Lipidomic analysis of local inflammation models shows a specific systemic acute phase response to lipopolysaccharides.

Toll-like receptors (TLR) are crucial for recognizing bacterial, viral or fungal pathogens and to orchestrate the appropriate immune response. The widely expressed TLR2 and TLR4 differentially recognize various pathogens to initiate partly overlapping immune cascades. To better understand the physiological consequences of both immune responses, we performed comparative lipidomic analyses of local paw inflammation in mice induced by the TLR2 and TLR4 agonists, zymosan and lipopolysaccharide (LPS), respectively, which are commonly used in models for inflammation and inflammatory pain. Doses for both agonists were chosen to cause mechanical hypersensitivity with identical strength and duration. Lipidomic analysis showed 5 h after LPS or zymosan injection in both models an increase of ether-phosphatidylcholines (PC O) and their corresponding lyso species with additional lipids being increased only in response to LPS. However, zymosan induced stronger immune cell recruitment and edema formation as compared to LPS. Importantly, only in LPS-induced inflammation the lipid profile in the contralateral paw was altered. Fittingly, the plasma level of various cytokines and chemokines, including IL-1ß and IL-6, were significantly increased only in LPS-treated mice. Accordingly LPS induced distinct changes in the lipid profiles of ipsilateral and contralateral paws. Here, oxydized fatty acids, phosphatidylcholines and phosphatidylethanolamines were uniquely upregulated on the contralateral side. Thus, both models cause increased levels of PC O and lyso-PC O lipids at the site of inflammation pointing at a common role in inflammation. Also, LPS initiates systemic changes, which can be detected by changes in the lipid profiles.

Evaluation of lung parenchyma, blood vessels, and peripheral blood lymphocytes as a potential source of acute phase reactants in patients with COPD.

Background: Previous studies have shown that the arterial wall is a potential source of inflammatory markers in COPD. Here, we sought to compare the expression of acute phase reactants (APRs) in COPD patients and controls both at the local (pulmonary arteries and lung parenchyma) and systemic (peripheral blood leukocytes and plasma) compartments. Methods: Consecutive patients undergoing elective surgery for suspected primary lung cancer were eligible for the study. Patients were categorized either as COPD or control group based on the spirometry results. Pulmonary arteries and lung parenchyma sections, peripheral blood leukocytes, and plasma samples were obtained from all participants. Gene expression levels of C-reactive protein (CRP) and serum amyloid A (SAA1, SAA2, and SAA4) were evaluated in tissue samples and peripheral blood leukocytes by reverse transciption-PCR. Plasma CRP and SAA protein levels were measured by enzyme-linked immunosorbent assays. Proteins were evaluated in paraffin-embedded lung tissues by immunohistochemistry. Results: A total of 40 patients with COPD and 62 controls were enrolled. We did not find significant differences in the gene expression between COPD and control group. Both CRP and SAA were overexpressed in the lung parenchyma compared with pulmonary arteries and peripheral blood leukocytes. The expression of SAA was significantly higher in the lung parenchyma than in the pulmonary artery (2-fold higher for SAA1 and SAA4, P=0.015 and P<0.001, respectively; 8-fold higher for SAA2, P<0.001) and peripheral blood leukocytes (16-fold higher for SAA1, 439-fold higher for SAA2, and 5-fold higher for SAA4; P<0.001). No correlation between plasma levels of inflammatory markers and their expression in the lung and peripheral blood leukocytes was observed. Conclusions: The expression of SAA in lung parenchyma is higher than in pulmonary artery and peripheral blood leukocytes. Notably, no associations were noted between lung expression of APRs and their circulating plasma levels, making the leakage of inflammatory proteins from the lung to the bloodstream unlikely. Based on these results, other potential sources of systemic inflammation in COPD (eg, the liver) need further scrutiny.

Increased perioperative C-reactive protein and decreased postoperative albumin is associated with acute posttraumatic osteomyelitis in patients with high-energy tibial fractures.

