Sepsis, a major clinical problem with high morbidity and mortality, is caused by overwhelming systemic host-inflammatory response. Toll-like receptors (TLRs) play a fundamental role in induction of hyperinflammation and tissue damage in sepsis. In this study, we demonstrate a protective role of TLR9 inhibition against the dysregulated inflammatory response and tissue injury in sepsis. TLR9 deficiency decreased the mortality of mice following cecal ligation and puncture (CLP)-induced sepsis. TLR9 knockout mice showed dampened p38 activation and augmented Akt phosphorylation in the spleen, lung and liver. In addition, TLR9 deficiency decreased the levels of inflammatory cytokines and attenuated splenic apoptosis after CLP. These results indicate that TLR9 inhibition might offer a novel therapeutic strategy for the management of sepsis.

The mechanisms responsible for myocardial dysfunction in the setting of sepsis remain undefined. Fas ligation with its cognate ligand (FasL) induces apoptosis and activates cellular inflammatory responses associated with tissue injury. We determined whether interruption of Fas/FasL interaction by cardiac-specific expression of soluble Fas (sFas), a competitive inhibitor of FasL, would improve myocardial dysfunction and inflammation in a lipopolysacharide (LPS)-induced mouse model of sepsis. Wild-type (WT) and sFas transgenic mice were injected intraperitoneally with 10 mg/kg LPS or with an equivalent volume of saline. At 18 h after LPS administration, echocardiographic evaluation revealed a significant decrease in left ventricular fractional shortening in the WT mice, whereas the fractional shortening was preserved in the sFas mice. Activation of nuclear factor-kappa B (NF-κB) and the increase in the transcript levels of proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 resulting from LPS treatment were attenuated in the myocardium of sFas mice. sFas expression also inhibited LPS-induced upregulation of Toll-like receptor 4 (TLR-4) and inducible nitric oxide synthase (iNOS), and formation of peroxynitrite in the myocardium. LPS-induced increase in caspase-3/7 activity and apoptotic cell death were suppressed in sFas mice compared with WT mice. LPS-induced lung injury and increase in lung water content were also significantly reduced in sFas mice. These data indicate that neutralization of FasL by expression of sFas significantly preserves cardiac function and reduces inflammatory responses in the heart, suggesting that Fas/FasL signaling pathway is important in mediating the deleterious effects of LPS on myocardial function.

The phosphoinositide 3-kinases (PI3Ks) are a conserved family of signal transduction enzymes that are involved in regulating cellular activation, inflammatory responses, chemotaxis, and apoptosis. We have discovered that a carbohydrate ligand, glucan, will stimulate the endogenous PI3K/Akt signaling pathway. This article reviews the current data on the role of the PI3K/Akt signaling pathway as a negative feedback mechanism or compensatory regulator of septic and inflammatory responses. Of greater importance, the data reviewed in this article suggest that modulation of the PI3K/ Akt signaling pathway can reduce the morbidity and mortality associated with septic and I/R injury. Thus, manipulation of the endogenous PI3K/Akt signaling pathway may represent a new and novel therapeutic approach to management of important diseases.

Glucans are fungal cell wall polysaccharides which stimulate innate immune responses. We determined the minimum unit ligand that would bind to glucan receptors on human U937 cells using laminarin-derived pentaose, hexaose, and heptaose glucan polymers. When U937 membranes were pretreated with the oligosaccharides and passed over a glucan surface, only the heptasaccharide inhibited the interaction of glucan with membrane receptors at a Kd of 31 μM (95% CI 20-48 μM) and 100% inhibition. However, the glucan heptasaccharide did not stimulate U937 monocyte NFκB signaling, nor did it increase survival in a murine model of polymicrobial sepsis. Laminarin, a larger and more complex glucan polymer (Mw=7700 g/mol), only partially inhibited binding (61±4%) at a Kd of 2.6 μM (99% CI 1.7-4.2 μM) with characteristics of a single binding site. These results indicate that a heptasaccharide is the smallest unit ligand recognized by macrophage glucan receptors. The data also indicate the presence of at least two glucan-binding sites on U937 cells and that the binding sites on human monocyte/macrophages can discriminate between glucan polymers. The heptasaccharide and laminarin were receptor antagonists, but they were not receptor agonists with respect to activation of NFκB-dependent signaling pathways or protection against experimental sepsis.

