SNX8 enables lysosome reformation and reverses lysosomal storage disorder.

Lysosomal Storage Disorders (LSDs), which share common phenotypes, including enlarged lysosomes and defective lysosomal storage, are caused by mutations in lysosome-related genes. Although gene therapies and enzyme replacement therapies have been explored, there are currently no effective routine therapies against LSDs. During lysosome reformation, which occurs when the functional lysosome pool is reduced, lysosomal lipids and proteins are recycled to restore lysosome functions. Here we report that the sorting nexin protein SNX8 promotes lysosome tubulation, a process that is required for lysosome reformation, and that loss of SNX8 leads to phenotypes characteristic of LSDs in human cells. SNX8 overexpression rescued features of LSDs in cells, and AAV-based delivery of SNX8 to the brain rescued LSD phenotypes in mice. Importantly, by screening a natural compound library, we identified three small molecules that enhanced SNX8-lysosome binding and reversed LSD phenotypes in human cells and in mice. Altogether, our results provide a potential solution for the treatment of LSDs.

A comparative study of spectral and luminescent properties of Eu3+-doped cation-deficient perovskite phosphors.

Eu3+ is not only a major red-emitting activator, but also an excellent spectral probe ion. This work reports the Eu3+-sites and luminescence in the cation-deficient perovskite tungstates, A-site deficient SrLa2(Mg2W2)O12 [Sr1/2□1/2La(MgW)O6] and B-site deficient Sr2La2(MgW2)O12 [SrLa(Mg1/2□1/2W)O6]. The 7F0→5D0 excitation spectra of Eu3+ activators in two lattices were measured via pulsed dye laser. In SrLa2(Mg2W2)O12:Eu3+, there is only one 7F0→5D0 transition, which could be related to the Eu3+ center on La3+ sites; while, two 7F0→5D0 transitions in Sr2La2(MgW2)O12 indicate Eu3+ ions occupy Sr2+ in addition to La3+, resulting in the luminescent centers related to heterovalent substitution defects. The different Eu3+ sites make two phosphors exhibit different red luminescence properties. SrLa2(Mg2W2)O12:Eu3+ shows higher luminescent efficiency and thermal quenching due to its regular distribution of the activators resulting in lower dispersion losses of the energy transfer. The experimental results show that rare earth ions occupy different crystallographic positions in A-site and B-site deficient perovskite oxides, and this microstructure can be important for the corresponding luminescent properties.

Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders.

Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS-STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann-Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs.

The Expression of Two Distinct Sets of Glycolytic Enzymes Reveals Differential Effects of Glycolytic Reprogramming on Pancreatic Ductal Tumorigenesis in Mice.

Pancreatic ductal adenocarcinoma (PDAC) is associated with enhanced aerobic glycolysis through elevated glucose uptake and the upregulated expression of genes encoding rate-limiting glycolytic enzymes. However, the direct impact of altered glycolytic pathways on pancreatic tumor progression has not been thoroughly investigated. Here, we utilized two strains of BAC transgenic mice with pancreatic expression of two distinct sets of glycolytic genes each arranged in a polycistronic fashion (PFKFB3-HK2-GLUT1 and LDHA-PDK1, respectively) to investigate the role of altered glycolysis on the development of pancreatic ductal tumor development in the Pdx1-Cre; LSL-KrasG12D mice. The overexpression of the two sets of glycolytic genes exhibited no significant effects on tumor development in the 4-5-month-old mice (the PanIN2 lesions stage). In the 9-10-month-old mice, the overexpression of PFKFB3-HK2-GLUT1 significantly accelerated PanIN3 progression, exhibiting elevated levels of ductal cell marker CK19 and tumor fibrosis. Surprisingly, the overexpression of LDHA-PDK1 significantly attenuated the progression of PanIN3 in the 9-10-month-old mice with significantly downregulated levels of CK19 and fibrosis. Therefore, distinct set of glycolytic enzymes that are involved in different glycolytic routes exhibited contrasting effects on pancreatic ductal tumor development depending on the tumor stages, providing novel insights into the complexity of the glycolytic pathway in the perspective of PDAC development and therapy.

Train-your-brain program to reduce depression, anxiety, and stress in stroke survivors: a pilot community-based cognitive intervention study.

