Combining multiple continuous tests for the diagnosis of kidney impairment in the absence of a gold standard

Receiver operating characteristic (ROC) curves are commonly used to summarize the classification accuracy of diagnostic tests. It is not uncommon in medical practice that multiple diagnostic tests are routinely performed or multiple disease markers are available for the same individuals. When the true disease status is verified by a gold standard (GS) test, a variety of methods have been proposed to combine such potential correlated tests to increase the accuracy of disease diagnosis. In this article, we propose a method of combining multiple diagnostic tests in the absence of a GS. We assume that the test values and their classification accuracies are dependent on covariates. Simulation studies are performed to examine the performance of the combination method. The proposed method is applied to data from a population-based aging study to compare the accuracy of three screening tests for kidney function and to estimate the prevalence of moderate kidney impairment.     

Local magnetic delivery of adeno-associated virus AAV2(quad Y-F)-mediated BDNF gene therapy restores hearing after noise injury

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Effect of antimicrobial peptides HNP-1 and hBD-1 on Staphylococcus aureus strains in vitro and in vivo

The aims of this study were: (i) To investigate the activity of recombinant AMPs HNP-1 and hBD-1 in combination with cefotaxime against Staphylococcus aureus strains (MSSA and MRSA) in vitro using checkerboard method; (ii) To investigate the activity of HNP-1 and hBD-1 encapsulated in silicon nanoparticles (niosomes) in the treatment of MRSA-infected wound in rats. For this S. aureus strains (MSSA and MRSA) were isolated from patients with diabetic foot infection. Cefotaxime, recombinant HNP-1 and hBD-1 (in all possible combinations with each other) were used for testing by the checkerboard method. Two niosomal topical gels with HNP-1/hBD-1 were prepared to treat MRSA-infected wounds in rats. Gels were administered once a day, the control group–without treatment. Wound healing rate was calculated on the 4th, 9th and 16th days of the experiment and compared using one-way ANOVA with Bonferroni correction. MIC of HNP-1 for MSSA and MRSA was the same–1 mg/L. MIC of hBD-1 for MSSA and MRSA was also the same–0.5 mg/L. Topical gels with niosomal HNP-1 (or hBD-1) showed a significantly faster wound healing in comparison with the control. The data obtained open up prospects for use of AMPs encapsulated in silica nanoparticles for the development of new antibiotics.     

Drug-loaded gold/iron/gold plasmonic nanoparticles for magnetic targeted chemo-photothermal treatment of rheumatoid arthritis

We have developed methotrexate (MTX)-loaded poly(lactic-co-glycolic acid, PLGA) gold (Au)/iron (Fe)/gold (Au) half-shell nanoparticles conjugated with arginine-glycine-aspartic acid (RGD), which can be applied for magnetic targeted chemo-photothermal treatment, and in vivo multimodal imaging of rheumatoid arthritis (RA). Upon near-infrared (NIR) irradiation, local heat is generated at the inflammation region due to the NIR resonance of Au half-shells and MTX release from PLGA nanoparticles is accelerated. The Fe half-shell layer embedded between the Au half-shell layers enables in vivo T₂-magnetic resonance (MR) imaging in addition to NIR absorbance imaging. Furthermore, the delivery of the nanoparticles to the inflammation region in collagen-induced arthritic (CIA) mice, and their retention can be enhanced under external magnetic field. When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects with an MTX dosages of only 0.05% dosage compared to free MTX therapy for the treatment of RA.     

Macrophage repolarization with targeted alginate nanoparticles containing IL-10 plasmid DNA for the treatment of experimental arthritis

In this study, we have shown for the first time the effectiveness of a non-viral gene transfection strategy to re-polarize macrophages from M1 to M2 functional sub-type for the treatment of rheumatoid arthritis (RA). An anti-inflammatory (IL-10) cytokine encoding plasmid DNA was successfully encapsulated into non-condensing alginate based nanoparticles and the surface of the nano-carriers was modified with tuftsin peptide to achieve active macrophage targeting. Enhanced localization of tuftsin-modified alginate nanoparticles was observed in the inflamed paws of arthritic rats upon intraperitoneal administration. Importantly, targeted nanoparticle treatment was successful in reprogramming macrophage phenotype balance as ∼66% of total synovial macrophages from arthritic rats treated with the IL-10 plasmid DNA loaded tuftsin/alginate nanoparticles were in the M2 state compared to ∼9% of macrophages in the M2 state from untreated arthritic rats. Treatment significantly reduced systemic and joint tissue pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) expression and prevented the progression of inflammation and joint damage as revealed by magnetic resonance imaging and histology. Treatment enabled animals to retain their mobility throughout the course of study, whereas untreated animals suffered from impaired mobility. Overall, this study demonstrates that targeted alginate nanoparticles loaded with IL-10 plasmid DNA can efficiently re-polarize macrophages from an M1 to an M2 state, offering a novel treatment paradigm for treatment of chronic inflammatory diseases.     

