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Sinomenine (SIN) is commonly used as part of rheumatoid arthritis (RA) therapy in China, but there is still no published evidence of the efficacy of SIN monotherapy. This work investigates the efficacy and safety of SIN in treating RA patients and analyzes the correlation between ornithine level and the alleviation of disease activity in RA patients. In this 24 week, randomized, placebo-controlled, double-blind clinical trial, people with mild to moderate RA were randomly assigned (1:1:1, stratified by hospital) to receive SIN (120 mg, twice daily), methotrexate (MTX) (10 mg per week), or SIN + MTX therapy. The primary outcome was the proportion of patients who achieved a 50% improvement in the American College of Rheumatology (ACR) criteria at week 24 and who showed improvement according to the clinical disease activity index (CDAI). In this prospective subgroup analysis, we also assessed whether the 24 week alterations of disease activity in the treatment group were significantly correlated to the levels of blood ornithine. Of the 135 enrolled participants, 38, 39, and 36 patients were treated with SIN, MTX, and SIN + MTX, respectively. In the SIN-treated group, 52.63% of patients achieved ACR50 after 24 weeks of treatment, which was comparable to the results in the MTX-treated and SIN + MTX-treated groups. Hepatic and gastrointestinal disorders were the main adverse events; however, the ratio of patients suffering from hepatic disorder in the SIN group (1/38) was much lower than that in the MTX (10/39) and SIN + MTX (8/36) groups. A total of 221 serum samples were collected at the four follow-up time points in the three treatments, and the levels of ornithine, citrulline, and arginine were obtained through ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS). The serum ornithine level decreased after the 24 week treatment along with a decrease in disease activity, and may reflect therapeutic responses with a sensitivity value of 80%. In conclusion, SIN revealed a comparable efficacy to MTX for treating RA patients, but with fewer side effects. In addition, the serum ornithine level was found for the first time to have a close correlation with the alleviation of RA, which shows the value of this measure as an assessment indicator of drugs in treating RA.

ObjectivesTo evaluate the clinical and economic consequences of continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) in children and adolescents with type 1 diabetes mellitus (T1DM) from a public health care system in developed areas of developing country, considering changes in glycemic Control, daily insulin requirements, lipid profile, body mass index (BMI), frequency of severe hypoglycemia and Diabetic Ketoacidosis (DKA) and diabetic complications.MethodsThis was a retrospective cohort study of children and adolescents with T1DM. Data were collected at baseline and the end of every year including glycated hemoglobin (HbA1c), insulin dose, lipid profile, blood pressure, and adverse events (severe hypoglycemia and DKA). The Cost-effectiveness analysis was performed using the IQVIA CORE Diabetes Model (CDM) to simulate diabetes progression by utilizing the clinical data obtained from the two groups. The main outcome measures were Life Expectancy, Quality adjusted life years (QALYs), Total Costs and Incremental Costs and Effectiveness Ratio (ICER) of CSII compared with MDI in Chinese pediatric patients with T1DM in Qingdao City (60 years).ResultsMean HbA1c values and daily insulin doses were significantly lower in those receiving CSII therapy throughout follow-up. Mean direct lifetime costs were ¥ 67,137 higher with CSII treatment than with MDI for pediatric patients. Treatment with CSII was associated with an improvement in life expectancy of 0.41 years for pediatric patients compared with MDI based on CORE diabetes model simulation. The corresponding gains in QALYs were 0.42. These data produced corresponding ICER is ¥ 161,815 per QALY for pediatric T1DM patients in Qingdao. Sensitivity analyses suggested that our base-case assumptions were mostly robust.ConclusionsCSII is associated with improved long‐term clinical outcomes compared with MDI. Based on this model analysis, CSII appears to be more cost-effective for the Qingdao TIDM pediatric population and health care system.

