Low dose irinotecan improves advanced lupus nephritis in mice potentially by changing DNA relaxation and anti–double-stranded DNA binding

Objective Albeit clear advances in the treatment of SLE, many patients still present with refractory lupus nephritis requiring new treatment strategies for this disease. Here we determined whether reduced doses of the topoisomerase I inhibitor irinotecan, which is known as chemotherapeutic agent, were able to suppress SLE in NZB/W F1 mice. We further evaluated the potential mechanism how irinotecan influenced the course of SLE. Methods NZB/W F1 mice were treated with low dose irinotecan either from week 24 of age or from established glomerulonephritis defined by a proteinuria ≥grade 3+. Binding of anti-dsDNA antibodies was measured by ELISA; and DNA relaxation was visualized by gel electrophoresis. Results Significantly reduced irinotecan dosages improved lupus nephritis and prolonged survival in NZB/W F1 mice. The lowest dose successfully used for the treatment of established murine lupus nephritis was more than 50 times lower than the dose usually applied for chemotherapy in humans. As a mechanism, low dose irinotecan reduced B cell activity; however, the levels of B cell activity in irinotecan-treated mice were similar to those in Balb/c mice of the same age suggesting that irinotecan did not induce a clear immunosuppression. In addition, incubation of double-stranded (ds) DNA with topoisomerase I increased binding of murine and human anti-dsDNA antibodies showing for the first time that relaxed DNA is more susceptible to anti-dsDNA antibody binding. This effect was reversed by addition of the topoisomerase I inhibitor camptothecin. Conclusion Our results propose topoisomerase I inhibitors as a novel and targeted therapy for SLE. © 2014 American College of Rheumatology.

Selective uptake, distribution, and redistribution of Cd-109, Co-57, Zn-65, Ni-63, and Cs-134 via xylem and phloem in the heavy metal hyperaccumulator Solanum nigrum L

The focus of this article was to explore the translocation of Cd-109, Co-57, Zn-65, Ni-63, and Cs-134 via xylem and phloem in the newly found hyperaccumulator Solanum nigrum L. Two experiments with the uptake via the roots and transport of Cd-109, Co-57, and Zn-65 labeled by roots, and the redistribution of Cd-109, Zn-65, Co-57, Ni-63, and Cs-134 using flap label in S. nigrum in a hydroponic culture with a standard nutrient solution were conducted. The results showed that Cd-109 added for 24 h to the nutrient medium of young plants was rapidly taken up, transferred to the shoot, and accumulated in the cotyledons and the oldest leaves but was not efficiently redistributed within the shoot afterward leading to a rather low content in the fruits. In contrast, Co-57 was more slowly taken up and released to the shoot, but afterward, this element was redistributed from older leaves to younger leaves and maturing fruits. Zn-65 was rapidly taken up and transferred to the shoot (mainly to the youngest leaves and not to the cotyledons). Afterward, this radionuclide was redistributed within the shoot to the youngest organs and finally accumulated in the maturing fruits. After flap labeling, all five heavy metals tested (Cd-109, Co-57, Zn-65, Ni-63, Cs-134) were exported from the labeled leaf and redistributed within the plant. The accumulation in the fruits was most pronounced for Ni-63 and Zn-65, while a relatively high percentage of Co-57 was finally found in the roots. Cs-134 was roughly in the middle of them. The transport of Cd-109 differed from that previously reported for wheat or lupin and might be important for the potential of S. nigrum to hyperaccumulate cadmium.

Multiple inert gas elimination technique by micropore membrane inlet mass spectrometry--a comparison with reference gas chromatography.

