Comparison of the efficacy and safety of leflunomide versus placebo combined with basic prednisone therapy in patients with active disease phase of Takayasu arteritis: study protocol for a randomized, double-blinded controlled trial (Takayasu arteritis clinical trial in China: TACTIC).

Background: Takayasu arteritis (TAK) is an immune-induced granulomatous vasculitis that occurs primarily in young Asian women. Our previous cohort studies have indicated that leflunomide (LEF), which can lead to rapid induction and might be a promising alternative treatment for TAK. Objectives: To compare the efficacy and safety of LEF versus placebo combined with prednisone for active TAK in a Chinese population. Design: This will be a multicenter, randomized, double-blinded controlled trial aiming to recruit 116 TAK patients with active disease. This study will last 52 weeks. Methods and analysis: Participants will be assigned randomly to the LEF intervention arm or placebo control arm at a 1:1 ratio. Initially, LEF combined with prednisone will be given to the intervention arm and a placebo tablet combined with prednisone will be given to the placebo arm. At the end of week 24, subjects who achieved clinical remission or partial clinical remission will proceed to maintenance therapy with LEF to the end of week 52; those who did not achieve clinical remission or partial clinical remission in the LEF intervention arm will drop out from the study, and those in the placebo control arm will switch to LEF treatment to week 52. The primary endpoint will be the clinical remission rate of LEF versus placebo at the end of week 24. The secondary endpoints will be the time to clinical remission, mean dose of prednisone, disease recurrence, time to recurrence, adverse events, as well as clinical remission in subjects who switched from the placebo control arm to LEF therapy after week 24. Intention to treat will be the primary analysis. Discussion: This is the first randomized double-blinded placebo-controlled trial to clarify the efficacy and safety of LEF in treating active TAK. The results will provide more evidence for TAK management. Registration: ClinicalTrials.gov identifier: NCT02981979.

Association between long-term ambient air pollution exposure and the risk of breast cancer: a systematic review and meta-analysis.

Breast cancer is a complex and multifactorial disease which stems significantly from both environmental and genetic factors. A growing number of epidemiological studies have suggested that ambient air pollution (AAP) exposure may play an important role in breast cancer development. However, no consistency has been reached concerning whether high levels of air pollutant exposure were related to increased breast cancer risk among the current evidence. To further clarify such association of long-term AAP exposure with risk of breast cancer, a systematic review and meta-analysis of available evidence was performed. An extensive literature search in 3 academic databases was conducted before March 10, 2020. The risk of bias (RoB) for each individual study was evaluated with a domain-based assessment tool, developed by the National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT). Meta-estimates for air pollutant-breast cancer combinations were calculated for a standardized increment in exposure by random-effect models. The confidence level in the body of evidence and the certainty of evidence was also assessed for each air pollutant-breast cancer combination. The initial search identified 5446 studies, and 18 of them were eligible. The pooled analysis found an increased risk of breast cancer was associated with an increase in each 10 µg/m3 in nitrogen dioxide (NO2) exposure (hazard ratio (HR) = 1.02, 95% confidence interval (CI) = 1.01, 1.04), while particulate matter with aerodynamic diameters ≤ 2.5 µm and 10 µm (PM2.5, PM10) revealed no statistically significant associations with breast cancer risk. Our evaluation on the certainty of evidence indicates that there was a "moderate level of evidence" in the body of evidence for an association of NO2 exposure with an increased breast cancer risk and an "inadequate level of evidence" in the body of evidence for an association of PM2.5 and PM10 exposure with an increased breast cancer risk. Our study suggests long-term exposure to NO2 is related to an increased risk of breast cancer. However, in consideration of the limitations, further studies, especially performed in developing countries, with improvements in exposure assessment, outcome ascertainment, and confounder adjustment, are needed to draw a definite evidence of a causal relationship.

Investigation on factors related to uterine fibroids in rural women of northern Anhui province.

