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Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats. Am J Physiol Gastrointest Liver Physiol 280: G968-G973, 2001.--Sepsis is the leading cause of death in surgical intensive care units. Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP. In male Sprague-Dawley rats, hepatic necrosis, as determined by serum [Alpha]-glutathione S-transferase ([Alpha]-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP. Apoptosis, evaluated using both terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and morphological examination, was minimal after both CLP and 2CLP. Regeneration, assayed by staining tissue for incorporation of exogenously administered bromodeoxyuridine, was present after CLP but not after 2CLP. To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined. After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle. Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis. necrosis; apoptosis; liver; hepatocyte; cytokines; tumor necrosis factor; interleukin-1; interleukin-6; bromodeoxyuridine; tunel; [Alpha]-glutathione S-transferase; cyclin D1; LRF-1; JunB

Background: New daily persistent headache (NDPH) is a challenging and understudied primary headache disorder with no known effective treatment. Although the International Classification of Headache Disorders criteria require that the new onset continuous headache be present for at least three months before diagnosing NDPH, the biologic basis for when a new, continuous headache starts to behave as NDPH is unknown, and some pediatric headache experts consider that the minimum duration criterion could be shorter. Methods: In this retrospective study, we reviewed the intake questionnaires and medical records of 5–17 year-olds seen in neurology clinic for headache at the Children's Hospital of Philadelphia. Those with a new onset continuous headache of at least one month in duration were eligible. The patient's self-report and clinician's description both had to indicate that the headache was new, of abrupt onset, and continuous to be included, although patients were allowed to have a prior history of infrequent headaches. We compared headache outcomes at last follow-up and at one year after continuous headache onset between those who had a continuous headache duration of 1 to <3 months ("new onset headache", or NOH) at first visit vs. those with ≥3 months (NDPH). We used multivariate regression modeling to examine for predictors of headache outcomes. Results: Of 472 patient records reviewed, 172 met the inclusion criteria for analysis. Of these, 84 had a headache duration of 1 to <3 months in duration and 88 had a duration of ≥3 months. Those with shorter duration continuous headache were younger (median (interquartile range) 13.5 (11.1–15.7) vs. 15.1 (12.3–16.5) years, and less likely to have previously received a prescription preventive for the continuous headache (n = 14 (17%) vs. 26 (30%), p = 0.046), but were otherwise similar to those with NDPH in terms of baseline clinical and demographic variables. Sixty-five (74%) of those with NDPH and 60 (71%) with NOH had follow-up data. At last clinic follow-up, 41/65 (63%) with NDPH and 43/60 (72%) with NOH had experienced any headache benefit (p = 0.307), although 39/65 (60%) with NDPH and 29/60 (48%) with NOH still had continuous headache (p = 0.191). Headache duration was not associated with outcomes in multivariate regression modeling. Conclusions: Headache outcomes of children and adolescents with new onset continuous headache, whether of 1 to <3 months (NOH) or ≥3 months in duration (NDPH) are suboptimal. More research is needed to improve treatment outcomes for this patient population. [ABSTRACT FROM AUTHOR]

Objective: Hepatic dysfunction is an important but poorly understood component of sepsis. In severe sepsis, liver dysfunction is characterized by cholestasis, steatosis, hepatocellular injury, impaired regeneration, a decreased response to the cytokine interleukin-6, and high mortality. To determine whether loss of interleukin-6 activity caused hepatic dysfunction and mortality, we induced sepsis in wild-type (interleukin-6 +/+) and interleukin-6 knockout (interleukin-6 -/-) mice. We hypothesized that sepsis in interleukin-6 -/- mice would increase cholestasis, steatosis, hepatocellular injury, and mortality and impair hepatocyte regeneration., Design: Randomized prospective experimental study., Setting: University medical laboratory., Subjects: Male adolescent C57Bl6 interleukin-6 +/+ and interleukin-6 -/- mice., Interventions: Mild sepsis was induced using cecal ligation and single puncture (CLP). Severe, lethal sepsis was induced using cecal ligation and double puncture (2CLP). Some mice received recombinant human interleukin-6 at the time of CLP/2CLP. All animals were fluid resuscitated at the time of surgery and every 24 hrs thereafter. In survival cohorts, mortality at 16, 24, 48, and 72 hrs was recorded. In separate cohorts, surviving animals were killed at 24 and 48 hrs, and liver tissue was harvested. A separate cohort of mice received bromodeoxyuridine for detection of regeneration., Measurements and Main Results: 2CLP was 100% fatal within the first 12 hrs in interleukin-6 -/- mice. Mortality from 2CLP in interleukin-6 +/+ mice before 24 hrs was nil but was 90% by 72 hrs. At 72 hrs, CLP was 40% fatal in interleukin-6 +/+ mice but 90% in interleukin-6 -/- mice. CLP induced cholestasis, steatosis, and hepatocellular injury in interleukin-6 -/-, but not interleukin-6 +/+, mice. Regeneration was absent following CLP in interleukin-6 -/- animals but occurred in interleukin-6 +/+ mice. Early administration of recombinant human interleukin-6 did not reverse abnormalities in interleukin-6 -/- mice., Conclusions: The absence of interleukin-6 is an important determinant of hepatic dysfunction and mortality in sepsis.

Previous studies have demonstrated sepsis-specific changes in the transcription of key hepatic genes. However, the role of hepatic transcription factors in sepsis-associated organ dysfunction has not been well established. We hypothesize that the binding activities of C/EBPalpha and beta, HNF-1alpha, and HNF-3 transiently decrease during mild sepsis but persistently decrease after fulminant sepsis, and that the decrease in this binding activity correlates in time and severity with previously described decreases in the transcription of key hepatic genes. Male C57/BL6 mice had nonlethal sepsis induced by cecal ligation and single puncture (CLP) and fulminant sepsis via cecal ligation and double puncture (2CLP). Sham-operated and unoperated animals served as controls. Transcription factor binding activity was assessed with electrophoretic mobility shift assays. C/EBP-a and HNF-1alpha binding activity decreased transiently after CLP and persistently after 2CLP. Binding activity of both C/EBP-beta and HNF-3 were unchanged. The decrease in C/EBP-a and HNF-1alpha binding activities correlated in time and magnitude with the decreased hepatic gene transcription previously observed in sepsis. Furthermore, the loss of activity after 2CLP correlated in time with outcome. Sepsis decreases DNA binding activities of C/EBPalpha and HNF-1alpha, two key hepatocyte transcription factors, in a time course consistent with down-regulation of their target hepatic genes. Therefore, alterations in transcription factor binding are likely important in the transcriptional modulation that is characteristic of hepatic dysfunction in sepsis.