Monocyte-derived SDF1 supports optic nerve regeneration and alters retinal ganglion cells' response to Pten deletion.

Although mammalian retinal ganglion cells (RGCs) normally cannot regenerate axons nor survive after optic nerve injury, this failure is partially reversed by inducing sterile inflammation in the eye. Infiltrative myeloid cells express the axogenic protein oncomodulin (Ocm) but additional, as-yet-unidentified, factors are also required. We show here that infiltrative macrophages express stromal cell­derived factor 1 (SDF1, CXCL12), which plays a central role in this regard. Among many growth factors tested in culture, only SDF1 enhances Ocm activity, an effect mediated through intracellular cyclic AMP (cAMP) elevation and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation. SDF1 deficiency in myeloid cells (CXCL12flx/flxLysM-Cre−/+ mice) or deletion of the SDF1 receptor CXCR4 in RGCs (intraocular AAV2-Cre in CXCR4flx/flx mice) or SDF1 antagonist AMD3100 greatly suppresses inflammation-induced regeneration and decreases RGC survival to baseline levels. Conversely, SDF1 induces optic nerve regeneration and RGC survival, and, when combined with Ocm/cAMP, SDF1 increases axon regeneration to levels similar to those induced by intraocular inflammation. In contrast to deletion of phosphatase and tensin homolog (Pten), which promotes regeneration selectively from αRGCs, SDF1 promotes regeneration from non-αRGCs and enables the latter cells to respond robustly to Pten deletion; however, SDF1 surprisingly diminishes the response of αRGCs to Pten deletion. When combined with inflammation and Pten deletion, SDF1 enables many RGCs to regenerate axons the entire length of the optic nerve. Thus, SDF1 complements the effects of Ocm in mediating inflammation-induced regeneration and enables different RGC subtypes to respond to Pten deletion.

Effect of artificial pancreas system use on glycaemic control among pregnant women with type 1 diabetes mellitus: A meta-analysis of randomized controlled trials.

AIM: To assess the efficacy of artificial pancreas systems (APS) use among pregnant women with type 1 diabetes mellitus (T1DM) by conducting a meta-analysis. METHODS: We searched five databases, including EMBASE, Web of Science, PubMed, Cochrane Library and SCOPUS, for literature on APS use among pregnant women with T1DM before October 9, 2023. The primary endpoint was 24-hour time in range (TIR; 3.5-7.8 mmol/L). Secondary endpoints included glycaemic metrics for 24-hour (mean blood glucose [MBG], time above range [TAR], time below range [TBR]), and overnight TIR and TBR. RESULTS: We identified four randomized controlled trials involving 164 participants; one study with 16 participants focused on overnight APS use, and the other three focused on 24-hour APS use. Compared with standard care, APS exhibited a favourable effect on 24-hour TIR (standard mean difference [SMD] = 0.53, 95% confidence interval [CI] 0.25, 0.80, P < 0.001), overnight TIR (SMD = 0.67, 95% CI 0.39, 0.95, P < 0.001), and overnight TBR (<3.5 mmol/L; SMD = -0.49, 95% CI -0.77, -0.21 P < 0.001), while there was no significant difference in 24-hour TAR, 24-hour TBR, or MBG between the two groups. We further conducted subgroup analyses after removing the trial focused on overnight APS use and showed that 24-hour APS use reduced not only the 24-hour TIR (SMD = 0.41, 95% CI 0.12, 0.71; P = 0.007) but also the 24-hour TBR (<2.8 mmol/L; SMD = -0.77, 95% CI -1.32, -0.23, P = 0.006). CONCLUSION: Our findings suggest that APS might improve 24-hour TIR and overnight glycaemic control, and 24-hour APS use also significantly reduced 24-hour TBR (2.8 mmol/L) among pregnant women with T1DM.

Therapeutic properties, biological effects, antiliver cancer, and anticolon cancer effects of some natural compounds: A biochemical approach.