AIM: Given the increasing prevalence of hysteromyoma among the Chinese rural women of childbearing age, it is imperative that more attention should be given to researching risk factors that predispose women to this condition so that early preventive measures may be taken. Our study investigates potential risk factors for uterine fibroids such as participants' demographic characteristics (age, ethnicity, education), physiological characteristics (age at menarche, primiparous age), and the occurrence of several different female reproductive diseases (vaginitis, pelvic inflammatory disease). METHODS: 2200 rural women of reproductive age were screened from a cross-sectional study carried out in the northern Anhui province. Data were collected by questionnaire surveys, gynecological and laboratory examinations and were subjected to univariate and multivariate analysis to evaluate the risk factors for uterine fibroids. RESULTS: Of the 2200 women, 440 had uterine fibroids. In general, women with endometriosis, ovarian cysts and early menarche were more likely to suffer from hysteromyoma. Factors including higher parity, late age of first childbirth, and a regular menstrual cycle were associated with the reduced risk of uterine fibroids. CONCLUSIONS: Our findings indicate that parameters such as earlier age of menarche, early primiparous age, lower parity and a variety of female reproductive diseases were associated with an increased risk of uterine fibroids. These findings may be used to guide the formulation of effective prevention and intervention protocols to improve the reproductive health of rural women.

Effectiveness of Oil-Layered Albumin Microbubbles Produced Using Microfluidic T-Junctions in Series for In Vitro Inhibition of Tumor Cells.

This work focuses on the synthesis of oil-layered microbubbles using two microfluidic T-junctions in series and evaluation of the effectiveness of these microbubbles loaded with doxorubicin and curcumin for cell invasion arrest from 3D spheroid models of triple negative breast cancer (TNBC), MDA-MB-231 cell line. Albumin microbubbles coated in the drug-laden oil layer were synthesized using a new method of connecting two microfluidic T-mixers in series. Double-layered microbubbles thus produced consist of an innermost core of nitrogen gas encapsulated in an aqueous layer of bovine serum albumin (BSA) which in turn, is coated with an outer layer of silicone oil. In order to identify the process conditions leading to the formation of double-layered microbubbles, a regime map was constructed based on capillary numbers for aqueous and oil phases. The microbubble formation regime transitions from double-layered to single layer microbubbles and then to formation of single oil droplets upon gradual change in flow rates of aqueous and oil phases. In vitro dissolution studies of double-layered microbubbles in an air-saturated environment indicated that a complete dissolution of such bubbles produces an oil droplet devoid of a gas bubble. Incorporation of doxorubicin and curcumin was found to produce a synergistic effect, which resulted in higher cell deaths in 2D monolayers of TNBC cells and inhibition of cell proliferation from 3D spheroid models of TNBC cells compared to the control.

Regional difference in the susceptibility of non-alcoholic fatty liver disease in China.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a global health problem with high geographic heterogeneity. We aimed to investigate regional-specific concomitant rate of NAFLD and quantitative relationship between liver fat content (LFC) and glucose metabolism parameters in representative clinical populations from six provinces/municipalities of China. RESEARCH DESIGN AND METHODS: A total of 2420 eligible Han Chinese were enrolled consecutively from 10 clinics of obesity, diabetes and metabolic diseases located at six provinces/municipalities of China, and divided into North (Tianjin, Shandong and Heilongjiang) and South (Shanghai, Jiangsu and Henan) groups according to their geographical latitude and proximity of NAFLD concomitant rate. LFC was assessed by a quantitative ultrasound method. Multivariate regression models and analysis of covariance were used to assess the regional difference in the risk of NAFLD. RESULTS: The concomitant rate of NAFLD was 23.3%, 44.0% and 55.3% in individuals with normal glucose tolerance (NGT), pre-diabetes and diabetes, respectively. A higher concomitant rate of NAFLD was found in the participants from the North comparing with the South group, regardless of glucose metabolism status (34.7% vs 16.2% in NGT, 61.5% vs 34.7% in pre-diabetes and 67.1% vs 48.1% in diabetes). This regional difference remained significant after adjustment for age, gender, alcohol drinking, cigarette smoking, confounding metabolic parameters and liver enzymes. For any given blood glucose, participants from the North had higher LFC than those from the South group. CONCLUSIONS: Half of Han Chinese with pre-diabetes/type 2 diabetes had NAFLD, and the individuals from the North cities were more susceptible to NAFLD.

Verticillium dahliae VdTHI20, Involved in Pyrimidine Biosynthesis, Is Required for DNA Repair Functions and Pathogenicity.

