Clinical efficacy of the bared external anal sphincter (BEAS) in high horseshoe-shaped anal fistulas: Protocol for a real-world, prospective cohort study.

Background: High horseshoe-shaped anal fistula (HHAF) is a complex disease that manifests in the perianal region and typically requires surgical intervention for treatment. However, the current therapeutic approaches are limited by the high rates of postoperative recurrence and anal incontinence. To overcome the limitations of traditional surgical approaches, we introduce the bared external anal sphincter (BEAS) technique. Our study aims to compare the clinical efficacy of BEAS surgery with that of the modified Hanley procedure in a real-world setting. Materials and methods: This single-centre, prospective cohort study will be conducted in a tertiary hospital in China and aims to evaluate the short-term clinical efficacy and safety of BEAS surgery and modified Hanley surgery in HHAF patients from March 2024 to March 2026. Data from the prospective database of this tertiary referral hospital will be used to obtain insights into the clinical outcomes of these surgical treatments. The primary outcome of this study will be the wound healing rate within six months, while the secondary outcomes will include the time to return to work, the maximum visual analogue scale pain score (VAS-PS) within 1-5 days postsurgery, and the Cleveland Clinic Florida Incontinence Score (CCF-IS) and Quality of Life in Anal Fistula Questionnaire Score (QoLAF-QS) at 1, 3, and 6 months postsurgery. Moreover, logistic regression analysis will be used to explore the risk factors for anal fistula recurrence after the BEAS procedure. Discussion: This will be the first cohort study to evaluate the differences in therapeutic outcomes between patients who undergo BEAS surgery and patients who undergo surgery via the modified Hanley procedure. By conducting a detailed observation of the efficacy and treatment results of these two surgical methods, this study aims to reveal the differences the clinical effectiveness of these approaches and to provide evidence-based support for future randomized controlled trials (RCTs).

Liver X receptor inverse agonist SR9243 attenuates rheumatoid arthritis via modulating glycolytic metabolism of macrophages.

Liver X receptors (LXRs) which link lipid metabolism and inflammation, were overexpressed in experimental rheumatoid arthritis (RA) rats as observed in our previous studies, while suppression of LXRα by silybin ameliorates arthritis and abnormal lipid metabolism. However, the role of LXRs in RA remains undefined. In this study, we investigated the inhibition role of LXRs in the polarization and activation of M1 macrophage by using a special LXRs inverse agonist SR9243, which led to ameliorating the progression of adjuvant-induced arthritis (AIA) in rats. Mechanistically, SR9243 disrupted the LPS/IFN-γ-induced Warburg effect in M1 macrophages, while glycolysis inhibitor 2-DG attenuated the inhibition effect of SR9243 on M1 polarization and the cytokines expression of M1 macrophages including iNOS, TNF-α, and IL-6 in vitro. Furthermore, SR9243 downregulated key glycolytic enzymes, including LDH-A, HK2, G6PD, GLUT1, and HIF-1α in M1 macrophages, which is mediated by increased phosphorylation of AMPK (Thr172) and reduced downstream phosphorylation of mTOR (Ser2448). Importantly, gene silencing of LXRs compromises the inhibition effect of SR9243 on M1 macrophage polarization and activation. Collectively, for the first time, our findings suggest that the LXR inverse agonist SR9243 mitigates adjuvant-induced rheumatoid arthritis and protects against bone erosion by inhibiting M1 macrophage polarization and activation through modulation of glycolytic metabolism via the AMPK/mTOR/HIF-1α pathway.

Evaluation of combined epiretinal membrane removal with intravitreal triamcinolone injection utilizing ectopic inner foveal layer staging scheme.

OBJECTIVE: To investigate the macular morphological and visual outcomes of combined idiopathic epiretinal membrane (iERM) removal with triamcinolone acetonide (TA) injection based on consideration of the ectopic inner foveal layer (EIFL) staging scheme. METHODS: Retrospective case-control study. The clinical data of 84 eyes of 84 patients who underwent vitrectomy for iERM between 2018 and 2022 were reviewed. The enrolled subjects were divided into the TA and non-TA groups. Fifty-one eyes received intravitreal TA injection following vitrectomy and ERM peeling (TA group), and 33 were only treated by standard vitrectomy and ERM peeling (non-TA group). Preoperative and postoperative EIFL stages, central foveal thickness (CFT), and best-corrected visual acuity (BCVA) were compared between both groups. RESULTS: After a mean follow-up of 7.69 ± 3.68 months, both groups exhibited significant improvement in EIFL stages (P < 0.01), with no discernible advantage observed in the TA group. The TA and non-TA groups demonstrated improvement in the EIFL stages in 56.86 and 63.64% of eyes, respectively (P = 0.43). The CFT and BCVA significantly improved in both groups at the final visit (P < 0.01). However, CFT in the non-TA group displayed a more significant reduction during the follow-up (P < 0.03). Subgroup analysis revealed no significant differences in postoperative CFT and BCVA between the two groups in cases with or without continuous EIFL (P > 0.10). CONCLUSION: Our findings indicate that combined intravitreal TA injection following ERM removal conferred no significant benefits in alleviating macular thickening or improving visual acuity in iERM.

Short-chain fatty acids mitigate Methamphetamine-induced hepatic injuries in a Sigma-1 receptor-dependent manner.

Methamphetamine (Meth) is a potent psychostimulant with well-established hepatotoxicity. Gut microbiota-derived short-chain fatty acids (SCFAs) have been reported to yield beneficial effects on the liver. In this study, we aim to further reveal the mechanisms of Meth-induced hepatic injuries and investigate the potential protective effects of SCFAs. Herein, mice were intraperitoneally injected with 15 mg/kg Meth to induce hepatic injuries. The composition of fecal microbiota and SCFAs was profiled using 16 S rRNA sequencing and Gas Chromatography/Mass Spectrometry (GC/MS) analysis, respectively. Subsequently, SCFAs supplementation was performed to evaluate the protective effects against hepatic injuries. Additionally, Sigma-1 receptor knockout (S1R-/-) mice and fluvoxamine (Flu), an agonist of S1R, were introduced to investigate the mechanisms underlying the protective effects of SCFAs. Our results showed that Meth activated S1R and induced hepatic autophagy, inflammation, and oxidative stress by stimulating the MAPK/ERK pathway. Meanwhile, Meth disrupted SCFAs product-related microbiota, leading to a reduction in fecal SCFAs (especially Acetic acid and Propanoic acid). Accompanied by the optimization of gut microbiota, SCFAs supplementation normalized S1R expression and ameliorated Meth-induced hepatic injuries by repressing the MAPK/ERK pathway. Effectively, S1R knockout repressed Meth-induced activation of the MAPK/ERK pathway and further ameliorated hepatic injuries. Finally, the overexpression of S1R stimulated the MAPK/ERK pathway and yielded comparable adverse phenotypes to Meth administration. These findings suggest that Meth-induced hepatic injuries relied on the activation of S1R, which could be alleviated by SCFAs supplementation. Our study confirms the crucial role of S1R in Meth-induced hepatic injuries for the first time and provides a potential preemptive therapy.

[Preparation and application of chromatographic stationary phase based on two-dimensional materials].

The stationary phase is the heart of chromatographic separation technology and a critical contributor to the overall separation performance of a chromatographic separation technique. However, traditional silicon-based materials designed for this purpose usually feature complex preparation processes, suboptimal permeability, pronounced mass-transfer resistance, and limited pH-range compatibility. These limitations have spurred ongoing research efforts aimed at developing new chromatographic stationary phases characterized by higher separation efficiency, adaptable selectivity, and a broader scope of applicability. In this context, the scientific community has made significant strides toward the development of new-generation materials suitable for use as chromatographic stationary phases. These materials include carbon-based nanomaterial arrays, carbon quantum dots, and two-dimensional (2D) materials. 2D-materials are characterized by nanometer-scale thicknesses, extensive specific surface areas, distinctive layered structures, and outstanding mechanical properties under standard conditions. Thus, these materials demonstrate excellent utility in various applications, such as electrical and thermal conductivity enhancements, gas storage and separation solutions, membrane separation technologies, and catalysis. Graphene, which is arguably the most popular 2D-material used for chromatographic separation, consists of a 2D-lattice of carbon atoms arranged in a single layer, with a large specific surface area and efficient adsorption properties. Its widespread adoption in research and various industries is a testament to its versatility and effectiveness. In addition to graphene, the scientific community has developed various 2D-materials that mirror the layered structures of graphene, such as boron nitride, transition-metal sulfides, and 2D porous organic frameworks, all of which offer unique advantages. 2D porous organic frameworks, in particular, have received attention because of their nanosheet morphology, one-dimensional pores, and special interlayer forces; thus, these frameworks are considered promising candidate chromatographic stationary phase materials. Such recognition is especially true for 2D-metal organic frameworks (MOFs) and 2D-covalent organic frameworks (COFs), which exhibit low densities, high porosities, and substantial specific surface areas. The modifiability of these materials, in terms of pore size, shape, functional groups, and layer-stacking arrangements allows for excellent separation selectivity, highlighting their promising potential in chromatographic separation. Compared with their three-dimensional counterparts, 2D-MOFs feature a simple pore structure that offers reduced mass-transfer resistance and enhanced column efficiency. These attributes highlight the advantages of 2D-MOF nanosheets as chromatographic stationary phases. Similarly, 2D-COFs, given their high specific surface area and porosity, not only exhibit great thermal stability and chemical tolerance but also support a wide selection of solvents and operational conditions. Therefore, their role in the preparation of chromatographic stationary phases is considered highly promising. This review discusses the latest research developments in 2D porous organic framework materials in the context of gas- and liquid-chromatographic stationary phases. It introduces the synthesis methods for these novel materials, elucidates their retention mechanisms, and describes the applications of other 2D-materials, such as graphene, its derivatives, graphitic carbon nitride, and boron nitride, in chromatography. This review aims to shed light on the promising development prospects and future directions of 2D-materials in the field of chromatographic separation, offering valuable insights into the rational design and application of new 2D-materials in chromatography.

Polystyrene nanoplastics exacerbate aflatoxin B1-induced hepatic injuries by modulating the gut-liver axis.

Dietary pollution of Aflatoxin B1 (AFB1) poses a great threat to global food safety, which can result in serious hepatic injuries. Following the widespread use of plastic tableware, co-exposure to microplastics and AFB1 has dramatically increased. However, whether microplastics could exert synergistic effects with AFB1 and amplify its hepatotoxicity, and the underlying mechanisms are still unelucidated. Here, mice were orally exposed to 100 nm polystyrene nanoplastics (NPs) and AFB1 to investigate the influences of NPs on AFB1-induced hepatic injuries. We found that exposure to only NPs or AFB1 resulted in colonic inflammation and the impairment of the intestinal barrier, which was exacerbated by combined exposure to NPs and AFB1. Meanwhile, co-exposure to NPs exacerbated AFB1-induced dysbiosis of gut microbiota and remodeling of the fecal metabolome. Moreover, NPs and AFB1 co-exposure exhibited higher levels of systemic inflammatory factors compared to AFB1 exposure. Additionally, NPs co-exposure further exacerbated AFB1-induced hepatic fibrosis and inflammation, which could be associated with the overactivation of the TLR4/MyD88/NF-κB pathway. Notably, Spearman's correlation analysis revealed that the exacerbation of NPs co-exposure was closely associated with microbial dysbiosis. Furthermore, microbiota from NPs-exposed mice (NPsFMT) partly reproduced the exacerbation of NPs on AFB1-induced systemic and hepatic inflammation, but not fibrosis. In summary, our findings indicate that gut microbiota could be involved in the exacerbation of NPs on AFB1-induced hepatic injuries, highlighting the health risks of NPs.

The cytokine genes of Oncorhynchus masou formosanus include a defective interleukin-4/13A gene.

Oncorhynchus masou formosanus (Formosa landlocked salmon) is a critically endangered salmonid fish endemic to Taiwan. To begin to understand how its drastic change in lifestyle from anadromous to exclusively river-dwelling is reflected in its immune genes, we characterized the genes encoding six cytokines (IL-2A, IL-2B, IL-4/13A, IL-4/13B1, IL-4/13B2, and IL-17A/F2a) important for T cell responses as no genomic data is available for this fish. Interestingly, all genes appeared homozygous indicative of a genetic bottleneck. The IL2 and IL17A/F2a genes and their products are highly similar to their characterized homologs in Oncorhynchus mykiss (rainbow trout) and other salmonid fish. Two notable differences were observed in IL4/13 family important for type 2 immune responses. First, O. m. formosanus carries not only one but two genes encoding IL-4/13B1 proteins and expansions of these genes are present in other salmonid fish. Second, the OmfoIL4/13A gene carries a 228 bp deletion that results in a premature stop codon and hence a non-functional IL-4/13A cytokine. This suggests a reduced ability for T cell responses against parasitic infections in this species.

Novel perfluorocarbon-based oxygenation therapy alleviates Post-SAH hypoxic brain injury by inhibiting HIF-1α.

