End-tidal carbon dioxide as a goal of early sepsis therapy
Guirgis, Faheem W; Williams, Deborah J; Kalynych, Colleen J; Hardy, Mary E; Jones, Alan E; Dodani, Sunita; Wears, Robert L
OBJECTIVE:To determine the use of end-tidal carbon dioxide (etco2) as an end point of sepsis resuscitation. METHODS:This was a prospective, observational, single-center cohort study of emergency department patients receiving treatment for severe sepsis with a quantitative resuscitation protocol. Three etco2 readings were taken during a 1-minute time frame at 0, 3, and 6 hours of treatment. Linear regression was used to characterize the association between etco2 and central venous oxygen saturation (SCVo2) and lactate and also to determine the relationship between their change. Analysis of variance was used to determine the relationship between etco2 and disposition. RESULTS:Sixty-nine patients were included in our final analysis. For baseline values, linear regression failed to show a relationship between etco2 and SCVo2 (ÃŽÂ² = -0.04, t(70) = -0.53, P = .60) but showed a nearly significant relationship (ÃŽÂ² = -0.51, t(70) = -1.90, P = .06) with lactate. There was no significant relationship between etco2 and SCVo2 at 3 hours (ÃŽÂ² = 0.12, t(70) = 1.43, P = .16) or 6 hours (ÃŽÂ² = 0.05, t(64) = 0.82, P = .67). There was also no significant relationship between 6-hour change in etco2 and change in SCVo2 (ÃŽÂ² = 0.04, t(64) = 0.43, P = .67) or lactate (ÃŽÂ² = 0.04, t(59) = 0.52, P = .60) or disposition (F(4) = 0.78, P = .54). CONCLUSION/CONCLUSIONS:End-tidal carbon dioxide is unlikely to be a useful clinical end point for sepsis resuscitation, although it may be useful as a triage tool in suspected sepsis because baseline values may reflect initial lactate.
A Plasmodium falciparum transcriptional cyclin-dependent kinase-related kinase with a crucial role in parasite proliferation associates with histone deacetylase activity
Halbert, Jean; Ayong, Lawrence; Equinet, Leila; Le Roch, Karine; Hardy, Mary; Goldring, Dean; Reininger, Luc; Waters, Norman; Chakrabarti, Debopam; Doerig, Christian
Cyclin-dependent protein kinases (CDKs) are key regulators of the eukaryotic cell cycle and of the eukaryotic transcription machinery. Here we report the characterization of Pfcrk-3 (Plasmodium falciparum CDK-related kinase 3; PlasmoDB identifier PFD0740w), an unusually large CDK-related protein whose kinase domain displays maximal homology to those CDKs which, in other eukaryotes, are involved in the control of transcription. The closest enzyme in Saccharomyces cerevisiae is BUR1 (bypass upstream activating sequence requirement 1), known to control gene expression through interaction with chromatin modification enzymes. Consistent with this, immunofluorescence data show that Pfcrk-3 colocalizes with histones. We show that recombinant Pfcrk-3 associates with histone H1 kinase activity in parasite extracts and that this association is detectable even if the catalytic domain of Pfcrk-3 is rendered inactive by site-directed mutagenesis, indicating that Pfcrk-3 is part of a complex that includes other protein kinases. Immunoprecipitates obtained from extracts of transgenic parasites expressing hemagglutinin (HA)-tagged Pfcrk-3 by using an anti-HA antibody displayed both protein kinase and histone deacetylase activities. Reverse genetics data show that the pfcrk-3 locus can be targeted only if the genetic modification does not cause a loss of function. Taken together, our data strongly suggest that Pfcrk-3 fulfils a crucial role in the intraerythrocytic development of P. falciparum, presumably through chromatin modification-dependent regulation of gene expression.