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1.  Lung Protective Ventilation Induces Immunotolerance and Nitric Oxide Metabolites in Porcine Experimental Postoperative Sepsis 
PLoS ONE  2013;8(12):e83182.
Low tidal volume ventilation is beneficial in patients with severe pulmonary dysfunction and would, in theory, reduce postoperative complications if implemented during routine surgery. The study aimed to investigate whether low tidal volume ventilation and high positive end-expiratory pressure (PEEP) in a large animal model of postoperative sepsis would attenuate the systemic inflammatory response and organ dysfunction. Thirty healthy pigs were randomized to three groups: Group Prot-7h, i.e. protective ventilation for 7 h, was ventilated with a tidal volume of 6 mL x kg-1 for 7 h; group Prot-5h, i.e. protective ventilation for 5 h, was ventilated with a tidal volume of 10 mL x kg-1 for 2 h, after which the group was ventilated with a tidal volume of 6 mL x kg-1; and a control group that was ventilated with a tidal volume of 10 mL x kg-1 for 7 h. In groups Prot-7h and Prot-5h PEEP was 5 cmH2O for 2 h and 10 cmH2O for 5 h. In the control group PEEP was 5 cmH2O for the entire experiment. After surgery for 2 h, postoperative sepsis was simulated with an endotoxin infusion for 5 h. Low tidal volume ventilation combined with higher PEEP led to lower levels of interleukin 6 and 10 in plasma, higher PaO2/FiO2, better preserved functional residual capacity and lower plasma troponin I as compared with animals ventilated with a medium high tidal volume and lower PEEP. The beneficial effects of protective ventilation were seen despite greater reductions in cardiac index and oxygen delivery index. In the immediate postoperative phase low VT ventilation with higher PEEP was associated with reduced ex vivo plasma capacity to produce TNF-α upon endotoxin stimulation and higher nitrite levels in urine. These findings might represent mechanistic explanations for the attenuation of systemic inflammation and inflammatory-induced organ dysfunction.
doi:10.1371/journal.pone.0083182
PMCID: PMC3861481  PMID: 24349457
2.  Outcome predictors of intra-articular glucocorticoid treatment for knee synovitis in patients with rheumatoid arthritis – a prospective cohort study 
Arthritis Research & Therapy  2014;16(3):R129.
Introduction
Intra-articular glucocorticoid treatment (IAGC) is widely used for symptom relief in arthritis. However, knowledge of factors predicting treatment outcome is limited. The aim of the present study was to identify response predictors of IAGC for knee synovitis in patients with rheumatoid arthritis (RA).
Methods
In this study 121 RA patients with synovitis of the knee were treated with intra-articular injections of 20 mg triamcinolone hexacetonide. They were followed for six months and the rate of clinical relapse was studied. Non-responders (relapse within 6 months) and responders were compared regarding patient characteristics and knee joint damage as determined by the Larsen-Dale index. In addition, matched samples of serum and synovial fluid were analysed for factors reflecting the inflammatory process (C-reactive protein, interleukin 6, tumour necrosis factor alpha, vascular endothelial growth factor), joint tissue turnover (cartilage oligomeric matrix protein, metalloproteinase 3), and autoimmunity (antinuclear antibodies, antibodies against citrullinated peptides, rheumatoid factor).
Results
During the observation period, 48 knees relapsed (40%). Non-responders had more radiographic joint damage than responders (P = 0.002) and the pre-treatment vascular endothelial growth factor (VEGF) level in synovial fluid was significantly higher in non-responders (P = 0.002).
Conclusions
Joint destruction is associated with poor outcome of IAGC for knee synovitis in RA. In addition, higher levels of VEGF in synovial fluid are found in non-responders, suggesting that locally produced VEGF is a biomarker for recurrence of synovial hyperplasia and the risk for arthritis relapse.
doi:10.1186/ar4586
PMCID: PMC4095577  PMID: 24950951
3.  Veno-venous extracorporeal CO2 removal for the treatment of severe respiratory acidosis: pathophysiological and technical considerations 
Critical Care  2014;18(3):R124.
Introduction
While non-invasive ventilation aimed at avoiding intubation has become the modality of choice to treat mild to moderate acute respiratory acidosis, many severely acidotic patients (pH <7.20) still need intubation. Extracorporeal veno-venous CO2 removal (ECCO2R) could prove to be an alternative. The present animal study tested in a systematic fashion technical requirements for successful ECCO2R in terms of cannula size, blood and sweep gas flow.
Methods
ECCO2R with a 0.98 m2 surface oxygenator was performed in six acidotic (pH <7.20) pigs using either a 14.5 French (Fr) or a 19Fr catheter, with sweep gas flow rates of 8 and 16 L/minute, respectively. During each experiment the blood flow was incrementally increased to a maximum of 400 mL/minute (14.5Fr catheter) and 1000 mL/minute (19Fr catheter).