Natural compounds, such as carotenoids, flavonoids, anthocyanins, or terpenoids, are physiologically active components found in plants (pigments), often known as phytochemicals or phytonutrients. The in vitro cytotoxic and anticolon cancer effects of biologically bavachin, bavachinin, artepillin C, and aromadendrin compounds against SW48, SNU-C1, COLO 205, RKO, LS411N, and SW1417 cancer cell lines were assessed. Results of enzymes and antibacterial, antifungal were in level of micromolar that is good impacts. These natural compounds may be antidiabetic, anticancer, and antibacterial candidates for drug design. IC50 results were obtained between 14-19 and 5-119 µM for α-amylase and α-glucosidase, respectively. Good inhibitor Bavachinin was detected for both enzymes (IC50 for α-amylase: 14.37 µM and IC50 for α-glucosidase: 5.27 µM). The chemical activities of aromadendrin, artepillin C, bavachin, and bavachinin against pancreatic α-amylase and α-glucosidase were assessed by conducting the molecular docking study. The chemical activities of aromadendrin, artepillin C, bavachin, and bavachinin against some of the expressed surface receptor proteins (CD44, CD47, CXCR4, EGFR, folate receptor, HER2, and endothelin receptor) in the mentioned cell lines were investigated using the molecular docking calculations. The results illustrated the atomic-level properties and potential interactions. These chemicals have high binding affinities to the enzymes and proteins, according to the docking scores. In addition, the compounds formed strong contacts with the enzymes and receptors. Thus, these compounds could be potential inhibitors for enzymes and cancer cells.

Visual outcome of various dose of glucocorticoids treatment in nonarteritic anterior ischemic optic neuropathy- a retrospective analysis.

BACKGROUND AND PURPOSE: The objective of this investigation was to assess the therapeutic efficacy of distinct glucocorticoid therapy dosages in the management of acute nonarteritic anterior ischemic optic neuropathy (NAION). MATERIALS AND METHODS: This retrospective, unmasked, and non-randomized study included a total of 85 patients. The patients were categorized into four groups: Group 1 (control) consisted of 15 patients who did not receive glucocorticoids, Group 2 included 16 patients administered with oral prednisone at a dosage of 1 mg/kg/d for 14 days, Group 3 comprised 30 patients who received 250 units of methylprednisolone once daily for 3 days, followed by oral prednisone at a dosage of 1 mg/kg/d for 11 days, and Group 4 encompassed 24 patients who received 500 units of methylprednisolone once daily for 3 days, followed by oral prednisone at a dosage of 1 mg/kg/d for 11 days. The best-corrected visual acuity (BCVA) was assessed at baseline and the final follow-up (> 7 days post-treatment). The changes in visual acuity between baseline and the 7-14 day follow-up, as well as between baseline and the concluding appraisal, were employed as metrics for assessing the extent of visual enhancement. RESULTS: No significant differences were noted in the final visual outcomes or in the changes between final visual acuity and baseline across the four groups. In Group 1 (control), the best-corrected visual acuity (BCVA) remained unchanged during final follow-ups compared to baseline. Conversely, the intervention groups exhibited statistically significant enhancements in BCVA during final follow-up (p = 0.012, p = 0.03, and p = 0.009 for Group 2, Group 3, and Group 4, respectively) when compared to baseline. During the 7-14 day follow-up, there was a significant difference in the changes between baseline BCVA and follow-up BCVA across the groups (p = 0.035). Go a step further by Bonferroni correction for multiple comparisons, group 4 showed a greater change in vision compared with group1 (p = 0.045). CONCLUSION: Our study on acute nonarteritic anterior ischemic optic neuropathy (NAION) showed no significant final visual outcome differences. Nevertheless, Groups 2, 3, and 4 demonstrated improved best-corrected visual acuity (BCVA) during the final follow-up. Notably, a 500-unit dose of methylprednisolone resulted in short-term BCVA enhancement. This suggests potential consideration of 500 units of methylprednisolone for short-term NAION vision improvement, despite its limited long-term impact.

Agonist of growth hormone-releasing hormone enhances retinal ganglion cell protection induced by macrophages after optic nerve injury.