The mismatching of alveolar ventilation and perfusion (VA/Q) is the major determinant of impaired gas exchange. The gold standard for measuring VA/Q distributions is based on measurements of the elimination and retention of infused inert gases. Conventional multiple inert gas elimination technique (MIGET) uses gas chromatography (GC) to measure the inert gas partial pressures, which requires tonometry of blood samples with a gas that can then be injected into the chromatograph. The method is laborious and requires meticulous care. A new technique based on micropore membrane inlet mass spectrometry (MMIMS) facilitates the handling of blood and gas samples and provides nearly real-time analysis. In this study we compared MIGET by GC and MMIMS in 10 piglets: 1) 3 with healthy lungs; 2) 4 with oleic acid injury; and 3) 3 with isolated left lower lobe ventilation. The different protocols ensured a large range of normal and abnormal VA/Q distributions. Eight inert gases (SF6, krypton, ethane, cyclopropane, desflurane, enflurane, diethyl ether, and acetone) were infused; six of these gases were measured with MMIMS, and six were measured with GC. We found close agreement of retention and excretion of the gases and the constructed VA/Q distributions between GC and MMIMS, and predicted PaO2 from both methods compared well with measured PaO2. VA/Q by GC produced more widely dispersed modes than MMIMS, explained in part by differences in the algorithms used to calculate VA/Q distributions. In conclusion, MMIMS enables faster measurement of VA/Q, is less demanding than GC, and produces comparable results.

Relationship between genome and epigenome - challenges and requirements for future research

Understanding the links between genetic, epigenetic and non-genetic factors throughout the lifespan and across generations and their role in disease susceptibility and disease progression offer entirely new avenues and solutions to major problems in our society. To overcome the numerous challenges, we have come up with nine major conclusions to set the vision for future policies and research agendas at the European level.

Die theokratische Frage. Zur politischen Ethik des Heidelberger Katechismus

Die politische Ethik des Heidelberger Katechismus zielt - anders als oft vermutet und reformierter Theologie unterstellt - nicht auf eine theokratische Gesellschaftsform, sondern schränkt die staatliche Autorität gerade ein. In der Fortführung und Präzisierung solcher politischer Ethik lässt sich - im Vergleich der Konzeptionen des reformierten Theologen Karl Barth und des französischen Philosophen Claude Lefort - geradezu eine spezifische Affinität von Protestantismus und Demokratie ausmachen, die mit der notwendigen Offenhaltung der Position der Macht zu tun hat.

The prevalence and predictive value of dipstick urine protein in HIV-positive persons in Europe.

INTRODUCTION Proteinuria (PTU) is an important marker for the development and progression of renal disease, cardiovascular disease and death, but there is limited information about the prevalence and factors associated with confirmed PTU in predominantly white European HIV+ persons, especially in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m(2). PATIENTS AND METHODS Baseline was defined as the first of two consecutive dipstick urine protein (DPU) measurements during prospective follow-up >1/6/2011 (when systematic data collection began). PTU was defined as two consecutive DUP >1+ (>30 mg/dL) >3 months apart; persons with eGFR <60 at either DPU measurement were excluded. Logistic regression investigated factors associated with PTU. RESULTS A total of 1,640 persons were included, participants were mainly white (n=1,517, 92.5%), male (n=1296, 79.0%) and men having sex with men (n=809; 49.3%). Median age at baseline was 45 (IQR 37-52 years), and CD4 was 570 (IQR 406-760/mm(3)). The median baseline date was 2/12 (IQR 11/11-6/12), and median eGFR was 99 (IQR 88-109 mL/min/1.73 m(2)). Sixty-nine persons had PTU (4.2%, 95% CI 3.2-4.7%). Persons with diabetes had increased odds of PTU, as were those with a prior non-AIDS (1) or AIDS event and those with prior exposure to indinavir. Among females, those with a normal eGFR (>90) and those with prior abacavir use had lower odds of PTU (Figure 1). CONCLUSIONS One in 25 persons with eGFR>60 had confirmed proteinuria at baseline. Factors associated with PTU were similar to those associated with CKD. The lack of association with antiretrovirals, particularly tenofovir, may be due to the cross-sectional design of this study, and additional follow-up is required to address progression to PTU in those without PTU at baseline. It may also suggest other markers are needed to capture the deteriorating renal function associated with antiretrovirals may be needed at higher eGFRs. Our findings suggest PTU is an early marker for impaired renal function.

Electrochemical simulation of phase I metabolism for 21 drugs using four different working electrodes in an automated screening setup with MS detection.

BACKGROUND Electrochemical conversion of xenobiotics has been shown to mimic human phase I metabolism for a few compounds. MATERIALS & METHODS Twenty-one compounds were analyzed with a semiautomated electrochemical setup and mass spectrometry detection. RESULTS The system was able to mimic some metabolic pathways, such as oxygen gain, dealkylation and deiodination, but many of the expected and known metabolites were not produced. CONCLUSION Electrochemical conversion is a useful approach for the preparative synthesis of some types of metabolites, but as a screening method for unknown phase I metabolites, the method is, in our opinion, inferior to incubation with human liver microsomes and in vivo experiments with laboratory animals, for example.