Introduction: Stroke is a major cause of death and disability worldwide, and it often results in depression, anxiety, stress, and cognitive impairment in survivors. There is a lack of community-based cognitive interventions for stroke survivors. This pilot single trial aimed to assess the feasibility, acceptability, and perceived effectiveness of a community-based cognitive intervention program called Train-Your-Brain (TYB) for stroke survivors and caregivers. The study focused on improvements in emotional and psychological well-being, as well as cognitive functioning. Methods: A quasi-experimental design was used in this study. A total of 48 participants were recruited and assessed using Depression, Anxiety, Stress Scale - 21 items (DASS-21), Montreal Cognitive Assessment (MoCA) and Symbol Digits Modality Test (SDMT) before and after the intervention. The TYB program consisted of nine sessions and was conducted via the Zoom software application. Participants provided feedback on the program, highlighting areas for improvement. Results: Twenty-seven stroke survivors and 21 caregivers completed the program. Participants expressed high satisfaction with the TYB program but recommended avoiding assessments in December and customizing the program for stroke survivors and caregivers. Stroke survivors showed significant improvements in depression and stress scores, while caregivers experienced no significant improvements after the program. While there was a slight improvement in stroke survivors' cognitive scores after the program, it was not statistically significant. Caregivers, however, experienced a significant decline in cognitive scores. Discussion: The TYB program provided group support and validation, resulting in improved mood and reduced stress among stroke survivors. Cultural collectivism played a significant role in fostering group cohesion. However, the program's limited focus on caregivers and timing of assessments during the December holidays may have affected the outcomes. The TYB program demonstrated feasibility and potential effectiveness in alleviating psychological distress and enhancing cognitive function among stroke survivors. Future research should explore long-term effects, larger sample sizes, and non-English-speaking populations to enhance generalizability. Tailored interventions for caregivers are necessary.

Young Adults' Use of Mobile Food Delivery Apps and the Potential Impacts on Diet During the COVID-19 Pandemic: Mixed Methods Study.

BACKGROUND: A poor diet contributes substantially to the development of noncommunicable diseases. In Singapore, it is recommended to consume at least 2 servings of fruits and vegetables daily to reduce the risk of developing noncommunicable diseases. However, the adherence rate among young adults is low. The COVID-19 pandemic has led to frequent users of mobile food delivery apps (MFDAs) adopting unhealthy eating habits, including high consumption of sugar-sweetened beverages, making it crucial to gain a deeper understanding of the underlying factors driving their use patterns. OBJECTIVE: We aimed to examine the use patterns of MFDAs among young adults during the COVID-19 pandemic; investigate the association between MFDA use and sociodemographic factors, dietary factors, and BMI; identify the underlying reasons for the observed use patterns of MFDAs among users; and compare the influences of MFDA use between frequent and infrequent users. METHODS: A sequential mixed methods design was used involving a web-based survey and in-depth interviews with a subset of respondents. Poisson regression and thematic analysis were used to analyze the quantitative and qualitative data, respectively. RESULTS: The quantitative results revealed that 41.7% (150/360) of participants reported using MFDAs frequently, defined as at least once a week. Although not substantial, the study found that frequent users were less likely to consume 2 servings of vegetables per day and more likely to drink sugar-sweetened beverages. Nineteen individuals who had participated in the quantitative component were selected for and completed the interviews. Qualitative analysis identified 4 primary themes: deliberations about other sources of meals versus meals purchased via MFDAs, convenience is vital, preference for unhealthy meals ordered from MFDAs most of the time, and cost is king. Before making any purchase, MFDA users consider all these themes at the same time, with cost being the most important influential factor. A conceptual framework based on these themes was presented. Lack of culinary skills and COVID-19 restrictions were also found to influence frequent use. CONCLUSIONS: This study suggests that interventions should focus on promoting healthy dietary patterns in young adults who frequently use MFDAs. Teaching cooking skills, especially among young male individuals, and time management skills could be useful to reduce reliance on MFDAs. This study highlights the need for public health policies that make healthy food options more affordable and accessible. Given the unintended changes in behavior during the pandemic, such as reduced physical activity, sedentary behavior, and altered eating patterns, it is essential to consider behavior change in interventions aimed at promoting healthy lifestyles among young adults who frequently use MFDAs. Further research is needed to evaluate the effectiveness of interventions during COVID-19 restrictions and assess the impact of the post-COVID-19 new normal on dietary patterns and physical activity levels.

