Clastogenic effects of acrylamide in mouse bone marrow cells

Acrylamide, known to induce dominant-lethal mutations (Shelby et al., 1986; Smith et al., 1986) and heritable translocations (Shelby et al., 1987) in rodent germ cells, was hitherto a questionable clastogen in rodent bone marrow (Shiraishi, 1978). Therefore, it was tested for chromosomal aberrations in mouse bone marrow cells, spermatogonia and by the micronucleus test. The intraperitoneally injected doses ranged from 50 to 150 mg/kg. In the chromosomal bone marrow test and the micronucleus assay positive results were obtained with acrylamide, and in the latter test the effect increased linearly with dose. Chromosomal aberrations were not induced in differentiating spermatogonia by the acute acrylamide treatment. Cisplatin was used as a positive control and gave the expected positive response in all 3 tests. The present results demonstrate that acrylamide is no exception among clastogens. It breaks chromosomes not only in mammalian germ cells but also in somatic cells.     

Prototypes for automating product system model assembly

The International Journal of Life Cycle Assessment - The flexibility of life cycle inventory (LCI) background data selection is increasing with the increasing availability of data, but this comes...     

Emergy as a Life Cycle Impact Assessment Indicator

Founded in thermodynamics and systems ecology, emergy evaluation is a method to associate a product with its dependencies on all upstream environmental and resource flows using a common unit of energy. Emergy is thus proposed as an indicator of aggregate resource use for life cycle assessment (LCA). An LCA of gold mining, based on an original life cycle inventory of a large gold mine in Peru, is used to demonstrate how emergy can be incorporated as an impact indicator into a process‐based LCA model. The results demonstrate the usefulness of emergy in the LCA context. The adaptation of emergy evaluation, traditionally performed outside of the LCA framework, requires changes to the conventional accounting rules and the incorporation of uncertainty estimations of the emergy conversion factors, or unit emergy values. At the same time, traditional LCA boundaries are extended to incorporate the environmental processes that provide for raw resources, including ores. The total environmental contribution to the product, doré, is dominated by mining and metallurgical processes and not the geological processes forming the gold ore. The measure of environmental contribution to 1 gram (g) of doré is 6.8E + 12 solar‐equivalent Joules (sej) and can be considered accurate within a factor of 2. These results are useful in assessing a process in light of available resources, which is essential to measuring long‐term sustainability. Comparisons are made between emergy and other measures of resource use, and recommendations are made for future incorporation of emergy into LCA that will result in greater consistency with existing life cycle inventory (LCI) databases and other LCA indicators.     

Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis

Multiple sclerosis is characterised by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca²⁺ overload and subsequent activation of calcium‐dependent damage pathways. Thus, the inhibition of Ca²⁺ influx by pharmacological modulation of Ca²⁺ channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L‐type voltage‐gated calcium channel blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE ), an established experimental paradigm for multiple sclerosis. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL /J mice immunised with encephalitic myelin peptide PLP _139–151, specifically in late‐stage disease. Furthermore, supporting these data, administration of nimodipine to MOG _35–55‐immunised C57BL /6 mice starting at the peak of pre‐established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal β‐amyloid precursor protein accumulation in the cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen‐specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS ‐specific effect of L‐type voltage‐gated calcium channel blockade to inflammation‐induced neurodegeneration.

     

Na,K-ATPase Activity in Mouse Muscle is Regulated by AMPK and PGC-1α

Methyl-β-cyclodextrins (MβCDs) are molecules that are extensively used to remove and to load cholesterol (Chol) from artificial and natural membranes; however, the mechanism of Chol extraction by MβCD from pure lipids or from complex mixtures is not fully understood. One of the outstanding questions in this field is the capability of MβCD to remove Chol from lipid domains having different packing. Here, we investigated the specificity of MβCD to remove Chol from coexisting macrodomains with different lipid packing. We used giant unilamellar vesicles (GUVs) made of 1,2-dioleoylphosphatidylcholine:1,2-dipalmitoylphatidylcholine:free cholesterol, 1:1:1 molar ratio at 27°C. Under these conditions, individual GUVs present Chol distributed into l _o and l _d phases. The two phases can be distinguished and visualized using Laurdan generalized polarization and two-photon excitation fluorescence microscopy. Our data indicate that MβCD removes Chol preferentially from the more disordered phase. The process of selective Chol removal is dependent on the MβCD concentration. At high concentrations, MβCD also removes phospholipids.     

