Effect of ferric citrate on hippocampal iron accumulation and widespread molecular alterations associated with cognitive disorder in an ovariectomized mice model.

OBJECTIVE: Nowadays, the prevalence of cognitive impairment in women has gradually increased, especially in postmenopausal women. There were few studies on the mechanistic effects of iron exposure on neurotoxicity in postmenopausal women. The aim of this study is to investigate the effect of iron accumulation on cognitive ability in ovariectomized mice and its possible mechanism and to provide a scientific basis for the prevention of cognitive dysfunction in postmenopausal women. METHODS: Female C57BL/6N ovariectomized model mice were induced with ferric citrate (FAC). The mice were randomly divided into 5 groups: control, sham, ovariectomized (Ovx), Ovx + 50 mg/kg FAC (Ovx + l), and Ovx + 100 mg/kg FAC (Ovx + h). The impact of motor and cognitive function was verified by a series of behavioral tests. The levels of serum iron parameters, malondialdehyde, and superoxide dismutase were measured. The ultrastructure of mice hippocampal microglia was imaged by transmission electron microscopy. The differential expression of hippocampal proteins was analyzed by Tandem Mass Tag labeling. RESULTS: Movement and cognitive function in Ovx + l/Ovx + h mice were significantly decreased compared to control and Sham mice. Then, iron exposure caused histopathological changes in the hippocampus of mice. In addition, proteomic analysis revealed that 29/27/41 proteins were differentially expressed in the hippocampus when compared by Ovx vs. Sham, Ovx + l vs. Ovx, as well as Ovx + h vs. Ovx + l groups, respectively. Moreover, transferrin receptor protein (TFR1) and divalent metal transporter 1 (DMT1) protein expression were significantly increased in the iron accumulation mice model with ovariectomy. CONCLUSION: Iron exposure could cause histopathological damage in the hippocampus of ovariectomised mice and, by altering hippocampal proteomics, particularly the expression of hippocampal iron metabolism-related proteins, could further influence cognitive impairment in ovariectomized mice.

Novel Genetic Loci in Early-Onset Gout Derived From Whole-Genome Sequencing of an Adolescent Gout Cohort.

OBJECTIVE: Mechanisms underlying the adolescent-onset and early-onset gout are unclear. This study aimed to discover variants associated with early-onset gout. METHODS: We conducted whole-genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12 to 19 years) to discover common and low-frequency single-nucleotide variants (SNVs) associated with gout. Candidate common SNVs were genotyped in an early-onset gout cohort of 2,834 individuals (gout onset ≤30 years old), and meta-analysis was performed with the discovery and replication cohorts to identify loci associated with early-onset gout. Transcriptome and epigenomic analyses, quantitative real-time polymerase chain reaction and RNA sequencing in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated the regulation and function of candidate gene RCOR1. RESULTS: In addition to ABCG2, a urate transporter previously linked to pediatric-onset and early-onset gout, we identified two novel loci (Pmeta < 5.0 × 10-8): rs12887440 (RCOR1) and rs35213808 (FSTL5-MIR4454). Additionally, we found associations at ABCG2 and SLC22A12 that were driven by low-frequency SNVs. SNVs in RCOR1 were linked to elevated blood leukocyte messenger RNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. CONCLUSION: This is the first comprehensive genetic characterization of adolescent-onset gout. The identified risk loci of early-onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout.

Overexpression of SmUGGT1 Confers Imidacloprid Resistance to Sitobion miscanthi (Takahashi).

Sitobion miscanthi, the main species of wheat aphids, is one kind of harmful pest. Chemical insecticides are the important agrochemical products to effectively control wheat aphids. However, the broad application has led to serious resistance of pests to several insecticides, and understanding insecticide resistance mechanisms is critical for integrated pest management. In this study, SmUGGT1, a new uridine diphosphate (UDP)-glycosyltransferase (UGT) gene, was cloned and more strongly expressed in the SM-R (the resistant strain to imidacloprid) than in the SM-S (the susceptible strain to imidacloprid). The increased susceptibility to imidacloprid was observed after silencing SmUGGT1, indicating that it can be related to the resistance to imidacloprid. Subsequently, SmUGGT1 regulated post-transcriptionally in the coding sequences (CDs) by miR-81 was verified and involved in the resistance to imidacloprid in S. miscanthi. This finding is crucial in the roles of UGT involved in insecticide resistance management in pests.

microRNA-3037 targeting CYP6CY2 confers imidacloprid resistance to Sitobion miscanthi (Takahashi).