Optic neuropathies are leading causes of irreversible visual impairment and blindness, currently affecting more than 100 million people worldwide. Glaucoma is a group of optic neuropathies attributed to progressive degeneration of retinal ganglion cells (RGCs). We have previously demonstrated an increase in survival of RGCs by the activation of macrophages, whereas the inhibition of macrophages was involved in the alleviation on endotoxin-induced inflammation by antagonist of growth hormone-releasing hormone (GHRH). Herein, we hypothesized that GHRH receptor (GHRH-R) signaling could be involved in the survival of RGCs mediated by inflammation. We found the expression of GHRH-R in RGCs of adult rat retina. After optic nerve crush, subcutaneous application of GHRH agonist MR-409 or antagonist MIA-602 promoted the survival of RGCs. Both the GHRH agonist and antagonist increased the phosphorylation of Akt in the retina, but only agonist MR-409 promoted microglia activation in the retina. The antagonist MIA-602 reduced significantly the expression of inflammation-related genes Il1b, Il6, and Tnf Moreover, agonist MR-409 further enhanced the promotion of RGC survival by lens injury or zymosan-induced macrophage activation, whereas antagonist MIA-602 attenuated the enhancement in RGC survival. Our findings reveal the protective effect of agonistic analogs of GHRH on RGCs in rats after optic nerve injury and its additive effect to macrophage activation, indicating a therapeutic potential of GHRH agonists for the protection of RGCs against optic neuropathies especially in glaucoma.

The Role of Gut Microbiota in Neuromyelitis Optica Spectrum Disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, disabling inflammatory disease of the central nervous system (CNS). Aquaporin-4 (AQP4)-specific T cells play a key role in the pathogenesis of NMOSD. In addition to immune factors, T cells recognizing the AQP4 epitope showed cross-reactivity with homologous peptide sequences in C. perfringens proteins, suggesting that the gut microbiota plays an integral role in the pathogenicity of NMOSD. In this review, we summarize research on the involvement of the gut microbiota in the pathophysiology of NMOSD and its possible pathogenic mechanisms. Among them, Clostridium perfringens and Streptococcus have been confirmed to play a role by multiple studies. Based on this evidence, metabolites produced by gut microbes, such as short-chain fatty acids (SCFAs), tryptophan (Trp), and bile acid (BA) metabolites, have also been found to affect immune cell metabolism. Therefore, the role of the gut microbiota in the pathophysiology of NMOSD is very important. Alterations in the composition of the gut microbiota can lead to pathological changes and alter the formation of microbiota-derived components and metabolites. It can serve as a biomarker for disease onset and progression and as a potential disease-modifying therapy.

Traditional Chinese medicine invigorating the spleen and kidney promotes HBsAg seroclearance in the mouse model.

Traditional Chinese medicine (TCM) is often used as an adjuvant or alternative therapy for abnormal liver biochemistry or liver fibrosis associated with chronic hepatitis B (CHB). However, the role of TCM in HBsAg seroclearance remains unclear. We aimed at exploring the role and possible mechanisms of TCM in HBsAg seroclearance. Fifteen widely used TCM granules invigorating the spleen and kidneys were screened. C57BL/6J mice were administered daily with TCM granules by gavage for 1 week. The effect of TCM on the M1 polarization of macrophages was measured using a CD86 assay. According to the principles of formulating prescriptions, three single TCM with the most noticeable effect on M1 polarization, accompanied by two other TCM granules, were used to develop a TCM formula. The hepatitis B virus-expressing mouse model was constructed by hydrodynamic injection of the pAAV/HBV1.2 plasmid. Hepatitis B virus-expressing mice were gavaged daily with phosphate-buffered saline (PBS), TCM formula, or Codonopsis Radix, for 1 week. HBsAg, HBeAg, and hepatitis B virus DNA levels were measured. In addition, gut microbiota was profiled using 16S rDNA sequencing. Several TCM granules showed significant effects on M1 polarization. The TCM formula accelerated HBsAg seroclearance compared with the Codonopsis Radix and PBS groups. Intrahepatic M1 polarization, as indicated by flow cytometry and immunohistochemistry, was induced in the TCM formula and Codonopsis Radix groups. The abundance of Alloprevotella significantly increased in the TCM formula and Codonopsis Radix groups. These results demonstrate that the TCM formula for invigorating the spleen and kidney can accelerate HBsAg seroclearance. This effect can be attributed, at least in part, to M1 polarization of intrahepatic macrophages.

A pregnancy-specific Glucose management indicator derived from continuous glucose monitoring in pregnant women with type 1 diabetes.

OBJECTIVE: Glucose management indicator (GMI) is a core metric derived from continuous glucose monitoring (CGM) and is widely used to evaluate glucose control in patients with diabetes. No study has explored the pregnancy-specific GMI. This study aimed to derive a best-fitting model to calculate GMI from mean blood glucose (MBG) obtained from CGM among pregnant women with type 1 diabetes mellitus (T1DM). METHODS: A total of 272 CGM data and corresponding laboratory HbA1c from 98 pregnant women with T1DM in the CARNATION study were analysed in this study. Continuous glucose monitoring data were collected to calculate MBG, time-in-range (TIR), and glycaemic variability parameters. The relationships between the MBG and HbA1c during pregnancy and postpartum were explored. Mix-effect regression analysis with polynomial terms and cross-validation method was conducted to investigate the best-fitting model to calculate GMI from MBG obtained by CGM. RESULTS: The pregnant women had a mean age of 28.9 ± 3.8 years, with a diabetes duration of 8.8 ± 6.2 years and a mean body mass index (BMI) of 21.1 ± 2.5 kg/m2 . The HbA1c levels were 6.1 ± 1.0% and 6.4 ± 1.0% during pregnancy and at postpartum (p = 0.024). The MBG levels were lower during pregnancy than those at postpartum (6.5 ± 1.1 mmol/L vs. 7.1 ± 1.5 mmol/L, p = 0.008). After adjusting the confounders of haemoglobin (Hb), BMI, trimesters, disease duration, mean amplitude of glycaemic excursions and CV%, we developed a pregnancy-specific GMI-MBG equation: GMI for pregnancy (%) = 0.84-0.28* [Trimester] + 0.08 * [ BMI in kg/m2 ] + 0.01 * [Hb in g/mL] + 0.50 * [MBG in mmol/L]. CONCLUSIONS: We derived a pregnancy-specific GMI equation, which should be recommended for antenatal clinical care. CLINICAL TRIAL REGISTRY NUMBER: ChiCTR1900025955.

Lyonensinols A - C, 24-Norursane-Type Triterpenoids from the Twigs and Leaves of Lyonia doyonensis and Their Potential Anti-inflammatory and PTP1B Inhibitory Activities.

Lyonia doyonensis is a deciduous shrub native to high-altitude regions of Asia. So far, there is no report on any chemical and biological properties of L. doyonensis. An EtOH extract of L. doyonensis twigs and leaves showed inhibitory activities on protein tyrosine phosphatase 1B and lipopolysaccharide-induced inflammation in BV-2 microglial cells. A phytochemical investigation of this extract led to the isolation of a, so far only ambiguously described, 24-norursane-type triterpenoid, now named lyonensinol A (1: ), along with its two new derivatives, lyonensinols B and C (2: and 3: ), and six known triterpenoids (4 - 9: ). Their structures were elucidated by detailed analysis of spectroscopic data. A combination of chemical conversions, electronic circular dichroism, and Mo2(OAc)4-induced electronic circular dichroism was used to confirm their absolute configurations. Lyonensinols B (2: ) and C (3: ) represent the first examples of norursane-type triterpenoids acylated with a p-coumaroyl moiety. The potential anti-inflammatory and protein tyrosine phosphatase 1B inhibitory activities of all the isolates were evaluated. Compounds 3, 7: , and 8: at 10 µM showed potent inhibitory activities on lipopolysaccharide-induced nitric oxide production in BV-2 microglial cells, with nitric oxide levels decreasing to 31.5, 41.9, and 27.1%, respectively, while compounds 3, 4, 7: , and 8: exhibited notable inhibitory activities against protein tyrosine phosphatase 1B, with IC50 values ranging from 1.7 to 18.2 µM. Interestingly, compounds 3: and 8: , bearing a C-3 trans-p-coumaroyl group, showed not only more potent anti-inflammatory effects, but also exhibited stronger protein tyrosine phosphatase 1B inhibition than their respective stereoisomers (2: and 7: ) with a cis-p-coumaroyl group.

Acute phase clinical manifestations of patients with Vogt-Koyanagi-Harada disease in Southern China.