Micro-scale modeling of pesticide degradation coupled to carbon turnover in the detritusphere: model description and sensitivity analysis

Microbiologically active biogeochemical interfaces are excellent systems to study soil functions such as pesticide degradation at the micro-scale. In particular, in the detritusphere pesticide degradation is accelerated by input of fresh organic carbon from litter into the adjacent soil. This observed priming effect suggests: (i) pesticide degradation is strongly coupled to carbon turnover, (ii) it is controlled by size and activity of the microbial community and (iii) sorption and transport of dissolved carbonaceous compounds and pesticides might regulate substrate availability and in turn decomposition processes. We present a new mechanistic 1D model (PEsticide degradation Coupled to CArbon turnover in the Detritusphere, PECCAD) which implements these hypotheses. The new model explicitly considers growth and activity of bacteria, fungi and specific pesticide degraders in response to substrate availability. Enhanced pesticide degradation due to availability of a second source of carbon (dissolved organic carbon) is implemented in the model structure via two mechanisms. First, additional substrate is utilized simultaneously with the pesticide by bacterial pesticide degraders resulting in an increase in their size and activity. Second, stimulation of fungal growth and activity by additional substrates leads directly to higher pesticide degradation via co-metabolism. Thus, PECCAD implicitly accounts for litter-stimulated production and activity of unspecific fungal enzymes responsible for co-metabolic pesticide degradation. With a global sensitivity analysis we identified high-leverage model parameters and input. In combination with appropriate experimental data, PECCAD can serve as a tool to elucidate regulation mechanisms of accelerated pesticide degradation in the detritusphere.     

Guidance for product category rule development: process,outcome, and next steps

Purpose

The development of product category rules (PCRs) is inconsistent among the program operators using ISO 14025 as the basis. Furthermore, the existence of several other product claim standards and specifications that require analogous rules for making product claims has the potential to reduce any consistency in PCRs present in the ISO 14025 domain and result in unnecessary duplication of PCRs. These inconsistencies and duplications can be attributed to (a) insufficient specificity in related standards, (b) the presence of several standards and specifications, (c) lack of/limited coordination among program operators, and (d) lack of a single global database for PCRs. As a result, current PCR development threatens the legitimacy of life cycle assessment-based product claims.

Process

Through discussions over the past few years, in multistakeholder organizations, it has become clear that more guidance on the development of PCRs is necessary. In response to this need, the Product Category Rule Guidance Development Initiative (www.pcrguidance.org) was launched as an independent multistakeholder effort in early 2012. The premise for the Initiative was that the Guidance would be created by a voluntary group of international stakeholders that would share ownership of the outputs.

Outcome

The Guidance is now published, along with supplementary materials, on the Initiative website. The guidance document specifies requirements, recommendations, and options on (1) steps to be taken before PCR creation; (2) elements of a PCR; (3) review, publication, and use of PCRs; and (4) best practices for PCR development and management. Supplementary materials include a PCR template, a conformity assessment form, and a list of program operators from around the world.

Conclusions

The Guidance will help reduce cost and time to develop a PCR by supporting the adaptation of an existing PCR or by building on elements from existing PCRs. It will help reduce confusion and frustration when creating PCRs that are based on one or more standards and programs. Overall, the Guidance is a robust handbook for consistency and clarity in the development of PCRs.     

Interferon-β-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab

Background

Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO.

Case presentation

We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization.

Conclusion

Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses.