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Background Microglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF-κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential molecular mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment. Methods The Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to determine the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot analysis were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI. Results The results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI. Conclusions These results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.

To explore the effectiveness of family participatory clown therapy in venipuncture in hospitalized children. We recruited 104 children aged 3 to 6 years for a non-randomized controlled trial from March to December 2022. All participants required peripheral venepuncture infusions for treatment. The children were assigned to either the control group (n = 52) or the experimental group (n = 52).Standard care was utilized in the control group. In the experimental group, two clown nurses and a parent provided family participatory clown therapy for 35-45 minutes per child before, during, and after venipuncture. We assessed children's pain (FLACC and W-B FPS), anxiety (VAS-A), medical fear (CFS), crying incidence, compliance, parental anxiety (S-AI), and parental satisfaction. At venipuncture, the FLACC score was lower in the experimental group (4.46±2.053) compared to the control group (5.96±2.441), the W-B FPS score was also lower in the experimental group (4.96±2.392) than in the control group (6.35±2.266), with a statistically significant difference (P<0.05).The children in the experimental group had lower levels of anxiety, medical fear, crying, and parental anxiety than the control group. In addition, child compliance and parent satisfaction were higher in the experimental group than in the control group, with statistically significant differences (P<0.05). Family participatory clown therapy can reduce pain, anxiety, medical fear, and crying during venipuncture in children. It can also improve venipuncture compliance, reduce parental anxiety, and increase parental satisfaction.

Background Onasemnogene abeparvovec (OA) is an adeno-associated virus vector-based gene therapy indicated for the treatment of paediatric patients with spinal muscular atrophy(SMA) with biallelic mutations in the survival motor neuron 1 (SMN1) gene. This study focused on analysis of the postmarketing adverse events(AEs) of onasemnogene abeparvovec (OA) reported in the US Food and Drug Administration public data open project (openFDA) database to assess the safety of OA in the real world and to provide a reference for the rational use of this drug in the clinic. Results In total, 1,959 AEs were reported with “onasemnogene abeparvovec” as the primary suspected drug. The top 5 most frequent AEs were pyrexia (461 cases), vomiting (434 cases), aspartate aminotransferase increase (284 cases), alanine aminotransferase increase (260 cases), and hepatic enzyme increase (237 cases). A total of 77 alert signals were generated, 60 of which were not included in the drug label. The top 5 signals included troponin I increase ( ROR of 895.21, 95% CI: 734.43-1091.18), troponin T increase ( ROR of 313.30, 95% CI:220.85-444.44), rhinovirus infection ( ROR of 175.80, 95% CI:130.86-236.17), troponin increase ( ROR of 143.49, 95% CI:114.96–179.10), and increased bronchial secretion ( ROR of 142.71, 95% CI:96.63-210.77). Further analysis of AEs associated with gender and age differences identified 14 high-risk signals related to gender and 10 high-risk signals related to age. Female patients should be vigilant for vomiting, thrombotic microangiopathy, increased troponin T, proteinuria, haematuria, haemolytic anaemia, urinary tract infection, generalised oedema, and atypical haemolytic uraemic syndrome. Male patients should be alert to increased hepatic enzyme, increased bronchial secretion, respiratory tract infection, pallor, and increased blood creatine phosphokinase MB. Patients under 2 years of age should be vigilant for lethargy, increased monocyte count, decreased blood creatinine, and decreased neutrophil count. Patients over 2 years of age should be alert to hypertension, haematuria, rhinovirus infection, increased blood creatine phosphokinase, headache, and malaise. Conclusions Mining of OA alert signals using the openFDA database provides supplementary information on AEs not included in the drug label. Clinical attention should be focused on common, strong-signal, and label-unmentioned AEs to optimise medication regimens and control risks in clinical use.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) attenuate inflammatory responses in the central nervous system, leading to neuroprotective effects. Inhibition of histone deacetylase 3 (HDAC3) has neuroprotective effects after spinal cord injury (SCI) through the SIRT1 pathway, but the pathophysiological mechanisms of SCI are complex and the interactions between ω-3 PUFAs and organelles remain largely unknown. This study aimed to investigate the effect of ω-3 PUFAs on endoplasmic reticulum (ER) stress-induced neuroinflammation through the HDAC3/peroxisome proliferator-activated receptor-γ coactivator (PGC)-1ɑ pathway after SCI. To this end, a contusion-induced SCI rat model was established to evaluate the effects of ω-3 PUFAs on ER stress-mediated inflammation in SCI. ER stress was rapidly induced in spinal cord lesions after SCI and was significantly reduced after ω-3 PUFA treatment. Consistent with reduced ER stress, HDAC3 expression levels and inflammatory responses were decreased, and PGC-1ɑ expression levels were increased after SCI. We found that ω-3 PUFA treatment attenuated ER stress through HDAC3 inhibition, thereby reducing SCI-induced inflammation. Taken together, these results suggest a role for ω-3 PUFA in protecting against SCI-induced neuroinflammation and promoting neurological functional recovery by regulating the histone deacetylase 3/ peroxisome proliferator-activated receptor-γ coactivator pathway.