Background Limited data is available on retinal vessel morphology in the north China. The study aimed to evaluate the prevalence of retinal vascular abnormalities (RVAs) and investigate their associations with the self-reported diagnosis of cardiovascular and cerebrovascsular diseases (CCVds) in a rural adult population of northeast China. Methods A population-based, cross-sectional study was conducted, using the cluster random sampling method. One eye of each participant was photographed with a non-mydriatic fundus camera. RVAs including focal and general arteriolar narrowing (FAN and GAN), arteriovenous nicking (AVN), arteriolar sheathing (AS), and retinopathy were evaluated. Data on self-reported diagnosis of cardiovascular and cerebrovascular diseases and status of smoking and alcohol drinking were obtained from questionnaires. Results Among the 6267 participants with an age ≥ 50 years, photographs were obtained of 99.2%, with quality sufficient to perform retinal evaluations in 82.5%. The prevalence of FAN, AVN, AS, retinopathy and GAN were 9.1, 8.9, 5.0, 6.6 and 6.2%, respectively. All the retinal lesions were associated with hypertension (all P Conclusions The overall prevalence of retinal microvascular abnormalities in this population was relatively higher than that reported in other regions of the world. Retinopathy is associated with the self-reported diagnosis of stroke while AVN was associated with the self-reported diagnosis of CHD, but the remaining retinal lesions were not consistently associated with CCVds. Thus, an examination of retinal microvascular characteristics may offer clues to CCVds and could be a potentially novel biomarkers for CCVds risk.

Endothelial dysfunction is associated with the risk of cardiovascular complications in diabetic patients. Endothelial progenitor cells (EPCs) and flow-mediated dilation (FMD) are common markers of endothelial function. In this study, we aim to investigate whether the DPP-4 inhibitor saxagliptin modulate EPCs number and FMD in newly diagnosed, treatment-naive type 2 diabetic patients. This was a controlled, randomized, open-label clinical trial. Saxagliptin group and metformin group consumed either saxagliptin 5 mg per day or metformin 1 500 mg per day respectively for 12 weeks. Changes of FMD and EPCs number after 12-week intervention were the primary endpoints. 31 patients were initially enrolled and randomized to saxagliptin group (n=16) and metformin group (n=15). 27 patients completed the trial (saxagliptin group n=14 and metformin group n=13), and 4 patients dropped out during the study. FMD and EPCs number increased significantly in both saxagliptin group and metformin group, and there was no significant difference between groups. 2-h postprandial plasma glucose, HbA1c and diastolic blood pressure improved significantly in both groups, and there was no significant difference between groups. Saxagliptin and metformin had comparable beneficial effects on endothelial function.

A novel and selective spectrofluorometric method for pyrophosphate (PPi) assay in aqueous solution was developed in this contribution on the basis of the enhanced fluorescence intensity of trypsin-stabilized copper clusters (CuNCs). Mechanism investigation showed that PPi can make the CuNCs dispersed, concomitantly resulting in the improved quantum yield and the enhanced fluorescence emission of the CuNCs. A good linear relationship in the range of 78 μM–20 mM was achieved between the enhanced fluorescence intensity of the CuNCs at 455 nm and the logarithm of PPi concentration with the detection limit (3σ) of 101 nM. By this approach, we can achieve simple, fast and inexpensive detection of PPi.

PURPOSE To identify differential changes in proteins and metabolites underlying "fast" type 1 (T1DC) and "slow" type 2 (T2DC) diabetic cataract (DC) formation in rat. METHODS Rat models of types 1 and 2 diabetes consisted of streptozotocin injection without and with high-fat diet, respectively. Cataract progression was examined weekly. At week 6, total protein changes were comparatively and quantitatively assessed by two-dimensional differential in-gel electrophoresis (2-D DIGE) coupled with mass spectrometry, and relevant metabolic changes were examined. Differences in high molecular weight (HMW) crystallin species between diabetic and control lenses were similarly identified. RESULTS Cataracts were morphologically different and progressed more slowly in T2DC versus T1DC. αA-crystallin, βB2-crystallin, and βA4-crystallin were significantly decreased in both DC types versus control. αB-crystallin was increased while βB1-crystallin was markedly decreased in T2DC. In T1DC, γB-crystallin and γS-crystallin fragmentation were increased. High-fat diet by itself had little impact, except for lowering γS-crystallin fragmentation. Despite significantly decreased opacity, a greater decrease in intermediate filaments (IFs) and more HMW crystallin species were observed in T2DC versus T1DC. However, aldose reductase expression and activity and sorbitol levels were increased to a greater extent in T1DC, while reduced glutathione (GSH) and reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) levels were decreased to a greater extent and adenosine triphosphate (ATP) level was much lower in T1DC versus T2DC. CONCLUSIONS The results suggest that osmotic damage, GSH loss, and decreased ATP production might be important pathological mechanisms in T1DC formation, whereas crystallin modification and cross-linking/aggregation as well as IF degradation may play more crucial roles in T2DC formation.

