Cytokine and molecular networks in sepsis cases: a network biology approach

Background

Sepsis is a life-threatening condition of organ dysfunction caused by a dysregulated host immune response to infection. We performed network analysis of cytokine molecules and compared network structures between a systematic inflammatory response syndrome (SIRS) or normal control (NC) group and a sepsis group.

Results

We recruited SIRS (n = 33) and sepsis (n = 89) patients from electronic medical records (EMR) according to whether data on PCT, CRP, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p70, IL-13, IL-17, IL-22, TNF-α, and IFN-γ levels were available. From the public GEO dataset, GSE66099, GSE9960, GSE95233, GSE57065 were downloaded. Genes corresponding to 15 molecules were extracted from an expression array. A correlation matrix was formed for the 15 molecules and statistically significant molecular pairs were used as pairs for network analysis of coexpression. The number of molecular or gene expression pairs significantly correlated among the SIRS or control and sepsis groups are as follows for datasets: EMR, 15 and 15; GEO66099-1, 13 and 15; GEO9960, 13 and 11; GSE95233, 13 and 8; GSE66099-2, 15 and 14; GSE57065, 14 and 13, respectively. Network analysis revealed that network diameter, number of nodes and shortest path were equal to or lower in the sepsis group.

Conclusions

The coexpression network in sepsis patients was relatively small sized and had lower shortest paths compared with the SIRS group or healthy control group. Cytokines with one degree (k = 1) are increased in sepsis group compared with SIRS or healthy control group. IL-9 and IL-2 were not included in network of sepsis group indicating that these cytokines showed no correlation with other cytokines. These data might imply that cytokines tend to be dysregulated in the sepsis group compared to that of SIRS or normal control groups

     

The chemopreventive effect of Ginkgo biloba and Silybum marianum extracts on hepatocarcinogenesis in rats

Background/objective

This study was designed to evaluate the potential chemopreventive activities of Ginkgo biloba extract (EGb) and Silybum marianum extract (silymarin) against hepatocarcinogenesis induced by N-nitrosodiethylamine (NDEA) in rats.

Methods

Rats were divided into 6 groups. Group 1 served as normal control rats. Group 2 animals were intragastrically administrated NDEA at a dose of 10 mg/kg five times a week for 12 weeks to induce hepatocellular carcinoma (HCC). Groups 3 and 4 animals were pretreated with silymarin and EGb respectively. Groups 5 and 6 animals were posttreated with silymarin and EGb respectively. The investigated parameters in serum are alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT) and vascular endothelial growth factor (VEGF). The investigated parameters in liver tissue are malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and comet assay parameters.

Results

In NDEA group, MDA level was elevated with subsequent decrease in GSH level and SOD, GPx and GR activities. In addition, NDEA group revealed a significant increase in serum ALT, AST and GGT activities and VEGF level. Furthermore, NDEA administrated animals showed a marked increase in comet assay parameters. These biochemical alterations induced by NDEA were confirmed by the histopathological examination of rat livers intoxicated with NDEA that showed an obvious cellular damage and well differentiated HCC. In contrast, silymarin+NDEA treated groups (3&;5) and EGb+NDEA treated groups (4&;6) showed a significant decrease in MDA level and a significant increase in GSH content and SOD, GPx and GR activities compared to NDEA group. Silymarin and EGb also beneficially down-regulated the increase in serum ALT, AST, GGT activities and VEGF level induced by NDEA. In addition, silymarin and EGb significantly decreased comet assay parameters. Histopathological examination of rat livers treated with either silymarin or EGb exhibited an improvement in the liver architecture compared to NDEA group.

Conclusions

The obtained findings suggested that silymarin and EGb may have beneficial chemopreventive roles against hepatocarcinogenesis through their antioxidant, antiangiogenic and antigenotoxic activities.     

Clinical Significance of Soluble Hemoglobin Scavenger Receptor CD163 (sCD163) in Sepsis, a Prospective Study

Objective

We investigated serum soluble CD163 (sCD163) levels for use in the diagnosis, severity assessment, and prognosis of sepsis in the critical ill patients and compared sCD163 with other infection-related variables.

Methods

During july 2010 and April 2011, serum was obtained from 102 sepsis patients (days 1, 3, 5, 7, and 10 after admission to an ICU) and 30 systemic inflammatory response syndrome (SIRS) patients with no sepsis diagnosed. Serum levels of sCD163, procalcitonon (PCT), and C reactive protein (CRP) were determined respectively. Sequential organ failure assessment (SOFA) scores for sepsis patients were also recorded. Then evaluated their roles in sepsis.

Results

The sCD163 levels were 0.88(0.78–1.00)ug/mL for SIRS patients, 1.50(0.92–2.00)ug/mL for moderate sepsis patients, and 2.95(2.18–5.57)ug/mL for severe sepsis patients on day1. The areas under the ROC curves for sCD163, CRP, and PCT for the diagnosis of sepsis were, respectively, 0.856(95%CI: 0.791–0.921), 0.696(95%CI: 0.595–0.797), and 0.629(95%CI: 0.495–0.763), At the recommended cut-off 1.49 ug/mL for sCD163, the sensitivity is 74.0% with 93.3% specificity. Based on 28-day survivals, sCD163 levels in the surviving group stay constant, while they tended to gradually increase in the non-surviving group.The area under the ROC curve for sCD163 for sepsis prognosis was 0.706(95%CI 0.558–0.804). Levels of sCD163 with cut-off point >2.84 ug/mL have sensitivity of 55.8.0%, specificity 80.4%.Common risk factors for death and sCD163 were included in multivariate logistic regression analysis; the odds ratios (OR) for sCD163 and SOFA scores for sepsis prognosis were 1.173 and 1.396, respectively (P<0.05). Spearman rank correlation analysis showed that sCD163 was weakly, but positively correlated with CRP, PCT, and SOFA scores (0.2< r <0.4, P<0.0001), but not with leukocyte counts (r <0.2, P = 0.450).

Conclusion

Serum sCD163 is superior to PCT and CRP for the diagnosis of sepsis and differentiate the severity of sepsis. sCD163 levels were more sensitive for dynamic evaluations of sepsis prognosis. Serum sCD163 and SOFA scores are prognostic factors for sepsis.

Trial Registration

www.chictr.org ChiCTR-ONC-10000812      

Therapeutic electric stimulation does not affect immune status in healthy individuals – a preliminary report

Background

For the treatment of low back pain, the following three scenarios of posterior lumbar interbody fusion (PLIF) were usually used, i.e., PLIF procedure with autogenous iliac bone (PAIB model), PLIF with cages made of PEEK (PCP model) or titanium (Ti) (PCT model) materiel. But the benefits or adverse effects among the three surgical scenarios were still not fully understood.

Method

Finite element analysis (FEA), as an efficient tool for the analysis of lumbar diseases, was used to establish a three-dimensional nonlinear L1-S1 FE model (intact model) with the ligaments of solid elements. Then it was modified to simulate the three scenarios of PLIF. 10?Nm moments with 400?N preload were applied to the upper L1 vertebral body under the loading conditions of extension, flexion, lateral bending and torsion, respectively.

Results

Different mechanical parameters were calculated to evaluate the differences among the three surgical models. The lowest stresses on the bone grafts and the greatest stresses on endplate were found in the PCT model. The PCP model obtained considerable stresses on the bone grafts and less stresses on ligaments. But the changes of stresses on the adjacent discs and endplate were minimal in the PAIB model.

Conclusions

The PCT model was inferior to the other two models. Both the PCP and PAIB models had their own relative merits. The findings provide theoretical basis for the choice of a suitable surgical scenario for different patients.     

Molecular monitoring of the Leu-164 mutation of dihydrofolate reductase in a highly sulfadoxine/pyrimethamine-resistant area in Africa

Background

Procalcitonin (PCT) is closely correlated with parasite burden and clinical outcome in falciparum malaria. The role of PCT in tertian malaria has not previously been investigated.

Patients and methods

PCT serum levels in 37 patients with tertian malaria were analysed. Clinical and laboratory parameters were assessed and statistically correlated both to the initial PCT levels and during the course of the disease.