Variation of amniotic fluid γ-glutamyl transferase level at 19-23 +6 gestational weeks in normal pregnancies / 中华围产医学杂志

Objective:To detect the levels of γ-glutamyl transferase (GGT) in the amniotic fluid of normal pregnancies at 19-23 +6 gestational weeks and to analyze the changes in GGT level with gestational age. Methods:This study retrospectively collected the amniotic fluid supernatant from 383 singleton pregnant women (102, 103, 82, 68 and 28 cases at 19-19 +6, 20-20 +6, 21-21 +6, 22-22 +6, 23-23 +6 weeks of gestation, respectively) who underwent amniocentesis for prenatal diagnosis but had normal genetic diagnosis results in Cheeloo Hospital of Shandong University from January 2021 to September 2022. The levels of GGT in the amniotic fluid supernatant were tested and the statistical parameters including xˉ± s, min-max, median ( M), P1, P2.5, P5, P95, P97.5 and P99 values of GGT levels at each gestational week were calculated. GGT were non-normal data and converted into natural logarithms (lnGGT), and a least square linear regression equation was established to analyze the relationship between lnGGT and gestational week. Results:At 19-19 +6, 20-20 +6, 21-21 +6, 22-22 +6, and 23-23 +6 gestational weeks, the xˉ± s of amniotic fluid GGT were (385.8±235.7), (331.8±219.4), (253.7±197.9), (226.7±166.4), and (155.3±96.8) U/L, and the weekly declines were 14.0%, 23.5%, 10.6%, and 31.5%, respectively; the M values were 311.0, 288.0, 199.0, 160.5, and 105.5 U/L, and the weekly declines were 7.4%, 30.9%, 19.3%, and 34.3%, respectively; the P1- P99 were 67.1-1 404.5, 63.2-1 189.1, 36.0-849.8, 44.0-787.3, and 32.0-375.6 U/L, respectively. lnGGT was negatively correlated with gestational age ( R 2=0.148, P<0.001). Conclusions:In normal pregnancies at 19-23 +6 gestational weeks, GGT levels in amniotic fluid decrease with gestational age. Therefore, gestational age should be considered when establishing the reference value for amniotic fluid GGT in normal pregnancies.

The coupling of mitoproteolysis and oxidative phosphorylation enables tracking of an active mitochondrial state through MitoTimer fluorescence.

The regulation of mitochondria function and health is a central node in tissue maintenance, ageing as well as the pathogenesis of various diseases. However, the maintenance of an active mitochondrial functional state and its quality control mechanisms remain incompletely understood. By studying mice with a mitochondria-targeted reporter that shifts its fluorescence from "green" to "red" with time (MitoTimer), we found MitoTimer fluorescence spectrum was heavily dependent on the oxidative metabolic state in the skeletal muscle fibers. The mitoproteolytic activity was enhanced in an energy dependent manner, and accelerated the turnover of MitoTimer protein and respiratory chain substrate, responsible for a green predominant MitoTimer fluorescence spectrum under the oxidative conditions. PGC1α, as well as anti-ageing regents promoted enhanced mitoproteolysis. In addition, cells with the green predominant mitochondria exhibited lower levels of MitoSox and protein carbonylation, indicating a favorable redox state. Thus, we identified MitoTimer as a probe for mitoproteolytic activity in vivo and found a heightened control of mitoproteolysis in the oxidative metabolic state, providing a framework for understanding the maintenance of active oxidative metabolism while limiting oxidative damages.

Investigating Psychological Differences Between Nurses and Other Health Care Workers From the Asia-Pacific Region During the Early Phase of COVID-19: Machine Learning Approach.