BACKGROUNDS: To characterize the acute phase clinical manifestations and visual outcomes of the patients with Vogt-Koyanagi Harada (VKH) disease in southern China. METHODS: In total, 186 patients with acute-onset VKH disease were recruited. The demographic data, clinical signs, ophthalmic examinations, and visual outcomes were analyzed. RESULTS: Among the 186 VKH patients, 3 were diagnosed as complete VKH, 125 as incomplete VKH, and 58 as probable VKH. All patients visited the hospital within 3 months of onset and complained of decreased vision. For the extraocular manifestations, 121 patients (65%) referred neurological symptoms. Anterior chamber activity was negative in most eyes within an onset of 7 days, which increased slightly with onset beyond 1 week. Exudative retinal detachment (366 eyes, 98%) and optic disc hyperaemia (314 eyes, 84%) were commonly observed at presentation. A typical ancillary examination helped with the diagnosis of VKH. Systemic corticosteroid therapy was prescribed. The logMAR best-corrected visual acuity improved significantly from 0.74 ± 0.54 at baseline to 0.12 ± 0.24 at the 1-year follow-up visit. The recurrence rate was 18% in the follow-up visits. Erythrocyte sedimentation rate and C-reactive protein were significantly correlated to VKH recurrences. CONCLUSION: Posterior uveitis, followed by mild anterior uveitis, is the typical initial manifestation in the acute phase of Chinese VKH patients. Visual outcome improvement is promising in most patients receiving systemic corticosteroid therapy in the acute phase. Detection of the clinical features at the initial onset of VKH could facilitate early treatment and better vision improvement.

Optic nerve diseases and regeneration: How far are we from the promised land?

The retinal ganglion cells (RGCs) are the sole output neurons that connect information from the retina to the brain. Optic neuropathies such as glaucoma, trauma, inflammation, ischemia and hereditary optic neuropathy can cause RGC loss and axon damage, and lead to partial or total loss of vision, which is an irreversible process in mammals. The accurate diagnoses of optic neuropathies are crucial for timely treatments to prevent irrevocable RGCs loss. After severe ON damage in optic neuropathies, promoting RGC axon regeneration is vital for restoring vision. Clearance of neuronal debris, decreased intrinsic growth capacity, and the presence of inhibitory factors have been shown to contribute to the failure of post-traumatic CNS regeneration. Here, we review the current understanding of manifestations and treatments of various common optic neuropathies. We also summarise the current known mechanisms of RGC survival and axon regeneration in mammals, including specific intrinsic signalling pathways, key transcription factors, reprogramming genes, inflammation-related regeneration factors, stem cell therapy, and combination therapies. Significant differences in RGC subtypes in survival and regenerative capacity after injury have also been found. Finally, we highlight the developmental states and non-mammalian species that are capable of regenerating RGC axons after injury, and cellular state reprogramming for neural repair.

Unraveling the Lignin Structural Variation in Different Bamboo Species.

The structure of cellulolytic enzyme lignin (CEL) prepared from three bamboo species (Neosinocalamus affinis, Bambusa lapidea, and Dendrocalamus brandisii) has been characterized by different analytical methods. The chemical composition analysis revealed a higher lignin content, up to 32.6% of B. lapidea as compared to that of N. affinis (20.7%) and D. brandisii (23.8%). The results indicated that bamboo lignin was a p-hydroxyphenyl-guaiacyl-syringyl (H-G-S) lignin associated with p-coumarates and ferulates. Advanced NMR analyses displayed that the isolated CELs were extensively acylated at the γ-carbon of the lignin side chain (with either acetate and/or p-coumarate groups). Moreover, a predominance of S over G lignin moieties was found in CELs of N. affinis and B. lapidea, with the lowest S/G ratio observed in D. brandisii lignin. Catalytic hydrogenolysis of lignin demonstrated that 4-propyl-substituted syringol/guaiacol and propanol guaiacol/syringol derived from ß-O-4' moieties, and methyl coumarate/ferulate derived from hydroxycinnamic units were identified as the six major monomeric products. We anticipate that the insights of this work could shed light on the sufficient understanding of lignin, which could open a new avenue to facilitate the efficient utilization of bamboo.

Effects of Washed Microbiota Transplantation on Serum Uric Acid Levels, Symptoms, and Intestinal Barrier Function in Patients with Acute and Recurrent Gout: A Pilot Study.