The wheat aphid Sitobion miscanthi is a dominant and destructive pest in agricultural production. Insecticides are the main substances used for effective control of wheat aphids. However, their extensive application has caused severe resistance of wheat aphids to some insecticides; therefore, exploring resistance mechanisms is essential for wheat aphid management. In the present study, CYP6CY2, a new P450 gene, was isolated and overexpressed in the imidacloprid-resistant strain (SM-R) compared to the imidacloprid-susceptible strain (SM-S). The increased sensitivity of S. miscanthi to imidacloprid after knockdown of CYP6CY2 indicates that it could be associated with imidacloprid resistance. Subsequently, the posttranscriptional regulation of CYP6CY2 in the 3' UTR by miR-3037 was confirmed, and CYP6CY2 participated in imidacloprid resistance. This finding is critical for determining the role of P450 in relation to the resistance of S. miscanthi to imidacloprid. It is of great significance to understand this regulatory mechanism of P450 expression in the resistance of S. miscanthi to neonicotinoids.

Blood-based inflammatory protein biomarker panel for the prediction of relapse and severity in patients with neuromyelitis optica spectrum disorder: A prospective cohort study.

BACKGROUND: To date, most existing models for predicting neuromyelitis optica spectrum disorder (NMOSD) are based primarily on clinical characteristics. Blood-based NMOSD severity and prognostic predictive immune- and inflammation-related biomarkers are needed. We aimed to investigate the associations between plasma inflammatory biomarkers and relapse and attack severity in NMOSD. METHODS: This two-step, single-center prospective cohort study included discovery and validation cohorts. We quantified 92 plasma inflammatory proteins by using Olink's proximity extension assay and identified differentially expressed proteins in the relapse group (relapse within 1 year of follow-up) and severe attack group. To define a new molecular prognostic model, we calculated the risk score of each patient based on the key protein signatures and validated the results in the validation cohort. RESULTS: The relapse prediction model, including FGF-23, DNER, GDNF, and SLAMF1, predicted the 1-year relapse risk. The severe attack prediction model, including PD-L1 and MCP-2, predicted the severe clinical attack risk. Both the relapse and severe attack prediction models demonstrated good discriminative ability and high accuracy in the validation cohort. CONCLUSIONS: Our discovered biomarker signature and prediction models may complement current clinical risk stratification approaches. These inflammatory biomarkers could contribute to the discovery of therapeutic interventions and prevent NMOSD progression.

Relationship between dietary knowledge, food preference, and long-short term health status among Chinese adults.

BACKGROUND AND OBJECTIVES: In recent years, with the improvement of people's living standards and changes in dietary patterns, dietary knowledge and food preference have been playing an increasingly crucial role in health. The aim of our study was to examine the relationship between dietary knowledge, food preference, and long-short term health status among Chinese adults aged 18-70. METHODS AND STUDY DESIGN: This study employed cross-sectional data from the 2015 China Health and Nutrition Survey obtained from 4822 adults. We utilized self-assessed health status as an indicator of long-term health status and utilized sickness in the last four weeks as a measure of short-term health status. Taking advantage of ordered probit regression, long-term health status was regressed on all predictors, while the binary logistic regression was used to analyze the factors influencing short-term health status. The propensity score matching is employed to account for potential selection bias in analysis, thereby increasing the robustness and credibility of results. RESULTS: The analysis revealed that dietary knowledge and food preference can improve an individual's long-term health status significantly. However, there is no evidence to show that short-term health status is affected by food preference. Furthermore, dietary knowledge is negatively associated with short-term health status. CONCLUSIONS: These findings highlight the importance of dietary education and healthy eating habits in improving the long-term health status of Chinese adults. The study suggests implications for public health strategies aimed at enhancing the health and well-being of Chinese adults.