BACKGROUND: Early diagnosis of acute posttraumatic osteomyelitis (POM) is of vital importance for avoiding devastating complications. Diagnosing POM is difficult due to the lack of a highly specific and sensitive test, such as in myocardial infarct, stroke and intracranial bleeding. Serum inflammatory markers, C-reactive protein (CRP), procalcitonin (PCT), white blood cells (WBC) can support clinical findings but they are not able to differentiate between inflammatory response to infection and the host response to non-infection insult with high specificity and sensitivity. AIM: The objectives of the study were to investigate whether the biochemical and immunoinflammatory patient profile could facilitate postoperative monitoring, guide the antibiotic treatment and timing of revision surgery. PATIENTS AND METHODS: This prospective nonrandomised cohort study included 86 patients after high-energy injury to the shin requiring primary surgical treatment (open or closed reduction and internal fixation of tibial fracture). Values of the biochemical and immunoinflammatory profile were measured on admission (ADD), first postoperative day (POD1) and fourth-postoperative day (POD4). RESULTS: We discovered on our sample that the development of POM is associated with increased CRP on ADD, POD1 and decreased albumins on POD4. Further studies are needed to prove that these differences can be useful in diagnosing the risk of infection. The assessment of other important risk factors such as: the extent of soft tissue damage, multiple fractures, transfusion rate, need for conversion primary external fixation to intramedullary (IM) nailing or locking plate fixation can empower our clinical judgment of POM. CONCLUSIONS: We can improve prediction of posttraumatic osteomyelitis by using the perioperative inflammatory biomarker CRP in combination with postoperative albumins levels and other associated independent risk factors.

Is cord blood hepcidin influenced by the low-grade acute-phase response occurring during delivery? A small-scale longitudinal study.

AIM: To measure serum hepcidin in late pregnancy and in cord blood, and to analyze relationship between hepcidin, interleukin-6, and biomarkers of fetal iron status. MATERIALS AND METHODS: Data from 15 uncomplicated singleton pregnancies were analyzed longitudinally in trimester 3 (T3) and at birth. RESULTS: In T3, S-ferritin (median 14 µg/L) and transferrin (median 4.0 g/L) indicated low iron status, whereas the median soluble transferrin receptor (sTfR) was 4.0 mg/L, i.e. within the reference interval. Median T3 S-hepcidin was 7.8 ng/mL. Later on in cord blood, ferritin concentration (180 µg/L) were significantly higher, transferrin concentration (1.8 g/L) were significantly lower, and both sTfR (4.7 mg/L) and S-hepcidin concentrations (30.5 ng/mL) were significantly higher than maternal T3 concentrations. At the same time, cord blood interleukin-6 indicated an activated acute-phase reaction. In T3, after logarithmic transformation, there was a significant correlation between S-hepcidin and both S-ferritin (r = 0.691) and sTfR (r = -0.825). There was also a significant correlation between S-ferritin and both sTfR (r = -0.729) and transferrin (r = 0.549) in T3. CONCLUSIONS: Although S-ferritin, S-hepcidin, and sTfR were correlated during pregnancy, these relationships were not apparent in umbilical cord blood. Further, cord blood interleukin-6 indicated an activated acute-phase response, and sTfR, which is known to be unaffected by inflammation, indicated a low iron status in cord blood. Thus, instead of representing an enhanced iron status, the data appear to suggest that hepcidin and ferritin in cord blood may be influenced by the low-grade acute-phase response that occurs during delivery.

Indscators of blood lipid profile, acute phase reactions and uric acid in patients with arterial hypertension combined with connective tissue dysplasia.

OBJECTIVE: Introduction:Changes in the cardiovascular system can be divided into 2 groups due to the connective tissue dysplasia (CTD) and changes in the circulatory system, caused by pathological processes that arose on the basis of the connective structures failure. One of the risk factors of arterial hypertension (AH) remaining insufficiently studied is collagen pathology - nondifferentiated connective tissue dysplasia (NCTD). The presence of connective tissue in all organs and systems, the common origin of smooth muscles, blood and lymph from mesenchyma leads to dysplastic changes in any organ and system. NCTD is morphologically characterized by changes in collagen, elastic fibrils, glycoproteins, proteoglycans and fibroblasts, which are based on hereditary mutations of genes encoding the synthesis and spatial organization of collagen, structural proteins and protein-hydrocarbon complexes, enzymes and cofactors to them. The aim was to study external and internal phenotypic signs of CTD, indicators of blood lipid spectrum, acute phase reactions and uric acid in patients with hypertension associated with CTD. PATIENTS AND METHODS: Materials and methods: The study implied examination of 52 patients (19 women and 33 men) with AH of the 2-nd stage from 1-st to 3-rd degrees and CTD manifestations, which were on inpatient treatment in the cardiology department of the Lviv City Communal Clinical Emergency Hospital. The average age of patients was 61.14 ± 2.58 years. Patients were divided into 3 groups depending on the degree of hypertension. The first group (n = 5) included patients with AH of the 1-st degree, the second (n = 28) - with AH of the 2-nd degree, the third (n = 19) - with AH of the 3-rd degree. The control group consisted of 25 practically healthy persons. Patients underwent checkup, palpation, percussion, auscultation, laboratory examinations (blood lipid spectrum, CRP, serumukoid content and uric acid), instrumental studies (ECG, echocardiography, DBPM, ultrasound examination of the internal organs and lower limbs vessels, ultrasound examination of the sleep and vertebral arteries, X-ray examination of the bone and articular system), consultation of an ophthalmologist, a neuropathologist, a traumatologist and a dentist. RESULTS: Results: In a comparative analysis between the control group and patients with stage ІІ hypertension of 1-3 grades, in 84.6% cases external and internal CTD signs were observed, and in 15.4% cases there were no manifestations. In applying the diagnostic criteria for assessing signs of CTD and stigmata of dysebryogenesis, different numbers of points were defined depending on the severity of the AH. The highest quantity of points was found in patients of the 3-rd group (30,8 ± 0,81), which indicates a significant presence of external signs of CTD in comparison with the 1-st and 2-nd groups of patients (25.2 ± 1.38 and 26.7 ± 0.72), respectively. CONCLUSION: Conclusions: The external and internal phenotypic signs of CTD of medium and severe expressiveness degree were revealed, however, most commonly they were observed in patients with hypertension of grade 3. The presence of positive correlations between the levels of TC, HDL-C, LDL-C, AC, UA and TG indicates its direct role in the pathogenesis of hypertension, and the combination with CTD complicates the underlined pathology. Screening of the studied indicators can improve the prognosis of the course and development of cardiovascular complications.

Impact of chronic and acute inflammation on extra- and intracellular iron homeostasis.

Inflammation has a major impact on iron homeostasis. This review focuses on acute and chronic inflammation as it affects iron trafficking and, as a result, the availability of this essential micronutrient to the host. In situations of microbial infection, not only the host is affected but also the offending microorganisms, which, in general, not only require iron for their own growth but have evolved mechanisms to obtain it from the infected host. Key players in mammalian iron trafficking include several types of cells important to iron acquisition, homeostasis, and hematopoiesis (enterocytes, hepatocytes, macrophages, hematopoietic cells, and in the case of pregnancy, placental syncytiotrophoblast cells) and several forms of chaperone proteins, including, for nonheme iron, the transport protein transferrin and the intracellular iron-storage protein ferritin, and for heme iron, the chaperone proteins haptoglobin and hemopexin. Additional key players are the cell membrane-associated iron transporters, particularly ferroportin (FPN), the only protein known to modulate iron export from cells, and finally, the iron-regulatory hormone hepcidin, which, in addition to having antibacterial activity, regulates the functions of FPN. Interestingly, the impact of infection on iron homeostasis differs among pathogens whose mode of infection is mainly intracellular or extracellular. Understanding how inflammation affects each of these processes may be crucial for understanding how inflammation affects iron status, indicators of iron sufficiency, and iron supplementation during inflammation and how it may potentially result in a beneficial or detrimental impact on the host.

Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction.

Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII-containing HDL (-28% and -44.8%, respectively) and of medium-sized HDL (-10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (-18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (-25.5, -41.1 and -30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL-cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1-CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction.

[Transient detection of lupus anticoagulant in acute phase of Kawasaki disease].

  In Kawasaki disease (KD), endothelial damage and an elevation in coagulant factors provoke thrombosis. Lupus anticoagulant (LA) is strongly associated with the risk of thrombosis in patients with antiphospholipid syndrome; however, there has been no report of positive LA in KD patients. A previously healthy, 2-year-old boy was admitted due to fever, bilateral conjunctivitis, redness of the lips, and unilateral cervical lymphadenopathy. Typical Kawasaki disease was diagnosed on day 5 of illness. Adenovirus antigens were detected in his stool. After the KD symptoms were successfully treated with intravenous immunoglobulin, his activated partial thromboplastin time (APTT) increased to 88 seconds at eight days of illness. The cross-mixing test showed an inhibition pattern, and the presence of LA was proved using diluted Russell's viper venom time. APPT elongation improved due to continued low dose aspirin therapy without thromboembolisms. The possibility of contamination by LA was low because six other patients treated with the same immunoglobulin lot showed no APTT elongation. We speculated that KD-related infections led to the presence of LA, which may have triggered the thrombosis. Further accumulation of data is warranted to elucidate the role of LA in KD patients.

Correlations between the levels of acute infection markers and serum albumin in elderly patients with hip fracture.

OBJECTIVE: The aim of this study was to explore a clinical index that could predict the decline of serum albumin (ALB) in elderly patients (over 60 years old) with hip fractures in 2014. METHODS: All the data came from the retrospective survey, and the correlations between the ALB changes and acute infection markers were then analyzed using correlation analysis. The changes of infection markers and ALB before and after surgery were compared using the t test. RESULTS: There was no correlation of the serum ALB blood with interleukin-6 (IL-6) (r = 0.072, P = 0.588), C-reactive protein (CRP) (r = -0.249, P = 0.057), or calcitonin (PCT) (r = -0.038, P = 0.775) when patients were admitted, but it was negatively correlated with the total amount of infection markers (TAIMs) (r = -0.301, P = 0.020). The postoperative levels of IL-6 (154.23 ± 177.14 pg/mL) (P < 0.001), CRP (69.52 ± 39.84 mg/L) (P < 0.001), and PCT (1.27 ± 2.4 ng/mL) (P < 0.001) were significantly increased than those before surgery [IL-6 (44.96 ± 54.58 pg/mL), CRP (31.78 ± 29.90 mg/L), and PCT (0.42 ± 1.06 ng/mL)]. The postoperative level of serum ALB (29.93 ± 3.02 g/L) was significantly reduced than that before surgery (33.95 ± 3.69 g/L) (P < 0.001). The serum ALB level was negatively correlated with IL-6 (r = -0.333, P = 0.015) before surgery, but not correlated with TAIMs (r = -0.256, P = 0.061). The serum ALB level was negatively correlated with IL-6 (r = -0.292, P = 0.034) and TAIMs (r = -0.271, P = 0.050) after surgery. CONCLUSIONS: The serum IL-6 level could predict the changes of ALB during the disease process.

Long-Term Impact of Postoperative Complications on Cancer Recurrence Following Lung Cancer Surgery.