Preparation,characterization and in vitro activities evaluation of solid lipid nanoparticles based on PEG-40 stearate for antifungal drugs vaginal delivery

The present article reports the preparation, characterization and performance evaluation of solid lipid nanoparticles (SLNs) based on polyoxyethylene-40 stearate (PEG-40 stearate) for the administration of antifungal agents such as ketoconazole and clotrimazole. These nanoparticles could be useful in the treatment of vaginal infections sustained by Candida albicans. In particular, PEG-40 stearate was made to react with acryloyl chloride in order to introduce an easily polymerizable moiety for the creation of a second shell and to ensure a slow drug release. In addition, the differences on the release profiles between PEG-40 stearate-based nanoparticles, PEG-40 stearate acrylate based and polymerized ones, were analyzed under conditions, simulating the typical environment of Candida albicans infection. Then, the antifungal activity of nanoparticles was also evaluated in terms of minimal inhibitory concentration. Moreover, the nanoparticles were submitted to in vitro studies for evaluating the drug permeability at the site of action. Results indicated that the obtained particles are potentially useful for the treatment of vaginal infections sustained by Candida albicans.     

Gender difference in hepatic toxicity of titanium dioxide nanoparticles after subchronic oral exposure in Sprague‐Dawley rats

Existing literature pointed out that the liver may be the target organ of toxicity induced by titanium dioxide nanoparticles (TiO₂ NPs) via oral exposure. Gender differences in health effects widely exist and relevant toxicological research is important for safety assessment. To explore the gender susceptibility of TiO₂ NP‐induced hepatic toxicity and the underlying mechanism, we examined female and male Sprague‐Dawley rats administrated with TiO₂ NPs orally at doses of 0, 2, 10 and 50 mg/kg body weight per day for 90 days. The serum biochemical indicators and liver pathological observation were used to assess hepatic toxicity. We found significant hepatic toxicity could be induced by subchronic oral exposure to TiO₂ NPs, which was more obvious and severe in female rats. No accumulation of TiO₂ NPs in the liver was observed, indicating that hepatic toxicity may not be caused through direct pathways. Oxidized glutathione, lipid peroxidation products increased significantly and reduced glutathione decreased significantly in the liver of rats in repeated TiO₂ NP‐exposed groups. Hematological parameters of white blood cells and inflammatory cytokines in serum including interleukin 1α, interleukin 4 and tumor necrosis factor also increased significantly. Indirect pathways through initiating oxidative stress and inflammatory responses were suggested as the possible mechanism of the hepatic toxicity in this experiment. The higher sensitivity to redox homeostasis imbalance and inflammation of female rats may be the main reason for gender differences. Our research suggested that gender should be a susceptible factor for identifying and monitoring long‐term oral toxicity of TiO₂ NPs.     

Lycopene and resveratrol ameliorate zinc oxide nanoparticles-induced oxidative stress in Nile tilapia,Oreochromis niloticus

Industrial products contained nano-zinc oxide (ZnONP) can gain access to the aquaculture environment causing hazardous effects on the living biota. Therefore, this work was planned to examine the ameliorative effects of dietary supplementation of lycopene (LYC) and/or resveratrol (RES) against ZnONP toxicity in Nile tilapia. Five groups with 20 fish each were used; Control, received tap water only; ZnONP group, was intoxicated with ZnONP (50 mg/L); ZnONP-LYC group, was exposed to ZnONP and LYC (500 mg/ kg of the diet); ZnONP-RES group, was exposed to ZnONP and RES (50 mg/kg of the diet); ZnONP-LYC-RES group, was exposed to ZnONP and a combination of LYC and RES. The experiment was continued for 30 days. Fish blood and tissues were then assembled for determination of liver and kidney function and oxidative stress status in liver, kidney, and gills tissue. Results revealed a considerable elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), cholesterol, urea, and creatinine with a noticeable lowering of total proteins and albumin serum levels in response to ZnONP intoxication. In addition, there were significant increase in malondialdehyde (MDA) and reduction in the reduced-glutathione (GSH) levels and superoxide dismutase (SOD) and catalase (CAT) activities. However, treatment with LYC and/or RES ameliorated the ZnONP-inflicted oxidative stress which possibly attributed to their beneficial antioxidant activities.