Verticillium dahliae (V. dahliae) infects roots and colonizes the vascular vessels of host plants, significantly reducing the economic yield of cotton and other crops. In this study, the protein VdTHI20, which is involved in the thiamine biosynthesis pathway, was characterized by knocking out the corresponding VdTHI20 gene in V. dahliae via Agrobacterium tumefaciens-mediated transformation (ATMT). The deletion of VdTHI20 resulted in several phenotypic defects in vegetative growth and conidiation and in impaired virulence in tobacco seedlings. We show that VdTHI20 increases the tolerance of V. dahliae to UV damage. The impaired vegetative growth of ΔVdTHI20 mutant strains was restored by complementation with a functional copy of the VdTHI20 gene or by supplementation with additional thiamine. Furthermore, the root infection and colonization of the ΔVdTHI20 mutant strains were suppressed, as indicated by green fluorescent protein (GFP)-labelling under microscope observation. When the RNAi constructs of VdTHI20 were used to transform Nicotiana benthamiana, the transgenic lines expressing dsVdTHI20 showed elevated resistance to V. dahliae. Together, these results suggest that VdTHI20 plays a significant role in the pathogenicity of V. dahliae. In addition, the pathogenesis-related gene VdTHI20 exhibits potential for controlling V. dahliae in important crops.

An in vitro Evaluation of the Effect of Transient Electromagnetic Fields on Pacemakers and Clinical Mitigation Measures.

Background: The effect of transient electromagnetic fields on the function of pacemakers is not well-evaluated. There is a lack of effective methods for clinicians to reduce electromagnetic susceptibility (EMS) during implantation of pacemakers. This study aimed to evaluate whether a novel method of handling the excess leads in the pocket can lower the EMS of pacemakers and consequently reduce the effect of electromagnetic interference caused by transient electromagnetic fields on pacemakers. Methods: An in vitro chest model was established to simulate the clinical condition of dual-chamber pacemaker implantation. Three different intertwining patterns of excess leads were examined: parallel, twisted once, and multiple twisted-pair. Oscillated currents were injected into a copper electrical wire set horizontally above the model to create a radiated magnetic field to simulate the transient daily electromagnetic exposure of pacemakers. The electromagnetic induction of current was measured. The occurrence of EMS-related adverse events was evaluated when the induced pulsed voltage was applied. Results: Transient electromagnetic fields can induce electromagnetic noise in the pacing loop and inhibit the release of pacing pulses. The multiple twisted-pair intertwining pattern of excess leads was associated with a lower induced voltage amplitude than both the parallel and once-twisted patterns (P < 0.001). Even once twisted could significantly reduce induced voltage amplitude compared to not twisted (P < 0.001). A lower incidence of pacing inhibition was also observed in the multiple twisted-pair group than in the other two groups (P < 0.001). Conclusions: Transient electromagnetic fields can cause pacing inhibition. Twisting the excess leads for multiple turns in the pocket is an effective method to reduce the EMS of the dual-chamber pacemaker.

Dorsoventral photosynthetic asymmetry of tobacco leaves in response to direct and diffuse light.

Plants can change leaf forms, adjusting light conditions on their adaxial and abaxial surfaces, to adapt to light environments and enhance their light use efficiencies. The difference between photosynthesis on the two leaf sides (dorsoventral asymmetry) is an important factor that affects light use efficiency. However, photosynthetic dorsoventral asymmetry is rarely compared under direct and diffuse light conditions. To estimate the impacts of recently reported alterations in direct and diffuse light in the sky radiation on plant carbon assimilation, variations in morphology between the two leaf sides in tobacco (Nicotiana tabacum L.) were investigated, and the dorsoventral responses of photosynthesis to illuminating directions were compared in direct and diffuse light. Dorsoventral asymmetry was reflected in stomatal densities, anatomic structures, and photochemical traits, which caused markedly different photosynthetic rates as well as stomatal conductances both in direct and diffuse light. However, the degree of photosynthetic asymmetry was weakened in diffuse light. The diffuse light caused a greater stomatal conductance on the abaxial side than direct light, which resulted in reduced photosynthetic asymmetry. In addition, the photosynthetic dorsoventral asymmetry could be affected by the photosynthetic photon flux density. These results contribute to understanding the dorsoventral regulation of photosynthesis in bifacial leaves, and provide a reference for breeding to cope with the increase in the proportion of diffuse light in the future.

Calpain-10 drives podocyte apoptosis and renal injury in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a progressive microvascular complication of diabetes mellitus (DM), driven largely by podocyte apoptosis. The cysteine protease Calpain 10 is known to augment apoptosis and necrosis, and is a potential therapeutic target in DN. METHODS: Type 2 diabetes was induced in SD rats by high-fat diet (HFD) feeding and streptozotocin (STZ) injections, and simulated in vitro by culturing conditionally immortalized mouse podocytes in hyperlipidemic (PA, 100 µM) conditions. The rate of apoptosis in the renal tissues and cultured podocytes was determined by TUNEL assay. The expression of Calpain 10 and its biological effects were assayed by real-time PCR, Western blotting, immunofluorescence and electron microscopy. RESULTS: Calpain 10 was up-regulated in the kidneys of DN rats, as well as immortalized mouse podocytes. High levels of Calpain 10 was associated with renal dysfunction and tissue destruction, and podocyte injury and apoptosis. Knockdown of Calpain 10 protected podocytes by decreasing apoptosis rate, and upregulated nephrin. CONCLUSION: Calpain 10 is a pro-apoptotic factor in DN, and can be targeted for treating glomerular diseases.

Formation Mechanism, Geometric Stability and Catalytic Activity of a Single Iron Atom Supported on N-Doped Graphene.

Based on density functional theory (DFT) calculations, the formation geometries, stability and catalytic properties of single-atom iron anchored on xN-doped graphene (xN-graphene-Fe, x=1, 2, 3) sheet are systemically investigated. It is found that the different kinds and numbers of gas reactants can effectively regulate the electronic structure and magnetic properties of the 3 N-graphene-Fe system. For NO and CO oxidation reactions, the coadsorption configurations of NO/O2 and CO/O2 molecules on a reactive substrate as the initial state are comparably analyzed. The NO oxidation reactions through the Langmuir-Hinshelwood (LH) and Eley-Rideal (ER) mechanisms have relatively smaller energy barriers than those of the CO oxidation processes. In comparison, the preadsorbed 2NO reacting with 2CO molecules (2NO+2CO→2CO2 +N2 ) through ER reactions (<0.4 eV) are energetically more favorable processes. These results can provide beneficial references for theoretical studies on NO and CO oxidation and designing graphene-based catalyst for toxic gas removal.

Astragaloside IV inhibits glucose-induced epithelial-mesenchymal transition of podocytes through autophagy enhancement via the SIRT-NF-κB p65 axis.

Both autophagy and podocyte epithelial-mesenchymal transition (EMT) are critical factors in glomerular diseases that involve proteinuria and fibrosis. Here, we sought to determine whether plant-derived saponin astragaloside IV (AS-IV) was able to reverse renal fibrosis and improve renal function through regulation of autophagy and podocyte EMT. Cultured immortalized mouse podocytes and KK-Ay mice models of diabetes were exposed to AS-IV. Western blotting, real-time PCR, immunofluorescence and histochemistry were used to analyze markers of autophagy and podocyte EMT. We observed that AS-IV inhibited glucose-induced podocyte EMT and enhanced autophagy by decreasing NF-κB subunit p65 acetylation as well as increasing Sirtuin1 (SIRT1) expression. Treatment of the cells and animal models with a SIRT1 inhibitor EX527 was able to reverse these effects. The SIRT1 activator SRT1720 was also found to decrease p65 acetylation and enhance autophagy in glucose-induced podocyte EMT. Additionally, further treatment with autophagy inhibitor 3-methyladenine was able to reverse the effects of AS-IV on podocyte EMT, while the autophagy activator rapamycin or the NF-κB pathway inhibitor ammonium pyrrolidinedithiocarbamate (PDTC) were able to reverse glucose-induced podocyte EMT. Notably, both renal fibrosis and renal function in diabetic KK-Ay mice were improved after treatment with AS-IV. These findings support AS-IV as a renoprotective agent that likely exerts its effects on podocyte EMT through modulation of the SIRT1-NF-κB pathway and autophagy activation. Further studies are required to clarify the role of AS-IV as a potential therapeutic agent in glomerular diseases.

Astragaloside IV represses high glucose-induced mesangial cells activation by enhancing autophagy via SIRT1 deacetylation of NF-κB p65 subunit.

AIM: Mesangial cell (MC) activation plays an important role in many glomerular diseases associated with renal fibrosis, including diabetic kidney disease (DKD). The aim of this study was to determine whether Astragaloside IV (AS-IV) modulated MC activation in DKD via autophagy by specifically regulating the autophagy inducer sirtuin 1 (SIRT1). METHODS: Cultured MCs and diabetic KK-Ay mice were treated with AS-IV, and the markers and regulatory mediators of autophagy were analyzed using Western blotting, real-time PCR, ELISA and IF. RESULTS: AS-IV inhibited MC activation and enhanced autophagy in hyperglycemic conditions by increasing SIRT1 expression and decreasing NF-κB p65 acetylation. In addition, the SIRT1 activator SRT1720 enhanced autophagy and decreased p65 acetylation during hyperglycemia-induced MC activation. Opposite effects were seen with the SIRT1 inhibitor EX527. Furthermore, the ameliorative effect of AS-IV on MCs was abolished by the autophagy inhibitor 3-MA, while the autophagy activator rapamycin restored hyperglycemia-induced MC activation. Finally, AS-IV improved renal function and fibrosis in the diabetic KK-Ay mice. CONCLUSION: AS-IV ameliorated renal function and morphology by inducing autophagy and inhibiting MC activation through the SIRT1-NF-κB pathway, indicating a potential therapeutic role of AS-IV in glomerular diseases.