Predictors of Inadequate Serum Urate Response to Low-Dose Febuxostat in Male Patients with Gout.

Objective: This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables. Methods: We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA<6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set. Results: Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR. Conclusion: Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.

Elevated liver enzymes in the first trimester are associated with gestational diabetes mellitus: A prospective cohort study.

AIMS: Previous studies have found that a single liver enzyme may predict gestational diabetes mellitus (GDM), but the results have been inconsistent. This study aimed to explore the associations of liver enzymes in early pregnancy with risk of GDM, as well as to independently rank risk factors. METHODS: This prospective cohort study included 1295 women who underwent liver enzyme measurements during early pregnancy and completed GDM assessment in mid-pregnancy. Logistic regression and restricted cubic spline analyses were conducted to assess the relationship between liver enzymes and risk of GDM. Back-propagation artificial neural network was performed to rank independently risk factors of GDM. RESULTS: Women diagnosed with GDM exhibited significantly higher levels of liver enzymes than those without GDM (all p < 0.05). The highest quartile of liver enzymes was associated with higher risk of GDM compared with the lowest quartile, with adjusted odds ratio (ORs) ranging from 2.76 to 8.11 (all p < 0.05). Moreover, the ORs of GDM increased linearly with liver enzymes level (all P for overall association <0.001). Furthermore, Back-propagation artificial neural network identified γ-gamma-glutamyl transferase (GGT) as accounting for the highest proportion in the ranking of GDM risk prediction weights (up to 20.8%). CONCLUSIONS: Single or total elevations of liver enzymes in early pregnancy could predict the GDM occurrence, in which GGT, alkaline Phosphatase, and aspartate aminotransferase were the three most important independent risk factors.

Mediating Effect of Insulin-Like Growth Factor-I Underlying the Link Between Vitamin D and Gestational Diabetes Mellitus.

Vitamin D was well-known to be associated with gestational diabetes mellitus (GDM). Insulin-like growth factor-I (IGF-I) has been linked to vitamin D and GDM, respectively. We hypothesize that changes in IGF-I metabolism induced by 25(OH)D3 might contribute to GDM. Therefore, we investigated the independent and combined relationships of serum 25(OH)D3 and IGF-I concentrations with GDM risk, and the mediation effect of IGF-I on 25(OH)D3. A total of 278 pregnant women (including 125 cases and 153 controls) were recruited in our current study. Maternal serum 25(OH)D3 and IGF-I were measured in the second trimester. Logistic regression models were used to estimate the associations of 25(OH)D3 and IGF-I concentrations with the risk of GDM. Mediation analyses were used to explore the mediation effect of IGF-I on the association between 25(OH)D3 and the risk of GDM. After adjusted for the confounded factors, both the third and fourth quartile of 25(OH)D3 decreased the risk of GDM (OR = 0.226; 95% CI, 0.103-0.494; OR = 0.109; 95% CI, 0.045-0.265, respectively) compared to the first quartile of 25(OH)D3. However, the third and fourth quartile of serum IGF-I (OR = 5.174; 95% CI, 2.287-11.705; OR = 12.784; 95% CI, 5.292-30.879, respectively) increased the risk of GDM compared to the first quartile of serum IGF-I. Mediation analyses suggested that 19.62% of the associations between 25(OH)D3 and GDM might be mediated by IGF-I. The lower concentration of serum 25(OH)D3 or higher IGF-I in the second trimester was associated with an increased risk of GDM. The serum IGF-I level might be a potential mediator between 25(OH)D3 and GDM.

Clinical characteristics of adolescent-onset gout in Chinese: A hospital-based cross-sectional study.