Results
Amelioration of severe respiratory acidosis was only feasible when blood flow rates of 750 to 1000 mL/minute (19Fr catheter) were used. Maximal CO2-elimination was 146.1 ± 22.6 mL/minute, while pH increased from 7.13 ± 0.08 to 7.41 ± 0.07 (blood flow of 1000 mL/minute; sweep gas flow 16 L/minute). Accordingly, a sweep gas flow of 8 L/minute resulted in a maximal CO2-elimination rate of 138.0 ± 16.9 mL/minute. The 14.5Fr catheter allowed a maximum CO2 elimination rate of 77.9 mL/minute, which did not result in the normalization of pH.
Conclusions
Veno-venous ECCO2R may serve as a treatment option for severe respiratory acidosis. In this porcine model, ECCO2R was most effective when using blood flow rates ranging between 750 and 1000 mL/minute, while an increase in sweep gas flow from 8 to 16 L/minute had less impact on ECCO2R in this setting.
doi:10.1186/cc13928
PMCID: PMC4095596  PMID: 24942014
4.  A nationwide postal questionnaire survey: the presence of airway guidelines in anaesthesia department in Sweden 
BMC Anesthesiology  2014;14:25.
Background
In Sweden, airway guidelines aimed toward improving patient safety have been recommended by the Swedish Society of Anaesthesia and Intensive Care Medicine. Adherence to evidence-based airway guidelines is known to be generally poor in Sweden. The aim of this study was to determine whether airway guidelines are present in Swedish anaesthesia departments.
Methods
A nationwide postal questionnaire inquiring about the presence of airway guidelines was sent out to directors of Swedish anaesthesia departments (n = 74). The structured questionnaire was based on a review of the Swedish Society of Anaesthesia and Intensive Care voluntary recommendations of guidelines for airway management. Mean, standard deviation, minimum/maximum, percentage (%) and number of general anaesthesia performed per year as frequency (n), were used to describe, each hospital type (university, county, private). For comparison between hospitals type and available written airway guidelines were cross tabulation used and analysed using Pearson’s Chi-Square tests. A p- value of less than 0 .05 was judged significant.
Results
In total 68 directors who were responsible for the anaesthesia departments returned the questionnaire, which give a response rate of 92% (n 68 of 74). The presence of guidelines showing an airway algorithm was reported by 68% of the departments; 52% reported having a written patient information card in case of a difficult airway and guidelines for difficult airways, respectively; 43% reported the presence of guidelines for preoperative assessment; 31% had guidelines for Rapid Sequence Intubation; 26% reported criteria for performing an awake intubation; and 21% reported guidelines for awake fibre-optic intubation. A prescription for the registered nurse anaesthetist for performing tracheal intubation was reported by 24%. The most frequently pre-printed preoperative elements in the anaesthesia record form were dental status and head and neck mobility.
Conclusions
Despite recommendations from the national anaesthesia society, the presence of airway guidelines in Swedish anaesthesia departments is low. From the perspective of safety for both patients and the anaesthesia staff, airway management guidelines should be considered a higher priority.
doi:10.1186/1471-2253-14-25
PMCID: PMC3996174  PMID: 24708670
Airway guidelines; Airway management; Patient safety
5.  Serum pentraxin 3 concentrations in neonates 
doi:10.3109/03009734.2013.878770
PMCID: PMC3916723  PMID: 24438192
6.  Beneficial Antimicrobial Effect of the Addition of an Aminoglycoside to a β-Lactam Antibiotic in an E. coli Porcine Intensive Care Severe Sepsis Model 
PLoS ONE  2014;9(2):e90441.
This study aimed to determine whether the addition of an aminoglycoside to a ß-lactam antibiotic increases the antimicrobial effect during the early phase of Gram-negative severe sepsis/septic shock. A porcine model was selected that considered each animal’s individual blood bactericidal capacity. Escherichia coli, susceptible to both antibiotics, was given to healthy pigs intravenously during 3 h. At 2 h, the animals were randomized to a 20-min infusion with either cefuroxime alone (n = 9), a combination of cefuroxime+tobramycin (n = 9), or saline (control, n = 9). Blood samples were collected hourly for cultures and quantitative polymerase chain reaction (PCR). Bacterial growth in the organs after 6 h was chosen as the primary endpoint. A blood sample was obtained at baseline before start of bacterial infusion for ex vivo investigation of the blood bactericidal capacity. At 1 h after the administration of the antibiotics, a second blood sample was taken for ex vivo investigation of the antibiotic-induced blood killing activity. All animals developed severe sepsis/septic shock. Blood cultures and PCR rapidly became negative after completed bacterial infusion. Antibiotic-induced blood killing activity was significantly greater in the combination group than in the cefuroxime group (p<0.001). Growth of bacteria in the spleen was reduced in the two antibiotic groups compared with the controls (p<0.01); no difference was noted between the two antibiotic groups. Bacterial growth in the liver was significantly less in the combination group than in the cefuroxime group (p<0.05). High blood bactericidal capacity at baseline was associated with decreased growth in the blood and spleen (p<0.05). The addition of tobramycin to cefuroxime results in increased antibiotic-induced blood killing activity and less bacteria in the liver than cefuroxime alone. Individual blood bactericidal capacity may have a significant effect on antimicrobial outcome.
doi:10.1371/journal.pone.0090441
PMCID: PMC3938751  PMID: 24587365
7.  Serum Cathepsin S Is Associated With Decreased Insulin Sensitivity and the Development of Type 2 Diabetes in a Community-Based Cohort of Elderly Men 
Diabetes Care  2012;36(1):163-165.