Results

PCT levels rose for one day after commencing treatment and declined thereafter. However, there was no significant correlation with parasite burden, clinical parameters, laboratory values, or the presence of semi-immunity. Before treatment, the majority of patients showed normal or slightly elevated PCT levels (< 2.5 ng/ml), but PCT was markedly elevated (4.8 – 47 ng/ml) in one third of the population. The two groups did not differ by any other of the assessed parameters. Thus, while the post-treatment course of PCT resembles falciparum malaria, the lack of correlation between disease severity and even high PCT levels in a large proportion of patients is intriguing.

Conclusions

There is a fundamental difference in the relationship of PCT with tertian malaria not seen in other infectious diseases in which elevated PCT levels have been observed. This suggests distinct pathophysiological pathways in malaria.     

Procalcitonin Identifies Cell Injury,Not Bacterial Infection,in Acute Liver Failure

Background

Because acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF.

Method

Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls.

Results

Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups–non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL.

Summary/Conclusions

While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.     

Complement Depletion Deteriorates Clinical Outcomes of Severe Abdominal Sepsis: A Conspirator of Infection and Coagulopathy in Crime?

Background

The complement depletion commonly occurred during sepsis, but it was often underestimated compared with severe infection or coagulation dysfunction.

Objective

This study was designed to investigate the alteration of complement system in patients with severe abdominal sepsis and evaluate the role of complement depletion in prognosis of such patients. The relationship between complement depletion and infection or coagulopathy was also explored.

Methods

Forty-five patients with severe abdominal sepsis were prospectively conducted among individuals referral to SICU. Currently recommended treatments, such as early goal-directed resuscitation, source control and antibiotics therapy, were performed. Acute physiology and chronic health evaluation II (APACHE II) and sepsis related organ failure assessment (SOFA) scores were employed to evaluate severity. Plasma levels of C3, C4, CRP, PCT, D-dimer and other parameters were detected within eight times of observation. The 28-day mortality, length of stay, and postoperative complications were compared between complement depletion and non-complement depletion groups.

Results

Within the study period, eight (17.8%) patients died, five of them suffering from complement depletion. The overall incidence of complement depletion was 64.4%. At admission, mean complement C3 and C4 levels were 0.70 and 0.13 mg/mL, respectively. Using ROC analysis for mortality prediction, the area under the curve of C3 was 0.926 (95% CI, 0.845–0.998, P<0.001), with optimal cutpoint value of 0.578 mg/mL. Complement C3 depletion was shown to be no correlation to severity scores, however, strongly correlated with elevated D-dimer, PCT concentrations and increased postoperative complications.

Conclusions

Complement C3 depletion was found to be connected to poor prognosis in severe abdominal sepsis. This depletion seems to be associated with coagulopathy and aggravated infection during sepsis, which should be paid close attention in critical care.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01568853","term_id":"NCT01568853"}}NCT01568853     

脓毒症患儿内生吗啡动态变化及临床意义

目的:检测脓毒症患儿血清内生吗啡(EM)动态变化,探讨脓毒症患儿血清EM水平的临床意义。方法:选择2017年6月-2018年2月华中科技大学同济医学院附属同济医院收治的30例伴有严重脓毒症或脓毒症休克的患儿作为脓毒症组,30例全身炎症反应综合征(SIRS)患儿作为SIRS组,30例健康儿童作为对照组。脓毒症组、SIRS组及对照组分别于入组后第1、3、6、9天抽取外周静脉血,采用免疫荧光法检测血清降钙素原(PCT)水平,采用酶联免疫吸附试验(ELISA)测定血清EM水平,采用流式细胞术(FCM)检测细胞免疫功能。结果:SIRS组、脓毒症组患儿的第1、3、6天血清PCT水平显著高于对照组,且随时间延长PCT水平逐渐降低,至第9天降至正常水平(P0.05),而脓毒症组与SIRS组间血清PCT水平无统计学差异(P0.05)。脓毒症组第1、3、6天血清EM水平均高于SIRS组(P0.05),第9天两组血清EM水平比较差异无统计学意义(P0.05)。脓毒症组EM水平随时间延长而降低,至第9天降至SIRS组的水平(P0.05)。与SIRS组相比,第1天脓毒症组的CD3~+T细胞数量增多(P0.05),两组CD4~+、CD8~+T细胞数量、CD4~+/CD8~+比例比较无统计学差异(P0.05)。结论:脓毒症患儿中血清EM水平较高,有可能作为诊断脓毒症特异性较高的生物标志物。     

The measurement of woody root decomposition using two methodologies in a Sitka spruce forest ecosystem

Background and aims

The decomposition of roots is an important process in the loss of carbon (C) and the mineralization of nitrogen (N) in forest ecosystems. The early stage decomposition rate of Sitka spruce (Picea sitchensis (Bong.) Carr.) roots was determined using trenched plots and decomposition bags.