In comparison to other stroke types, subarachnoid hemorrhage (SAH) is characterized by an early age of onset and often results in poor prognosis. The inadequate blood flow at the site of the lesion leads to localized oxygen deprivation, increased level of hypoxia-inducible factor-1α (HIF-1α), and triggers inflammatory responses and oxidative stress, ultimately causing hypoxic brain damage. Despite the potential benefits of oxygen (O2) administration, there is currently a lack of efficient focal site O2 delivery following SAH. Conventional clinical O2 supply methods, such as transnasal oxygenation and hyperbaric oxygen therapy, do not show the ideal therapeutic effect in severe SAH patients. The perfluorocarbon oxygen carrier (PFOC) demonstrates efficacy in transporting O2 and responding to elevated levels of CO2 at the lesion site. Through cellular experiments, we determined that PFOC oxygenation serves as an effective therapeutic approach in inhibiting hypoxia. Furthermore, our animal experiments showed that PFOC oxygenation outperforms O2 breathing, leading to microglia phenotypic switching and the suppression of inflammatory response via the inhibition of HIF-1α. Therefore, as a new type of O2 therapy after SAH, PFOC oxygenation can effectively reduce hypoxic brain injury and improve neurological function.

ROS-induced oxidative stress and mitochondrial dysfunction: a possible mechanism responsible for noise-induced ribbon synaptic damage.

Evidence suggests that damage to the ribbon synapses (RS) may be the main cause of auditory dysfunction in noise-induced hearing loss (NIHL). Oxidative stress is implicated in the pathophysiology of synaptic damage. However, the relationship between oxidative stress and RS damage in NIHL remains unclear. To investigate the hypothesis that noise-induced oxidative stress is a key factor in synaptic damage within the inner ear, we conducted a study using mice subjected to single or repeated noise exposure (NE). We assessed auditory function using auditory brainstem response (ABR) test and examined cochlear morphology by immunofluorescence staining. The results showed that mice that experienced a single NE exhibited a threshold shift and recovered within two weeks. The ABR wave I latencies were prolonged, and the amplitudes decreased, suggesting RS dysfunction. These changes were also demonstrated by the loss of RS as evidenced by immunofluorescence staining. However, we observed threshold shifts that did not return to baseline levels following secondary NE. Additionally, ABR wave I latencies and amplitudes exhibited notable changes. Immunofluorescence staining indicated not only severe damage to RS but also loss of outer hair cells. We also noted decreased T-AOC, ATP, and mitochondrial membrane potential levels, alongside increased hydrogen peroxide concentrations post-NE. Furthermore, the expression levels of 4-HNE and 8-OHdG in the cochlea were notably elevated. Collectively, our findings suggest that the production of reactive oxygen species leads to oxidative damage in the cochlea. This mitochondrial dysfunction consequently contributes to the loss of RS, precipitating an early onset of NIHL.

Neutrophil-to-lymphocyte ratio associated with symptomatic saccular unruptured intracranial aneurysm.

BACKGROUND AND PURPOSE: Whether symptomatic unruptured intracranial aneurysms (UIAs) lead to change in circulating inflammation remains unclear. This study aims to evaluate the role of hematological inflammatory indicators in predicting symptomatic UIA. METHODS: Adult patients diagnosed with saccular intracranial aneurysm from March 2019 to September 2023 were recruited retrospectively. Clinical and laboratory data, including the white blood cells (WBC), neutral counts (NEUT), lymphocyte counts (LYM), and monocyte counts (MONO) of each patient, were collected. The neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) were calculated as NLR = NEUT/LYM, LMR = LYM/MONO, SII = PLT*NEUT/LYM. The hematological inflammatory indicators were compared in symptomatic saccular and asymptomatic UIA patients. Multivariable logistic regression analyses were performed to explore the factors predicting symptomatic UIA. RESULTS: One hundred and fifty UIA patients with a mean age of 58.5 ± 12.4 were included, of which 68% were females. The NLR and LMR were significantly associated with symptomatic UIA, and the association remained in small UIAs (< 7 mm). The multiple logistic regression analysis showed that NLR was independently associated with symptomatic UIA. On ROC curve analysis, the optimal cutoff value of NLR to differentiate symptomatic from asymptomatic was 2.38. In addition, LMR was significantly associated with symptomatic UIA smaller than 7 mm. CONCLUSION: There was a significant correlation between NLR and symptomatic UIA. The NLR was independently associated with symptomatic UIA.