OBJECTIVE
To investigate associations between serum cathepsin S, impaired insulin sensitivity, defective insulin secretion, and diabetes risk in a community-based sample of elderly men without diabetes.
RESEARCH DESIGN AND METHODS
Serum cathepsin S, insulin sensitivity (euglycemic-hyperinsulinemic clamp), and insulin secretion (early insulin response during an oral glucose tolerance test) were measured in 905 participants of the Uppsala Longitudinal Study of Adult Men (mean age, 71 years). Thirty participants developed diabetes during 6 years of follow-up.
RESULTS
After adjustment for age, anthropometric variables, and inflammatory markers, higher cathepsin S was associated with decreased insulin sensitivity (regression coefficient per SD increase −0.09 [95% CI −0.14 to −0.04], P = 0.001), but no association with early insulin response was found. Moreover, higher cathepsin S was associated with a higher risk for developing diabetes (odds ratio per SD increase 1.48 [1.08–2.01], P = 0.01).
CONCLUSIONS
Cathepsin S activity appears to be involved in the early dysregulation of glucose and insulin metabolism.
doi:10.2337/dc12-0494
PMCID: PMC3526243  PMID: 22923671
8.  Transcriptome-Mining for Single-Copy Nuclear Markers in Ferns 
PLoS ONE  2013;8(10):e76957.
Background
Molecular phylogenetic investigations have revolutionized our understanding of the evolutionary history of ferns—the second-most species-rich major group of vascular plants, and the sister clade to seed plants. The general absence of genomic resources available for this important group of plants, however, has resulted in the strong dependence of these studies on plastid data; nuclear or mitochondrial data have been rarely used. In this study, we utilize transcriptome data to design primers for nuclear markers for use in studies of fern evolutionary biology, and demonstrate the utility of these markers across the largest order of ferns, the Polypodiales.
Principal Findings
We present 20 novel single-copy nuclear regions, across 10 distinct protein-coding genes: ApPEFP_C, cryptochrome 2, cryptochrome 4, DET1, gapCpSh, IBR3, pgiC, SQD1, TPLATE, and transducin. These loci, individually and in combination, show strong resolving power across the Polypodiales phylogeny, and are readily amplified and sequenced from our genomic DNA test set (from 15 diploid Polypodiales species). For each region, we also present transcriptome alignments of the focal locus and related paralogs—curated broadly across ferns—that will allow researchers to develop their own primer sets for fern taxa outside of the Polypodiales. Analyses of sequence data generated from our genomic DNA test set reveal strong effects of partitioning schemes on support levels and, to a much lesser extent, on topology. A model partitioned by codon position is strongly favored, and analyses of the combined data yield a Polypodiales phylogeny that is well-supported and consistent with earlier studies of this group.
Conclusions
The 20 single-copy regions presented here more than triple the single-copy nuclear regions available for use in ferns. They provide a much-needed opportunity to assess plastid-derived hypotheses of relationships within the ferns, and increase our capacity to explore aspects of fern evolution previously unavailable to scientific investigation.
doi:10.1371/journal.pone.0076957
PMCID: PMC3792871  PMID: 24116189
9.  Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study 
Introduction
While microvascular disease is well described in systemic sclerosis (SSc), it is still unclear whether the occurrence of ischemic macrovascular events and atherosclerosis is enhanced among patients with SSc.
Methods
In this study, 111 SSc patients (74% of prevalent cases in Stockholm County) and 105 age- and sex-comparable population controls were investigated. Previous ischemic arterial events were tabulated. As surrogate measures of atherosclerosis, plaque occurrence and intima-media thickness (IMT) were determined with carotid ultrasound and the ankle-brachial index (ABI) was calculated. Traditional cardiovascular risk factors were recorded and we also measured biomarkers indicating systemic inflammation and endothelial activation/dysfunction.