BACKGROUND: Postoperative complications are associated with poor cancer-specific survival in various types of cancer surgery. Recent studies suggest that systemic inflammation induced by surgical trauma can accelerate the adhesion of circulating tumor cells to the vascular endothelium of distant organs, resulting in early cancer recurrence. We investigated the impact of postoperative cardiopulmonary complications on cancer recurrence following lung cancer surgery. METHODS: From a prospective database of 675 consecutive patients who underwent curative surgery for lung cancer between 2007 and 2012, the incidence of postoperative cardiopulmonary complications, white blood cell counts, and C-reactive protein levels were evaluated in the acute phase after surgery. Four patients had both cardiovascular and respiratory complications. The remaining 671 patients were divided into 3 groups: patients without cardiopulmonary complications; those with cardiovascular complications; and those with respiratory complications. The incidence of cancer recurrence was compared among the three groups. RESULTS: Postoperative cardiovascular or respiratory complications were identified in 94 (14%) or 25 (4%) patients, respectively. Postoperative white blood cell counts and C-reactive protein levels were significantly higher in those with postoperative respiratory complications than in those without. There was a significantly higher incidence of cancer recurrence in those with postoperative respiratory complications than in those without (48.0 vs. 16.8%; p < 0.0001). Multiple regression analysis adjusted for age, sex, and pathological staging showed that the incidence of postoperative respiratory complications was a significant predictor of cancer recurrence. CONCLUSIONS: The presence of respiratory complications following lung cancer surgery was a significant predictor of cancer recurrence.

Comparison of acute phase reaction and postoperative stress in pigs undergoing video-assisted thoracoscopic versus thoracotomy pneumonectomy.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has been used for many thoracic diseases as an alternate approach to thoracotomy. The aim of this study was to compare the surgical outcome of pneumonectomy using VATS with that using thoracotomy pneumonectomy in pigs. Fourteen pigs were equally divided into two groups; one group underwent VATS and the other group underwent transthoracic pneumonectomy. We monitored pre-, intra-, and post-operative physiologic parameters, along with blood cell count, serum C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and cortisol. The differences between the two approaches were analyzed. RESULTS: Mean surgical time in the VATS group (160.6 ± 16.2 min) was significantly longer than that in the thoracotomy group (123.7 ± 13.2 min). In both groups, CRP and IL-6 concentrations were significantly increased at postoperative 4 h, and then gradually decreased to preoperative levels. CRP and IL-6 at postoperative day 1 were significant lower in the VATS group compared with the thoracotomy group. SAA was significantly increased at postoperative days 1 and 3 in both groups compared with preoperative levels. Cortisol was significantly increased immediately after surgery in both groups compared with preoperative levels, and was significantly higher in the thoracotomy group than the VATS group at postoperative 4 h and 1 day. CONCLUSIONS: There was no difference between the two groups in physiologic parameters and blood cell count. However, the results indicate that VATS resulted in a smaller incision, less acute-phase reaction, less stress and less pain compared with thoracotomy pneumonectomy.

Comparison of the acute-phase response after laparoscopic versus open aortobifemoral bypass surgery: a substudy of a randomized controlled trial.

PURPOSE: Minimally invasive surgical techniques have been shown to reduce the inflammatory response related to a surgical procedure. The main objective of our study was to measure the inflammatory response in patients undergoing a totally laparoscopic versus open aortobifemoral bypass surgery. This is the first randomized trial on subjects in this population. PATIENTS AND METHODS: This is a substudy of a larger randomized controlled multicenter trial (Norwegian Laparoscopic Aortic Surgery Trial). Thirty consecutive patients with severe aortoiliac occlusive disease eligible for aortobifemoral bypass surgery were randomized to either a totally laparoscopic (n=14) or an open surgical procedure (n=16). The inflammatory response was measured by perioperative monitoring of serum interleukin-6 (IL-6), IL-8, and C-reactive protein (CRP) at six different time points. RESULTS: The inflammatory reaction caused by the laparoscopic procedure was reduced compared with open surgery. IL-6 was significantly lower after the laparoscopic procedure, measured by comparing area under the curve (AUC), and after adjusting for the confounding effect of coronary heart disease (P=0.010). The differences in serum levels of IL-8 and CRP did not reach statistical significance. CONCLUSION: In this substudy of a randomized controlled trial comparing laparoscopic and open aortobifemoral bypass surgeries, we found a decreased perioperative inflammatory response after the laparoscopic procedure measured by comparing AUC for serum IL-6.

