P75NTR+CD64+ neutrophils promote sepsis-induced acute lung injury.

Patients suffering from sepsis-induced acute lung injury (ALI) exhibit a high mortality rate, and their prognosis is closely associated with infiltration of neutrophils into the lungs. In this study, we found a significant elevation of CD64+ neutrophils, which highly expressed p75 neurotrophin receptor (p75NTR) in peripheral blood of mice and patients with sepsis-induced ALI. p75NTR+CD64+ neutrophils were also abundantly expressed in the lung of ALI mice induced by lipopolysaccharide. Conditional knock-out of the myeloid lineage's p75NTR gene improved the survival rates, attenuated lung tissue inflammation, reduced neutrophil infiltration and enhanced the phagocytic functions of CD64+ neutrophils. In vitro, p75NTR+CD64+ neutrophils exhibited an upregulation and compromised phagocytic activity in blood samples of ALI patients. Blocking p75NTR activity by soluble p75NTR extracellular domain peptide (p75ECD-Fc) boosted CD64+ neutrophils phagocytic activity and reduced inflammatory cytokine production via regulation of the NF-κB activity. The findings strongly indicate that p75NTR+CD64+ neutrophils are a novel pathogenic neutrophil subpopulation promoting sepsis-induced ALI.

Bony Congenital Nasolacrimal Duct Obstruction: A Novel Phenotype of Aplasia of Lacrimal and Major Salivary Glands.

PURPOSE: Aplasia of lacrimal and salivary glands (ALSG) is a syndromic disorder characterized by aplasia of lacrimal and salivary systems. Reported ophthalmic manifestations of ALSG include aplasia of lacrimal glands, punctal agenesis, lacrimal sac mucocele, and membranous congenital nasolacrimal duct obstruction (CNLDO). Bony CNLDO, a rare clinical entity, has not been associated with any syndromic disorder. This study investigated the relationship between genetic mutations and bony CNLDO in 3 Chinese families with ALSG. DESIGN: Single-center observational case study. PARTICIPANTS: Three Chinese families with bony CNLDO, including 7 affected and 9 healthy family members. METHODS: Slit-lamp ophthalmic examination, comprehensive physical examination, orbital computed tomography (CT) imaging, cervicofacial magnetic resonance imaging, audiometry, and whole exome sequencing on periphery blood were performed. Variants were cross-referenced with 1000 control genomes and various population databases. Pathologic variants were identified using bioinformatic tools. MAIN OUTCOME MEASURES: Clinical examination, diagnostic imaging, whole exome sequencing, and bioinformatic analysis findings. RESULTS: Affected patients showed decreased tear production on the Schimer I test and reduced tear breakup time. Bony CNLDO was observed on CT, showing unilateral or bilateral bony termination at the middle or terminal segment of the nasolacrimal canal. Magnetic resonance imaging showed aplasia or absence of lacrimal, parotid, and submandibular glands. Physical examination revealed normal ears, digits, and facial morphology. Audiometry and dental assessment were conducted on the pediatric patients and yielded normal results. The clinical characteristics of patients aligned with a diagnosis of ALSG. Genomic analysis revealed 3 novel heterozygous missense mutations of the Fgf10 gene: c.316T→C, c.327C→G, and c.332T→G. The inheritance pattern was autosomal dominant with variable penetrance. These variants were not observed in 1000 control genomes and population databases. These variant positions also were shown to be highly conserved across various animal species. Mutated genes and proteins were predicted as deleterious with most computational models, with a few suggesting they may be benign. CONCLUSIONS: Bony CNLDO was identified as a novel phenotype of ALSG implicated by missense mutations of highly conserved residues in the Fgf10 gene. These cases broadened our knowledge of Fgf10-related phenotypes and prompted clinicians to consider syndromic associations in patients with bony CNLDO. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

DL-3-n-Butylphthalide Ameliorates Post-stroke Emotional Disorders by Suppressing Neuroinflammation and PANoptosis.

Post-stroke emotional disorders such as post-stroke anxiety and post-stroke depression are typical symptoms in patients with stroke. They are closely associated with poor prognosis and low quality of life. The State Food and Drug Administration of China has approved DL-3-n-butylphthalide (NBP) as a treatment for ischemic stroke (IS). Clinical research has shown that NBP alleviates anxiety and depressive symptoms in patients with IS. Therefore, this study explored the role and molecular mechanisms of NBP in cases of post-stroke emotional disorders using network pharmacology and experimental validation. The results showed that NBP treatment significantly increased the percentage of time spent in the center of the middle cerebral artery occlusion (MCAO) rats in the open field test and the percentage of sucrose consumption in the sucrose preference test. Network pharmacology results suggest that NBP may regulate neuroinflammation and cell death. Further experiments revealed that NBP inhibited the toll-like receptor 4/nuclear factor kappa B signaling pathway, decreased the level of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6, and M1-type microglia markers (CD68, inducible nitric oxide synthase), and reduced the expression of PANoptosis-related molecules including caspase-1, caspase-3, caspase-8, gasdermin D, and mixed lineage kinase domain-like protein in the hippocampus of the MACO rats. These findings demonstrate that the mechanisms through which NBP ameliorates post-stroke emotional disorders in rats are associated with inhibiting neuroinflammation and PANoptosis, providing a new strategy and experimental basis for treating post-stroke emotional disorders.