OBJECTIVE: Adolescent-onset gout has a greater impact on the lives and health of patients than adult-onset gout. However, there is a relative lack of clinical information on adolescent-onset gout. Hence, we analyzed a Chinese cohort. METHODS: We studied clinical features of 9,003 Chinese patients. Gout onset age of 12 - 19 years is defined as adolescent-onset group (AG), 20 - 40 years as early-onset group (EG), and 41 - 64 years as late-onset group (LG). Multivariable regression analysis evaluated factors associated with recurrent flares, serum urate (SU) levels, and underexcretion type in AG. RESULTS: Compared with EG and LG, the AG had higher SU levels [AG: 9.5 (2.2) mg/dL, EG: 8.6 (2.1) mg/dL, LG: 7.73 (2.0) mg/dL, P < 0.001], higher percentage of positive family history of gout (AG: 41.8 %, EG: 29.6 %, LG: 24.6 %, P < 0.001), underexcretion type (AG: 62.4 %, EG: 62.5 %, LG: 58.8 %, P = 0.04), recurrent flares (AG: 78.1 %, EG: 70.3 %, LG: 68.9 %, P = 0.01). Urate-lowering therapy (ULT) initiated [OR 6.58 (95 % CI 1.35 - 32.00)] and hypercholesterolemia [OR 4.16 (95 % CI 1.28 - 13.53)] were associated with recurrent flares. eGFR was identified to be a significant variable of increasing SU levels [beta -0.24 (95 % CI -0.04 to -0.01)]. Hypertriglyceridemia [OR 0.35 (95 % CI 0.17 - 0.71)] was related to underexcretion type. CONCLUSION: Adolescent-onset gout patients had clinically distinctive features with higher SU levels, BMI, positive gout family history, underexcretion type and recurrent flares. These specific populations were less likely to achieve ULT target, requiring more clinical attention.

In vitro drug release and cartilage interface lubrication properties of biomimetic polymers.

Osteoarthritis is a degenerative disease that is widely found in the elderly population, with a trend towards a younger age group in recent years. In the early stages of arthritis, patients are treated with hyaluronic acid injections and anti-inflammatory drugs. However, it has been found that hyaluronic acid can only play a supportive role and does not have a lubricating effect, and due to the absence of blood vessels, nerves, and lymphatic vessels in the articular cartilage, the oral anti-inflammatory drugs cannot reach the interface of the inflammatory joints adequately, and the drug utilisation rate is low. Herein, we designed and prepared a brush-like bionic lubricant for joint lubrication and drug loading. The poly(2-methyl-2-oxazoline) branched chain was grafted onto the hyaluronic acid main chain by ring-opening polymerisation and graft polymerisation to form a brush-like bionic lubricin containing multiple hydrophilic groups, which was self-assembled to encapsulate the drug by using its multi-branched special structure for drug loading. The friction behaviour tests on the articular cartilage surface showed that the prepared bionic lubricin has excellent lubrication effect, with a minimum friction coefficient of 0.036 close to the lubrication effect of natural synovial fluid, which is mainly due to the hydrophilic groups on its molecular chain that can adsorb the water molecules and form a hydration layer at the cartilage interface, which plays the role of hydration lubrication. In addition, in vitro drug release studies showed that the synthesised drug-loading biomimetic lubricin had a certain drug release capacity, and the maximum drug release rate could reach 77.8 % at 72 h. The synthesis of this bionic lubricant with dual functions of lubrication and drug release provides a new idea for the treatment of osteoarthritis.

Hyperuricemia Subtypes Classified According to Renal Uric Acid Handling Manifesting Distinct Phenotypic and Genetic Profiles in People With Gout.

OBJECTIVE: Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts. METHODS: Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) previously identified as gout risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes. RESULTS: Of the 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non-diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at onset, lower SU, and eGFR. Thirteen SNPs were associated with gout with 6 shared loci and subtype-dependent risk loci patterns. High polygenic risk scores were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53-15.12), RUE subtype (OR = 2.18, 95% CI 1.57-3.03), and combined subtype (OR = 6.32, 95% CI 4.22-9.48) compared with low polygenic risk scores. CONCLUSION: Hyperuricemia subtypes classified according to renal uric acid handling have subtype-specific clinical and genetic features, suggesting subtype-unique pathophysiologic mechanisms.

Projections from infralimbic medial prefrontal cortex glutamatergic outputs to amygdala mediates opioid induced hyperalgesia in male rats.