A new autofluorescent and pH-sensitive multifunctional drug release system is developed in this contribution by layer-by-layer assembly of chitosan (CHI)/dialdehyde starch (DAS) polyelectrolyte multilayers (PEM) onto mesoporous silica nanoparticles (MSN) surface. The formed mesoporous silica composites can be used as drug delivery carriers, which have very slow drug release rate at pH 7.4, but have very fast drug release rate at pH 5.0 owing to the breakage of C N bonds of the CHI/DAS multilayers under acidic condition. As a proof of concept, folic acid (FA) has been conjugated to the outer surface of the mesoporous silica composites by the amide reaction in order to deliver target anticancer drug, and it is found that cellular uptake of the folate conjugated doxorubicin-loaded nanoparticles in folate receptor-overexpressing HeLa cells is much higher than that of non-folate receptor-overexpressing A549 cells, indicating that successful targeting drug release has realized.

A new type of highly selective aptamer-labeled fluorescent silica nanoparticles [Apt-tris(2,2′-bipyridyl)ruthenium(II)@SiO2 NPs] were prepared through the reverse microemulsion method by using prolonged fluorescence lifetime ruthenium complexes of tris(2,2′-bipyridyl)ruthenium(II) (Ru(bpy) 3 2+ ) as the source of the fluorescence for cellular prion protein imaging. Investigations showed that the newly prepared Ru(bpy) 3 2+ @SiO2 NPs possessed superior advantages of strong fluorescence, low toxicity, and easy surface modification for bioconjugation. Cell imaging experiments indicated that Apt-Ru(bpy) 3 2+ @SiO2 NPs had great tendency to human bone marrow neuroblastoma cells (SK-N-SH cells), since they can express large amount of prion protein on the surface of the cell, while in HeLa cells this phenomenon disappeared for the reason that HeLa cells cannot express prion proteins.

In this contribution, an organic small molecule (OSM)-participating interaction between its aptamer and graphene oxide (GO) is investigated by taking coralyne as an example. Based on their interactions, a simple, rapid, highly sensitive and selective fluorometric method for the detection of coralyne is developed. GO can effectively quench the fluorescence of dye-labeled aptamer, while stronger binding of the aptamer and its target can make the fluorescence be recovered, which have been well demonstrated by the studies of the fluorescence spectra, fluorescence anisotropy, and circular dichroism spectra. In this case, the coralyne can be quantificationally detected by the variation of the fluorescence intensity, where GO acts as an efficient signal-to-background enhancer. With the increase of the coralyne, the fluorescence intensity increases gradually and linearly proportional to the concentration of the coralyne in the range of 10-700 nmol L(-1). This method is reliable, and has been successfully applied for the detection of coralyne in complicated matrixes.

Here, a rapid, simple and sensitive method for visual detection of tetracycline antibiotics (TCs) was developed based on the turned on fluorescence induced by a metal-organic coordination polymer of Zn(bix) [bix=1,4-bis(imidazol-1-ylmethyl)benzene]. Tetracycline antibiotics, such as tetracycline hydrochloride (TC), doxycycline hyclate (DC), chlortetracycline hydrochloride (CTC) and oxytetracyline hydrochloride (OTC), showed very weak fluorescence in Tris-HCl buffer of pH 8.68-9.40. However, the fluorescence intensities of these TCs were greatly enhanced in the presence of Zn(bix) and were found to be proportional to the concentrations of TCs. Accordingly, TCs could be quantitatively determined with the detection limits of 12.0, 6.0, 19.0 and 19.0nM for TC, DC, CTC and OTC, respectively. Furthermore, this fluorimetric method was successfully applied to the determination of DC contents in doxycycline hyclate tablets from three factories with satisfactory results compared with the HPLC method. Also, the interaction mechanism between TCs and Zn(bix) was investigated by the absorption spectra, fluorescence spectra and circular dichroism spectra. The results showed that TCs could interact with Zn(bix) to form TCs-Zn(bix) ternary complexes and the turned on fluorescence was mainly ascribed to the restricted conformational rotation of TCs molecules through coordination with Zn(II) from the polymeric networks of Zn(bix).

A label-free and sensitive fluorescence method for recognition of sequence-specific DNA using DNA-intercalating dye and metal–organic frameworks (MOFs) is developed. Here, MIL-101 (Cr3F(H2O)2O[(O2C)–C6H4–(CO2)]3·nH2O) is introduced as a quenching platform to decrease the high background fluorescence of SYBR Green I (SG)/probe DNA complex. Mechanism investigations show that MIL-101 can strongly adsorb the SG/probe DNA complex through π–π stacking and electrostatic interactions, and as a consequence, the fluorescence of the SG dye is greatly quenched. While in the presence of target DNA, the as-formed rigid double-stranded (ds) structure of DNA will be far away from the surface of MIL-101; meanwhile, the SG dye can be bound with the dsDNA in the mode of intercalation and minor groove binding, resulting in enhancement of the SG dye fluorescence. The increased signal-to-background ratio has a linear relationship with the concentration of target DNA in the range of 0.1–14 nM. It is confirmed that the detection limit is 73 pM (3σ), which is much lower than that based on the carbon nanotubes and graphene oxide platform. Moreover, one-base-mismatched target DNA can be discriminated effectively. With the introduction of MIL-101, the signal-to-background ratio has been improved ∼8-fold, demonstrating that MIL-101 is an efficient low-background signal platform.

We proposed the coupling and competition of second harmonic generation (SHG) and acousto-optic (AO) interaction in periodically poled lithium niobate (PPLN). The reciprocal vector of PPLN compensates the SHG wave-vector mismatch when quasi-phase-matching (QPM) condition is satisfied, while phonons with suitable frequencies may affect it by scattering photons to different polarization state. Second harmonic waves' intensities, polarization states and even phases thus could be manipulated instantly through AO interaction.

Acousto-optic (AO) tunable second harmonic generation (SHG) was proposed in periodically poled lithium niobate (PPLN). The acoustic wave could either be induced from an external transducer or self-generated in PPLN driving with a cross-field radio frequency field. The reciprocal vector of PPLN compensates the SHG wave-vector mismatch when quasi-phase- matching (QPM) condition is satisfied, while phonons with suitable frequencies may affect it by scattering photons to different polarization state. The QPM SHG and AO polarization rotation are coupled together. Second harmonic waves' intensities, polarization states and even phases thus could be manipulated instantly through AO interaction.

In this paper, a new approach for respiratory syncytial virus (RSV) gene sequence detection was described based on the fluorescence resonance energy transfer (FRET) from oligonucleotide-templated silver nanoclusters (DNA–AgNCs) to multi-walled carbon nanotubes (MWCNTs). The specific DNA scaffold combines two fragments: one is enriched with a cytosine sequence fragment (C12) that can result in DNA–AgNCs with a high quantum yield via a chemical reduction method, and the other is the probe fragment (5′-AAA AAT GGG GCA AAT A-3′) which can selectively bind to the gene for RSV. Thus, the as-prepared AgNCs can exhibit enhanced fluorescence when binding to the target DNA sequence and forming a double helix. Because of the introduction of MWCNTs, which can quench the fluorescence of the DNA–AgNCs with an extraordinarily high quenching efficiency (85.8%), a relatively high signal-to-background ratio was achieved. The fluorescence ratio of the DNA–AgNCs was enhanced in a linearly proportional manner to the concentration of the target in the range of 31.25 nM to 2.00 μM with a detection limit (3σ) of 24.00 nM.

To identify an agent with specific activity against human lens epithelial cells (HLECs), we confirmed the presence of glucocorticoid receptors (GRs) and GR-α genes and evaluated whether GRs have a relationship with the apoptotic process in cultured HLECs. We also determined whether the inhibitor RU486 could rescue the cells from apoptosis when the HLECs were exposed to dexamethasone (Dex), a steroid, in 4 concentrations for 4 periods, or were co-treated with the antagonist RU486. We found that Dex, which has been used as a medical agent for a long time, resulted in increased expression of GRE-luciferase, the GR-α gene and GR-protein and, in contrast, decreased the viability of HLECs. The expression of Bax protein was increased in an earlier stage in contrast to the expression of Bcl-2 protein, which was increased in a later stage. Caspase-3 activity was significantly increased under lower concentrations of Dex in the last stage. The nuclear morphology of HLECs showed an obvious apoptotic phenomenon under greater concentrations of Dex in the last stage. However, RU486, a GR antagonist, could partially inhibit GR and Bax expressions and the expression of caspase-3 was increased so that there was not a decrease in the ratio of apoptotic cells and an increase in the viability of HLECs. Our data showed that GRs had a partial relationship to the apoptotic process of HLECs when exposed to Dex and RU486 did not rescue the cells fully. Because of its toxicity, RU486 did not provide a therapeutic benefit in a glucocorticoid induced cataract (GIC) for the in vitro model, however, its activity and pathway targeting should still be studied further with appropriate drug combinations.