Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptor γ agonists

Background and Objectives The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD). Materials and Methods The PCK rat is a slowly progressing cystic model while the Wpk-/- rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4–28). Wpk-/- rats were fed with pharmacological (2.0 mg/kg BW) and sub-pharmacologic (0.2 mg/kg BW) doses of pioglitazone from day 5 to 18. At termination, kidney weights of treated versus untreated cystic animals were used to determine efficacy. The current studies were also compared with previous studies containing higher doses of PPARγ agonists. The concentrations used in the animals were calculated with reference to equivalent human doses for both drugs. Results The current studies demonstrate: 1) that low, pharmacologically relevant, doses of the PPARγ agonists effectively inhibit cyst growth; 2) there is a class action of the drugs with both commercially available PPARγ agonists, rosiglitazone, and pioglitazone, inhibiting cyst growth; 3) the drugs showed efficacy in two different preclinical cystic models. In the PCK rat, animals fed with a sub-pharmacological dose of rosiglitazone for 24 weeks had significantly lower kidney weights than untreated animals (3.68 ± 0.13 g vs. 4.17 ± 0. 11 g, respectively, P < 0.01) while treatment with a pharmacologic dose had no significant effect on kidney weight. The rapidly progressing Wpk-/- rats were fed with pharmacological and sub-pharmacologic doses of pioglitazone from day 5 to 18 and the kidneys were compared with non-treated, cystic animals. Kidney weights on the pharmacologic dose were not statistically lower than the untreated animals while rats fed a sub-pharmacologic dose showed a significant decrease compared with untreated animals (3.35 ± 0.15 g vs. 4.55 ± 0.46 g, respectively, P = 0.045). Conclusion Concentrations of PPARγ agonists below the human equivalent diabetic doses are effective in slowing cyst growth in two rodent models of PKD

A Cerberus‐Inspired Anti‐Infective Multicomponent Gatekeeper Hydrogel against Infections with the Emerging “Superbug” Yeast Candida auris

The pathogenic yeast Candida auris has received increasing attention due to its ability to cause fatal infections, its resistance toward important fungicides, and its ability to persist on surfaces including medical devices in hospitals. To brace health care systems for this considerable risk, alternative therapeutic approaches such as antifungal peptides are urgently needed. In clinical wound care, a significant focus has been directed toward novel surgical (wound) dressings as first defense lines against C. auris. Inspired by Cerberus the Greek mythological “hound of Hades” that prevents the living from entering and the dead from leaving hell, the preparation of a gatekeeper hybrid hydrogel is reported featuring lectin-mediated high-affinity immobilization of C. auris cells from a collagen gel as a model substratum in combination with a release of an antifungal peptide drug to kill the trapped cells. The vision is an efficient and safe two-layer medical composite hydrogel for the treatment of severe wound infections that typically occur in hospitals. Providing this new armament to the repertoire of possibilities for wound care in critical (intensive care) units may open new routes to shield and defend patients from infections and clinical facilities from spreading and invasion of C. auris and probably other fungal pathogens

Fundamentale Steuerreformen für Deutschland: die Unternehmensteuerreform 2008, die Duale Einkommensteuer und die Einheitssteuer im Vergleich

In den letzten Jahren wurde eine Vielzahl an Steuerreformvorschlägen in Deutschland unterbreitet. Zu den aktuellen gehören neben der Unternehmensteuerreform 2008 (UntSt-Reform), die Duale Einkommensteuer des Sachverständigenrates (DIT) und die Kirchhof'sche Einheitssteuer. Dieser Aufsatz quantifiziert und vergleicht die gesamtwirtschaftlichen Auswirkungen dieser Steuerreformvorschläge mithilfe des eigens für Deutschland entwickelten dynamischen, allgemeinen Gleichgewichtsmodells ifoMod. Wie die Ergebnisse zeigen, bewirken die DIT und die Einheitssteuer einen positiven Impuls auf das Wirtschaftswachstum, während sich die UntSt-Reform als leichte Wachstumsbremse herausstellt. Im Hinblick auf die Wohlfahrtsaspekte der Reformen erzielt lediglich die DIT positive Resultate. Die UntSt-Reform hemmt insbesondere die Investitionstätigkeit der Kapitalgesellschaften, da diese Unternehmen mit Einführung der Abgeltungssteuer auf Dividenden und Wertzuwächse einer Doppelbesteuerung unterliegen. Dennoch generiert diese als einzige Reform einen langfristigen Finanzierungsüberschuss.The past years have seen several tax reform proposals being put forward in Germany. The most prominent ones count the Business Tax Reform 2008 (BTR 2008), the Dual Income Tax (DIT) proposal advanced by the German Council of Economic Advisors and Kirchhof's flat tax. We analyze, compare and quantify the effects of these reform proposals by applying ifoMOD, a dynamic computable general equilibrium (CGE) model. ifoMOD was in particular developed to simulate the effects of capital income tax reforms for the German economy. The simulation results show that both the DIT and the flat tax have a positive stimulus for economic growth while the BTR 2008 slightly impedes growth. Regarding the welfare effects of the reforms, the DIT is the only reform proposal which achieves positive results. The BTR 2008 impedes in particular the investment activity of corporate firms since these are effectively subject to double taxation following the introduction of a withholding tax on dividends and capital gains. Nevertheless, this reform proposal is the only one which generates a financing surplus in the long run