Acute lung injury induced by whole gastric fluid: hepatic acute phase response contributes to increase lung antiprotease protection.

BACKGROUND: Gastric contents aspiration in humans is a risk factor for severe respiratory failure with elevated mortality. Although aspiration-induced local lung inflammation has been studied in animal models, little is known about extrapulmonary effects of aspiration. We investigated whether a single orotracheal instillation of whole gastric fluid elicits a liver acute phase response and if this response contributes to enrich the alveolar spaces with proteins having antiprotease activity. METHODS: In anesthetized Sprague-Dawley rats receiving whole gastric fluid, we studied at different times after instillation (4 h -7 days): changes in blood cytokines and acute phase proteins (fibrinogen and the antiproteases alpha1-antitrypsin and alpha2-macroglobulin) as well as liver mRNA expression of the two antiproteases. The impact of the systemic changes on lung antiprotease defense was evaluated by measuring levels and bioactivity of antiproteases in broncho-alveolar lavage fluid (BALF). Markers of alveolar-capillary barrier derangement were also studied. Non-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used. RESULTS: Severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage and PMNn cell infiltration was seen in the first 24 h and later resolved. Despite a large increase in several lung cytokines, only IL-6 was found elevated in blood, preceding increased liver expression and blood concentration of both antiproteases. These changes, with an acute phase response profile, were significantly larger for alpha2-macroglobulin (40-fold increment in expression with 12-fold elevation in blood protein concentration) than for alpha1-antitrypsin (2-3 fold increment in expression with 0.5-fold elevation in blood protein concentration). Both the increment in capillary-alveolar antiprotease concentration gradient due to increased antiprotease liver synthesis and a timely-associated derangement of the alveolar-capillary barrier induced by aspiration, contributed a 58-fold and a 190-fold increase in BALF alpha1-antitrypsin and alpha2-macroglobulin levels respectively (p < 0.001). CONCLUSIONS: Gastric contents-induced acute lung injury elicits a liver acute phase response characterized by increased mRNA expression of antiproteases and elevation of blood antiprotease concentrations. Hepatic changes act in concert with derangement of the alveolar capillary barrier to enrich alveolar spaces with antiproteases. These findings may have significant implications decreasing protease burden, limiting injury in this and other models of acute lung injury and likely, in recurrent aspiration.

Occupational exposure levels of bioaerosol components are associated with serum levels of the acute phase protein Serum Amyloid A in greenhouse workers.

BACKGROUND: Occupational exposure to particles may be associated with increased inflammation of the airways. Animal experiments suggest that inhaled particles also induce a pulmonary acute phase response, leading to systemic circulation of acute phase proteins. Greenhouse workers are exposed to elevated levels of bioaerosols. The objective of this study is to assess whether greenhouse workers personal exposure to bioaerosol components was associated with serum levels of the acute phase proteins Serum Amyloid A (SAA) and C-reactive protein (CRP). METHODS: SAA and CRP levels were determined in serum sampled repeatedly from 33 greenhouse workers. Blood was drawn repeatedly on Mondays and Thursdays during work weeks. Acute phase protein levels were compared to levels in a comparison group of 42 people and related to individual exposure levels to endotoxin, dust, bacteria, fungi and ß-glucan. RESULTS: Serum levels of SAA and CRP were not significantly different in greenhouse workers and a reference group, or on the two work days. In a mixed model, SAA levels were positively associated with endotoxin exposure levels (p = 0.0007). Results for fungi were not clear. CRP levels were positively associated with endotoxin exposures (p = 0.022). Furthermore, when workers were categorized into three groups based on SAA and CRP serum levels endotoxin exposure was highest in the group with the highest SAA levels and in the group with middle and highest CRP levels. SAA and CRP levels were elevated in workers with asthma. CONCLUSION: Greenhouse workers did not have elevated serum levels of SAA and CRP compared to a reference group. However, occupational exposure to endotoxin was positively associated with serum levels of the acute phase proteins SAA and CRP. Preventive measures to reduce endotoxin exposure may be beneficial.