BACKGROUND: As the COVID-19 pandemic evolves, challenges in frontline work continue to impose a significant psychological impact on nurses. However, there is a lack of data on how nurses fared compared to other health care workers in the Asia-Pacific region. OBJECTIVE: This study aims to investigate (1) the psychological outcome characteristics of nurses in different Asia-Pacific countries and (2) psychological differences between nurses, doctors, and nonmedical health care workers. METHODS: Exploratory data analysis and visualization were conducted on the data collected through surveys. A machine learning modeling approach was adopted to further discern the key psychological characteristics differentiating nurses from other health care workers. Decision tree-based machine learning models (Light Gradient Boosting Machine, GradientBoost, and RandomForest) were built to predict whether a set of psychological distress characteristics (ie, depression, anxiety, stress, intrusion, avoidance, and hyperarousal) belong to a nurse. Shapley Additive Explanation (SHAP) values were extracted to identify the prominent characteristics of each of these models. The common prominent characteristic among these models is akin to the most distinctive psychological characteristic that differentiates nurses from other health care workers. RESULTS: Nurses had relatively higher percentages of having normal or unchanged psychological distress symptoms relative to other health care workers (n=233-260 [86.0%-95.9%] vs n=187-199 [74.8%-91.7%]). Among those without psychological symptoms, nurses constituted a higher proportion than doctors and nonmedical health care workers (n=194 [40.2%], n=142 [29.5%], and n=146 [30.3%], respectively). Nurses in Vietnam showed the highest level of depression, stress, intrusion, avoidance, and hyperarousal symptoms compared to those in Singapore, Malaysia, and Indonesia. Nurses in Singapore had the highest level of anxiety. In addition, nurses had the lowest level of stress, which is the most distinctive psychological outcome characteristic derived from machine learning models, compared to other health care workers. Data for India were excluded from the analysis due to the differing psychological response pattern observed in nurses in India. A large number of female nurses emigrating from South India could not have psychologically coped well without the support from family members while living alone in other states. CONCLUSIONS: Nurses were least psychologically affected compared to doctors and other health care workers. Different contexts, cultures, and points in the pandemic curve may have contributed to differing patterns of psychological outcomes amongst nurses in various Asia-Pacific countries. It is important that all health care workers practice self-care and render peer support to bolster psychological resilience for effective coping. In addition, this study also demonstrated the potential use of decision tree-based machine learning models and SHAP value plots in identifying contributing factors of sophisticated problems in the health care industry.

ZnFe2O4-Ni5P4 Mott-Schottky Heterojunctions to Promote Kinetics for Advanced Li-S Batteries.

The practical progress of lithium-sulfur batteries is hindered by the serious shuttle effect and the slow oxidation-reduction kinetics of polysulfides. Herein, the ZnFe2O4-Ni5P4 Mott-Schottky heterojunction material is prepared to address these issues. Benefitting from a self-generated built-in electric field, ZnFe2O4-Ni5P4 as an efficient bidirectional catalysis regulates the charge distribution at the interface and accelerates electron transfer. Meanwhile, the synergy of the strong adsorption capacity derived from metal oxides and the outstanding catalytic performance that comes from metal phosphides strengthens the adsorption of polysulfides, reduces the energy barrier during the reaction, accelerates the conversion between sulfur species, and further accelerates the reaction kinetics. Hence, the cell with ZnFe2O4-Ni5P4/S harvests a high discharge capacity of 1132.4 mAh g-1 at 0.5C and displays a high Coulombic efficiency of 99.3% after 700 cycles. The ZnFe2O4-Ni5P4/S battery still maintains a capacity of 610.1 mAh g-1 with 84.4% capacity retention after 150 cycles at 0.1C under a high sulfur loading of 3.2 mg cm-2. This work provides a favorable reference and advanced guidance for developing Mott-Schottky heterojunctions in lithium-sulfur batteries.

A Decreased Absolute Number of Treg Cells in Patients with Active Rheumatoid Arthritis is Associated with Elevated Serum Osteopontin Levels with Disease Progression.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic and refractory autoimmune disease characterized by synovial inflammation with unknown aetiology. Immune system dysfunction mediated by CD4+ T lymphocytes, which is regulated by the cytokine osteopontin (OPN), plays an important role in the pathogenesis of RA. METHODS: In this study, the levels of peripheral CD4+ T subsets and serum OPN in patients with active RA were measured and analysed to determine the possible pathogenesis of RA and to provide potential therapeutic targets. RESULTS: Serum OPN levels in both patients with active RA and patients with refractory RA were higher than those in healthy controls (HCs). Compared with HCs, the absolute numbers of Th2 cells increased in patients with active RA, while the absolute counts of Th1 and Treg cells decreased. There was no significant difference in CD4+ T subset levels between new-onset and refractory patients. As the condition persisted or deteriorated, a gradual increase in the levels of OPN and gradual declines in the absolute counts of Th1 and Treg cells were observed in patients with active RA. The fewest Th1 and Treg cells and the highest OPN levels were observed in patients with high disease activity. The serum OPN level was only significantly negatively correlated with the absolute counts of Treg cells in the CD4+ T lymphocyte subsets. CONCLUSIONS: Fewer Treg cells with the increase in disease activity may be related to the increased OPN concentration, which may provide new ideas and directions for the targeted immunoregulatory treatment of RA.