Results
Mean age was 62 ± 12 years for patients and controls. Ischemic arterial events were more common, due to increased occurrence of ischemic heart disease (IHD) and ischemic peripheral vascular disease (IPVD), in the patient group (12% vs. 4%, P = 0.03 and 9% vs. 0%, P = 0.003 respectively). On a group level, there was no difference regarding the occurrence of ischemic cerebrovascular disease, the frequency of plaques, IMT or ABI between SSc patients and controls. Subgroup analyses revealed that patients with anticentromere antibodies (ACA+) had more plaques and more ischemic arterial events compared to other SSc patients (67% vs. 39% and 32% vs. 11%; P = 0.006 and P = 0.01, respectively) and compared to controls (67% vs. 41% and 32% vs. 7%, P = 0.02 and P = 0.0003, respectively). Biomarkers of inflammation/endothelial activation were generally increased among SSc patients.
Conclusions
Patients with SSc are at enhanced risk for IHD and IPVD. The ACA+ SSc subgroup was particularly affected with both ischemic arterial events and premature atherosclerosis. The microvascular vulnerability of ACA+ patients is previously well documented. We demonstrate that ACA+ SSc patients have an enhanced risk of macrovascular injury as well. This group should be followed closely and modifiable cardiovascular risk factors should be treated at an early stage.
doi:10.1186/ar4267
PMCID: PMC3979018  PMID: 23945149
10.  Lifestyle intervention is associated with decreased concentrations of circulating pentraxin 3 independent of CRP decrease 
Upsala Journal of Medical Sciences  2013;118(3):165-168.
Objectives
Pentraxin 3 (PTX3) is an acute phase marker, which is produced at the site of infection or inflammation in contrast to CRP that is mainly synthesized by the liver. The aim of the present study was to see if lifestyle interventions/weight loss would lead to decreased blood plasma concentrations of PTX3.
Methods
Study subjects (n = 31) were recruited to a lifestyle intervention program aiming at increased physical activity, improved eating habits, and weight loss. High-sensitivity C-reactive protein (CRP) and PTX3 methods were used for analysis of CRP and PTX3 in plasma samples collected at inclusion and after 4 and 8 weeks of treatment.
Results
Wilcoxon paired samples test showed a significant decrease in PTX3 concentrations from 2068 pg/mL at start to 2007 pg/mL at 4 weeks (P = 0.002) and 1748 pg/mL at 8 weeks (P = 0.003). The PTX3 decrease was not significantly correlated with a corresponding decrease in CRP or weight reduction.
Conclusions
The lifestyle intervention program resulted in a significant reduction of circulating concentrations of pentraxin 3 already after 4 and 8 weeks of treatment.
doi:10.3109/03009734.2013.801540
PMCID: PMC3713381  PMID: 23837595
Adult; body weight; CRP; human; inflammation; pentraxin 3; plasma
11.  Ruling out cardiac failure: Cost-benefit analysis of a sequential testing strategy with NT-proBNP before echocardiography 
Objectives
To estimate the possible economic benefit of a sequential testing strategy with NT-proBNP to reduce the number of echocardiographies.
Methods
Retrospective study in a third-party payer perspective. The costs were calculated from three Swedish counties: Blekinge, Östergötland, and Uppland. Two cut-off levels of NT-proBNP were used: 400 and 300 pg/mL. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for echocardiographies.
Results
The estimated costs for NT-proBNP tests and echocardiographies per county were reduced by 33%–36% with the 400 pg/mL cut-off and by 28%–29% with the 300 pg/mL cut-off. This corresponded to a yearly cost reduction of approximately €2–5 million per million inhabitants in these counties.
Conclusion
The use of NT-proBNP as a screening test could substantially reduce the number of echocardiographies in the diagnostic work-up of patients with suspected cardiac failure, as well as the associated costs.
doi:10.3109/03009734.2012.751471
PMCID: PMC3633333  PMID: 23230860
Cost; echocardiography; health economics; heart failure; laboratory test; NT-proBNP
12.  Endotoxin Tolerance Variation over 24 h during Porcine Endotoxemia: Association with Changes in Circulation and Organ Dysfunction 
PLoS ONE  2013;8(1):e53221.
Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.
doi:10.1371/journal.pone.0053221
PMCID: PMC3542331  PMID: 23326400
13.  Optimizing positive end-expiratory pressure by oscillatory mechanics minimizes tidal recruitment and distension: an experimental study in a lavage model of lung injury 
Critical Care  2012;16(6):R217.
Introduction
It is well established that during mechanical ventilation of patients with acute respiratory distress syndrome cyclic recruitment/derecruitment and overdistension are potentially injurious for lung tissues. We evaluated whether the forced oscillation technique (FOT) could be used to guide the ventilator settings in order to minimize cyclic lung recruitment/derecruitment and cyclic mechanical stress in an experimental model of acute lung injury.
Methods
We studied six pigs in which lung injury was induced by bronchoalveolar lavage. The animals were ventilated with a tidal volume of 6 ml/kg. Forced oscillations at 5 Hz were superimposed on the ventilation waveform. Pressure and flow were measured at the tip and at the inlet of the endotracheal tube respectively. Respiratory system reactance (Xrs) was computed from the pressure and flow signals and expressed in terms of oscillatory elastance (EX5). Positive end-expiratory pressure (PEEP) was increased from 0 to 24 cm H2O in steps of 4 cm H2O and subsequently decreased from 24 to 0 in steps of 2 cm H2O. At each PEEP step CT scans and EX5 were assessed at end-expiration and end-inspiration.
Results
During deflation the relationship between both end-expiratory and end-inspiratory EX5 and PEEP was a U-shaped curve with minimum values at PEEP = 13.4 ± 1.0 cm H2O (mean ± SD) and 13.0 ± 1.0 cm H2O respectively. EX5 was always higher at end-inspiration than at end-expiration, the difference between the average curves being minimal at 12 cm H2O. At this PEEP level, CT did not show any substantial sign of intra-tidal recruitment/derecruitment or expiratory lung collapse.
Conclusions
Using FOT it was possible to measure EX5 both at end-expiration and at end-inspiration. The optimal PEEP strategy based on end-expiratory EX5 minimized intra-tidal recruitment/derecruitment as assessed by CT, and the concurrent attenuation of intra-tidal variations of EX5 suggests that it may also minimize tidal mechanical stress.
doi:10.1186/cc11858
PMCID: PMC3672594  PMID: 23134702
14.  Inflammation, oxidative stress, glomerular filtration rate, and albuminuria in elderly men: a cross-sectional study 
BMC Research Notes  2012;5:537.
Background
The role of inflammation and oxidative stress in mild renal impairment in the elderly is not well studied. Accordingly, we aimed at investigating the associations between estimated glomerular filtration rate (eGFR), albumin/creatinine ratio (ACR), and markers of different inflammatory pathways and oxidative stress in a community based cohort of elderly men.
Findings
Cystatin C-based GFR, ACR, and biomarkers of cytokine-mediated inflammation (interleukin-6, high-sensitivity C-reactive protein[CRP], serum amyloid A[SAA]), cyclooxygenase-mediated inflammation (urinary prostaglandin F2α [PGF2α]), and oxidative stress (urinary F2 isoprostanes) were assessed in the Uppsala Longitudinal Study of Adult Men(n = 647, mean age 77 years).
Results
In linear regression models adjusting for age, BMI, smoking, blood pressure, LDL-cholesterol, HDL-cholesterol, triglycerides, and treatment with statins, ACE-inhibitors, ASA, and anti-inflammatory agents, eGFR was inversely associated with CRP, interleukin-6, and SAA (β-coefficient −0.13 to −0.19, p < 0.001 for all), and positively associated with urinary F2-isoprostanes (β-coefficient 0.09, p = 0.02). In line with this, ACR was positively associated with CRP, interleukin-6, and SAA (β- coefficient 0.09-0.12, p < 0.02 for all), and negatively associated with urinary F2-isoprostanes (β-coefficient −0.12, p = 0.002). The associations were similar but with lower regression coefficients in a sub-sample with normal eGFR (>60 ml/min/1.73 m2, n = 514), with the exception that F2-isoprostane and SAA were no longer associated with eGFR.
Conclusion
Our data indicate that cytokine-mediated inflammation is involved in the early stages of impaired kidney function in the elderly, but that cyclooxygenase-mediated inflammation does not play a role at this stage. The unexpected association between higher eGFR/lower albuminuria and increased F2-isoprostanes in urine merits further studies.
doi:10.1186/1756-0500-5-537
PMCID: PMC3527356  PMID: 23016573
Inflammation; Oxidative stress; Glomerular filtration rate and albuminuria
15.  Reference values of thirty-one frequently used laboratory markers for 75-year-old males and females 
Upsala Journal of Medical Sciences  2012;117(3):264-272.
Background
We have previously reported reference values for common clinical chemistry tests in healthy 70-year-old males and females. We have now repeated this study 5 years later to establish reference values also at the age of 75. It is important to have adequate reference values for elderly patients as biological markers may change over time, and adequate reference values are essential for correct clinical decisions.
Methods
We have investigated 31 frequently used laboratory markers in 75-year-old males (n = 354) and females (n = 373) without diabetes. The 2.5 and 97.5 percentiles for these markers were calculated according to the recommendations of the International Federation of Clinical Chemistry.
Results
Reference values are reported for 75-year-old males and females for 31 frequently used laboratory markers.
Conclusion
There were minor differences between reference intervals calculated with and without individuals with cardiovascular diseases. Several of the reference intervals differed from Scandinavian reference intervals based on younger individuals (Nordic Reference Interval Project).
doi:10.3109/03009734.2011.644873
PMCID: PMC3410285  PMID: 22300333
Clinical chemistry; geriatrics; immunoassays; laboratory tests
16.  Regional variation in use of exogenous and endogenous glomerular filtration rate (GFR) markers in Sweden 
Upsala Journal of Medical Sciences  2012;117(3):273-278.