INTRODUCTION: Gut dysbiosis has been reported to be closely associated with gout. Washed microbiota transplantation (WMT) is considered as an effective way to restore a healthy gut microbiota with less adverse events than the conventional fecal microbiota transplantation. In this study, we aimed to evaluate the effects of WMT on serum uric acid levels, symptoms, and the intestinal barrier function in patients with acute and recurrent gout. METHODS: We performed a pilot study of WMT for acute and recurrent gout. The primary outcome was the changes in the serum uric acid level and gout symptoms. The secondary outcomes included the changes in levels of diamine oxidase (DAO), D-lactic acid, and endotoxin. RESULTS: Eleven patients received WMT treatment. The averaged serum uric acid levels in patients with gout reduced after WMT (p = 0.031), accompanied with a decrease in the frequency and duration time of acute gout flares (p < 0.01). The levels of DAO, D-lactic acid, and endotoxin were higher in patients than in healthy donors (p < 0.05). After WMT treatment, the levels of DAO and endotoxin decreased (p < 0.05). CONCLUSIONS: WMT is effective for reducing serum uric acid levels and improving gout symptoms in patients with gout and contributes to improve their impaired intestinal barrier function.

Diagnostic performance of the metagenomic next-generation sequencing in lung biopsy tissues in patients suspected of having a local pulmonary infection.

PURPOSE: This study aims to evaluate the diagnostic application and performance of the metagenomic next-generation sequencing (mNGS) in patients suspected of local pulmonary infection by comparing it to the traditional pathogen detection methods in lung tissue specimens obtained by a computerized tomography-guided biopsy (CT-guided biopsy). METHODS: We retrospectively reviewed patients, admitted to the First Affiliated Hospital of Wenzhou Medical University, China from May 2018 to December 2020, who were suspected of local pulmonary infection. All cases received a CT-guided lung biopsy, tissue samples were sent both for conventional examinations (CE) and mNGS tests. The sensitivity and specificity of the two diagnostic approaches were compared. RESULTS: 106 patients enrolled, 76 patients were diagnosed with a pulmonary infection. Among 49 patients with identified pathogens, CE confirmed pathogenic infections in 32 cases. Mycobacterium spp. and fungi accounted for 37.5% (12/32) and 28.1% (9/32), respectively, with bacteria 34.4% (11/32). The mNGS examination detected extra pathogenic microorganisms in 22 patients that were consistent with the patients' clinical and radiographic pictures. The sensitivity of mNGS was 53.9% vs. 42.1% for the CE, while the specificity was 56.7% versus 96.7%. For detection rate, mNGS was significantly superior to CE in bacterial (96.3% vs. 40.7%, p < 0.05), and mixed infections (100% vs. 50%, p < 0.05), but inferior to CE in fungal (60% vs. 90%, p > 0.05) and Mycobacterium spp. infections (66.7% vs. 100%, p > 0.05) with no significant difference. Among 31 cases diagnosed with lung abscess, the diagnostic performance of the detection rate was 67.7% (21/31) in favour of mNGS compared to 29.0% (9/31) for CE (p < 0.05). Most polymicrobial infections were induced by anaerobic species that coexisted with Streptococcus constellatus. And Klebsiella pneumoniae was the most common isolated monomicrobial infection. CONCLUSIONS: The most commonly detected causative pathogens for local pulmonary infections were bacteria, Mycobacterium spp. and fungi. Compared with the CE, the advantages of mNGS in the pathogens detection lie in the discovery of bacterial and mixed infections, as well as in the detection of lung abscess. Conversely, mNGS is not good enough to be recommendable for the detection of Mycobacterium spp. and fungi.

Meconium-Stained Amniotic Fluid: Impact on Prognosis of Neonatal Bacterial Meningitis.

OBJECTIVES: Clinical data with respect to the impact of meconium on the prognosis of neonatal bacterial meningitis are scarce. Therefore, in this study, we aimed to determine whether meconium-stained amniotic fluid (MSAF) represents a risk factor for poor prognosis of neonatal bacterial meningitis in a confirmed case population. METHODS: This was a retrospective cohort study of 256 neonates diagnosed with bacterial meningitis hospitalized at one of three hospitals in Shantou, China, between October 2013 and September 2018. Clinical manifestation, laboratory test results and treatment were compared between the two groups, with outcomes dichotomized into 'good' or 'poor' prognosis. Multivariate analysis and follow-up logistic regression analysis were used to identify predictive factors of a poor outcome. RESULTS: Of the 256 neonates with BM, 95 (37.1%) had a good prognosis at discharge and 161 (62.9%) had a poor prognosis. In the poor prognosis group, 131/161 (79.4%) neonates had a permanent neurological sequelae and 19 (11.8%) had ≥2 sequelae. Of note, 11 neonates died. The rate of poor prognosis of BM was significantly higher among neonates with than without MSAF (26.1% vs. 12.6%, respectively; p < 0.05). A logistic multivariate analysis to evaluate the prognostic effect of MSAF to BM showed that neonatal with MSAF is more likely to have a worse prognosis of BM [unadjusted odds ratio (OR), 2.44, 95% confidence interval (CI), 1.24-5.10; adjusted OR, 2.31; 95% CI, 1.09-5.17]. CONCLUSION: MSAF is significantly associated with poor prognosis of neonatal bacterial meningitis. Therefore, in case of MSAF, more attention should be paid to neonatal bacterial meningitis.

