Septic shock is mediated in part by nitric oxide (NO) and tumour necrosis factor alpha (TNFalpha). NO is synthesized primarily from extracellular arginine. We tested the ability of an arginine-degrading enzyme to inhibit NO production in mice and to protect mice from the hypotension and lethality that occur after the administration of TNFalpha or endotoxin. Treatment of BALB/c mice with arginine deiminase (ADI) formulated with succinimidyl succinimide polyethylene glycol of M(r) 20000 (ADI-SS PEG(20000)) eliminated all measurable plasma arginine (from normal levels of approximately 155 microM arginine to 2 microM). In addition, ADI-SS PEG(20000) also inhibited the production of NO, as quantified by plasma nitrate+nitrite. Treatment of mice with TNFalpha or endotoxin resulted in a dose-dependent increase in NO production and lethality. Pretreatment of mice with ADI-SS PEG(20000) resulted in increased resistance to the lethal effects of TNFalpha and endotoxin. These observations are consistent with NO production resulting, to some extent, from the metabolism of extracellular arginine. The toxic effects of TNFalpha and endotoxin may be partially inhibited by enzymic degradation of plasma arginine by ADI-SS PEG(20000). Interestingly, pretreatment with ADI-SS PEG(20000) did not inhibit the anti-tumour activity of TNFalpha in vitro or in vivo. This treatment may allow greater amounts of TNFalpha, as well as other cytokines, to be administered while abrogating side effects such as hypotension and death.
There are few effective treatments of antisocial personality disorder (APD). Preliminary work suggests that the atypical antipsychotic quetiapine can decrease irritability, impulsivity, and aggressiveness. Data were collected from 4 patients with APD who were referred to a maximum-security inpatient psychiatric facility for pretrial evaluation and were treated with quetiapine. Quetiapine was effective in these patients as was indicated by a decrease in symptoms such as impulsivity, hostility, aggressiveness, irritability, and rage reactions. Typical dosage was 600 to 800 mg per day. Patients attributed their willingness to comply with quetiapine treatment to both the effectiveness of the drug and its favorable adverse-event profile. Quetiapine was successfully combined with mood stabilizers, particularly gabapentin, in patients with prominent affective instability. Quetiapine has demonstrated efficacy in aggression, impulsivity, and irritability and has proved to be an effective medication in these patients with APD. In addition, its favorable adverse-event profile makes patients willing to comply.
Septic shock is mediated in part by nitric oxide (NO) and tumour necrosis factor α (TNFα). NO is synthesized primarily from extracellular arginine. We tested the ability of an arginine-degrading enzyme to inhibit NO production in mice and to protect mice from the hypotension and lethality that occur after the administration of TNFα or endotoxin. Treatment of BALB/c mice with arginine deiminase (ADI) formulated with succinimidyl succinimide polyethylene glycol of Mr 20000 (ADI-SS PEG20000) eliminated all measurable plasma arginine (from normal levels of ∼155μM arginine to 2μM). In addition, ADI-SS PEG20000 also inhibited the production of NO, as quantified by plasma nitrate+nitrite. Treatment of mice with TNFα or endotoxin resulted in a dose-dependent increase in NO production and lethality. Pretreatment of mice with ADI-SS PEG20000 resulted in increased resistance to the lethal effects of TNFα and endotoxin. These observations are consistent with NO production resulting, to some extent, from the metabolism of extracellular arginine. The toxic effects of TNFα and endotoxin may be partially inhibited by enzymic degradation of plasma arginine by ADI-SS PEG20000. Interestingly, pretreatment with ADI-SS PEG20000 did not inhibit the anti-tumour activity of TNFα in vitro or in vivo. This treatment may allow greater amounts of TNFα, as well as other cytokines, to be administered while abrogating side effects such as hypotension and death.
Contrary to longstanding opinion, Descartes does not deny all feeling and awareness to non-human animals. Though he undoubtedly denies that animals think, a case can be made that he nonetheless would allow them organism consciousness, perceptual consciousness, access consciousness and even phenomenal consciousness. Descartes does not employ or accept an 'all-or-nothing' view of consciousness. He merely denies (not that this is a small thing) that animals have the capacity for self-conscious reflective reception or awareness of sensations and feelings.
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