C-reactive protein and the acute phase reaction in geriatric patients.

The C-reactive protein (CRP), first described as a serum component capable of precipitating the C-polysaccharide of pneumococci, is one of the most important proteins because the serum concentration rises in the acute phase reaction. The acute phase reaction is the nonspecific reaction of the body to noxious stimuli of the most varied kinds, such as infections, burns, neoplasms and tissue trauma. The CRP is synthesized in liver parenchymal cells by cytokines which are derived from stimulated leucocytes and released into the circulation. Because of its molecular structure and in synergy with the complement system, it is able to precipitate and/or lyse microorganisms, thereby rendering them harmless. Measurement of the serum CRP concentration can provide important information with respect to the diagnosis and monitoring of treatment. Due to immunosenescence in geriatric patients the synthesis of CRP appears to be limited to inflammatory stimuli; however, this phenomenon does not appear to be of major clinical relevance. Despite the introduction of new parameters of the acute phase reaction, sometimes with better performance, such as interleukin-6, procalcitonin and the soluble endotoxin receptor sCD14, measurement of CRP for diagnosis and treatment monitoring is still justified even in geriatric patients as testing is rapid, economic and nearly ubiquitously available round the clock. Biochemical markers of the acute phase reaction should always be interpreted together with the clinical picture and their specific limitations.

Markers of iron status are associated with stage of pregnancy and acute-phase response, but not with parity among pregnant women in Guinea-Bissau.

While prenatal Fe supplementation prevents maternal Fe deficiency and anaemia, it is uncertain whether it improves infant health outcomes, at least when taken by Fe-replete women. Inflammation as well as physiological changes complicates the assessment of Fe status during pregnancy. In the present study, we measured the concentrations of serum ferritin and soluble transferrin receptors (sTfR), Hb and the acute-phase proteins C-reactive protein (CRP) and α1-antichymotrypsin (ACT) in a cross-sectional study among 738 pregnant women attending antenatal care in Guinea-Bissau, West Africa. Multiple linear regression analysis was used to identify the predictors of Fe status markers. The mean gestational age was 23 (sd 7) weeks. Serum ferritin values were lower with progressing gestation, from 27% lower during weeks 16-20 of gestation up to 59% lower after 29 weeks of gestation compared with early pregnancy. Using cut-off values for Fe deficiency as established in non-pregnant individuals, 52% of the women had sTfR levels >2·3 mg/l, while only 25% had serum ferritin levels 2·3 mg/l decreased to 47% after adjustment for elevated serum CRP and ACT levels. On the contrary, the proportion of serum ferritin < 12 µg/l increased to 33% after adjustment for ACT and CRP. The high proportion of elevated serum sTfR calls for pregnancy-specific cut-offs since increased erythropoiesis is expected in response to increased plasma volume of pregnancy. The present study further underlines the need to adjust for inflammation when serum sTfR and serum ferritin are used to assess Fe status in pregnancy.

Thermal transitions in serum amyloid A in solution and on the lipid: implications for structure and stability of acute-phase HDL.

Serum amyloid A (SAA) is an acute-phase protein that circulates mainly on plasma HDL. SAA interactions with its functional ligands and its pathogenic deposition in reactive amyloidosis depend, in part, on the structural disorder of this protein and its propensity to oligomerize. In vivo, SAA can displace a substantial fraction of the major HDL protein, apoA-I, and thereby influence the structural remodeling and functions of acute-phase HDL in ways that are incompletely understood. We use murine SAA1.1 to report the first structural stability study of human plasma HDL that has been enriched with SAA. Calorimetric and spectroscopic analyses of these and other SAA-lipid systems reveal two surprising findings. First, progressive displacement of the exchangeable fraction of apoA-I by SAA has little effect on the structural stability of HDL and its fusion and release of core lipids. Consequently, the major determinant for HDL stability is the nonexchangeable apoA-I. A structural model explaining this observation is proposed, which is consistent with functional studies in acute-phase HDL. Second, we report an α-helix folding/unfolding transition in SAA in the presence of lipid at near-physiological temperatures. This new transition may have potentially important implications for normal functions of SAA and its pathogenic misfolding.