Increased glycolysis in skeletal muscle coordinates with adipose tissue in systemic metabolic homeostasis.

Insulin-independent glucose metabolism, including anaerobic glycolysis that is promoted in resistance training, plays critical roles in glucose disposal and systemic metabolic regulation. However, the underlying mechanisms are not completely understood. In this study, through genetically manipulating the glycolytic process by overexpressing human glucose transporter 1 (GLUT1), hexokinase 2 (HK2) and 6-phosphofructo-2-kinase-fructose-2,6-biphosphatase 3 (PFKFB3) in mouse skeletal muscle, we examined the impact of enhanced glycolysis in metabolic homeostasis. Enhanced glycolysis in skeletal muscle promoted accelerated glucose disposal, a lean phenotype and a high metabolic rate in mice despite attenuated lipid metabolism in muscle, even under High-Fat diet (HFD). Further study revealed that the glucose metabolite sensor carbohydrate-response element-binding protein (ChREBP) was activated in the highly glycolytic muscle and stimulated the elevation of plasma fibroblast growth factor 21 (FGF21), possibly mediating enhanced lipid oxidation in adipose tissue and contributing to a systemic effect. PFKFB3 was critically involved in promoting the glucose-sensing mechanism in myocytes. Thus, a high level of glycolysis in skeletal muscle may be intrinsically coupled to distal lipid metabolism through intracellular glucose sensing. This study provides novel insights for the benefit of resistance training and for manipulating insulin-independent glucose metabolism.

Characteristics and reference ranges of CD4+T cell subpopulations among healthy adult Han Chinese in Shanxi Province, North China.

BACKGROUND: Immunophenotyping of blood lymphocytes is an essential tool to evaluate the immune function of patients with immunodeficiency or autoimmunity. Predominately identified CD4+T cell subsets, Th1, Th2, Th17, as well as regulatory T (Treg) cells, play crucial roles in several immunological and pathological conditions. Considering the variations in cell counts among populations and ethnicities, specific CD4+T cell subset reference values need to be locally established to enable meaningful comparisons and accurate data interpretation in clinical and research settings. Therefore, the aim of this study was to establish distributions and reference ranges for blood CD4+T cell subpopulations in age- and sex-balanced healthy adults of a Han Chinese population in Shanxi Province, North China. METHODS: Peripheral blood CD4+T cell subsets were examined in 150 healthy volunteers (75 males, 75 females) aged 20-70 years with a four-color FACSCalibur flow cytometer. RESULTS: Reference value percentages (absolute counts, cells/µl) were defined as 95% of the population for cell types as follows: CD4+T, 23.78-51.07 (360-1127); Th1, 0.43-39.62 (2.64-276.21); Th2, 0.27-3.57 (1.80-27.14); Th17, 0.22-2.62 (1.10-19.54); and Treg, 2.17-7.94 (13.47-64.58). The ranges for the Th1:Th2 and Th17:Treg ratios were 0.59-52.37 and 0.04-0.76, respectively. Notably, a significant increase was observed in the values of Treg cells in older individuals, and the numbers of Treg cells in females also tended to decrease when compared to those in males. Therefore, we established the distribution and reference range of CD4+T cell subsets based on age and sex, demonstrating the lowest values of Treg cells in younger females. CONCLUSIONS: Collectively, our data provide population-, age-, and sex-specific distributions and reference ranges of circulating CD4+T cell subpopulations, which can be adopted to guide clinical decisions and interpretation of immunophenotyping data in the Han Chinese population in Taiyuan, Shanxi Province, China. In addition, the low expression of peripheral Treg cells in younger females may be associated with the predisposition of females to autoimmune diseases.

[Effect of Polyvinyl Alcohol/Graphene Oxide Aerogel on the Biological Characteristics of Acute Leukemia Cell Lines].