Background
Markers of renal function (glomerular filtration rate (GFR)) are frequently used in the Swedish health care. GFR is usually estimated based on plasma creatinine concentration, but plasma cystatin C concentration, creatinine clearance, iohexol clearance, and 51Cr-EDTA clearance are also used. These markers are all part of the daily patient care, but there is little specific information on the clinical use of these markers. The aim of this study was to compare the use of these various GFR markers in different parts of Sweden and potential changes over time.
Methods
Retrospective study using questionnaires to collect information for the years 2006–2009 divided per county on the specific use of GFR markers with type of test reports.
Results
Plasma/serum creatinine concentration (96%) is by far the dominating GFR marker in Sweden, while cystatin C concentration (3.5%), creatinine clearance (0.1%), iohexol clearance (0.1%), and 51Cr-EDTA clearance (0.1%) are less frequently used. The use of GFR markers, including creatinine, continues to increase on a national level with the exception of creatinine clearance and 51Cr-EDTA clearance. There were considerable variations between different counties in the use of GFR markers and the type of test reports that the laboratories provided.
Conclusions
The inter-county variations of GFR markers used in Sweden are large and indicate that savings associated with optimized test utilization in this regard could be substantial. Regional habits and traditions are likely to influence the variations in GFR marker use.
doi:10.3109/03009734.2012.664179
PMCID: PMC3410286  PMID: 22401136
Clinical chemistry tests; diagnostic tests; family practice; glomerular filtration rate; health care costs; physician's practice patterns
17.  24-Hour ambulatory blood pressure associates inversely with prostaglandin F2α, interleukin-6 and F2-isoprostane formation in a Swedish population of older men 
Vasoconstrictive prostaglandins (PGs), such as PGF2α, F2-isoprostanes, and systemic inflammation may be involved in the physiological regulation of blood pressure (BP) and the pathophysiology leading to hypertension. However, studies evaluating these parameters and BP in human populations are sparse. We analysed the cross-sectional associations between 24-hour ambulatory BP and urinary 15-keto-dihydro-PGF2α (indicator of PG-mediated vasoconstriction and inflammation), plasma interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid A (SAA) and urinary F2-isoprostanes (indicator of vasoconstriction and oxidative stress) in 619 men in a Swedish older population (Uppsala Longitudinal Study of Adult Men, age 78 years). Both systolic and diastolic 24-hour BP correlated inversely with concentrations of 15-keto-dihydro-PGF2α (P<0.01) and F2-isoprostanes (P<0.01) independent on other cardiovascular risk factors. Additionally, diastolic 24-hour BP inversely correlated with plasma IL-6 (P<0.05) and 24-hour pulse pressure showed a positive linear correlation with IL-6, CRP and SAA. In conclusion, high BP is associated with decreased formation of vasoconstrictive PGF2α and F2-isoprostanes in this population of older men. These findings, although unlike our original hypothesis, might have an important physiological function which needs to be further evaluated.
PMCID: PMC3342711  PMID: 22567175
Blood pressure; pulse pressure; eicosanoids; prostaglandin F2α; F2-isoprostanes; interleukin-6; inflammation; human; population
18.  Risk factors for cardiovascular mortality in patients with systemic lupus erythematosus, a prospective cohort study 
Introduction
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Cardiovascular disease (CVD) is common and a major cause of mortality. Studies on cardiovascular morbidity are abundant, whereas mortality studies focusing on cardiovascular outcomes are scarce. The aim of this study was to investigate causes of death and baseline predictors of overall (OM), non-vascular (N-VM), and specifically cardiovascular (CVM) mortality in SLE, and to evaluate systematic coronary risk evaluation (SCORE).
Methods
208 SLE patients were included 1995-1999 and followed up after 12 years. Clinical evaluation, CVD risk factors, and biomarkers were recorded at inclusion. Death certificates and autopsy protocols were collected. Causes of death were divided into CVM (ischemic vascular and general atherosclerotic diseases), N-VM and death due to pulmonary hypertension. Predictors of mortality were investigated using multivariable Cox regression. SCORE and standardized mortality ratio (SMR) were calculated.
Results
During follow-up 42 patients died at mean age of 62 years. SMR 2.4 (CI 1.7-3.0). 48% of deaths were caused by CVM. SCORE underestimated CVM but not to a significant level. Age, high cystatin C levels and established arterial disease were the strongest predictors for all- cause mortality. After adjusting for these in multivariable analyses, only smoking among traditional risk factors, and high soluble vascular cell adhesion molecule-1 (sVCAM-1), high sensitivity C-reactive protein (hsCRP), anti-beta2 glycoprotein-1 (abeta2GP1) and any antiphospholipid antibody (aPL) among biomarkers, remained predictive of CVM.