A score for predicting invasive pulmonary aspergillosis in immunocompetent critically ill patients.

BACKGROUND: Delayed treatment leads to increased mortality in critically ill patients with invasive pulmonary aspergillosis (IPA). We aimed to develop and validate a prediction score based on novel biomarkers and clinical risk factors to identify IPA in immunocompetent patients in the intensive care unit (ICU). METHODS: A retrospective study was conducted to collect medical information and novel biomarkers upon ICU admission. Risk factors adopted for the final prediction score were identified using multivariate logistic regression analysis. RESULTS: We retrospectively collected 1841 critical ill patients between January 2018 and August 2022. Patients with IPA had higher C-reactive protein-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio, systemic immune-inflammation index and lower prognostic nutritional index (PNI). Chronic obstructive pulmonary disease (COPD), continuous renal replacement therapy (CRRT), high dose of corticosteroids, broad-spectrum antibiotics, blood galactomannan (GM) positivity and high CAR were independent risk factors for IPA and were entered into the final prediction score. The score had good discrimination, with the area under receiver operating characteristic curve of 0.816 and 0.780 for the training and validation cohorts, respectively, and good calibration. CONCLUSION: A score based on six clinical and novel immunological biomarkers showed promising predictive value for antifungal treatment in immunocompetent ICU patients.

A prediction model for acute respiratory distress syndrome in immunocompetent adults with adenovirus-associated Pneumonia: a multicenter retrospective analysis.

BACKGROUND: In recent years, the number of human adenovirus (HAdV)-related pneumonia cases has increased in immunocompetent adults. Acute respiratory distress syndrome (ARDS) in these patients is the predominant cause of HADV-associated fatality rates. This study aimed to identify early risk factors to predict early HAdV-related ARDS. METHODS: Data from immunocompetent adults with HAdV pneumonia between June 2018 and May 2022 in ten tertiary general hospitals in central China was analyzed retrospectively. Patients were categorized into the ARDS group based on the Berlin definition. The prediction model of HAdV-related ARDS was developed using multivariate stepwise logistic regression and visualized using a nomogram. RESULTS: Of 102 patients with adenovirus pneumonia, 41 (40.2%) developed ARDS. Overall, most patients were male (94.1%), the median age was 38.0 years. Multivariate logistic regression showed that dyspnea, SOFA (Sequential Organ Failure Assessment) score, lactate dehydrogenase (LDH) and mechanical ventilation status were independent risk factors for this development, which has a high mortality rate (41.5%). Incorporating these factors, we established a nomogram with good concordance statistics of 0.904 (95% CI 0.844-0.963) which may help to predict early HAdV-related ARDS. CONCLUSION: A nomogram with good accuracy in the early prediction of ARDS in patients with HAdV-associated pneumonia may could contribute to the early management and effective treatment of severe HAdV infection.

Protective effects of the salt-induced kinase inhibitor HG-9-91-01 on sepsis-associated cognitive dysfunction in mice and the underlying mechanisms. / ç›è¯±å¯¼æ¿€é ¶æŠ‘åˆ¶å‰‚HG-9-91-01å¯¹å°é¼ è„“æ¯’ç—‡ç›¸å ³è®¤çŸ¥åŠŸèƒ½éšœç¢çš„ä¿æŠ¤ä½œç”¨åŠå ¶æœºåˆ¶.