Repeated use of opioid analgesics may cause a paradoxically exacerbated pain known as opioid-induced hyperalgesia (OIH), which hinders effective clinical intervention for severe pain. Currently, little is known about the neural circuits underlying OIH modulation. Previous studies suggest that laterocapsular division of the central nucleus of amygdala (CeLC) is critically involved in the regulation of OIH. Our purpose is to clarify the role of the projections from infralimbic medial prefrontal cortex (IL) to CeLC in OIH. We first produced an OIH model by repeated fentanyl subcutaneous injection in male rats. Immunofluorescence staining revealed that c-Fos-positive neurons were significantly increased in the right CeLC in OIH rats than the saline controls. Then, we used calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) labeling and the patch-clamp recordings with ex vivo optogenetics to detect the functional projections from glutamate pyramidal neurons in IL to the CeLC. The synaptic transmission from IL to CeLC, shown in the excitatory postsynaptic currents (eEPSCs), inhibitory postsynaptic currents (eIPSCs) and paired-pulse ratio (PPR), was observably enhanced after fentanyl administration. Moreover, optogenetic activation of this IL-CeLC pathway decreased c-Fos expression in CeLC and ameliorated mechanical and thermal pain in OIH. On the contrary, silencing this pathway by chemogenetics exacerbated OIH by activating the CeLC. Combined with the electrophysiology results, the enhanced synaptic transmission from IL to CeLC might be a cortical gain of IL to relieve OIH rather than a reason for OIH generation. Scaling up IL outputs to CeLC may be an effective neuromodulation strategy to treat OIH.

The association between retinol-binding protein 4 and risk of type 2 diabetes: A systematic review and meta-analysis.

Retinol-binding protein 4 (RBP4) was controversially associated with type 2 diabetes mellitus (T2DM). This meta-analysis aimed at evaluating the association between RBP4 level and T2DM risk. MEDLINE and EMBASE were searched to identify relevant studies up to 3 December 2022. Random effects model was used to pool multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Publication bias was estimated by Funnel plot and Egger's test, it was considered to be significant when P < 0.05. Eight studies including 8087 participants were finally included. Compared to those with the lowest level, subjects with the highest level of RBP4 have a higher risk of T2DM (OR = 1.47, 95% CI: 1.16-1.78, P < 0.001, I2 = 86.9%). No publication bias among the included studies was found (t = 0.94, P = 0.377). This meta-analysis indicated that high RBP4 level was associated with increasing risk of T2DM.

Response to febuxostat according to clinical subtypes of hyperuricemia: a prospective cohort study in primary gout.

BACKGROUND: While xanthine oxidase inhibitors target uric acid production, renal urate underexcretion is the predominant subtypes in gout. This study was to compare treatment response to the XOI febuxostat in a gout cohort according to clinical subtypes of hyperuricemia. METHODS: A prospective cohort study was conducted to compare the efficacy and safety of febuxostat (initially 20 mg daily, escalating to 40 mg daily if not at target) in 644 gout patients with the three major clinical subtypes for 12 weeks. Hyperuricemia was defined as the renal overload subtype, the renal underexcretion subtype, or the combined subtype based on UUE > or ≤ 600 mg/d/1.73 m2 and FEUA < or ≥ 5.5%. The primary endpoint was the rate of achieving serum urate (SU) < 6 mg/dL at week 12. RESULTS: Fewer participants with combined subtype achieved the SU target, 45.5% compared with 64.8% with overload subtype (P = 0.007), and 56.6% with underexcretion subtype (P = 0.022). More participants with combined subtype (82%) had febuxostat escalated to 40 mg than those with overload (62%, P = 0.001) or underexcretion subtype (68%, P = 0.001). In all participants, combined subtype hyperuricemia (OR = 0.64, 95%CI 0.41-0.99, P = 0.048) and baseline SU (OR = 0.74, 95%CI 0.62-0.89, P = 0.001) were independently associated with lower rates of achieving SU target. CONCLUSIONS: People with combined subtype have a lower response to febuxostat, compared to those with either overload or underexcretion subtype. Assessment of hyperuricemia subtype may provide useful clinical data in predicting febuxostat response.

Efficacy and safety of tart cherry supplementary citrate mixture on gout patients: a prospective, randomized, controlled study.

