Erythropoietin (EPO), recognized for its central role in erythropoiesis, also mediates neuroprotection when the recombinant form (r-Hu-EPO) is directly injected into ischemic rodent brain. We observed abundant expression of the EPO receptor at brain capillaries, which could provide a route for circulating EPO to enter the brain. In confirmation of this hypothesis, systemic administration of r-Hu-EPO before or up to 6 h after focal brain ischemia reduced injury by Ϸ50 -75%. R-Hu-EPO also ameliorates the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis, and the toxicity of kainate. Given r-Hu-EPO's excellent safety profile, clinical trials evaluating systemically administered r-Hu-EPO as a general neuroprotective treatment are warranted. E rythropoietin (EPO) and its receptor (EPO-R) function as primary mediators of the normal physiologic response to hypoxia. EPO, a glycoprotein that increases red cell mass to improve tissue oxygenation, is produced by the kidney in response to hypoxia. Recombinant human EPO (r-Hu-EPO) is effective and widely used for the treatment of anemia associated with renal failure, HIV infection, cancer, and surgery. However, like other members of the cytokine superfamily to which EPO and its receptor belong, both are expressed by other tissues, including the nervous system. Similar to its regulation in the periphery, EPO within the central nervous system is inducible by hypoxia (1-4). An in vivo neuroprotective function for EPO has been demonstrated by the observation that direct intracerebraventricular injection of r-Hu-EPO in advance of hypoxic͞ ischemic stress offers significant protection of neuronal tissue (5-7). A critical neuroprotective role for endogenous EPO in the central nervous system has been confirmed by the administration of soluble EPO-R, which neutralizes EPO, consequently exacerbating ischemic stress and increasing tissue injury (7).Hypoxia may not be the only relevant stimulus for brain EPO production, however, as metabolic disturbances, including hypoglycemia and strong neuronal depolarization, generate mitochondrial reactive oxygen species that may increase brain EPO expression through hypoxia inducible factor 1 (8). EPO may thus protect nervous tissue under any condition characterized by a relative deficiency of ATP in the face of increased metabolic demands. EPO has been shown to exhibit classic neurotrophic effects in vivo and in vitro (2, 9-11). The mechanism of action of EPO in erythropoiesis, neuroprotection, and neurotrophic effects ultimately may involve activation of the bcl-x family of antiapoptotic genes, promoting survival rather than apoptosis (12)(13)(14).Despite the demonstrated benefit of intrathecally administered r-Hu-EPO in preventing ischemic neuronal damage, direct delivery of r-Hu-EPO into the brain is not a practical approach in most clinical contexts. Systemic delivery of r-Hu-EPO has not been evaluated because of the perception that the brain EPO system is parallel and distinct from the control ...

Ischemic brain injury resulting from stroke arises from primary neuronal losses and by inflammatory responses. Previous studies suggest that erythropoietin (EPO) attenuates both processes. Although EPO is clearly antiapoptotic for neurons after experimental stroke, it is unknown whether EPO also directly modulates EPO receptor (EPO-R)–expressing glia, microglia, and other inflammatory cells. In these experiments, we show that recombinant human EPO (rhEPO; 5,000 U/kg body weight, i.p.) markedly reduces astrocyte activation and the recruitment of leukocytes and microglia into an infarction produced by middle cerebral artery occlusion in rats. In addition, ischemia-induced production of the proinflammatory cytokines tumor necrosis factor, interleukin 6, and monocyte chemoattractant protein 1 concentration is reduced by >50% after rhEPO administration. Similar results were also observed in mixed neuronal-glial cocultures exposed to the neuronal-selective toxin trimethyl tin. In contrast, rhEPO did not inhibit cytokine production by astrocyte cultures exposed to neuronal homogenates or modulate the response of human peripheral blood mononuclear cells, rat glial cells, or the brain to lipopolysaccharide. These findings suggest that rhEPO attenuates ischemia-induced inflammation by reducing neuronal death rather than by direct effects upon EPO-R–expressing inflammatory cells.

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Murine norovirus (MNV) was used as a surrogate to study resistance of human norovirus to disinfectants used in hospitals. MNV was sensitive to alcohol, alcohol hand rubs, bleach, and povidone iodine-based disinfectant. Real-time reverse transcription-PCR results indicated that the presence of viral RNA did not correlate with the presence of infectious virus.Human noroviruses (NoVs) are causative agents of gastroenteritis in all age classes (14). Human NoV is responsible for large outbreaks in community settings like nursing homes or hospitals, in which nosocomial infections have also been reported (11,15,29). Person-to-person, food-borne, and waterborne transmissions of NoV have been documented (11). Previous studies showed that NoVs were resistant in the environment (7,20) and suggested the risk of NoV transmission via contaminated surfaces (3, 13).The study of human NoV has been hampered by the lack of a cell culture system, as reviewed previously (9). To study resistance of human NoV to environmental factors or virucidal agents, cultivatable feline calicivirus (FCV) from the genus Vesivirus has been used as a surrogate until now (27). FCV is sensitive to ethanol, 1-propanol, and isopropanol (12, 21). FCV is also inactivated in the presence of sodium hypochlorite, chlorine dioxide, iodine, or glutaraldehyde (6,8,10,28,30). Alcohol-based hand rubs induced 1 to 2 log 10 50%-tissueculture-infective-dose reductions in the FCV titer in the presence of organic soil (16).Recently the first murine NoV (MNV) was characterized (18) and adapted to cell culture on murine macrophage-related cells (31). The MNV capsid structure, genomic organization, and replication cycle are very similar to those of human NoVs (18,26). Recently Cannon et al. showed that MNV and FCV were resistant to organic solvents and their inactivation rates were similar at 63 and 72°C (2). However, MNV was more resistant than FCV to basic and acidic pHs. Long-term resistance was also higher for MNV than for FCV at room temperature, once resuspended in stool material. Additionally, MNV could be effectively inactivated by liquid-and fog-based hypochlorous acid solutions on porous and nonporous surfaces (24). In this study, we determined whether alcohols (ethanol and isopropanol), alcohol-based hand rubs (Stérillium, Aniosgel 85NPC, and Purell), and commercial disinfectants (Asphène381, bleach, and Betadine), which are commonly used in French hospitals, could reduce the viral titer of MNV by 4 log 10 as required by European standards for virucidal efficacy, as reviewed previously (27). Plaque assay and realtime reverse transcription (RT)-PCR procedures were evaluated for the detection and the quantification of MNV.The RAW cells were maintained as described previously (31). MNV was propagated RAW cells in fetal bovine serum (FBS)-free Dulbecco's modified Eagle medium (DMEM) and harvested at 2 days postinfection. High-titer MNV stocks were prepared by ultracentrifugation of precleared MNV-infected cell lysate. For MNV titration, the cells were inoculated w...