Methods

Stumps of known age were trenched and quadrants (50?cm by 50?cm) excavated from randomly selected stumps every 6?months over 4?years, while the mass loss from buried roots in decomposition bags, divided among four diameter categories (ranging from fine roots <2?mm to large roots >50?mm), was monitored for 27?months. The C and N concentrations of excavated samples at different time points were analysed.

Results

The change in total root necromass per quadrant showed a higher decomposition rate-constant (k) of 0.24?±?0.068?year^?1 than the k-value of roots in decomposition bags (0.07?±?0.005?year^?1). The C concentration (47.24?±?0.609?%) did not significantly change with decomposition. There was a significant increase in the C:N ratio of roots in all diameter categories (fine: 48.92?%, small: 38.53?%, medium 11.71?%, large: 76.25?%) after 4?years of decomposition, driven by N loss. Root diameter accounted for 78?% of the variation in the N concentration of roots as decomposition progressed.

Conclusion

Though the trenched plot approach offered an alternative to the more common decomposition bag method for estimating root decomposition, high spatial variation and sampling difficulties may lead to an overestimation of the mass loss from trenched roots, thus, the decomposition bag method gives a more reliable decomposition rate-constant.     

Reasons given by mothers for discontinuing breastfeeding in Iran

Background

We have previously shown that in Iran, only 28% of infants were exclusively breastfed at six months, despite a high prevalence of breastfeeding at two years of age. The primary aim of this study was to investigate the reasons women discontinued exclusive breastfeeding.

Method

This retrospective study was based on questionnaires and interviews with 63,071 mothers of infants up to 24?months of age, divided into two populations: infants younger than six months and six months or older. The data were collected in 2005?C2006 from all 30 provinces of Iran.

Results

Only 5.3% of infants less than six months of age stopped breastfeeding (mean age of 3.2?months); more commonly in urban than rural areas. The most frequently cited reasons mothers gave for discontinuing exclusive breastfeeding were physicians?? recommendation (54%) and insufficient breast milk (self-perceived or true, 28%). Breastfeeding was common after six months of age: only 11% of infants discontinued breastfeeding, at a mean of 13.8?months. The most common reason for discontinuation at this age was insufficient breast milk (self-perceived or true, 45%). Maternal illness or medication (10%), infant illness (6%), and return to work (3%) were uncommon causes. Use of a pacifier was correlated with breastfeeding discontinuation. Maternal age and education was not associated with duration of breastfeeding. Multivariate analysis showed that using a pacifier and formula or other bottle feeding increased the risk of early cessation of breastfeeding.

Conclusions

Physicians and other health professionals have an important role to play in encouraging and supporting mothers to maintain breastfeeding.     

Relapse in resected lung cancer revisited: does intensified follow up really matter? A prospective study

Background

Interest in translational studies aimed at investigating biologic markers in predicting response to primary chemotherapy (PCT) in breast cancer has progressively increased. We conducted a pilot study to evaluate feasibility of evaluating biomarkers of response to PCT at one & 21 days after first cycle.

Methods

Adult, non-pregnant, non-lactating women with histologically confirmed infiltrating duct carcinoma underwent serial core biopsies after first cycle of PCT and these were scored for Ki-67, Bcl-2 and Caspase-3 using immunohistochemistry.

Results

We recruited 30 patients with a mean age of 51 years. We were successful 95.6% times in performing a core biopsy and of these 84.6% had adequate tissue in the cores harvested. After a mean of 4 cycles of PCT, 26 patients underwent surgery and good response was noted in 9 patients (30%) using Miller-Payne criteria. There was a trend noted in all markers, which appeared different in those with good response and poor response. Good responders had significantly higher Ki-67 and significantly lower Bcl-2 at baseline and a significant decrease in Ki-67 and Caspase-3 at 21 days after the first chemotherapy.

