Background & Aims
Sleep disturbances are common in patients with cirrhosis, but their determinants and effects on health-related quality of life are not well understood. We investigated the prevalence of disturbed sleep in these patients, factors associated with sleep disruption, and effects on quality of life.
Methods
We performed a prospective, cross-sectional study of 193 stable ambulatory patients with cirrhosis (154 with decompensated cirrhosis). Participants completed the Pittsburgh sleep questionnaire index (to assess sleep quality), the chronic liver disease questionnaire (CLDQ), muscle cramp questionnaires, and underwent neurocognitive testing. Actigraphy was performed in a subset of patients with normal and disturbed sleep. We collected serum samples from subjects with normal and disturbed sleep and performed non-targeted metabolomic analyses.
Results
Of the study subjects, 157 (81%) had disturbed sleep, with Pittsburgh sleep questionnaire index scores >5. Disturbed sleep was associated with muscle cramps, daytime somnolence, and decreased quality of life, based on CLDQ scores. Factors independently associated with disturbed sleep in logistic regression analysis included hypoalbuminemia, opiate therapy, and muscle cramps. Disturbed sleep was independently associated with CLDQ score (correlation parameter, −36.6; 95% CI, −24 to −49; P<.001) on linear regression. Disturbed sleep was associated with neurocognitive impairment and with significantly delayed bedtime and decreased total sleep time, measured by actigraphy. Disturbed sleep was associated with metabolome signatures of alterations to the intestinal microbiome and lipid, arginine, and urea cycle metabolism.
Conclusion
Most patients (81%) with advanced cirrhosis have disturbed sleep. This has negative effects on quality of life and is associated with disruptions of several metabolic pathways, including metabolism by the intestinal microbiota.
Sepsis is one of the main causes for morbidity and mortality in hospitalized patients. Moreover, sepsis associated complications involving impaired wound healing are common. Septic patients often require surgical interventions that in-turn may lead to further complications caused by impaired wound healing. We established a mouse model to the study delayed wound healing during sepsis distant to the septic focus point. For this reason cecal ligation and puncture (CLP) was combined with the creation of a superficial wound on the mouse ear. Control animals received the same procedure without CPL. Epithelialization was measured every second day by direct microscopic visualization up to complete closure of the wound. As interplay of TNF-α, TGF-β, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-α, TGF-β, MMP7, and TIMP1 were assessed immunohistochemical in samples of wounded ears harvested on days 2, 6, 10 and 16 after wounding. After induction of sepsis, animals showed a significant delay in wound epithelialization from day 2 to 12 compared to control animals. Complete wound healing was attained after mean 12.2± standard deviation (SD) 3.0 days in septic animals compared to 8.7± SD 1.7 days in the control group. Septic animals showed a significant reduction in local pro-inflammatory cytokine level of TNF-α on day 2 and day 6 as well as a reduced expression of TGF-β on day 2 in wounds. A significant lower expression of MMP7 as well as TIMP1 was also observed on day 2 after wounding. The induction of sepsis impairs wound healing distant to the septic focus point. We could demonstrate that expression of important cytokines for wound repair is deregulated after induction of sepsis. Thus restoring normal cytokine response locally in wounds could be a good strategy to enhance wound repair in sepsis.
Chronic ethanol abuse is known to increase susceptibility to infections after injury, in part, by modification of macrophage function. Several intracellular signalling mechanisms are involved in the initiation of inflammatory responses, including the nuclear factor-κB (NF-κB) pathway. In this study, we investigated the systemic and hepatic effect of chronic ethanol feeding on in vivo activation of NF-κB in NF-κBEGFP reporter gene mice. Specifically, the study focused on Kupffer cell proinflammatory cytokines IL-6 and TNF-α and activation of NF-κB after chronic ethanol feeding followed by in vitro stimulation with lipopolysaccharide (LPS). We found that chronic ethanol upregulated NF-κB activation and increased hepatic and systemic proinflammatory cytokine levels. Similarly, LPS-stimulated IL-1β release from whole blood was significantly enhanced in ethanol-fed mice. However, LPS significantly increased IL-6 and TNF-α levels. These results demonstrate that chronic ethanol feeding can improve the responsiveness of macrophage LPS-stimulated IL-6 and TNF-α production and indicate that this effect may result from ethanol-induced alterations in intracellular signalling through NF-κB. Furthermore, LPS and TNF-α stimulated the gene expression of different inflammatory mediators, in part, in a NF-κB-dependent manner.
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