OBJECTIVES: Sepsis-associated cognitive dysfunction is a common complication in patients with sepsis and lack of effective treatment. Its pathological mechanisms remain unclear. Salt-induced kinase (SIK) is an important molecule in the regulation of metabolism, immunity, and inflammatory response. It is associated with the development of many neurological diseases. This study aims to investigate the expression of SIK in the hippocampus of septic mice, and to evaluate the role and mechanism of the SIK inhibitor HG-9-91-01 in sepsis-associated cognitive dysfunction. METHODS: Firstly, C57BL/6 mice were randomly divided into a control group (Con group) and a sepsis model group [lipopolysaccharide (LPS) group]. The model group was injected intraperitoneally with LPS at a dose of 8 mg/kg and the Con group was injected with an equal volume of normal saline. Hippocampal tissues were harvested at 1, 3, and 6 days after injection and the expressions of SIK1, SIK2, and SIK3 were detected by real-time fluorescence quantitative PCR (qPCR) and Western blotting. Secondly, C57BL/6 mice were randomly divided into a Con group, a LPS group, and a SIK inhibitor group (HG group). The LPS and HG groups were injected with LPS to establish a sepsis model; in the HG group, HG-9-91-01 (10 mg/kg) was injected intraperitoneally at 3-6 days after LPS injection, and the LPS group was injected with the same volume of vehicle. Cognitive function was assessed at 7-11 days after LPS injection using the Morris water maze (MWM). Hippocampal tissues were harvested after the behavioral tests, and the mRNA levels of inflammatory factors and microglial markers were assessed by qPCR. The protein levels of inducible nitric oxide synthase (iNOS), CD68, ionized calcium binding adaptor molecule 1 (Iba-1), N-methyl-D-aspartate (NMDA) receptor (NR) subunit, cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1), and insulin-like growth factor 1 (IGF-1) were detected by Western blotting. Immunohistochemistry (IHC) was used to detect the expression of Iba-1 positive cells in the CA1, CA3 and dentate gyrus (DG) of the hippocampus, followed by Sholl analysis. RESULTS: Compared with the Con group, the mRNA and protein levels of SIK1, SIK2, and SIK3 in the hippocampus were increased in the LPS group (all P<0.05). Compared with the Con group, mice in the LPS group had a significantly longer escape latency, a lower percentage of target quadrant dwell time and a reduced locomotor speed (all P<0.05); the HG group had a decreased escape latency and an increased percentage of time spent in the target quadrant in comparison with the LPS group (both P<0.05). The mRNA levels of inflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6)], and the M1-type microglial markers iNOS and CD68 in the hippocampus of the LPS group were increased in comparison with the Con group, while the M2-type microglial markers CD206 and arginase-1 (Arg-1) were decreased. Compared with the LPS group, the mRNA levels of TNF-α, IL-1ß, IL-6, and iNOS were downregulated, while the levels of CD206 and Arg-1 were upregulated in the HG group (all P<0.05). The protein levels of iNOS, CD68, and Iba-1 in the hippocampus of the LPS group were increased in comparison with the Con group, but they were downregulated in the HG group in comparison with the LPS group (all P<0.05). The number of Iba-1 positive cells in CA1, CA3, and DG of the hippocampus was increased in the LPS group in comparison with the Con group, but they were decreased in the HG group in comparison with the LPS group (all P<0.05). Sholl analysis showed that the number of intersections at all radii between 8-38 µm from the microglial soma was decreased in the LPS group in comparison with the Con group (all P<0.05). Compared with the LPS group, the number of intersections at all radii between 14-20 µm was significantly increased in the HG group (all P<0.05). The protein levels of NR subunit NR1, NR2A, NR2B, and IGF-1 were downregulated in the hippocampus of the LPS group in comparison with the Con group, while the expression of phosphorylated CRTC1 (p-CRTC1) was increased. Compared with the LPS group, the levels of NR1, NR2A, NR2B, and IGF-1 were upregulated, while p-CRTC1 was downregulated in the HG group (all P<0.05). CONCLUSIONS: SIK expression is upregulated in the hippocampus of septic mice. The SIK inhibitor HG-9-91-01 ameliorates sepsis-associated cognitive dysfunction in mice, and the mechanism may involve in the activation of the CRTC1/IGF-1 pathway, inhibition of neuroinflammation, and enhancement of synaptic plasticity.

Comparison of concurrent chemoradiotherapy with radiotherapy alone for locally advanced esophageal squamous cell cancer in elderly patients: A randomized, multicenter, phase II clinical trial.

This randomized, multicenter, phase II clinical trial was performed to compare the safety and efficacy of concurrent chemoradiotherapy using S-1 (CCRT) with radiotherapy alone (RT) for elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC). All eligible patients were randomly assigned to the CCRT group or the RT group at a 1:1 ratio. The CCRT group received 50.4 Gy radiotherapy concurrent with S-1 and the RT group received 59.4 Gy radiotherapy alone. The primary endpoints were toxicity and the overall response rate (ORR), and the secondary endpoints were overall survival (OS) and progression-free survival (PFS). In total, 157 elderly patients with ESCC were recruited from December 2016 to March 2020. By June 2021, the median follow-up duration had reached 38 months. No grade 5 toxicities occurred in either group and the overall rate of severe toxicities (≥grade 3) was higher in the CCRT group (19.2% vs 7.6%; P = .037), particularly neutropenia (7.7% vs 1.3%; P = .06). The CCRT group presented a significantly higher ORR (83.3% vs 68.4%; P = .009) and prolonged PFS (25.7 vs 13.9 months; P = .026) than the RT group. The median OS was 27.3 months in the CCRT group and 19.1 months in the RT group (P = .59). For patients older than 70 years with locally advanced ESCC, concurrent chemoradiotherapy with S-1 had tolerable adverse effects and improved ORR and PFS compared to radiotherapy alone.