Conclusion

We report a detectable change in biomarkers as early as 24–48 hours after the first chemotherapy along with a definite trend in change that can possibly be used to predict response to chemotherapy in an individual patient. The statistical significance and clinical utility of such changes needs to be evaluated and confirmed in larger trials.     

Angiotensin-converting enzyme inhibition and food restriction in diabetic mice do not correct the increased sensitivity for ischemia-reperfusion injury

Background

Metabolic syndrome is characterized by insulin resistance, which is closely related to GLUT4 content in insulin-sensitive tissues. Thus, we evaluated the GLUT4 expression, insulin resistance and inflammation, characteristics of the metabolic syndrome, in an experimental model.

Methods

Spontaneously hypertensive neonate rats (18/group) were treated with monosodium glutamate (MetS) during 9 days, and compared with Wistar-Kyoto (C) and saline-treated SHR (H). Blood pressure (BP) and lipid levels, C-reactive protein (CRP), interleukin 6 (IL-6), TNF-?? and adiponectin were evaluated. GLUT4 protein was analysed in the heart, white adipose tissue and gastrocnemius. Studies were performed at 3 (3-mo), 6 (6-mo) and 9 (9-mo) months of age.

Results

MetS rats were more insulin resistant (p<0.001, all ages) and had higher BP (3-mo: p<0.001, 6-mo: p?=?0.001, 9-mo: p?=?0.015) as compared to C. At 6 months, CRP, IL-6 and TNF-?? were higher (p<0.001, all comparisons) in MetS rats vs H, but adiponectin was lower in MetS at 9 months (MetS: 32?±?2, H: 42?±?2, C: 45?±?2 pg/mL; p<0.001). GLUT4 protein was reduced in MetS as compared to C rats at 3, 6 and 9-mo, respectively (Heart: 54%, 50% and 57%; Gastrocnemius: 37%, 56% and 50%; Adipose tissue: 69%, 61% and 69%).

Conclusions

MSG-treated SHR presented all metabolic syndrome characteristics, as well as reduced GLUT4 content, which must play a key role in the impaired glycemic homeostasis of the metabolic syndrome.     

Discrepant Fibrinolytic Response in Plasma and Whole Blood during Experimental Endotoxemia in Healthy Volunteers

Background

Sepsis induces early activation of coagulation and fibrinolysis followed by late fibrinolytic shutdown and progressive endothelial damage. The aim of the present study was to investigate and compare the functional hemostatic response in whole blood and plasma during experimental human endotoxemia by the platelet function analyzer, Multiplate and by standard and modified thrombelastography (TEG).

Methods

Prospective physiologic study of nine healthy male volunteers undergoing endotoxemia by means of a 4-hour infusion of E. coli lipopolysaccharide (LPS, 0.5 ng/kg/hour), with blood sampled at baseline and at 4 h and 6 h. Physiological and standard biochemical data and coagulation tests, TEG (whole blood: TEG, heparinase-TEG, Functional Fibrinogen; plasma: TEG±tissue-type plasminogen activator (tPA)) and Multiplate (TRAPtest, ADPtest, ASPItest, COLtest) were recorded. Mixed models with Tukey post hoc tests and correlations were applied.

Results

Endotoxemia induced acute SIRS with increased HR, temperature, WBC, CRP and procalcitonin and decreased blood pressure. It also induced a hemostatic response with platelet consumption and reduced APTT while INR increased (all p<0.05). Platelet aggregation decreased (all tests, p<0.05), whereas TEG whole blood clot firmness increased (G, p = 0.05). Furthermore, during endotoxemia (4 h), whole blood fibrinolysis increased (clot lysis time (CLT), p<0.001) and Functional Fibrinogen clot strength decreased (p = 0.049). After endotoxemia (6 h), whole blood fibrinolysis was reduced (CLT, p<0.05). In contrast to findings in whole blood, the plasma fibrin clot became progressively more resistant towards tPA-induced fibrinolysis at both 4 h and 6 h (p<0.001).

