPGs) are important for the effective treatment of behavioral and psychological symptoms of dementia (BPSD). However, recommendations provided by different quality guidelines may lead to varied clinical practice outcomes. Objective: To assess the quality of available CPGs for the management of BPSD and summarize the best recommendations for treating BPSD. Methods: This was a systematic review of CPGs for the management of BPSD with data obtained from electronic databases and evaluated using the Appraisal of Guidelines for Research and Evaluation II instrument, consisting of six domains: "Scope and purpose", "Stakeholder involvement", "Rigor of development", "Clarity of presentation", "Applicability", and "Editorial independence". The criteria for high-quality guidelines were set as: the score of high-quality guidelines in the "Rigor of development" domain should be ≥60% and as well as a score of >60% in at least three other domains. High-quality guidelines were selected for recommendation extraction, and the final recommendations were formed in combination with the latest meta-analysis and randomized clinical-trial results. Results: In term of median scores in each domain for the six included CPGs, "Scope and purpose" (87.5%) scored better than all others, whereas "Applicability" (46.5%) was the domain with the lowest score. Four CPGs (2015 APA, 2018 NICE, 2018 CANADA, 2020 EAN) met the criteria of high-quality guidelines and were used to extract recommendations. From these four CPGs, nine specific recommendations related to the management of BPSD were summarized, of which seven were related to pharmacological treatment and two to non-pharmacological treatment. These recommendations covered the applicability of antipsychotic drugs, medication recommendations, withdrawal times, and several suitable non-pharmacological therapies. Conclusion: The quality of CPGs for the management of BPSD requires improvement, especially for the "Applicability" domain. For psychotic-like symptoms in dementia, the use of antipsychotics should be based on the individual's risk-benefit ratio, and the use of atypical antipsychotics seems to be a better choice. Non-pharmacological treatments may be suitable for emotional symptoms and sleep disorders. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020209204.

Antibiotics prescription for targeted therapy of pediatric invasive pneumococcal diseases in China: a multicenter retrospective study.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is a major cause of bacterial meningitis, septicemia and pneumonia in children. Inappropriate choice of antibiotic can have important adverse consequences for both the individual and the community. Here, we focused on penicillin/cefotaxime non-susceptibility of S. pneumoniae and evaluated appropriateness of targeted antibiotic therapy for children with IPD (invasive pneumococcal diseases) in China. METHODS: A multicenter retrospective study was conducted in 14 hospitals from 13 provinces in China. Antibiotics prescription, clinical features and resistance patterns of IPD cases from January 2012 to December 2017 were collected. Appropriateness of targeted antibiotics therapy was assessed. RESULTS: 806 IPD cases were collected. The non-susceptibility rates of S. pneumoniae to penicillin and cefotaxime were 40.9% and 20.7% respectively in 492 non-meningitis cases, whereas those were 73.2% and 43.0% respectively in 314 meningitis cases. Carbapenems were used in 21.3% of non-meningitis cases and 42.0% of meningitis cases for targeted therapy. For 390 non-meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were used in 17.9% and 8.7% of cases respectively for targeted therapy. For 179 meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were prescribed in 55.3% and 15.6% of cases respectively. Overall, inappropriate targeted therapies were identified in 361 (44.8%) of 806 IPD cases, including 232 (28.8%) cases with inappropriate use of carbapenems, 169 (21.0%) cases with inappropriate use of vancomycin and 62 (7.7%) cases with inappropriate use of linezolid. CONCLUSIONS: Antibiotic regimens for IPD definite therapy were often excessive with extensive prescription of carbapenems, vancomycin or linezolid in China. Antimicrobial stewardship programs should be implemented to improve antimicrobial use.

Prominent Striatum Amyloid Retention in Early-Onset Familial Alzheimer's Disease With PSEN1 Mutations: A Pilot PET/MR Study.

Background: With the advancements of amyloid imaging in recent years, this new imaging diagnostic method has aroused great interest from researchers. Till now, little is known regarding amyloid deposition specialty in patients with early-onset familial Alzheimer's disease (EOFAD), and even less is known about its role in cognitive impairments. Objectives: Our study aimed to evaluate the amyloid deposition in five patients with EOFAD, 15 patients with late-onset sporadic AD, and 12 healthy subjects utilizing 11C-labeled Pittsburgh compound-B (11C-PiB) amyloid PET imaging. Moreover, we figured out the correlation between striatal and cortical standardized uptake value ratios (SUVRs). We also investigated the correlation between 11C-PiB retention and cognitive presentation. Results: All patients with EOFAD showed high amyloid deposition in the striatum, a pattern that is not usually seen in patients with late-onset sporadic AD. The SUVR in the striatum, especially in the amygdala, showed significant correlations with cortex SUVR in EOFAD. However, neither striatal nor cortical 11C-PiB retention was related to cognitive decline. Conclusions: The amyloid distribution in patients with EOFAD differs from late-onset sporadic AD, with higher amyloid deposits in the striatum. Our study also demonstrated positive correlations in 11C-PiB retention between the striatum and other cortical areas. We revealed that the distribution of amyloid in the brain is not random but diffuses following the functional and anatomical connections. However, the degree and pattern of amyloid deposition were not correlated with cognitive deficits.

Febuxostat Attenuates Renal Damage besides Exerting Hypouricemic Effect in Streptozotocin-Induced Diabetic Rats.

Aim. In this study, we aimed to investigate the effects of febuxostat, a novel inhibitor of xanthine oxidase (XO), on renal damage in streptozotocin- (STZ-) induced diabetic rats. Methods. Diabetes was induced by the intraperitoneal injection of STZ in male Sprague-Dawley rats. Sham-injected rats served as controls. The control and diabetic rats were treated with and without febuxostat for 8 weeks, respectively. Fasting blood and 24-h urine samples were collected every 4 weeks. Rat livers were extracted for detecting gene expression, content, and bioactivity of XO. Results. Diabetic rats showed significantly increased serum uric acid (SUA), serum creatinine (SCr), and urea nitrogen (BUN) levels. Daily urinary albumin (UAE), uric acid (UUA), and creatinine (UCr) excretion were also significantly increased in these rats. In diabetic rats, at week 8, febuxostat decreased SUA by 18.9%, while UAA was increased by 52.0%. However, UCr and urinary urea nitrogen (UUN) levels remained unchanged, while SCr and BUN levels decreased by >30% in these rats. Although hepatic gene expression, content, and activity of XO increased significantly in diabetic rats, febuxostat only slightly decreased its content. Conclusions. Febuxostat significantly attenuated renal damage in STZ-induced diabetic rats in addition to exerting hypouricemic effect.

catena-Poly[[dinitratocopper(II)]-µ-4,4''-bis-(1H-benzimidazol-1-yl)-1,1':4',1''-terphen-yl].

In the title one-dimensional coordination polymer, [Cu(NO(3))(2)(C(32)H(22)N(4))](n), the Cu(2+) ion (site symmetry 2) is coordinated by two nitrate O atoms and two N atoms from two 4,4'-bis-(benzoimidazol-1-yl)terphenyl (L) ligands in a distorted cis-CuN(2)O(2) square-planar coordination geometry. An alternative description of the metal coordination geometry, if long Cu-O contacts to the bonded nitrate anions are considered, is an extremely distorted cis-CuN(2)O(4) octa-hedron. The complete L ligand is generated by crystallographic twofold symmetry and connects the metal ions into infinite chains propagating in [10[Formula: see text]]. The dihedral angle between the benzimidazole ring system and the adjacent benzene (B) ring is 51.12 (11)° and the dihedral angle between the B ring and the central ring is 19.45 (13)°.