OBJECTIVE: To investigate the effects of polyvinyl alcohol (PVA) + graphene oxide (GO, weight content 1 wt%) aerogel three-dimensional (3D) scaffolds culture system on the proliferation, phenotype and drug resistance of ALL cell line Jurkat and AML cell line HL-60. METHODS: Jurkat cells and HL-60 cells were seeded in PVA+GO aerogel scaffolds for culture, and the structure of cells were observed by the scanning electron microscopy. Cell proliferation activity was measured by Cell Counting Kit-8 (CCK-8), cell phenotypes were analyzed by flow cytometry after fluorescent staining, then were compared with 2D cultured cells. Ara-C was used in drug resistance experiment, and CCK8 was used to detected cell proliferation activity. RESULTS: The proliferation activity of Jurkat cells grown in aerogel scaffolds was higher than that by 2D cultured in long-term culture. However, in HL-60 cells, the proliferation activity on 3D scaffold only at the 8th to 20th day was higher than that on the traditional 2D culture. Expression of CD4 in Jurkat cells increased after culture for 30 days, but the cell phenotypes in the 3D aerogel scaffolds were similar to 2D cultured cells. Phenotype of HL-60 cells was certainly changed after culture for 30 days, the cells can be divided into CD13+CD14-CD45+HLA-DR+,CD13-CD14--CD45+HLA-DR+ and CD13-CD14-CD45+HLA-DR- groups, and a new CD13+CD14-CD45-HLA-DR+ group of cells appeared in the cells cultured in 3D scaffolds, but not in 2D cultured cells. Drug resistance experiments showed that Jurkat cells in aerogel scaffolds have stronger drug resistance than those in 2D culture. CONCLUSION: PVA+GO (1 wt%) aerogel scaffolds can improve the proliferation and drug resistance of leukemia cells, and the phenotypes were the same as those in 2D culture, which can be used for cell amplification and biology characteristics studies and drug experiments. However, cell phenotypes should be analyzed before culture, and the effects of phenotypes changes on drug resistance should be eliminated.

Sirolimus selectively increases circulating Treg cell numbers and restores the Th17/Treg balance in rheumatoid arthritis patients with low disease activity or in DAS28 remission who previously received conventional disease-modifying anti-rheumatic drugs.

OBJECTIVES: Regulatory T (Treg) cells are crucial players in the prevention of autoimmunity. Mechanistic target of rapamycin (mTOR) signalling negatively controls the development and function of Treg cells. The aim of the present study was to evaluate the effects of rapamycin, under the generic name sirolimus, on CD4+CD25+FoxP3+ Treg cells in rheumatoid arthritis (RA) patients with low disease activity or in DAS28 remission. METHODS: Fifty-five RA patients and 60 healthy controls were enrolled in this study. All patients had previously received conventional disease-modifying anti-rheumatic drugs (DMARDs) and were considered to have a low DAS28 score (≤3.2). Peripheral blood samples and clinical information were obtained at baseline and following 6 and 12 weeks of sirolimus treatment, or after 12 weeks of conventional treatment. Peripheral blood samples were also obtained from the healthy controls. The circulating levels of lymphocyte subpopulations were assessed by flow cytometry. RESULTS: Thirty-five patients received sirolimus and 20 patients continued treatment with conventional DMARDs. The absolute counts and proportions of CD4+CD25+FoxP3+ Treg cells were significantly lower in all RA patients with DAS28 ≤ 3.2 as compared with those in healthy controls. By contrast, the difference in circulating Th17 cell numbers was not significant. Sirolimus administration resulted in elevations in circulating Treg cell numbers and significant reductions in the Th17/Treg cell ratio, whereas the circulating level of Treg cells and the Th17/Treg cell ratio in patients under conventional treatment both showed a tendency of reduction. Furthermore, a greater proportion of patients under sirolimus treatment achieved DAS28-based remission at 12 weeks. CONCLUSIONS: Sirolimus can favourably expand Treg cells in RA patients with DAS28 ≤3.2, consequently restoring a healthy balance of Th17/Treg cells, which might improve the likelihood of long-term and sustained clinical remission and reduce the probability of disease flare-ups in RA.

Low-Dose Sirolimus Immunoregulation Therapy in Patients with Active Rheumatoid Arthritis: A 24-Week Follow-Up of the Randomized, Open-Label, Parallel-Controlled Trial.