Conclusions

Endotoxemia induced a hemostatic response with reduced primary but enhanced secondary hemostasis, enhanced early fibrinolysis and fibrinogen consumption followed by downregulation of fibrinolysis, with a discrepant fibrinolytic response in plasma and whole blood. The finding that blood cells are critically involved in the vasculo-fibrinolytic response to acute inflammation is important given that disturbances in the vascular system contribute significantly to morbidity and mortality in critically ill patients.     

A pig model of acute Staphylococcus aureus induced pyemia

Background

Sepsis caused by Staphylococcus aureus constitutes an important cause of morbidity and mortality in humans, and the incidence of this disease-entity is increasing. In this paper we describe the initial microbial dynamics and lesions in pigs experimentally infected with S. aureus, with the aim of mimicking human sepsis and pyemia.

Methods

The study was conducted in anaesthetized and intravenously inoculated pigs, and was based on bacteriological examination of blood and testing of blood for IL-6 and C-reactive protein. Following killing of the animals and necropsy bacteriological and histological examinations of different organs were performed 4, 5 or 6 h after inoculation.

Results

Clearance of bacteria from the blood was completed within the first 2 h in some of the pigs and the highest bacterial load was recorded in the lungs as compared to the spleen, liver and bones. This probably was a consequence of both the intravenous route of inoculation and the presence of pulmonary intravascular macrophages. Inoculation of bacteria induced formation of acute microabscesses in the lungs, spleen and liver, but not in the kidneys or bones. No generalized inflammatory response was recorded, i.e. IL-6 was not detected in the blood and C-reactive protein did not increase, probably because of the short time course of the study.

Conclusion

This study demonstrates the successful induction of acute pyemia (microabscesses), and forms a basis for future experiments that should include inoculation with strains of S. aureus isolated from man and an extension of the timeframe aiming at inducing sepsis, severe sepsis and septic shock.     

Sex-specific outcomes of diabetic patients with acute myocardial infarction who have undergone percutaneous coronary intervention: a register linkage study

Background

Chronic arterial stiffness contributes to the negative health effects of obesity and insulin resistance, which include hypertension, stroke, and increased cardiovascular and all-cause mortality. Weight loss and improved insulin sensitivity are individually associated with improved central arterial stiffness; however, their combined effects on arterial stiffness are poorly understood. The purpose of this study was to determine how insulin levels modify the improvements in arterial stiffness seen with weight loss in overweight and obese young adults.

Methods

To assess the effects of weight loss and decreased fasting insulin on vascular stiffness, we studied 339 participants in the Slow the Adverse Effects of Vascular Aging (SAVE) trial. At study entry, the participants were aged 20?C45, normotensive, non-diabetic, and had a body-mass index of 25?C39.9?kg/m². Measures of pulse wave velocity (PWV) in the central (carotid-femoral (cfPWV)), peripheral (femoral-ankle (faPWV)), and mixed (brachial-ankle (baPWV)) vascular beds were collected at baseline and 6?months. The effects of 6-month change in weight and insulin on measures of PWV were estimated using multivariate regression.

Results

After adjustment for baseline risk factors and change in systolic blood pressure, 6-month weight loss and 6-month change in fasting insulin independently predicted improvement in baPWV but not faPWV or cfPWV. There was a significant interaction between 6-month weight change and change in fasting insulin when predicting changes in baPWV (p?<?0.001). Individuals experiencing both weight loss and insulin reductions showed the greatest improvement in baPWV.

Conclusions

Young adults with excess weight who both lower their insulin levels and lose weight see the greatest improvement in vascular stiffness. This improvement in vascular stiffness with weight loss and insulin declines may occur throughout the vasculature and may not be limited to individual vascular beds.

Trial registration

NCT00366990     

C-Reactive Protein and Hemogram Parameters for the Non-Sepsis Systemic Inflammatory Response Syndrome and Sepsis: What Do They Mean?

Objectives

Sepsis is one of the most common reasons of increased mortality and morbidity in the intensive care unit. The changes in CRP levels and hemogram parameters and their combinations may help to distinguish sepsis from non-sepsis SIRS. The aim of this study is to investigate the CRP and hemogram parameters as an indicator of sepsis.