Conclusion
With the exception of smoking, traditional risk factors do not capture the main underlying risk factors for CVM in SLE. Rather, cystatin C levels, inflammatory and endothelial markers, and antiphospholipid antibodies (aPL) differentiate patients with favorable versus severe cardiovascular prognosis. Our results suggest that these new biomarkers are useful in evaluating the future risk of cardiovascular mortality in SLE patients.
doi:10.1186/ar3759
PMCID: PMC4060356  PMID: 22390680
19.  Three-year mortality among alcoholic patients after intensive care: a population-based cohort study 
Critical Care  2012;16(1):R5.
Introduction
Alcoholic patients comprise a large proportion of patients in intensive care units (ICUs). However, data are limited on the impact of alcoholism on mortality after intensive care.
Methods
We conducted a cohort study among 16,848 first-time ICU patients between 2001 and 2007 to examine 30-day and 3-year mortality among alcoholic patients. Alcoholic patients with and without complications of alcohol misuse (for example, alcoholic liver disease) were identified from previous hospital contacts for alcoholism-related conditions or redemption of a prescription for alcohol deterrents. Data on medication use, demographics, hospital diagnoses, and comorbidity were obtained from medical databases. We computed 30-day and 3-year mortality and mortality rate ratios (MRRs) by using Cox regression analysis, controlling for covariates.
Results
In total, 1,229 (7.3%) ICU patients were current alcoholics. Among alcoholic patients without complications of alcoholism (n = 785, 4.7% of the cohort), 30-day mortality was 15.9% compared with 19.7% among nonalcoholic patients. Compared with nonalcoholic patients, the adjusted 30-day MRR was 1.04 (95% confidence interval (CI), 0.87 to 1.25). Three-year mortality was 36.2% compared with 40.9% among nonalcoholic patients, corresponding to an adjusted 3-year MRR of 1.16 (95% CI, 1.03 to 1.31). For alcoholic patients with complications (n = 444, 2.6% of the cohort), 30-day mortality was 33.6%, and 3-year mortality was 64.5%, corresponding to adjusted MRRs, with nonalcoholics as the comparator, of 1.64 (95% CI, 1.38 to 1.95) and 1.67 (95% CI, 1.48 to 1.90), respectively.
Conclusions
Alcoholic ICU patients with chronic complications of alcoholism have substantially increased 30-day and 3-year mortality. In contrast, alcoholics without complications have no increased 30-day and only slightly increased 3- year mortality.
doi:10.1186/cc10603
PMCID: PMC3396230  PMID: 22226344
20.  Effect of prolonged standardized bed rest on cystatin C and other markers of cardiovascular risk 
BMC Physiology  2011;11:17.
Background
Sedentary lifestyle is associated with coronary artery disease but even shorter periods of physical inactivity may increase cardiovascular risk. Cystatin C is independently associated with cardiovascular disease and our objective was to investigate the relation between this novel biomarker and standardized bed rest. Research of immobilization physiology in humans is challenging because good biological models are in short supply. From the Women International Space simulation for Exploration study (WISE) we studied markers of atherosclerosis and kidney function, including cystatin C, in a standardized bed rest study on healthy volunteers. Fifteen healthy female volunteers participated in a 20-day ambulatory control period followed by 60 days of bed rest in head-down tilt position (-6°) 24 h a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training.
Results
Compared to baseline values there was a statistically significant increase in cystatin C in both groups after bed rest (P < 0.001). Glomerular filtration rate (GFR), calculated by both cystatin C and Cockcroft-Gault equation, decreased after bed rest while there were no differences in creatinine or creatine kinase levels. CRP did not change during bed rest in the exercise group, but there was an increase of CRP in the control group during recovery compared to both the baseline and the bed rest periods. The apo-B/apo-Ai ratio increased during bed rest and decreased again in the recovery period. Subjects experienced a small but statistically significant reduction in weight during bed rest and compared to baseline weights remained lower at day 8 of recovery.
Conclusion
During and following prolonged standardized bed rest the concentrations of several clinically relevant cardiovascular risk markers change.
doi:10.1186/1472-6793-11-17
PMCID: PMC3298483  PMID: 22152087
23.  Positive end-expiratory pressure optimization with forced oscillation technique reduces ventilator induced lung injury: a controlled experimental study in pigs with saline lavage lung injury 
Critical Care  2011;15(3):R126.
Introduction
Protocols using high levels of positive end-expiratory pressure (PEEP) in combination with low tidal volumes have been shown to reduce mortality in patients with severe acute respiratory distress syndrome (ARDS). However, the optimal method for setting PEEP is yet to be defined. It has been shown that respiratory system reactance (Xrs), measured by the forced oscillation technique (FOT) at 5 Hz, may be used to identify the minimal PEEP level required to maintain lung recruitment. The aim of the present study was to evaluate if using Xrs for setting PEEP would improve lung mechanics and reduce lung injury compared to an oxygenation-based approach.