BACKGROUND: We have reported previously the insufficient absolute number or functional defects of regulatory T cells (Tregs) in patients with rheumatoid arthritis (RA), challenging conventional unspecific immunosuppressive therapy. Sirolimus, a mTOR inhibitor, is reported to allow growth of functional Tregs; here, we investigated the efficacy of low-dose sirolimus combined with conventional immunosuppressants (sirolimus immunoregulation therapy) for RA treatment with lower side effects and better tolerance. METHODS: In this nonblinded and parallel-group trial, we randomly assigned 62 patients to receive conventional glucocorticoids and immunosuppressants with or without sirolimus at a dosage of 0.5 mg on alternate days for 24 weeks in a 2 : 1 ratio. The demographic features, clinical manifestations, and laboratory indicators including peripheral blood lymphocyte subgroups and CD4+T subsets were compared before and after the treatment. RESULTS: Finally, 37 patients in the sirolimus group and 18 in the conventional treated group completed the 6-month study. By 24 weeks, the patients with sirolimus experienced significant reduction in disease activity indicators including DAS28, ESR, and the number of tender joints and swollen joints (p < 0.001). Notably, they had a higher level of Tregs as compared with those with conventional therapy alone (p < 0.05), indicating that sirolimus could partly restore the reduced Tregs. Concomitantly, their usage of immunosuppressants for controlling disease activity was decreased as compared with the conventional group with no difference in blood routine, and liver and renal functions both before and after the treatment of sirolimus and between the two groups (p > 0.05). CONCLUSIONS: Low-dose sirolimus immunoregulatory therapy selectively upregulated Tregs and partly replaced the usage of immunosuppressants to control disease activity without overtreatment and evaluable side effect. Further study is required using a large sample of RA patients treated with sirolimus for a longer period. This trial is registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=17245).

Effectiveness of domestic recombinant follicle stimulating hormone in the course of controlled ovarian hyperstimulation using long protocol in patients with different ovarian reserve function / 中国实用妇科与产科杂志

OBJECTIVE: To explore the effect of domestic recombinant follicle stimulating hormone(rFSH)in the course of controlled ovarian hyperstimulation using long protocol in patients with different ovarian reserve functions.METHODS: A retrospective cohort study was made on 1284 patients who were treated with in vitro fertilization/intracytoplasmic sperm injection-embryo transfer with standard long protocol for ovulation induction from January 2016 to January 2018 in Reproductive Medicine Center,Yuhuangding Hospital of Yantai. According to their AMH level,they were divided into normal ovarian reserve group(AMH:1.2-4.5μg/L,678 patients)and high response group(AMH>4.5μg/L,606 patients).Each group was divided into domestic rFSH subgroup(Jinsaiheng)(340 patients in normal ovarian reserve group,330 patients in high response group)and imported rFSH subgroup(338 patients in normal ovarian reserve group,276 patients in high response group)according to the different use of gonadotrophin on the start-up day.The clinical and laboratory indexes of the two subgroups were compared under different ovarian reserve functions.RESULTS: Regardless of normal or high ovarian reserve function,there was no significant difference in Gn dosage[(1983.15±510.00)U vs.(1913.32±422.12)U,P=0.053;(1816.86±506.37)U vs.(1786.63±453.90)U,P=0.44],days of Gn[(8.96±1.33)days vs.(8.87±1.24)days,P=0.36;(9.45±1.51)days vs.(9.44±1.47)days,P=0.91],dosage of Hermetic[(144.20±67.39)U vs.(143.42±56.73)U,P=0.86;(149.52±62.38)U vs.(160.21±84.87)U,P=0.09],number of eggs obtained(8.14±3.57 vs.8.44±3.37,P=0.25;11.47±4.74 vs.11.66±4.49,P=0.62),MⅡoocyte rate(82.08% vs. 82.01%,P=0.96;82.78% vs. 82.94%,P=0.90),fertilization rate(82.17% vs. 80.98%,P=0.30;80.75% vs. 82.16%,P=0.33),cleavage rate(94.55% vs. 93.91%,P=0.52;94.12% vs. 94.84%,P=0.49),blastocyst formation rate(58.43% vs. 59.55%,P=0.69;61.14% vs. 63.09%,P=0.46),clinical pregnancy rate(59.49% vs. 56.54%,P=0.54;62.84% vs.58.70%,P=0.57),early abortion rate(7.36% vs. 6.80%,P=0.42;11.30% vs. 11.11%,P=0.93)or the incidence of moderate to severe ovarian hyperstimulation syndrome(OHSS)(3.53% vs. 4.73%,P=0.71;7.58% vs. 9.06%,P=0.53)between the two subgroups.However,the daily LH level of HCG in domestic rFSH group was significantly higher than that in imported rFSH group[(2.83±1.31)U/L vs.(2.49±1.14)U/L,P=0.007;(2.35±1.10)U/L vs.(2.11±0.94)U/L,P=0.005].In the normal ovarian reserve group,the daily E2 concentration of HCG and the number of follicles above 1.6 cm in the domestic rFSH group were lower,but the rate of good quality embryos was significantly higher(67.23% vs. 62.51%,P=0.038),the difference being statistically significant(P=0.038).CONCLUSION: Domestic rFSH has the same clinical pregnancy outcome as imported rFSH after ovulation induction,but domestic rFSH has higher LH concentration on hCG day after ovulation induction,and patients with normal ovarian reserve have higher good quality embyro rate after using domestic rFSH.