Genotypic Diversity and Epidemiology of Human Rhinovirus Among Children With Severe Acute Respiratory Tract Infection in Shanghai, 2013-2015.

Human rhinovirus (HRV), and particularly HRV-C, is increasingly recognized as a cause of severe acute respiratory infections (SARIs). However, little is known about the genotypic diversity and epidemiology of HRV among children with SARI. Thus, we investigated the genotypic diversity and epidemiology of HRV in children with SARI in China over a 2-year period. In total 1,003, nasopharyngeal aspirates were collected from children hospitalized with SARI in Shanghai from 2013 to 2015. HRV was screened for by a PCR method targeting the viral 5' UTR and was genotyped by sequencing of the VP4-VP2 region of the HRV genome. We also screened for 15 other common respiratory viruses to assess the prevalence of co-infection with HRV. The patient demographic and clinical data were reviewed. HRV was detected in 280 (27.9%) of the 1,003 specimens: HRV-A in 140 (14.0%), HRV-B in 21 (2.1%), HRV-C in 56 (5.6%), and HRV-untyped in 63 (6.3%). A phylogenetic analysis identified 77 genotypes (43 HRV-A, 10 HRV-B, and 24 HRV-C), among which A78, A12, A89, B70, C2, C6, and C24 predominated. HRV-A was detected mainly in winter 2013 and autumn 2014, while HRV-C detection peaked in autumn 2013 and 2014. The detection frequency of HRV-A was highest in patients <5 years old. Most HRV co-infections involved adenovirus, human bocavirus, and/or human respiratory syncytial virus. In conclusion, HRV-A and -C predominate in children with SARI in Shanghai. Among the 77 genotypes detected, A78, A12, A89, B70, C2, C6, and C24 were the most frequent. The HRV species responsible for SARIs differs according to season and age.

Serum triglyceride, high-density lipoprotein cholesterol, apolipoprotein B, and coronary heart disease in a Chinese population undergoing coronary angiography.

BACKGROUND: Increased serum triglyceride and apolipoprotein B (apoB) levels and decreased high-density lipoprotein cholesterol (HDL-C) levels are risk factors for cardiovascular diseases. The major types of dyslipidemia in Chinese population are hypertriglyceridemia and low HDL-C. OBJECTIVE: This study aimed to evaluate the effect of HDL-C, triglyceride, and apoB levels on the risk of coronary heart disease (CHD) in a Chinese population undergoing coronary angiography. METHODS: This was a cross-sectional study. A total of 1941 consecutive patients who were referred to coronary angiography for the evaluation of suspected CHD were recruited. Lipid parameters were measured after an overnight fast. Patients were diagnosed with CHD and without CHD based on the findings of the coronary angiography. RESULTS: There were 1363 angiography confirmed CHD patients and 578 non-CHD patients. In nonstatin users, the major types of dyslipidemia were hypertriglyceridemia combined with low HDL-C, isolated low HDL-C, and isolated hypertriglyceridemia, accounting for 21.60%, 19.70%, and 14.99%, respectively. In statin users, a low to moderate-intensity statin was effective in lowering low-density lipoprotein cholesterol (LDL-C). The proportion of reaching an LDL-C goal <2.6 mmol/L and <1.8 mmol/L in statin users was 83.20% and 55.19%, respectively. In nonstatin users, the triglyceride and apoB levels were higher and the HDL-C levels were lower in CHD patients compared with non-CHD patients after the adjustment of age, sex, body mass index, diabetes, smoking, and alcohol drinking (P = .002, .007, and .005, respectively). After adjusting for age, sex, body mass index, diabetes, hypertension, smoking and alcohol drinking, the quartiles of triglyceride, HDL-C, and apoB were associated with CHD (P for trend = .001, .005, and .003, respectively). CONCLUSION: Serum triglyceride, HDL-C, and apoB levels were independently associated with CHD in a Chinese population undergoing coronary angiography with a relatively low level of LDL-C and a high prevalence of hypertriglyceridemia and low HDL-C.