Delayed neutrophil apoptosis may enhance NET formation in ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a neutrophil-associated disease. Delayed neutrophil apoptosis and increased levels of neutrophil extracellular traps (NETs) have been described in ARDS. We aimed to investigate the relationship between these phenomena and their potential as inflammation drivers. We hypothesized that delayed neutrophil apoptosis might enhance NET formation in ARDS. METHOD: Our research was carried out in three aspects: clinical research, animal experiments, and in vitro experiments. First, we compared the difference between neutrophil apoptosis and NET levels in healthy controls and patients with ARDS and analyzed the correlation between neutrophil apoptosis and NET levels in ARDS. Then, we conducted animal experiments to verify the effect of neutrophil apoptosis on NET formation in Lipopolysaccharide-induced acute lung injury (LPS-ALI) mice. Furthermore, this study explored the relationship between neutrophil apoptosis and NETs at the cellular level. Apoptosis was assessed using morphological analysis, flow cytometry, and western blotting. NET formation was determined using immunofluorescence, PicoGreen assay, SYTOX Green staining, and western blotting. RESULTS: ARDS neutrophils lived longer because of delayed apoptosis, and the cyclin-dependent kinase inhibitor, AT7519, reversed this phenomenon both in ARDS neutrophils and neutrophils in bronchoalveolar lavage fluid (BALF) of LPS-ALI mice. Neutrophils in a medium containing pro-survival factors (LPS or GM-CSF) form more NETs, which can also be reversed by AT7519. Tissue damage can be reduced by promoting neutrophil apoptosis. CONCLUSIONS: Neutrophils with extended lifespan in ARDS usually enhance NET formation, which aggravates inflammation. Enhancing neutrophil apoptosis in ARDS can reduce the formation of NETs, inhibit inflammation, and consequently alleviate ARDS.

Clinical characteristics of infants with port-wine stain and glaucoma secondary to Sturge-Weber Syndrome.

BACKGROUND: Sturge-Weber Syndrome (SWS) is a rare disease involving the eye, skin, and brain. Port-wine stain (PWS) and glaucoma are common clinical manifestations. This study analysed the clinical characteristics of infants with PWS and glaucoma secondary to SWS. METHODS: Children with PWS and glaucoma secondary to SWS were enrolled. Data were extracted from ophthalmic and systemic examination findings. Ocular examinations included intraocular pressure, anterior segment and fundus examination, and ocular A-scan and B-scan ultrasonography. RESULTS: Fifty-seven patients were included, with a mean age of 9.9 ± 11.9 months, and 34 (59.6%) patients were male. In all, 61 eyes were diagnosed with glaucoma. Forty-one patients (71.9%) had unilateral facial PWS and glaucoma occurred on the same side. Eight patients (14.0%) had Mongolian spots and ten patients (17.5%) had epilepsy. Corneal changes included corneal oedema (n = 36 eyes, 59.0%), corneal opacity (n = 15 eyes, 24.6%), and Haab lines (n = 13 eyes, 21.3%). Mean corneal diameter and thickness in the eyes with glaucoma was larger than those in the unaffected eyes (12.2 ± 0.7 mm vs 10.8 ± 0.6 mm, P < 0.001; 681.2 ± 106.4 µm vs 578.2 ± 58.2 µm, P < 0.001). The eyes with glaucoma had higher IOP and larger axial length and C/D ratio (19.3 ± 6.2 mmHg vs 11.6 ± 4.2 mmHg, P < 0.001; 21.23 ± 1.93 mm vs 19.68 ± 1.61 mm, P < 0.001; and 0.57 ± 0.18 vs 0.24 ± 0.15, P < 0.001). Thirty-three (57.9%) and 25 (43.9%) patients showed diffuse choroidal haemangioma (DCH) and conjunctival/episcleral haemangiomas, respectively. Ten patients (17.5%) showed iris anterior insertion or hyperpigmentation in the anterior chamber angles. Six of them had Mongolian spots at the same time. CONCLUSIONS: Monocular glaucoma, DCH, and conjunctival/episcleral haemangiomas are common in SWS patients with PWS and glaucoma. Glaucomatous eyes have larger corneal diameter and axial length and thicker cornea. Patients with Mongolian spots have higher incidence of iris anterior insertion or hyperpigmentation in anterior chamber angle.

College students responding to the Chinese version of Cardiff fertility knowledge scale show deficiencies in their awareness: a cross-sectional survey in Hunan, China.