Comparative Proteomic Analysis of Liver Tissues and Serum in db/db Mice.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) affects one-quarter of individuals worldwide. Liver biopsy, as the current reliable method for NAFLD evaluation, causes low patient acceptance because of the nature of invasive sampling. Therefore, sensitive non-invasive serum biomarkers are urgently needed. RESULTS: The serum gene ontology (GO) classification and Kyoto encyclopedia of genes and genomes (KEGG) analysis revealed the DEPs enriched in pathways including JAK-STAT and FoxO. GO analysis indicated that serum DEPs were mainly involved in the cellular process, metabolic process, response to stimulus, and biological regulation. Hepatic proteomic KEGG analysis revealed the DEPs were mainly enriched in the PPAR signaling pathway, retinol metabolism, glycine, serine, and threonine metabolism, fatty acid elongation, biosynthesis of unsaturated fatty acids, glutathione metabolism, and steroid hormone biosynthesis. GO analysis revealed that DEPs predominantly participated in cellular, biological regulation, multicellular organismal, localization, signaling, multi-organism, and immune system processes. Protein-protein interaction (PPI) implied diverse clusters of the DEPs. Besides, the paralleled changes of the common upregulated and downregulated DEPs existed in both the liver and serum were validated in the mRNA expression of NRP1, MUP3, SERPINA1E, ALPL, and ALDOB as observed in our proteomic screening. METHODS: We conducted hepatic and serum proteomic analysis based on the leptin-receptor-deficient mouse (db/db), a well-established diabetic mouse model with overt obesity and NAFLD. The results show differentially expressed proteins (DEPs) in hepatic and serum proteomic analysis. A parallel reaction monitor (PRM) confirmed the authenticity of the selected DEPs. CONCLUSION: These results are supposed to offer sensitive non-invasive serum biomarkers for diabetes and NAFLD.

Current practice and perspectives of healthcare providers regarding preconception care for women with type 1 diabetes in China.

AIMS: We aimed to investigate the current practice and perspectives of healthcare providers (HCPs) regarding preconception care (PCC) for women with type 1 diabetes (T1D) in China. MATERIALS AND METHODS: A questionnaire based on in-depth interviews with HCPs involved in PCC was released online and advertised via doctor unions in China. The data were categorical variables and were analysed by multivariable logistic regression, Chi-square test, or Wilcoxon rank-sum test. RESULTS: From November 2016 to January 2017, 992 responses from 31 provinces of China were received (77.3% doctors and 22.7% nurses). Regarding the current status of PCC for T1D, 62.5% of HCPs treated ≤1 woman with T1D monthly on average. Only 16.5% thought they provided proper PCC, and 29.6% reported having sufficient knowledge. Regarding attitudes towards pregnancy with T1D, 92.2% were in favour of women with T1D getting pregnant after proper glycaemic control, and 94.7% perceived their worries regarding pregnancy. Regarding doctor-patient communication, 56.6% spent <10 min per visit, while 58.3% thought ≥20 min was required for adequate communication. HCPs emphasised the importance of multidisciplinary PCC, professional training, and social support. PCC practice was associated with hospital level (OR = 2.450, 95%CI: 1.580-3.799, p < 0.001), HCPs' experience of treating women with T1D (OR = 2.196, 95%CI: 1.516-3.180, p < 0.001), and their communication sufficiency (OR = 3.706, 95%CI: 2.550-5.387, p < 0.001). CONCLUSIONS: The current PCC practice for T1D in China was suboptimal and it was associated with hospital level, HCPs' experience and communication. It is necessary to reinforce professional training and appeal for social resources to improve PCC.

Targeting angiopoietin-like 3 in atherosclerosis: From bench to bedside.