Methods
17 pigs, in which acute lung injury (ALI) was induced by saline lavage, were studied. Animals were randomized into two groups: in the first PEEP was titrated according to Xrs (FOT group), in the control group PEEP was set according to the ARDSNet protocol (ARDSNet group). The duration of the trial was 12 hours. In both groups recruitment maneuvers (RM) were performed every 2 hours, increasing PEEP to 20 cmH2O. In the FOT group PEEP was titrated by monitoring Xrs while PEEP was reduced from 20 cmH2O in steps of 2 cmH2O. PEEP was considered optimal at the step before which Xrs started to decrease. Ventilatory parameters, lung mechanics, blood gases and hemodynamic parameters were recorded hourly. Lung injury was evaluated by histopathological analysis.
Results
The PEEP levels set in the FOT group were significantly higher compared to those set in the ARDSNet group during the whole trial. These higher values of PEEP resulted in improved lung mechanics, reduced driving pressure, improved oxygenation, with a trend for higher PaCO2 and lower systemic and pulmonary pressure. After 12 hours of ventilation, histopathological analysis showed a significantly lower score of lung injury in the FOT group compared to the ARDSNet group.
Conclusions
In a lavage model of lung injury a PEEP optimization strategy based on maximizing Xrs attenuated the signs of ventilator induced lung injury. The respiratory system reactance measured by FOT could thus be an important component in a strategy for delivering protective ventilation to patients with ARDS/acute lung injury.
doi:10.1186/cc10236
PMCID: PMC3218989  PMID: 21575220
24.  Cytokine-mediated inflammation is independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a community-based cohort of elderly men 
Both clinical and experimental studies suggest a close relation between an inflammatory state and insulin resistance. We investigated the association between cytokine-mediated inflammation (high sensitivity C reactive protein [hsCRP] and interleukin [IL] 6) and insulin sensitivity (insulin-mediated glucose disposal rate, assessed by the euglycemic insulin clamp) in a community-based cohort, with subgroup analyses of normal weight individuals without diabetes mellitus and metabolic syndrome (NCEP). hsCRP and IL-6 were inversely associated with insulin sensitivity (multivariable-adjusted regression coefficient for 1-SD increase of hsCRP -0.12 (-0.21-(-0.03), p=0.01) and of IL-6 -0.11 (-0.21-(-0.02), p=0.01) in models adjusting for age and components of the metabolic syndrome (systolic and diastolic blood pressure, antihypertensive drugs, HDL-cholesterol, triglycerides, fasting plasma glucose, waist circumference). The multivariable-adjusted association between hsCRP, IL-6 and insulin sensitivity were of a similar magnitude in normal weight individuals without diabetes and without the metabolic syndrome. Our data show that cytokine -mediated subclinical inflammation is independently associated with decreased insulin sensitivity also in apparently metabolically healthy normal weight individuals, indicating that the interplay between inflammatory processes and insulin resistance is present already in the early stages of the development of glucometabolic disease.
PMCID: PMC3113503  PMID: 21686140
Euglycemic insulin clamp; insulin sensitivity; inflammation; cytokines; metabolic syndrome; diabetes
25.  Preadmission beta-blocker use and 30-day mortality among patients in intensive care: a cohort study 
Critical Care  2011;15(2):R87.
Introduction
Beta-blockers have cardioprotective, metabolic and immunomodulating effects that may be beneficial to patients in intensive care. We examined the association between preadmission beta-blocker use and 30-day mortality following intensive care.
Methods
We identified 8,087 patients over age 45 admitted to one of three multidisciplinary intensive care units (ICUs) between 1999 and 2005. Data on the use of beta-blockers and medications, diagnosis, comorbidities, surgery, markers of socioeconomic status, laboratory tests upon ICU admission, and complete follow-up for mortality were obtained from medical databases. We computed probability of death within 30 days following ICU admission for beta-blocker users and non-users, and the odds ratio (OR) of death as a measure of relative risk using conditional logistic regression and also did a propensity score-matched analysis.
Results
Inclusion of all 8,087 ICU patients in a logistic regression analysis yielded an adjusted OR of 0.82 (95% confidence interval (CI): 0.71 to 0.94) for beta-blocker users compared with non-users. In the propensity score-matched analysis we matched all 1,556 beta-blocker users (19.2% of the entire cohort) with 1,556 non-users; the 30-day mortality was 25.7% among beta-blocker users and 31.4% among non-users (OR 0.74 (95% CI: 0.63 to 0.87)]. The OR was 0.69 (95% CI: 0.54 to 0.88) for surgical ICU patients and 0.71 (95% CI: 0.51 to 0.98) for medical ICU patients. The OR was 0.99 (95% CI: 0.67 to 1.47) among users of non-selective beta-blockers, and 0.70 (95% CI: 0.58 to 0.83) among users of cardioselective beta-blockers.
Conclusions
Preadmission beta-blocker use is associated with reduced mortality following ICU admission.
doi:10.1186/cc10085
PMCID: PMC3219345  PMID: 21385356

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