BACKGROUND: Low urine pH, which may be mediated by metabolic syndrome (MetS), is common in gout. Tart cherries are shown to improve MetS symptoms and possess anti-inflammatory properties. However, the efficacy of tart cherry supplements on urine pH has yet to be studied. OBJECTIVES: This study aimed to investigate the efficacy and safety of tart cherry supplementary citrate (TaCCi) mixture on urine pH, serum urate (sUA), C-reactive protein (CRP), and gout flares in gout patients initiating urate-lowering therapy (ULT), in comparison to citrate mixture and sodium bicarbonate. METHODS: A prospective, randomized (1:1:1), open-label, parallel-controlled trial was conducted among 282 men with gout and fasting urine pH ≤ 6, who were initiating ULT with febuxostat (initially 20 mg daily, escalating to 40 mg daily if serum urate ≥ 360 µmol/L). Participants were randomized to groups taking either sodium bicarbonate, citrate mixture, or TaCCi mixture. All participants were followed every 4 weeks until week 12. Urine pH and sUA were co-primary outcomes, with various biochemical and clinical secondary endpoints. RESULTS: Urine pH increased to a similar extent in all three groups. SUA levels declined in all three groups as well, with no significant differences observed between the groups. At week 12, the TaCCi mixture group exhibited a greater reduction in the urine albumin/creatinine ratio (UACR) compared to the other two groups (p < 0.05). Participants taking TaCCi mixture or citrate mixture experienced fewer gout flares than those in the sodium bicarbonate group over the study period (p < 0.05). Additionally, the TaCCi mixture group had a lower CRP level at week 12 relative to the other two groups (p < 0.01). Adverse events were similar across all three groups. CONCLUSION: The TaCCi mixture had similar efficacy and safety on urine alkalization and sUA-lowering as the citrate mixture and sodium bicarbonate in patients with gout. However, the TaCCi mixture resulted in greater improvements in UACR and CRP, which suggests that tart cherry supplements may provide additional benefits for renal protection and reduce inflammation in gout, particularly when starting ULT. TRIAL REGISTRATION: This project was registered in ChiCTR ( www.chictr.org.cn ), with the registration number: ChiCTR2100050749.

Meta-analysis on last ten years of clinical injection of bone marrow-derived and umbilical cord MSC to reverse cirrhosis or rescue patients with acute-on-chronic liver failure.

BACKGROUND: Recent studies have shown that mesenchymal stem cell (MSC) therapy has potential therapeutic effects for patients with end-stage liver diseases. However, a consensus on the efficacy and safety of MSCs has not been reached. METHODS: A systemic literature review was conducted by searching the Cochrane Library and PubMed databases for articles that evaluated the impact of MSC therapy on the outcomes among patients with end-stage liver disease. Various parameters, including pre- and post-treatment model of end-stage liver disease (MELD) score, serum albumin (ALB), total bilirubin (TB), coagulation function, aminotransferase, and survival rate, were evaluated. RESULTS: This meta-analysis included a final total of 13 studies and 854 patients. The results indicated improved liver parameters following MSC therapy at different time points, including in terms of MELD score, TB level, and ALB level, compared with conventional treatment. Furthermore, the MSC treatment increased the overall survival rate among patients with liver cirrhosis and acute-on-chronic liver failure (ACLF). The changes in transaminase level and coagulation function differed between the different therapies at various post-treatment time points, indicating that MSC therapy provided no significant benefits in this regard. The further subgroup analysis stratified by liver background revealed that patients with ACLF benefit more from MSC therapy at most time points with improved liver function, including in terms of MELD score, TB level, and ALB level. In addition, no serious side effects or adverse events were reported following MSC therapy. CONCLUSIONS: The meta-analysis results suggest that MSC therapy is safe and results in improved liver function and survival rates among patients with end-stage liver disease. The subgroup analysis stratified by liver background indicated that patients with ACLF benefit more from MSC therapy than patients with liver cirrhosis at most time points.

Synergistic material modification-induced optimization of interfacial charge transfer and surface hydrogen adsorption.

Being chemically stable, low cost and made from abundant resources, titanium dioxide (TiO2) possesses the most desired advantages for photocatalytic applications. However, the intrinsic limits of high surface hydrogen adsorption energy, wide band gap, low separation rate and rapid recombination of the photogenerated charge carriers greatly hamper its utilization. To address these issues, the present work combines density functional theory (DFT) calculations with rational modifications of TiO2 with nickel doping and an ultra-thin shield of fluorinated carbon (FNT) for application in the photocatalytic hydrogen evolution reaction (HER). Comprehensive studies imply that the synergistic modifications not only optimize the surface H adsorption, but also facilitate the interfacial charge transfer and simultaneously prevent the photochemical and chemical corrosion of the catalysts. In good agreement with the theoretical predictions, the resulting FNT photocatalysts demonstrate an optimal HER efficiency of 13.0 mmol g-1 h-1, nearly 33-times and over three-times beyond that of the pristine TiO2 (0.4 mmol g-1 h-1) and the Ni-doped TiO2 (4.2 mmol g-1 h-1), respectively. Moreover, the composite also exhibits excellent stability with a well-reproducible HER performance over a 66-hour cyclic HER test of 15 cycles.

Implication of different frailty criteria in older people with atrial fibrillation: a prospective cohort study.

BACKGROUND: the prevalence of physical and multidimensional frailty and their prognostic impact on clinical outcomes in patients with atrial fibrillation (AF) is unclear. OBJECTIVE: to evaluated frailty in a cohort of patients with AF according to different criteria, and studied the prevalence and its prognostic impact on clinical outcomes. METHODS: in this multicenter prospective cohort, 197 inpatients ≥ 65 years old with AF were recruited from September 2018 to April 2019.We used Fried Frailty phenotype (Fried) to assess physical frailty, and comprehensive geriatric assessment-frailty index (CGA-FI) to assess multidimensional frailty. The primary outcome was a composite of all-cause mortality or rehospitalization. RESULTS: the prevalence of frailty was determined as 34.5% by Fried, 42.6% by CGA-FI. Malnutrition and ≥ 7 medications were independently associated with frailty. Kaplan-Meier survival curve showed that the presence of frailty by CGA-FI had significantly lower all-cause mortality or rehospitalization survival rate (log-rank P = 0.04) within 1 year. Multivariate Cox regression adjusted for age and sex showed that the frailty by CGA-FI was significantly associated with the risk of all-cause mortality or rehospitalization within 1 year (HR 1.79, 95% CI 1.10-2.90). However, those associations were absent with the physical frailty. After broader multivariate adjustment, those associations were no longer statistically significant for both types of frailty. CONCLUSIONS: in older people with AF, Multidimensional frailty is more significantly associated with a composite of all-cause mortality or rehospitalization within 1 year than physical frailty, but these association are attenuated after multivariate adjustment. CLINICAL TRIAL REGISTRATION: ChiCTR1800017204; date of registration: 07/18/2018.

A lubricant and adhesive hydrogel cross-linked from hyaluronic acid and chitosan for articular cartilage regeneration.

Trauma-induced articular cartilage damages are common in clinical practice. Hydrogels have been used to fill the cartilage defects and act as extracellular matrices for cell migration and tissue regeneration. Lubrication and stability of the filler materials are essential to achieve a satisfying healing effect in cartilage regeneration. However, conventional hydrogels failed to provide a lubricous effect, or could not anchor to the wound to maintain a stable curing effect. Herein, we fabricated dually cross-linked hydrogels using oxidized hyaluronic acid (OHA) and N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) methacrylate (HTCCMA). The OHA/HTCCMA hydrogels, which were dynamically cross-linked and then covalently cross-linked by photo-irradiation, showed appropriate rheological properties and self-healing capability. The hydrogels exhibited moderate and stable tissue adhesion property due to formation of dynamic covalent bonds with the cartilage surface. The coefficient of friction values were 0.065 and 0.078 for the dynamically cross-linked and double-cross-linked hydrogels, respectively, demonstrating superior lubrication. In vitro studies showed that the hydrogels had good antibacterial ability and promoted cell proliferation. In vivo studies confirmed that the hydrogels were biocompatible and biodegradable, and exhibited a robust regenerating ability for articular cartilage. This lubricant-adhesive hydrogel is expected to be promising for the treatment of joint injuries as well as regeneration.