Background The trajectory of recovery after sepsis varies. Survivors may have considerable ongoing limitations, requiring a caregiver for a prolonged period. Objectives To learn about experiences, quality of life, coping, resilience, and social support of caregiver caring for survivors of sepsis. Methods We conducted a convergent mixed-methods study, recruiting informal caregivers of patients who had survived sepsis in the past year and were readmitted to the intensive care unit with sepsis. Individual face-to-face, semistructured interviews and validated surveys on quality of life, coping, caregiver burden, resilience, and social support were administered to caregivers. Interview transcripts were analyzed using content analysis. Surveys were scored and summarized using descriptive statistics. Results Caregivers were primarily middle-aged, White, and female. Half were spouses of their care recipient. Caregivers reported some deficits in mobility, pain, and anxiety/depression. Coping styles varied, with engaged coping being more prevalent. Most caregivers reported mild to moderate burden, all reported either normal or high resilience levels, and types of social support were similar. However, interviews and survey findings were not always consistent. Major themes that emerged from the analysis included (1) advocating for and protecting their loved one, (2) coping with caregiving, (3) uncertain future, (4) rewards of caregiving, and (5) need to optimize communication with family. Discussion Caregivers of sepsis survivors are protective of their care recipient and use a variety of strategies to advocate for their loved one and to cope with the uncertainty involved in a new intensive care unit admission. More advocacy and support are needed for this population.

Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNɣ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis. Hoyer, Naxerova, et al. generate a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. They find that local injury activates macrophages in remote organs and that these adaptations were damaging or protective in different settings.

Sepsis-induced myeloid-derived suppressor cells (MDSCs) contribute to immunosuppression associated with sepsis. We reported that the CCAAT enhancer-binding protein C/EBPβ activates microRNA (miR)-21 and miR-181b expressions, which induce transcription factor NFI-A to support the generation and expansion of MDSCs in the bone marrow and spleens of septic mice. Here, using a conditional knockout mouse model lacking C/EBPβ in the myeloid lineage, we find that without C/EBPβ, myeloid progenitor cells could not express miR-21 or miR-181b, and ectopic expression of C/EBPβ in the C/EBPβ-deficient myeloid progenitors activated the expression of the two miRNAs. Moreover, C/EBPβ-reconstituted myeloid cells expressed IL-10 and reduced T cell proliferation and function, similar to control MDSCs that express C/EBPβ. Exogenous expression of miR-21 and miR-181b in the C/EBPβ-deficient myeloid progenitors from septic mice produced similar results. Notably, NFI-A-dependent transactivation of NF-kB MDSC generating pathway was reversed in the C/EBPβ-deficient myeloid progenitors from septic mice. Together, these results support that decreasing C/EBPβ expression prevents MDSC generation and decreases immunosuppression in septic mice, providing a target for sepsis treatment.

Bakgrund: Sepsis är ett mycket allvarligt sjukdomstillstånd. Det definieras som ett syndrom som uppstår på grund av ett onormalt svar på infektion och kan resultera i livshotande organdysfunktion.  Patienter som överlever sepsis drabbas ofta av komplikationer i efterförloppet som kan påverka den hälsorelaterade livskvaliteten. Syfte: Att undersöka hur patienter som har vårdats för sepsis bedömer sin hälsorelaterade livskvalitet i efterförloppet. Metod: En beskrivande design med allmän litteraturstudie som metod. Studiens resultat baserades på tio vetenskapliga originalartiklar från databaserna CINAHL, Google Scholar och PubMed. Artiklarna har analyserats enligt Fribergs metod. Resultat: Patienter bedömde sin hälsorelaterade livskvalitet som försämrad i efterförloppet av sepsis. Både den mentala och fysiska hälsorelaterade livskvaliteten påverkades men den fysiska påverkades mest. Patienterna bedömde sin hälsorelaterade livskvalitet som sämst vid tre månader efter insjuknande. Den mentala hälsorelaterade livskvaliteten började förbättras vid sex månader. Förbättringen av den fysiska hälsorelaterade livskvaliteten var långsam och värdena var fortfarande relativt låga vid 12 månader. När mätningar gjordes med ett annat mer sammanfattande instrument (EQ-5D) så uppstod inte samma skillnader som i MCS och PCS.  Slutsats: Den hälsorelaterade livskvaliteten visade sig vara påverkad hos patienter både fysiskt och mentalt efter sepsis. Att återfå sin hälsorelaterade livskvalitet som den var innan insjuknandet tar tid och upprepade besök inom sjukvården. Denna patientgrupp är sjuklig, sårbar och beroende av sjukvården både under sjukdomstiden och i rehabiliteringsfasen. Mer information ger ökad kunskap som kan användas av sjuksköterskan för att förbättra sitt arbete med denna patientgrupp avseende dess hälsorelaterade livskvalitet.

>Magister Scientiae - MSc / Introduction: A common complication of poorly managed mandible fractures is infection. There is a consensus amongst clinicians in treating infected mandible fractures in an immediate setting. The approach includes drainage of the purulent discharge, debridement of the fracture, removal of teeth in the fracture line and immediate fixation. Fixation can be load bearing or load sharing in nature. Although clinicians advocate for the use of a reconstruction load bearing plate, a double miniplate fixation could be an alternative. Aim: The aim is to assess the outcomes of double miniplate osteosynthesis in the immediate management of infected mandible fractures Material and method: A prospective cohort study was conducted. The sample size was 20 (n =20). Infections were treated with an incision and drainage and the fractures fixated with a double miniplate fixation system. Pain scores, fracture union, fracture stability and surgical times were measured. Follow–up visits included one week, six weeks and three months respectively.

Bakgrund: Sepsis klassificeras som en systemisk, livshotande överreaktion på en infektion där kroppens eget försvar leder till skador på människans vävnader och organ. Vanligaste symtomen på sepsis är förändrad andningsfrekvens, hög puls, sänkt blodtryck och en hög eller låg kroppstemperatur. I Sverige drabbas cirka 40,000 människor av sepsis varje år, varav 4000–6000 avlider. Det har visat sig att tidig identifiering av tillståndet och snabb start av behandling sänker mortaliteten. Syfte: Syftet med denna studie var att kartlägga bedömningsinstrument och dess förmåga att identifiera sepsis hos vuxna utifrån sensitivitet och specificitet. Metod: Denna litteraturstudie använde sig av åtta artiklar med kvantitativ metod. Artikelsökningarna har gjorts via databaserna CINAHL och PubMed. Artiklarna har därefter granskats enligt Olsson och Sörensens bedömningsmall för kvantitativa studier. Resultat: Nio bedömningsinstrument identifierades. Resultatet visade att SOFA har högst sensitivitet och specificitet samtidigt. Konklusion:  Denna litteraturstudie visade på att ingående instrument har en stor spridning i sensitivitet och specificitet. Resultaten visar att mer forskning behövs för att utforma ett bedömningsinstrument som fungerar i fler vårdmiljöer. / Background: Sepsis is classified as a systemic, life-threatening overreaction to infection, were the body’s own defences lead to damages to human tissue and organs. The most common symptoms are altered respiratory rate, elevated heart rate, hypotension and an increase or decrease in temperature. The incidence in Sweden is 40,000 annually, of which 4000–6000 do not survive. It has been shown that early identification and prompt start of treatment lowers mortality. Aim: The aim of this study was to map the assessment instruments used to identify sepsis in adults and their abilities from a sensitivity and specificity standpoint. Methods: This study used a quantitative literature review approach based on eight articles. The searches were conducted with the use of search engines CINAHL and PubMed. The articles were then examined with use of Olsson & Sörensens template for quantitative article review.  Results: The study found nine assessment instruments for sepsis. The results show that SOFA had the highest sensitivity and specificity simultaneously. Conclusion: The results of this study found that the instruments showed extensive distribution in sensitivity and specificity. More research is required to create an instrument that works in more caregiving facilities.