Toxic Epidermal Necrolysis after Pemetrexed and Cisplatin for Non-Small Cell Lung Cancer in a Patient with Sharp Syndrome

Background: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees. Case Report: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone. Conclusion: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases

Rapid sediment re-deposition may limit carbon release during catastrophic thermokarst lake drainage

ACKNOWLEDGMENTS We thank Georgina Heldreich for valuable discussions on delta formation, and the two constructive anonymous reviews, which greatly improved the manuscript.Peer reviewedPublisher PD

Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism

Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production

International Society of Urological Pathology Consensus Conference on Current Issues in Bladder Cancer. Working Group 4

Molecular subtyping has been a major focus of bladder cancer research over the past decade. Despite many promising associations with clinical outcomes and treatment response, its clinical impact has yet to be defined. As part of the 2022 International Society of Urological Pathology Conference on Bladder Cancer, we reviewed the current state of the science for bladder cancer molecular subtyping. Our review included several different subtyping systems. We derived the following 7 principles, which summarize progress and challenges of molecular subtyping: (1) bladder cancer has 3 major molecular subtypes: luminal, basal-squamous, and neuroendocrine; (2) signatures of the tumor microenvironment differ greatly among bladder cancers, particularly among luminal tumors; (3) luminal bladder cancers are biologically diverse, and much of this diversity results from differences in features unrelated to the tumor microenvironment, such as FGFR3 signaling and RB1 inactivation; (4) molecular subtype of bladder cancer associates with tumor stage and histomorphology; (5) many subtyping systems include idiosyncrasies, such as subtypes recognized by no other system; (6) there are broad fuzzy borders between molecular subtypes, and cases that fall on these fuzzy borders are often classified differently by different subtyping systems; and (7) when there are histomorphologically distinct regions within a single tumor, the molecular subtypes of these regions are often discordant. We reviewed several use cases for molecular subtyping, highlighting their promise as clinical biomarkers. Finally, we conclude that data are currently insufficient to support the routine use of molecular subtyping to guide bladder cancer management, an opinion shared with the majority of conference attendees. We also conclude that molecular subtype should not be considered an "intrinsic" property of a tumor but should instead be considered the result of a specific laboratory test, performed using a specific testing platform and classification algorithm, validated for a specific clinical application

The Economic Crisis and Residential Electricity Consumption in Spanish Provinces: A Spatial Econometric Analysis

This paper presents an empirical analysis of residential electricity demand considering the existence of spatial effects. This analysis has been performed using aggregate panel data at the province level for 46 Spanish provinces for the period from 2001 to 2009. For this purpose, we estimated a log-log demand equation using a spatial autoregressive model with autoregressive disturbances (SARAR). The purpose of this empirical analysis is to determine the influence of price, income, and spatial spillovers on residential electricity demand in Spain. We are particularly interested in analyzing the impact of household disposable income variation across provinces observed during the economic crisis period from 2008-2009. The estimation results show relatively high income elasticity and relatively low price elasticity. Furthermore, the results show the presence of spatial effects in Spanish residential electricity consumption

Magnetic clouds in the solar wind: A numerical assessment study of analytical models

Magnetic clouds (MCs) are "magnetized plasma clouds" moving in the solar wind. MCs transport magnetic flux and helicity away from the Sun. These structures are not stationary but feature temporal evolution as they propagate in the solar wind. Simplified analytical models are frequently used for the description of MCs, and fit certain observational data well. The goal of the present study is to investigate numerically the validity of an analytical model which is widely used for the description of MCs, and to determine under which conditions this model's implied assumptions cease to be valid. A numerical approach is applied. Analytical solutions that have been derived in previous studies are implemented in a \textbf{3-D magnetohydrodynamic} simulation code as initial conditions. Initially, the analytical model represents the main observational features of the MCs. However, these characteristics prevail only if the structure moves with a velocity close to the velocity of the background flow. In this case an MC's evolution can quite accurately be described using an analytic, self-similar approach. The dynamics of the magnetic structures which move with a velocity significantly above or below that of the velocity of the solar wind is investigated in detail. Besides the standard case in which MCs only expand and propagate in the solar wind, the case of an MC rotating around its axis of symmetry is also considered, and the resulting influence on the MC's dynamics is studied