Exploring predictors of medication adherence among inpatients with schizophrenia in Singapore's mental health settings: A non-experimental study.

Schizophrenia is a mental disorder, which is marked by frequent relapses. The main reason for relapse is nonadherence to antipsychotics. A cross-sectional, correlational research study was conducted with a convenience sample of 92 participants. The primary aim of this study was to explore the predictors of medication adherence among inpatients with schizophrenia hospitalised at tertiary hospitals in Singapore. Post-hoc analysis revealed that insight, religion, side effects, types of antipsychotics, social support from significant others, nurse-client relationship, were significant predictive factors. Results from this study added knowledge to the nursing literature about medication adherence of schizophrenia patients and in Singapore setting.

Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits IL-6/sIL-6R-induced RANKL expression in fibroblast-like synoviocytes via suppression of the JAK2/STAT3 and p38MAPK signaling pathway.

Although conventional combination therapy is effective for most patients with rheumatoid arthritis (RA), many still do not respond to current therapies. Therefore, novel combination regimens that better target cellular processes involved in RA pathogenesis are required. Preliminary studies have demonstrated the beneficial effects of a combination of cyclophosphamide (CTX) and methotrexate (MTX) in models of RA. Using western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and immunofluorescent staining, we demonstrated that the combination of 4-hydroperoxy CTX (4-H-CTX) and MTX inhibited the expression of receptor activator of nuclear factor-κB ligand (RANKL) in fibroblast-like synoviocytes (FLS) treated with the interleukin (IL)-6/soluble IL-6 receptor (sIL-6R) complex. To elucidate the mechanisms underlying this effect, we treated RA-FLS with the JAK2/STAT3 inhibitor AG490 or p38MAPK inhibitor SB203580. The results showed that IL-6/sIL-6R-induced RANKL upregulation required phosphorylation-mediated activation of STAT3 and p38 signaling, and that 4-H-CTX and/or MTX inhibited RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3 and p38MAPK signaling. This study demonstrated for the first time the inhibitory effects of 4-H-CTX and MTX on RANKL expression in IL-6/sIL-6R-stimulated FLS via suppression of STAT3 and p38MAPK phosphorylation. These results identify promising therapeutic agents that might have clinical applications in patients with RA who are at high risk of bone erosion or do not respond well to conventional therapy.

Nurses' perception of knowledge, attitudes and reported practice towards patients with eating disorders: A concurrent mixed-methods study.

Eating disorders are complex disorders requiring specialised care, thus knowledge and attitudes are crucial for management. This study aims to examine nurses' knowledge, attitudes, reported practice, and perceptions towards patients with eating disorders in Singapore. A concurrent mixed-methods study was carried out in Southeast Asia's only psychiatric unit with eating disorders programme. Twenty nurses were recruited using census sampling. Quantitative data were analysed with descriptive and inferential statistics, while qualitative data were analysed with content and thematic analysis. Certain personal factors were associated with nurses' levels of perceived knowledge. Different attitudes towards managing these patients were identified during interview sessions.