Assessment of human iron status: A cross-sectional study comparing the clinical utility of different laboratory biomarkers and definitions of iron deficiency in daily practice.

OBJECTIVES: No full international consensus exists on disease markers to be used for assessing the human iron status. Therefore this study was conducted to compare performances of serum ferritin and transferrin saturation (TSAT) versus soluble transferrin receptor (sTfR)/log ferritin and reticulocyte hemoglobin content (CHr), also known as Thomas-plot, in the diagnosis of iron deficiency (ID). DESIGN AND METHODS: A total of 445 consecutive hospitalized patients, referred for routine testing of the actual iron status, were included. Logistic regression models for the probability of functional ID (CHr<28pg) were constructed for all 445 patients, for 225 patients without (C-reactive protein [CRP]≤0.5mg/dL) and 220 patients with acute-phase reaction (CRP>0.5mg/dL). RESULTS: Based on the Thomas-plot analyses, 153/445 (34.38%) patients were identified with ID. When ID was diagnosed by means of serum ferritin levels<30ng/mL and TSAT levels<20%, 105/445 (23.60%) and 215/445 (48.31%) patients were identified with ID, respectively. The sTfR/log ferritin ratio showed the best positive predictive values (PPV) (62.50 and 64.41%) to indicate functional ID in patients without as well as with acute-phase reaction compared to sTfR (58.14 and 61.67%), ferritin (32.50 and 32.86%) and TSAT (26.74 and 42.86%). CONCLUSIONS: In clinical practice, the prevalence of ID and the accuracy to detect functional ID are dependent on marker selection and its definition. Regarding the results of this work, for laboratory investigation of ID, however, we suggest using Thomas-plot analyses in combination with ferritin single-marker measurements to efficiently identify patients with ID.

Detection and quantification of hypo- and hypergranulated neutrophils on the new Sysmex XN hematology analyzer: establishment of an adapted reference interval for the neutrophil-granularity-intensity compared to XE-technology in adult patients.

BACKGROUND: Since the recent introduction of Sysmex hematology analyzers of the XN-series it can be expected that the values of individual hematological parameters might differ between the new XN and the well-established XE platform. One such parameter is called Neutrophil-Granularity-Intensity or NEUT-GI on the XN-series and NEUT-X on the XE-series. Both parameters are used by clinicians to calculate the Granularity-Index (GI-Index), an important tool to detect hypo- or hypergranulated neutrophils occurring during myelodysplasia or inflammation. The aims of this study were to determine if previously reported reference intervals for NEUT-X can be used for NEUT-GI as well and if the GI-Indices on both analyzer platforms correlate with each other. METHODS: NEUT-GI and NEUT-X were assessed in a set of 789 blood samples (n = 543 samples from adult intensive care units and n = 246 samples from adult "blood-healthy" control patients) and the corresponding Granularity-Indices were calculated for all samples using data obtained from XE-5000 and XN-1000 hematology analyzers. RESULTS: NEUT-GI and NEUT-X correlated significantly with each other (r2: 0.6512; p < 0.0001) with statistically significant higher values for NEUT-GI compared to NEUT-X in the control group (p < 0.0001) as well as in the ICU patients (p < 0.0001). This indicated that previously established reference intervals for NEUT-X cannot be used for NEUT-GI. In contrast, the GI-Indices showed no statistically significant difference between the analyzers in both groups. The GI-Indices were higher in the ICU patients compared to the control group on both analyzer platforms (p < 0.0001), as would be expected. CONCLUSIONS: Our study revealed the emphatic need for a new reference interval for NEUT-GI on the XN platform. The resulting 95% reference intervals were 140.91 - 160.46 channels for NEUT-GI and 129.20 - 142.33 channels for NEUT-X. The GI-Indices showed no significant statistical difference between the XN- and XE-series in both cohorts.