Omega-3 polyunsaturated fatty acids (tt>-3 PUFAs) attenuate inflammatory responses in the central nervous system, leading to neuroprotective effects. Inhibition of histone deacetylase 3 (HDAC3) has neuroprotective effects after spinal cord injury (SCI) through the SIRT1 pathway, but the pathophysiological mechanisms of SCI are complex and the interactions between C0-3 PUFAs and organelles remain largely unknown. This study aimed to investigate the effect of C0-3 PUFAs on endoplasmic reticulum (ER) stress-induced neuroinflammation through the HDAC3/peroxisome proliferator-activated receptor-y coactivator (PGC)-1a pathway after SCI. To this end, a contusion-induced SCI rat model was established to evaluate the effects of C0-3 PUFAs on ER stress-mediated inflammation in SCI. ER stress was rapidly induced in spinal cord lesions after SCI and was significantly reduced after C0-3 PUFA treatment. Consistent with reduced ER stress, HDAC3 expression levels and inflammatory responses were decreased, and PGC-1a expression levels were increased after SCI. We found that C0-3 PUFA treatment attenuated ER stress through HDAC3 inhibition, thereby reducing SCI-induced inflammation. Taken together, these results suggest a role for C0-3 PUFA in protecting against SCI-induced neuroinflammation and promoting neurological functional recovery by regulating the histone deacetylase 3/ peroxisome proliferator-activated receptor-y coactivator pathway.

In this paper, the ethylene/oxygen/nitrogen premixed flame instabilities induced by incident and reflected shock wave were investigated numerically. The effects of grid resolutions and chemical mechanisms on the flame bubble deformation process are evaluated. In the computational frame, the 2D multi-component Navier–Stokes equations with second-order flux-difference splitting scheme were used; the stiff chemical source term was integrated using an implicit ordinary differential equations (ODEs) solver. The two ethylene/oxygen/nitrogen chemical mechanisms, namely 3-step reduced mechanism and 35-step elementary skeletal mechanism, were used to examine the reliability of chemistry. On the other hand, the different grid sizes, Δx × Δy = 0.25 × 0.5mm and Δx × Δy = 0.15 × 0.2mm, were implemented to examine the accuracy of the grid resolution. The computational results were qualitatively validated with experimental results of Thomas et al. (Combust Theory Model 5:573–594, 2001). Two chemical mechanisms and two grid resolutions used in present study can qualitatively reproduce the ethylene spherical flame instability process generated by an incident shock wave of Mach number 1.7. For the case of interaction between the flame and reflected shock waves, the 35-steps mechanism qualitatively predicts the physical process and is somewhat independent on the grid resolutions, while the 3-steps mechanism fails to reproduce the instability of ethylene flame for the two selected grid resolutions. It is concluded that the detailed chemical mechanism, which includes the chain elementary reactions of fuel combustion, describes the flame instability induced by shock wave, in spite of the fact that the flame thickness (reaction zone) is represented by 1–2 grids only.