Minimally invasive photopolymerization in intervertebral disc tissue cavities

Photopolymerized hydrogels are commonly used for a broad range of biomedical applications. As long as the polymer volume is accessible, gels can easily be hardened using light illumination. However, in clinics, especially for minimally invasive surgery, it becomes highly challenging to control photopolymerization. The ratios between polymerization- volume and radiating-surface-area are several orders of magnitude higher than for ex-vivo settings. Also tissue scattering occurs and influences the reaction. We developed a Monte Carlo model for photopolymerization, which takes into account the solid/liquid phase changes, moving solid/liquid-boundaries and refraction on these boundaries as well as tissue scattering in arbitrarily designable tissue cavities. The model provides a tool to tailor both the light probe and the scattering/absorption properties of the photopolymer for applications such as medical implants or tissue replacements. Based on the simulations, we have previously shown that by adding scattering additives to the liquid monomer, the photopolymerized volume was considerably increased. In this study, we have used bovine intervertebral disc cavities, as a model for spinal degeneration, to study photopolymerization in-vitro. The cavity is created by enzyme digestion. Using a custom designed probe, hydrogels were injected and photopolymerized. Magnetic resonance imaging (MRI) and visual inspection tools were employed to investigate the successful photopolymerization outcomes. The results provide insights for the development of novel endoscopic light-scattering polymerization probes paving the way for a new generation of implantable hydrogels.

Attitudes of Swiss veterinarians towards pain and analgesia in dogs and cats.

A survey was performed to evaluate the use of perioperative analgesia in dogs and cats by veterinary practitioners. Questions were grouped in seven sections recording personal data, education in veterinary analgesia, general ideology regarding treatment of perioperative pain, personal experience, assessment, and use of main analgesics to treat perioperative pain. A total of 258 received forms were analyzed. Based on 5 questions, 88 % showed excellent motivation to use perioperative pain therapy. The main reason declared for the use of analgesics was to relieve the patient from pain (64.1 %). Most veterinarians reported to routinely administer analgesics before (71 - 96 %) or after (2 - 23 %) surgery. The most used analgesics were non-steroidal anti-inflammatory drugs (carprofen, meloxicam) and opioids (butorphanol, buprenorphine). Animals were routinely evaluated for pain after recovery. Only 43.8 % of veterinarians declared to use loco-regional anaesthesia. Swiss veterinarians appear to recognize well the need for perioperative pain treatment. However, weakness was shown in evaluating pain severity, distinguishing between opioid classes, and using loco-regional anaesthesia.

A compilation of Western European terrestrial records 60–8 ka BP: towards an understanding of latitudinal climatic gradients

Terrestrial records of past climatic conditions, such as lake sediments and speleothems, provide data of great importance for understanding environmental changes. However, unlike marine and ice core records, terrestrial palaeodata are often not available in databases or in a format that is easily accessible to the non-specialist. As a consequence, many excellent terrestrial records are unknown to the broader palaeoclimate community and are not included in compilations, comparisons, or modelling exercises. Here we present a compilation of Western European terrestrial palaeo-records covering, entirely or partially, the 60–8-ka INTIMATE time period. The compilation contains 56 natural archives, including lake records, speleothems, ice cores, and terrestrial proxies in marine records. The compilation is limited to include records of high temporal resolution and/or records that provide climate proxies or quantitative reconstructions of environmental parameters, such as temperature or precipitation, and that are of relevance and interest to a broader community. We briefly review the different types of terrestrial archives, their respective proxies, their interpretation and their application for palaeoclimatic reconstructions. We also discuss the importance of independent chronologies and the issue of record synchronization. The aim of this exercise is to provide the wider palaeo-community with a consistent compilation of high-quality terrestrial records, to facilitate model-data comparisons, and to identify key areas of interest for future investigations. We use the compilation to investigate Western European latitudinal climate gradients during the deglacial period and, despite of poorly constrained chronologies for the older records, we summarize the main results obtained from NW and SW European terrestrial records before the LGM.