An Overlapping Case of Lupus Nephritis and IgG4-Related Kidney Disease

We report a case of a 71-year-old Filipino female who was admitted to the hospital for abdominal pain, vomiting and diarrhea of 8 days duration. The patient was found to have marked acute kidney injury (AKI), which required hemodialysis in the next 3 days. Extensive workup revealed hematuria, subnephrotic range proteinuria, elevated anti-nuclear antibody (ANA) and elevated total immunoglobulin G (IgG) levels, with normal IgG4 and anti-dsDNA levels. On kidney biopsy, mild membranous glomerulonephritis was found, along with autoimmune tubulointerstitial nephritis (TIN) with a full-house pattern of immune deposits. These findings were suggestive of lupus interstitial nephritis. However, IgG4+ plasma cells were detected in the interstitium by immunostaining, favoring a diagnosis of IgG4-related kidney disease (IgG4-RKD). Our case highlights the difficulty in differentiating lupus nephritis (LN) from IgG4-RKD in some patients, raising the suspicion that these two entities can co-exist

Needs assessment of Independent Media in the neighbourhood - a summary of the report produced for the European Commission’s DG NEAR

This summary presents the top-level findings of an eight-month research project aimed at assessing the needs of independent media in the EU Neighbourhood (East and South). The study was carried out by four international experts who visited 11 of the 16 partner countries and conducted interviews with more than 500 representatives from independent media, media support organisations and state bodies. They also reviewed around 800 studies, reports and articles covering media landscapes in the two regions.The aim of this initiative was to promote a better understanding of the challenges faced by independent media outlets in the target countries as well as to identify and highlight their development priorities. The experts also assessed the extent to which EU funding mechanisms are effective and appropriate in providing support to these stakeholders. The findings presented in the final report which was submitted to DG NEAR in February 2020 will help to inform EU funding programmes for independent media over the next four or five years.The research highlighted clear opportunities in both regions for bilateral engagement. Operating in an increasingly competitive and politicised market, independent media outlets share an interest in accessing funding to develop new content and explore innovative formats, particularly those that appeal to social media audiences. They also recognise the pressing need to diversify their revenue streams and increase their resilience to external pressures

Modulation of BACE1 Activity by Chemically Modified Aptamers

A modified DNA aptamer that binds BACE1, a therapeutic target involved in Alzheimer's disease has been developed. This ssXNA not only tightly binds to BACE1 but also inhibits its protease activity in vitro in the same range as a previously described unmodified aptamer. We report the in vitro selection of functional oligonucleotides incorporating two nucleobase modifications: 5‐chlorouracil and 7‐deazaadenine. The nucleoside analogue 5‐chloro‐2′‐deoxyuridine has already been explored as a replacement for thymidine in a chemically modified genome of a bacterium. Thus, 5‐chlorouracil modification is a good candidate to support genetic transfer in vivo as well as functional activity

A Reverse Logistics Network Model for Handling Returned Products

58827Due to the emergence of e-commerce and the proliferation of liberal return policies, product returns have become daily routines for many companies. Considering the significant impact of product returns on the company’s bottom line, a growing number of companies have attempted to streamline the reverse logistics process. Products are usually returned to initial collection points (ICPs) in small quantities and thus increase the unit shipping cost due to lack of freight discount opportunities. One way to address this issue is to aggregate the returned products into a larger shipment. However, such aggregation increases the holding time at the ICP, which in turn increases the inventory carrying costs. Considering this logistics dilemma, the main objectives of this research are to minimize the total cost by determining the optimal location and collection period of holding time of ICPs; determining the optimal location of a centralized return centre; transforming the nonlinear objective function of the proposed model formulation by Min et al. (2006a) into a linear form; and conducting a sensitivity analysis to the model solutions according to varying parameters such as shipping volume. Existing models and solution procedures are too complicated to solve real-world problems. Through a series of computational experiments, we discovered that the linearization model obtained the optimal solution at a fraction of the time used by the traditional nonlinear model and solution procedure, as well as the ability to handle up to 150 customers as compared to 30 in the conventional nonlinear model. As such, the proposed linear model is more suitable for actual industry applications than the existing models.S

Ezrin Ubiquitylation by the E3 Ubiquitin Ligase, WWP1, and Consequent Regulation of Hepatocyte Growth Factor Receptor Activity

The membrane cytoskeleton linker ezrin participates in several functions downstream of the receptor Met in response to Hepatocyte Growth Factor (HGF) stimulation. Here we report a novel interaction of ezrin with a HECT E3 ubiquitin ligase, WWP1/Aip5/Tiul1, a potential oncogene that undergoes genomic amplification and overexpression in human breast and prostate cancers. We show that ezrin binds to the WW domains of WWP1 via the consensus motif PPVY477 present in ezrin’s C-terminus. This association results in the ubiquitylation of ezrin, a process that requires an intact PPVY477 motif. Interestingly ezrin ubiquitylation does not target the protein for degradation by the proteasome. We find that ezrin ubiquitylation by WWP1 in epithelial cells leads to the upregulation of Met level in absence of HGF stimulation and increases the response of Met to HGF stimulation as measured by the ability of the cells to heal a wound. Interestingly this effect requires ubiquitylated ezrin since it can be rescued, after depletion of endogenous ezrin, by wild type ezrin but not by a mutant of ezrin that cannot be ubiquitylated. Taken together our data reveal a new role for ezrin in Met receptor stability and activity through its association with the E3 ubiquitin ligase WWP1. Given the role of Met in cell proliferation and tumorigenesis, our results may provide a mechanistic basis for understanding the role of ezrin in tumor progression

Silver confined within zeolite EMT nanoparticles: preparation and antibacterial properties

The preparation of pure zeolite nanocrystals (EMT-type framework) and their silver ion-exchanged (Ag+-EMT) and reduced silver (Ag0-EMT) forms is reported. The template-free zeolite nanocrystals are stabilized in water suspensions and used directly for silver ion-exchange and subsequent chemical reduction under microwave irradiation. The high porosity, low Si/Al ratio, high concentration of sodium and ultrasmall crystal size of the EMT-type zeolite permitted the introduction of a high amount of silver using short ion-exchange times in the range of 2–6 h. The killing efficacy of pure EMT, Ag+-EMT and Ag0-EMT against Escherichia coli was studied semi-quantitatively. The antibacterial activity increased with increasing Ag content for both types of samples (Ag+-EMT and Ag0-EMT). The Ag0-EMT samples show slightly enhanced antimicrobial efficacy compared to that of Ag+-EMT, however, the differences are not substantial and the preparation of Ag nanoparticles is not viable considering the complexity of preparation steps

Impact of Safety-Related Dose Reductions or Discontinuations on Sustained Virologic Response in HCV-Infected Patients: Results from the GUARD-C Cohort.

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced ≥1 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with ≥1 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not ≥5. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin.This study was sponsored by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Support for third-party writing assistance for this manuscript, furnished by Blair Jarvis MSc, ELS, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland