Nature medicine
-
Nitric oxide (NO) and peroxynitrite, formed from NO and superoxide anion, have been implicated as mediators of neuronal damage following focal ischemia, but their molecular targets have not been defined. One candidate pathway is DNA damage leading to activation of the nuclear enzyme, poly(ADP-ribose) polymerase (PARP), which catalyzes attachment of ADP ribose units from NAD to nuclear proteins following DNA damage. ⋯ We show that genetic disruption of PARP provides profound protection against glutamate-NO-mediated ischemic insults in vitro and major decreases in infarct volume after reversible middle cerebral artery occlusion. These results provide compelling evidence for a primary involvement of PARP activation in neuronal damage following focal ischemia and suggest that therapies designed towards inhibiting PARP may provide benefit in the treatment of cerebrovascular disease.
-
Neutralization of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1), decreases mortality in several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to animals, which succumb to shock during the first 72 hours, we found that many patients die much later with signs of opportunistic infections accompanied by downregulation of their monocytic HLA-DR expression and reduced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro. ⋯ Moreover, IFN-gamma applied to septic patients with low monocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte function resulted in clearance of sepsis in eight of nine patients. These data suggest that IFN-gamma treatment in carefully selected septic patients is a novel therapeutic strategy worth pursuing.
-
Sex differences in human responses to nociceptive stimuli and painful pathological conditions have generally indicated that women report higher pain levels or exhibit less tolerance than men for given stimulus intensities (reviewed in ref. 1 and 2). However, studies have not evaluated sex differences in analgesic responses. We recently reported that the opioid agonist-antagonist pentazocine, which acts predominantly at kappa-receptors, produced significantly better postoperative analgesia in females than in males in patients who underwent surgery for the removal of their third molars (wisdom teeth). ⋯ In order to determine whether there are sex differences associated with kappa-opioid agonism, the analgesic efficacy of two other predominantly kappa-opioid analgesics, nalbuphine and butorphanol; was compared in males and females who underwent surgery for the removal of third molar teeth. We found that both nalbuphine and butorphanol produced significantly greater analgesia in females as compared with males. Considering our earlier findings, we conclude that kappa-opioid analgesia is greater in females than in males, probably reflecting a difference in kappa-opioid-activated endogenous pain modulating circuits.