BACKGROUND: Fertility knowledge is vital to the fertility health of young people and greatly impacts their fertility choices. Delayed childbearing has been increasing in high-income countries, accompanied by the risk of involuntary childlessness or having fewer children than desired. The aim of this study was to investigate knowledge about fertility issues, the related influencing factors, the method of acquiring fertility knowledge, and the relationship between fertility knowledge and fertility intentions among college students. METHODS: An online cross-sectional survey of Chinese college students was conducted in Hunan Province from March to April 2018. A total of 867 college students from three comprehensive universities responded to a poster invitation utilizing the Chinese version of the Cardiff Fertility Knowledge Scale (CFKS-C). Data were explored and analysed by SPSS (version 22.0) software. Descriptive statistics, chi-squared tests, T-tests, and Pearson's correlations were used for the measurements. RESULTS: The average percent-correct score on the CFKS-C was 49.9% (SD = 20.8), with greater knowledge significantly related to living in a city district, being not single status, majoring in medicine, being in year 4 or above of study, and intention to have children (all p<0.05). A total of 81.9% of the participants reported that they would like to have children, the average score of the importance of childbearing was 6.3 (SD = 2.7), and the female score was lower than the male score (p = 0.001). A small positive relationship was observed between the CFKS-C and the importance of childbearing (r = 0.074, p = 0.035). Respondents indicated that they gained most of their knowledge from the media and internet (41.4%) and from schools (38.2%). CONCLUSION: Yong people in college have a modest level of fertility knowledge, a relatively low intention to have a child, and deficiencies in fertility health education. There is a need to improve the accessibility of fertility health services by developing a scientific and reliable fertility health promotion strategy.

An Interface-Bridged Organic-Inorganic Layer that Suppresses Dendrite Formation and Side Reactions for Ultra-Long-Life Aqueous Zinc Metal Anodes.

Aqueous zinc (Zn) batteries (AZBs) are widely considered as a promising candidate for next-generation energy storage owing to their excellent safety features. However, the application of a Zn anode is hindered by severe dendrite formation and side reactions. Herein, an interfacial bridged organic-inorganic hybrid protection layer (Nafion-Zn-X) is developed by complexing inorganic Zn-X zeolite nanoparticles with Nafion, which shifts ion transport from channel transport in Nafion to a hopping mechanism in the organic-inorganic interface. This unique organic-inorganic structure is found to effectively suppress dendrite growth and side reactions of the Zn anode. Consequently, the Zn@Nafion-Zn-X composite anode delivers high coulombic efficiency (ca. 97 %), deep Zn plating/stripping (10 mAh cm-2 ), and long cycle life (over 10 000 cycles). By tackling the intrinsic chemical/electrochemical issues, the proposed strategy provides a versatile remedy for the limited cycle life of the Zn anode.

Unravelling H+ /Zn2+ Synergistic Intercalation in a Novel Phase of Manganese Oxide for High-Performance Aqueous Rechargeable Battery.

Aqueous Zn-MnO2 batteries using mild electrolyte show great potential in large-scale energy storage (LSES) application, due to high safety and low cost. However, structure collapse of manganese oxides upon cycling caused by the conversion mechanism (e.g., from tunnel to layer structures for α-, ß-, and γ-phases) is one of the most urgent issues plaguing its practical applications. Herein, to avoid the phase conversion issue and enhance battery performance, a structurally robust novel phase of manganese oxide MnO2 H0.16 (H2 O)0.27 (MON) nanosheet with thickness of ≈2.5 nm is designed and synthesized as a promising cathode material, in which a nanosheet structure combined with a novel H+ /Zn2+ synergistic intercalation mechanism is demonstrated and evidenced. Accordingly, a high-performance Zn/MON cell is achieved, showing a high energy density of ≈228.5 Wh kg-1 , impressive cyclability with capacity retention of 96% at 0.5 C after 300 cycles, as well as exhibiting rate performance of 115.1 mAh g-1 at current rate of 10 C. To the best current knowledge, this H+ /Zn2+ synergistic intercalation mechanism is first reported in an aqueous battery system, which opens a new opportunity for development of high-performance aqueous Zn ion batteries for LSES.

Endoscopic dacryocystorhinostomy to treat congenital nasolacrimal canal dysplasia: a retrospective analysis in 40 children.

BACKGROUND: To investigate the therapeutic effectiveness and safety of endoscopic dacryocystorhinostomy (EN-DCR) to treat congenital nasolacrimal canal dysplasia (CNCD). METHODS: Forty children (50 eyes) with congenital nasolacrimal duct obstruction (CNLDO) and lacrimal bony dysplasia, including 8 children with bony atresia (10 eyes) and 32 with bony stenosis (40 eyes), were recruited in this retrospective study. Standardized EN-DCR was performed in all cases. The postoperative observations included relief of symptoms, fluorescein dye disappearance test (FDDT), syringing of lacrimal passages and anastomotic patency under nasal endoscopy. Patients were followed up for 8-18 months. RESULTS: Standardized EN-DCR surgery had a success (cure and improvement) rate of 100%, including a cure rate of 82% and an improvement rate of 18%. The cure rate among 40 cases of bony nasolacrimal duct stenosis was 82.5%, while that of 10 cases of bony nasolacrimal duct atresia was 80%. Statistical analysis showed that nether the receipt of other treatments before surgery nor the type of bony nasolacrimal duct dysplasia affected the cure rate. No significant complications were observed during postoperative follow-up except for four cases (4 eyes) that suffered middle turbinate and nasal mucosal adhesion and two cases with sinusitis. CONCLUSIONS: CNCD is a type of CNLDO that does not respond to conservative and conventional treatment. EN-DCR represents a safe and effective treatment for children with CNCD. In addition, the combination of EN-DCR with lacrimal CT scanning provides advantages over traditional lacrimal surgery in that it has a high success rate with a low incidence of complications.

Degradation of Mcl-1 through GSK-3ß Activation Regulates Apoptosis Induced by Bufalin in Non-Small Cell Lung Cancer H1975 Cells.

BACKGROUND/AIMS: Mcl-1, an anti-apoptotic Bcl-2 family member, is often overexpressed in non-small cell lung cancer (NSCLC). Bufalin has been reported to induce apoptosis in various tumor cells. However, there is no report showing that bufalin could downregulate Mcl-1 expression in NSCLC. METHODS: Cell proliferation was analyzed by cell counting kit-8 (CCK-8) assay in H1975 cells. Cell apoptosis was detected by flow cytometry. Mcl-1 mRNA was detected by RT-PCR. The expression of apoptosis-associated proteins in H1975 cells was detected by western blotting. The levels of Mcl-1 ubiquitination and NOXA were analyzed by Immunoprecipitation assay. RESULTS: Cell growth was inhibited by bufalin in a time and dose-dependent manner. Bufalin induced apoptosis in NSCLC cells by activating caspase cascades and downregulating Mcl-1 expression. However, overexpression of Mcl-1 diminished bufalin-induced apoptosis. Furthermore, bufalin did not reduce Mcl-1 mRNA expression in H1975 cells, but strongly promoted Mcl-1 protein degradation. Proteasome inhibitor MG132 markedly prevented the degradation of Mcl-1 and blocked bufalin-induced Mcl-1 reduction. Bufalin did not significantly affect NOXA protein levels, but downregulated the expression of p-GSK-3ß. GSK-3 inhibitor and GSK-3ß siRNA resulted in increased levels of Mcl-1 and reversed the bufalin-induced Mcl-1 degradation. CONCLUSION: Bufalin induced cell apoptosis in H1975 cells may be through downregulation of Mcl-1. Proteasomal degradation of Mcl-1 via GSK-3ß activation was involved in bufalin-induced apoptosis.

Myopia correction in children: a meta-analysis.

PURPOSE: The purpose of this study was to conduct a meta-analysis comparing rigid gas permeable lenses (RGP) with soft contact lenses (SCL), spectacles and orthokeratology (OK) lenses for myopia control with respect to axial length elongation, spherical equivalent and measures of corneal curvature. METHODS: Medline, Cochrane, EMBASE, and Google Scholar databases were searched to September 29, 2015 using the following keywords: rigid gas permeable contact lens; refractive error; and refractive abnormalities. Randomized controlled trials, two-arm prospective studies and retrospective studies of children with myopia treated with RGP lenses compared with spectacles, SCL, and OK lenses were included. Outcome measures were changes of axial length, spherical equivalent, flatter meridian, steeper meridian and corneal apical radius. RESULTS: Five studies were included. Three studies reported axial length change after 2-3 years of treatment with RGP lenses and SCL/spectacles and no difference between the groups was noted (pooled mean difference = -0.077, 95% confidence interval [CI]: -0.120 to 0.097, p = 0.840). Two studies reported a change of spherical equivalent after 2-3 years of treatment with RGP lenses and SCL/spectacles, and no difference between the groups was noted (pooled mean difference = 0.275, 95% CI: -0.390 to 0.941, p = 0.417). Two studies compared corneal curvature measures between RGP and OK lenses after 3-6 months of treatment and no differences in any measures of corneal curvature were seen. CONCLUSIONS: The effect of RGP lenses and SCL/spectacles on axial length elongation and spherical equivalent and of RGP and OK lenses on corneal curvature in children with myopia was similar.

Study on establishment and mechanics application of finite element model of bovine eye.

BACKGROUND: Glaucoma mainly induced by increased intraocular pressure (IOP), it was believed that the pressure that wall of eyeball withstands were determined by material properties of the tissue and stereoscopic geometry of the eyeball. In order to study the pressure changes in different parts of interior eyeball wall, it is necessary to develop a novel eye ball FEM with more accurate geometry and material properties. Use this model to study the stress changes in different parts of eyeball, especially the lamina cribrosa (LC) under normal physiological and pathological IOP, and provide a mathematical model for biomechanical studies of selected retinal ganglion cells (RGCs) death. METHODS: (1) Sclera was cut into 3.8-mm wide, 14.5-mm long strips, and cornea was cut into 9.5-mm-wide and 10-mm-long strips; (2) 858 Mini BionixII biomechanical loading instrument was used to stretch sclera and cornea. The stretching rate for sclera was 0.3 mm/s, 3 mm/s, 30 mm/s, 300 mm/s; and for cornea were 0.3 mm/s and 30 mm/s. The deformation-stress curve was recorded; (3) Naso-temporal and longitudinal distance of LC were measured; (4) Micro-CT was used to accurately scan fresh bovine eyes and obtain the geometrical image and data to establish bovine eye model. 3-D reconstruction was performed using these images and data to work out the geometric shape of bovine eye; (5) IOP levels for eyeball FEM was set and the inner wall of eyeball was used taken as load-bearing part. Simulated eyeball FE modeling was run under the IOP level of 10 mmHg, 30 mmHg, 60 mmHg and 100 mmHg, and the force condition of different parts of eyeball was recorded under different IOP levels. RESULTS: (1) We obtained the material parameters more in line with physiological conditions and established a more realistic eyeball model using reversed engineering of parameters optimization method to calculate the complex nonlinear super-elastic and viscoelastic parameters more accurately; (2) We observed the following phenomenon by simulating increased pressure using FEM: as simulative IOP increased, the stress concentration scope on the posterior half of sclera became narrower; in the meantime, the stress-concentration scope on the anterior half of scleral gradually expanded, and the stress on the central part of LC is highest. CONCLUSION: As simulative IOP increased, stress-concentration scope on the posterior half of sclera gradually narrowed; in the meantime, the stress-concentration scope on the anterior half of sclera gradually expanded, and the stress on the LC is mainly concentrated in the central part, suggesting that IOP is mainly concentrated in the anterior part of the eyeball as it increases. This might provide a biomechanical evidence to explain why RGCs in peripheral part die earlier than RGCs in central part under HIOP.

[Bufalin reverses hepatocyte growth factor-induced resistance to afatinib in H1975 lung cancer cells].

OBJECTIVE: To investigate the effects of bufalin in reversing hepatocyte growth factor (HGF)-induced resistance to afatinib in H1975 lung cancer cells, and explore its possible mechanism. METHODS: The afatinib-resistant H1975 lung cancer cells (H1975AR) were induced by exogenous HGF and transfected with recombinant adenoviral vector Ad-HGF-GFP. The cytostatic effects of bufalin, afatinib and bufalin plus afatinib on H1975AR cells were evaluated by MTT assay. The impact of combined therapy with bufalin and afatinib on invasion of H1975AR cells was determined by transwell migration assay. The concentrations of HGF in the culture supernatants of H1975/Vec and H1975/HGF cells were determined by ELISA. The expression of EGFR, cMET and EMT signal pathway-related proteins in H1975AR cells treated with bufalin, afatinib and bufalin plus afatinib were detected by Western blot. RESULTS: The results of MTT assay showed that afatinib did not inhibit the growth of H1975 cells, but after 72 h of the combined treatment with bufalin and afatinib and in the presence of HGF, the growth rate of H1975 cells was (38.67 ± 8.76)%, significantly lower than the growth rate of (63.45 ± 12.65)% in the H1975 cells treated with HGF alone (P < 0.05). The results of transwell migration assay showed that in the presence of HGF, afatinib plus bufalin combination therapy markedly decreased the number of invaded H1975 cells through the Matrigel chamber (48.98 ± 11.43), significantly lower than the 118.92 ± 37.29 of afatinib-treated or the 88.84 ± 19.53 of bufalin-treated cells (P < 0.05 for all). The result of ELISA showed that H1975/HGF cells secreted high levels of HGF, and afatinib and bufalin had no effect on the HGF secretion in H1975/HGF cells. The results of Western blot analysis showed that the expression of p-EGFR, p-cMet, p-AKT, p-ERK, vimentin and snail in H1975AR cells treated with bufalin puls afatinb was down-regulated markedly, and the expression of E-cadherin was up-regulated markedly. CONCLUSIONS: Combination of bufalin and afatinib strongly inhibits the growth of H1975AR lung cancer cells and decreases their invasion ability. The possible mechanism of combined treatment with bufalin and afatinib may be related to the blocking of cMet/PI3K/AKT and cMet/MAPK/ERK pathways and inhibiting of epithelial-mesenchymal transition.

[Efficacy of surgery on congenital nystagmus with convergence damping].

OBJECTIVE: To evaluate the efficacy of surgery in the treatment of congenital nystagmus with convergence damping. METHODS: Retrospective and comparative case series. Eight patients diagnosed as congenital nystagmus with convergence damping at Beijing Children's Hospital between September 2010 and September 2012 were enrolled in this study. The ages were 9.5 (12, 6) years old, and follow-up was 9 (24, 6) months. All patients received prism induced convergence and the same surgery of bimedial rectus recession and bilateral rectus tenotomy. The best corrected visual acuity, the range of fusion and the nystagmus waveforms were analyzed before and after surgery. RESULTS: The range of fusion was -3.75±1.83° to +19.38±3.16° before surgery and -3.88±1.55° to +19.00±3.02° after surgery; there was no significant difference (t=0.24, P=0.82). The binocular visual acuity increased from 0.21±0.15 without convergence to 0.28±0.18 using convergence; there was significant difference (t=-4.43, P=0.00). The visual acuity was 0.32±0.20 after surgery, significantly different from that before surgery without convergence (t=-5.29, P=0.00), but not significantly different from that before surgery using convergence (t=-2.12, P=0.07). Patients had significant improvements in the frequency (t=3.28, 3.02, P<0.05) and intensity of the nystagmus waveforms when using convergence and postoperatively (t=3.27, 3.48; P<0.05), but there was no significant improvement in the amplitude of the waveforms (t=1.31, 1.57, 0.31, P>0.05). CONCLUSIONS: Surgery for congenital nystagmus with convergence damping can provide expectations for ocular motor and visual results. The range of fusion should be wide enough, and the effect of convergence on the frequency is greater than that on the amplitude.

[Radiographic observation of nasolacrimal canal in congenital nasolacrimal canal agenesis].

OBJECTIVE: To explore the radiographic characteristics of nasolacrimal canals in congenital nasolacrimal canal agenesis. METHODS: Retrospective case series study. The images of Computed Tomography of 18 children with unilateral congenital nasolacrimal canal agenesis who were treated in Beijing Children's Hospital from January 2009 to June 2013 were studied. The common features of abnormal lacrimal canals were analyzed. The heights of bilateral lacrimal canals, anterioposterior and transverse diameters at the original level of lacrimal canal were measured. The traverse diameters, anteroposterior diameters, heights of bony nasolacrimal duct between affected side and normal side were compared using paired t tests. RESULTS: The initial segment of abnormal nasolacrimal canal showed no obvious abnormalities, but it became significant stenosis or even atresia at the middle and terminal segments. The transverse (4.72 ± 0.79) mm and anterioposterior diameters (5.45 ± 1.07) mm of affected sides were larger than the values of normal sides (3.42 ± 0.67) mm, (4.35 ± 1.01) mm at the original level of nasolacrimal canal with statistically significance (t = 5.665, P = 0.000; t = 6.610, P = 0.000). However, the height of nasolacrimal canal of normal sides were larger than the affected sides (t = 5.931, P = 0.000). CONCLUSIONS: Atresia position of congenital nasolacrimal canal agenesis always located in the terminal segment. High pressure in the nasolacrimal duct caused by bony obstruction leaded to the enlargement of nasolacrimal canal in affected side.

CK2 negatively regulates the extinction of remote fear memory.

Cognitive behavioral therapy, rooted in exposure therapy, is currently the primary approach employed in the treatment of anxiety-related conditions, including post-traumatic stress disorder (PTSD). In laboratory settings, fear extinction in animals is a commonly employed technique to investigate exposure therapy; however, the precise mechanisms underlying fear extinction remain elusive. Casein kinase 2 (CK2), which regulates neuroplasticity via phosphorylation of its substrates, has a significant influence in various neurological disorders, such as Alzheimer's disease and Parkinson's disease, as well as in the process of learning and memory. In this study, we adopted a classical Pavlovian fear conditioning model to investigate the involvement of CK2 in remote fear memory extinction and its underlying mechanisms. The results indicated that the activity of CK2 in the medial prefrontal cortex (mPFC) of mice was significantly upregulated after extinction training of remote cued fear memory. Notably, administration of the CK2 inhibitor CX-4945 prior to extinction training facilitated the extinction of remote fear memory. In addition, CX-4945 significantly upregulated the expression of p-ERK1/2 and p-CREB in the mPFC. Our results suggest that CK2 negatively regulates remote fear memory extinction, at least in part, by inhibiting the ERK-CREB pathway. These findings contribute to our understanding of the underlying mechanisms of remote cued fear extinction, thereby offering a theoretical foundation and identifying potential targets for the intervention and treatment of PTSD.