Atherosclerotic cardiovascular disease (ASCVD) is the largest cause of morbidity and mortality worldwide. Lipid-lowering therapies are the current major cornerstone of ASCVD management. Statins, ezetimibe, fibrates and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively reduce the plasma low-density lipoprotein cholesterol (LDL-C) level in most individuals at risk of atherosclerosis. Still, some patients (such as those with homozygous familial hypercholesterolaemia), who do not respond to standard therapies, and other patients who cannot take these agents, remain at a high risk of ASCVD. In recent years there has been tremendous progress in understanding the mechanism and efficacy of lipid-lowering strategies. Apart from the recently approved PCSK9 and ATP citrate lyase inhibitors, angiopoietin-like 3 (ANGPTL3) is another potential target for the treatment of dyslipidaemia and its clinical sequalae of atherosclerosis. ANGPTL3 is a pivotal modulator of plasma triglycerides (TG), LDL-C and high-density lipoprotein cholesterol (HDL-C) levels, achieved by inhibiting the activities of lipoprotein lipase and endothelial lipase. Familial combined hypolipidaemia is derived from the Angptl3 loss-of-function mutations, which leads to low levels of LDL-C, HDL-C and TG, and has a 34% decreased risk of ASCVD compared with non-carriers. To date, monoclonal antibodies (evinacumab) and antisense oligonucleotides against ANGPTL3 have been investigated in clinical trials for dyslipidaemia therapy. Herein, we review the biology and function of ANGPTL3, as well as the latest developments of ANGPTL3-targeted therapies. We also summarize evidence from basic research to clinical trials, with the aim of providing novel insights into the biological functions of ANGPTL3 and related targeted therapies.

A metal-organic framework with multienzyme activity as a biosensing platform for real-time electrochemical detection of nitric oxide and hydrogen peroxide.

A Metal-Organic Framework (MOFs) with large surface area, exposed active site, excellent catalytic performance and high chemical stability has been used as an artificial enzyme and designed for nonenzymatic electrochemical sensors. Here, a strategy of using an enhanced electrochemical sensing platform for the detection of nitic oxide (NO) and hydrogen peroxide (H2O2) was designed via a nano-metalloporphyrinic metal-organic framework (NporMOF(Fe)) as an electrode material. By taking advantage of the small size, high surface area and exposed Fe active site, the obtained NporMOF(Fe) displays excellent electrocatalytic activity toward NO and H2O2. The NporMOF(Fe) modified electrode shows high sensing ability toward the in situ generated NO in NO2- containing phosphate buffer (PB) solution with a wide linear detection range of 5 µM to 200 µM and a very low detection limit of 1.3 µM. Moreover, NporMOF(Fe) exhibits high electrocatalytic activity toward the reduction of H2O2 and the practical detection of H2O2 released from HeLa cells. Furthermore, the NporMOF(Fe) modified electrode shows excellent selectivity toward the detection of NO and H2O2 in the presence of other physiologically important analytes. This method shows excellent biosensing performance, implying the universal applicability of MOFs-based artificial nanozymes for biosensors and the potential application for third generation biosensors.

Targeting DNA-PK overcomes acquired resistance to third-generation EGFR-TKI osimertinib in non-small-cell lung cancer.

The third-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), represented by osimertinib, has achieved remarkable clinical outcomes in the treatment of non-small-cell lung cancer (NSCLC) with EGFR mutation. However, resistance eventually emerges in most patients and the underlying molecular mechanisms remain to be fully understood. In this study, we generated an osimertinib-acquired resistant lung cancer model from a NSCLC cell line H1975 harboring EGFR L858R and T790M mutations. We found that the capacity of DNA damage repair was compromised in the osimertinib resistant cells, evidenced by increased levels of γH2AX and higher intensity of the comet tail after withdrawal from cisplatin. Pharmacological inhibiting the activity or genetic knockdown the expression of DNA-PK, a key kinase in DNA damage response (DDR), sensitized the resistant cells to osimertinib. Combination of osimertinib with the DNA-PK inhibitor, PI-103, or NU7441, synergistically suppressed the proliferation of the resistant cells. Mechanistically, we revealed that DNA-PK inhibitor in combination with osimertinib resulted in prolonged DNA damage and cell cycle arrest. These findings shed new light on the mechanisms of osimertinib resistance in the aspect of DNA repair, and provide a rationale for targeting DNA-PK as a therapeutic strategy to overcome osimertinib-acquired resistance in NSCLC.