Observations are presented from calculations where a laminar spherical CH4/air flame was perturbed successively by incident and reflected shock waves reflected from a planar or concave wall. The two-dimensional axi-symmetric Navier–Stokes equations with detailed chemistry were used. The computational results were qualitatively validated with experiments which were performed in a standard shock tube arrangement. Under the influence of the incident shock wave, a Richtmyer–Meshkov instability is induced in the flame, and the distorted flame finally takes the form of two separated elliptical burning bubbles in the symmetric cross plane. Then, under subsequent interactions with the shock wave reflected from the planar or the concave wall, the flame takes a mushroom-like shape. Transverse waves produced by the shock reflection from the concave wall can compress the flame towards the axis, and the focusing shock generated on the concave wall will lead to a larger mushroom-like flame than that induced by the planar reflection.

Observations are presented from experiments and calculations where a laminar spherical CH4/air flame is perturbed successively by incident and reflected shock waves. The experiments are performed in a standard shock tube arrangement, in which a high-speed shadowgraph imaging system is used to record evolutions of the flame. Numerical simulations are conducted by using second-order wave propagation algorithms, based on two-dimensional axisymmetric Navier–Stokes equations with detailed chemical reactions. Qualitative agreements are obtained between the experimental and numerical results. Under actions of incident shock waves, Richtmyer–Meshkov instability responsible for the flame deformation is induced in the flame, and the distorted flame takes a barrel shape. Then, under subsequent actions of the shock wave reflected from a planar wall, the flame takes an inclined non-symmetrical kidney shape in a symmetric cross section, which means a mushroom-like shape of the flame comes finally into being. The vorticity direction in the ring cap has been altered by the reflected shock’s action, which makes the head of the mushroom-like flame extend quickly to the side wall.

Global surveillance indicates rising ceftazidime-avibactam resistance among carbapenem-resistant Klebsiella pneumoniae (CRKP), with sequence type 11 predominating in China. The contribution of blaKPC variants and porin alterations to high-level resistance remains significant. We employed whole-genome sequencing and functional analyses to characterise a CZA-resistant ST11 CRKP isolate recovered from a patient without prior exposure to ceftazidime-avibactam or carbapenems. The isolate harboured blaKPC-33 on a non-conjugative plasmid and multiple non-synonymous mutations in the porin gene ompK37, concomitant with high-level resistance to ceftazidime-avibactam and carbapenems while retaining susceptibility to tigecycline, polymyxin B and amikacin. blaKPC-33 coupled with OmpK37 alterations underpins dual resistance to ceftazidime-avibactam and carbapenems in ST11 CRKP, underscoring the need for genomic surveillance and rapid detection of this resistance mechanism.

Background To investigate whether metformin monotherapy or adjunctive therapy improves the prognosis in patients with any type of cancer compared to non-metformin users (age ≥18). Methods Databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) and clinical trial registries ( ClinicalTrials.gov ; the World Health Organization International Clinical Trials Registry Platform) were screened for randomized, controlled trials (RCT) reporting at least progression-free survival (PFS) and/or overall survival (OS). Main outcome measures included hazard ratios (HR), and combined HRs and 95% confidence intervals (CI) were calculated using random-effects models. Results Of the 8419 records screened, 22 RCTs comprising 5943 participants were included. Pooled HRs were not statistically significant in both PFS (HR 0.97, 95% CI 0.82–1.15, I 2  = 50%) and OS (HR 0.98, 95% CI 0.86–1.13, I 2  = 33%) for patients with cancer between the metformin and control groups. Subgroup analyses demonstrated that metformin treatment was associated with a marginally significant improvement in PFS in reproductive system cancers (HR 0.86, 95% CI 0.74–1.00) and a significantly worse PFS in digestive system cancers (HR 1.45, 95% CI 1.03–2.04). The PFS or OS was observed consistently across maintenance dose, diabetes exclusion, median follow-up, risk of bias, and combined antitumoral therapies. Conclusion Metformin treatment was not associated with cancer-related mortality in adults compared with placebo or no treatment. However, metformin implied beneficial effects in the PFS of the patients with reproductive system cancers but was related to a worse PFS in digestive system cancers. Systematic review registration PROSPERO registration number CRD42022324672.