Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease, in which activated microglia overexpressing ALS-linked SOD1 mutants (mSOD1) are known to contribute to neuronal death. However, it is unclear how mSOD1 expression affects micoglial activation and subsequently damages neurons. In this study, we created mSOD1-overexpressing BV-2 microglial cell lines. Following TLR2, but not TLR4 stimulation, we observed that overexpression of human SOD1 G93A, L8Q, or G10V mutant, as compared with the wild-type SOD1 or a mock control, significantly enhanced microglial secretion of a neurotoxic cytokine, tumor necrosis factor-␣ (TNF-␣), which was dependent on the NADPH-oxidase-mediated increased generation of reactive oxygen species (ROS). In further experiments, we demonstrated that mSOD1 expression regulated TNF-␣ secretion at a post-transcriptional level and involved ROS-sensitive TNF-␣-converting enzymes, e.g. ADAM10 and -17, which shed TNF-␣ from its membrane-anchored precursor. Together with a recent report that the function of SOD1, as a self-regulating redox sensor in NADPH oxidase-dependent ROS production, is lost due to its genetic mutations, we conclude that mSOD1 expression in ALS facilitates microglial neurotoxic inflammatory responses via TLR2, which is mediated by an uncontrolled ROS generation. The link, between mSOD1, innate immunity and NADPH oxidase, offers new opportunities in ALS therapies. Amyotrophic lateral sclerosis (ALS)2 is a progressive paralytic disease that usually leads to death within 3-5 years. It is pathologically characterized by degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. In 20% of the familial ALS patients, mutations in the human Cu,Zn superoxide dismutase (SOD1) gene can be found (1). Transgenic mice overexpressing high levels of mutated human SOD1 (mSOD1) can model this disease (2).Analysis of postmortem tissues from ALS patients and of mSOD1 transgenic mice revealed a marked microglia-dominated neuroinflammation (3,4,5,6). Microglial activation can also be visualized in patients by positron emission tomography using 11 C-labeled (R)-PK11195, a radioligand of microglial peripheral benzodiazepine receptors (7). This neuroinflammatory response coinciding with neuronal death and disease progression argues for a causal relationship. In mSOD1 transgenic mice, mSOD1 expression in microglial cells has been proven to be crucial for neuronal survival: 1) mSOD1-expressing neurons are protected from cell death by neighboring non-neuronal cells lacking mSOD1 expression (8); 2) the disease progression in the late stage can be blocked by specifically switching off mSOD1 expression in microglia (9); and 3) reconstruction of bone marrow of mSOD1 transgenic mice with wild-type (wt) SOD1-expressing precursor cells, which creates a pool of wtSOD1-expressing microglial cells, extends the life time of the mutant mice (10). However, nonspecific ablation of proliferating microglia in the mSOD1 transgenic mice did not prevent motor neuronal death (11). In a ...
BackgroundThe screening of hospital admission patients for methicillin resistant Staphylococcus aureus (MRSA) is of undisputed value in controlling and reducing the overall MRSA burden; yet, a concerted parallel universal screening intervention throughout all hospitals of an entire German Federal State has not yet been performed.Methodology/Principal FindingsDuring a four-week period, all 24 acute care hospitals of the State of Saarland participated in admission prevalence screening. Overall, 436/20,027 screened patients revealed MRSA carrier status (prevalence, 2.2/100 patients) with geriatrics and intensive care departments associated with highest prevalence (7.6/100 and 6.3/100, respectively). Risk factor analysis among 17,975 admission patients yielded MRSA history (OR, 4.3; CI95 2.7–6.8), a skin condition (OR, 3.2; CI95 2.1–5.0), and/or an indwelling catheter (OR, 2.2; CI95 1.4–3.5) among the leading risks. Hierarchical risk factor ascertainment of the six risk factors associated with highest odd’s ratios would require 31% of patients to be laboratory screened to allow for detection of 67% of all MRSA positive admission patients in the State.Conclusions/SignificanceState-wide admission prevalence screening in conjunction with risk factor ascertainment yields important information on the distribution of the MRSA burden for hospitals, and allows for data-based decisions on local or institutional MRSA screening policies considering risk factor prevalence and expected MRSA identification rates.
This is the first report of a PTS-associated pseudo-outbreak. The large number of falsely positive patient-related specimens in conjunction with the potential hazard of airborne and contact spread of multidrug-resistant microorganisms (in this case, GIM-1 carbapenem-resistant Acinetobacter species) underscores the need for implementation of infection control-based monitoring and operating procedures in a hospital PTS.
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