Methods

A total of 2777 patients admitted to the ICU of two centers between 2006–2013 were evaluated retrospectively. The patients were diagnosed as SIRS (-), non-sepsis SIRS and sepsis. The patients who were under 18 years old, re-admitted, diagnosed with hematological disease, on corticosteroid and immunosuppressive therapy, SIRS (-), culture negative, undocumented laboratory values and outcomes were excluded. 1257 patients were divided into 2 groups as non-sepsis SIRS and sepsis. The patients’ demographic data, CRP levels, hemogram parameters, length of ICU stay and mortality were recorded.

Results

1257 patients were categorized as non-sepsis SIRS (816, 64.9%) and sepsis (441, 35.1%). In the multivariate analysis, the likelihood of sepsis was increased 3.2 (2.2–4.6), 1.7 (1.2–2.4), 1.6 (1.2–2.1), 2.3 (1.4–3.8), 1.5 (1.1–2.1) times by the APACHE II≥13, SOFA score≥4, CRP≥4.0, Lym_C<0.45 and PLT_C<150 respectively (p<0.001 p = 0.007 p = 0.004 p<0.001 p = 0.027). The likelihood of sepsis was increased 18.1 (8.4–38.7) times by the combination of CRP≥4.0, lym_C<0.45 and PLT_C<150 (P<0.001).

Conclusions

While WBC_C, Neu_C, Neu%, NLCR and Eo_C are far from being the indicators to distinguish sepsis from non-sepsis SIRS, the combinations of CRP, Lym_C and PLT_C can be used to determine the likelihood of sepsis.     

Long Term Health-Related Quality of Life in Survivors of Sepsis in South West Wales: An Epidemiological Study

Introduction

Survivors of sepsis report persistent problems that can last years after hospital discharge. The main aim of this study was to investigate long-term health-related quality of life in survivors of SIRS and sepsis compared with Welsh normative data, controlling for age, length of stay and pre-existing conditions. The second aim was to investigate any differences in long-term health-related quality of life specifically with the patients categorised into three groups; SIRS, uncomplicated sepsis and severe sepsis/septic shock.

Methods

A prospective study design was used in order to investigate all sepsis patients either presenting to the Emergency Department or admitted to the Intensive Care Unit of a regional trauma centre. Baseline demographics, clinical characteristics and outcomes were collected and surviving patients were sent a SF-12v2 survey at between six months to two years post-hospital discharge.

Results

Quality of life was significantly reduced in all patients when compared to local normative data (all p<0.0001). Reductions in the physical components of health-related quality of life were more pronounced in severe sepsis/septic shock patients when compared to uncomplicated sepsis and SIRS patients, when controlling for age, pre-existing conditions, hospital and ICU length of stay.

Conclusions

This is the first observational study to specifically focus on the different groups of SIRS and sepsis patients to assess long-term quality of life. Local population norms were used for comparison, rather than UK-wide norms that fail to reflect the intricacies of a country’s population.     

Acute Lung Injury and Acute Kidney Injury Are Established by Four Hours in Experimental Sepsis and Are Improved with Pre,but Not Post,Sepsis Administration of TNF-α Antibodies

Introduction

Acute kidney injury (AKI) and acute lung injury (ALI) are serious complications of sepsis. AKI is often viewed as a late complication of sepsis. Notably, the onset of AKI relative to ALI is unclear as routine measures of kidney function (BUN and creatinine) are insensitive and increase late. In this study, we hypothesized that AKI and ALI would occur simultaneously due to a shared pathophysiology (i.e., TNF-α mediated systemic inflammatory response syndrome [SIRS]), but that sensitive markers of kidney function would be required to identify AKI.

Methods

Sepsis was induced in adult male C57B/6 mice with 5 different one time doses of intraperitoneal (IP) endotoxin (LPS) (0.00001, 0.0001, 0.001, 0.01, or 0.25 mg) or cecal ligation and puncture (CLP). SIRS was assessed by serum proinflammatory cytokines (TNF-α, IL-1β, CXCL1, IL-6), ALI was assessed by lung inflammation (lung myeloperoxidase [MPO] activity), and AKI was assessed by serum creatinine, BUN, and glomerular filtration rate (GFR) (by FITC-labeled inulin clearance) at 4 hours. 20 µgs of TNF-α antibody (Ab) or vehicle were injected IP 2 hours before or 2 hours after IP LPS.

Results

Serum cytokines increased with all 5 doses of LPS; AKI and ALI were detected within 4 hours of IP LPS or CLP, using sensitive markers of GFR and lung inflammation, respectively. Notably, creatinine did not increase with any dose; BUN increased with 0.01 and 0.25 mg. Remarkably, GFR was reduced 50% in the 0.001 mg LPS dose, demonstrating that dramatic loss of kidney function can occur in sepsis without a change in BUN or creatinine. Prophylactic TNF-α Ab reduced serum cytokines, lung MPO activity, and BUN; however, post-sepsis administration had no effect.

Conclusions

ALI and AKI occur together early in the course of sepsis and TNF-α plays a role in the early pathogenesis of both.     

Belowground carbon allocation and net primary and ecosystem productivities in apple trees (Malus domestica) as affected by soil water availability

Background and aims

Fruit orchards potential as carbon (C) sinks is virtually unknown. Moreover, despite their importance in the Mediterranean area, few data are available about the effect of the reduction in water availability on fruit tree productivity. Here we report the effect of two different irrigation regimes on net primary (NPP) and net ecosystem (NEP) productivities of an apple orchard in northern Italy in 2006.

Methods

Trees productivity and heterotrophic soil respiration were estimated by inventory and root exclusion methods, while belowground allocation with a C mass-balance approach.

Results

The NPP of the control (7.86?±?0.25?Mg?C ha^-1; mean ± SE) was significantly greater than that of water stressed trees (6.53?±?0.12?Mg?C ha^-1), and the ratio between above and below net primary productivity (ANPP/BNPP) was 1.88 and 0.98 respectively. However, the partitioning of ANPP and BNPP among aerial organs and among fine, coarse roots, and root litter was unaffected by the water regime. Although NEP was greater in the control than in stressed trees the C gain of the system after fruit removal (NEP_afr) was unaffected by water availability.

Conclusions

This study indicated an effect of water availability on C partitioning patterns above- and belowground, although there were no significant effects on the C sink potential as NEP_afr.     

Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle

Background

The present study examines the hypothesis that Akt (protein kinase B)/mTOR (mammalian target of rapamycin) signaling is increased in hypertrophic and decreased in atrophic denervated muscle. Protein expression and phosphorylation of Akt1, Akt2, glycogen synthase kinase-3beta (GSK-3beta), eukaryotic initiation factor 4E binding protein 1 (4EBP1), 70?kD ribosomal protein S6 kinase (p70S6K1) and ribosomal protein S6 (rpS6) were examined in six-days denervated mouse anterior tibial (atrophic) and hemidiaphragm (hypertrophic) muscles.

Results

In denervated hypertrophic muscle expression of total Akt1, Akt2, GSK-3beta, p70S6K1 and rpS6 proteins increased 2?C10 fold whereas total 4EBP1 protein remained unaltered. In denervated atrophic muscle Akt1 and Akt2 total protein increased 2?C16 fold. A small increase in expression of total rpS6 protein was also observed with no apparent changes in levels of total GSK-3beta, 4EBP1 or p70S6K1 proteins. The level of phosphorylated proteins increased 3?C13 fold for all the proteins in hypertrophic denervated muscle. No significant changes in phosphorylated Akt1 or GSK-3beta were detected in atrophic denervated muscle. The phosphorylation levels of Akt2, 4EBP1, p70S6K1 and rpS6 were increased 2?C18 fold in atrophic denervated muscle.

Conclusions

The results are consistent with increased Akt/mTOR signaling in hypertrophic skeletal muscle. Decreased levels of phosphorylated Akt (S473/S474) were not observed in denervated atrophic muscle and results downstream of mTOR indicate increased protein synthesis in denervated atrophic anterior tibial muscle as well as in denervated hypertrophic hemidiaphragm muscle. Increased protein degradation, rather than decreased protein synthesis, is likely to be responsible for the loss of muscle mass in denervated atrophic muscles.