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The essential trace element copper (Cu) is required for a range of physiologic processes, including wound healing and functioning of the immune system. The correct amount of Cu must be provided in parenteral nutrition (PN) if deficiency and toxicity are to be avoided. While provision in line with the standard recommendations should suffice for most patients, Cu requirements may be higher in patients with increased gastrointestinal losses and severe burns and lower in those with cholestasis. The tests of Cu status that are currently available for clinical use are unreliable. Serum Cu concentration is the most commonly ordered test but is insensitive to Cu deficiency and toxicity and is misleadingly increased during the acute phase response. These limitations make it difficult for prescribers to assess Cu status and to decide how much Cu to provide. There is a need for better tests of Cu status to be developed to decrease uncertainty and improve individualization of Cu dosing. More information is needed on Cu requirements in disease and Cu contamination of PN components and other intravenous fluids. New multi-trace element products should be developed that provide Cu doses in line with the 2012 American Society for Parenteral and Enteral Nutrition recommendations. This article discusses the evaluation and treatment of Cu deficiency and toxicity in patients treated with PN., (© 2017 by The American Society for Parenteral and Enteral Nutrition.)

Background: The platelet parameters and C-reactive protein (CRP) are markers reflecting a systemic inflammatory response. Among those, CRP is one of the major proteins helpful in determination of severity/activity of chronic spontaneous urticaria (CSU)., Aim: To determine relationships between platelet activation indices and serum concentration of CRP, the best marker of acute phase response, and their potential clinical use in CSU patients., Methods: Mean platelet volume (MPV), platelet distribution width (PDW), and platelet count as well as serum CRP concentration were measured in CSU patients, showing different degrees of urticarial severity, and in the healthy subjects., Results: No significant differences were found in MPV and PDW between CSU group and the healthy subjects. The platelet count was significantly higher in moderate-severe CSU than that of the controls and mild CSU patients. Serum CRP concentrations were significantly higher in CSU patients as compared with the healthy subjects and significantly correlated with the platelet count in CSU patients., Conclusions: Acute phase response in CSU is associated with the increased number of circulating platelets in patients with more severe symptoms. It seems that simple determination of platelet size indices is not a reliable indicator of CSU severity/activity.

The concentrations of trichloroacetic acid (tca)-soluble copper and caeruloplasmin were determined in 345 serum samples taken from cattle in March 1998 by eight Scottish Agricultural College veterinary disease surveillance centres serving areas with soils ranging from being 'high' in molybdenum (Thurso) to 'low' (Perth and St Boswells). The mean concentrations varied significantly between the centres, with Thurso having the lowest values for both variables. There were strong linear regressions (r>0.8) between caeruloplasmin and tca-soluble copper for each centre but no significant differences in slope or intercept between the areas with the highest and lowest soil molybdenum, and the pooled regression accounted for 88 per cent of the variation. The distribution of the ratios of caeruloplasmin to tca-soluble copper, unlike those of the individual variables, was not normal, and 70 per cent of the values fell within 10 per cent of the mean ratio of 20.3 mg/micromol and close to the 22 mg/micromol copper expected in pure caeruloplasmin. Low ratios were generally associated with low tca-soluble copper. Ratios above 24 were found in 8 per cent of the samples and were probably attributable to acute-phase reactions and the non-specificity of the assay for caeruloplasmin.

This study examined 328 CFS sera in a study with 17 CCFP, 8 Gulf War Veterans (GWV), 24 Prostate Cancer (PC), and 52 normal sera in the modified Membrane Immunobead Assay (MIA) procedure for CTX. Three hundred and twenty-eight CFS patients' sera were examined by the modified MIA with purified MAb-CTX and 91.2% gave a titre > or =1:40. 76% of the 17 CCFP sera samples and 100% of the 8 GWV sera samples also had a titre > or =1:40. 92.3% of 52 normal sera showed titres of 1:20 or less, while 4 gave titres of > or =1:40. In addition, 41 sera were examined for Anti-Cardiolipin (aCL) by a commercial ELISA procedure with 87.8% demonstrating IgM, IgM+IgA, or IgM+IgG aCL antibodies. These results showed mostly the IgM aCL antibody alone in the sera samples. In addition, 41 serum samples were examined for aCL, with 37 showing positive for aCL, representing 90.2% positive for the three disease categories examined: CFS, CCFP and GWV. Examination for antiMitochondrial-M2 autoantibody (aM-M2) in 28 patients (CFS (18), CCFP (5), and GWV (5)) was negative for aM-M2. Inhibition analysis with antigens, CTX, CFS "Acute Phase Lipids", commercial Cardiolipin (CL) and 1,2-Dipalmitoyl-sn-Glycero-3-[Phospho-L-Serine] (PS) and antibodies, MAb-CTX and aCL from patients' serum show that the phospholipids in CL and CTX are antigenically indistinguishable with antibodies MAb-CTX and CFS-aCL. Preliminary chemical analyses have shown the lipids to be phospholipids associated with CL of the mitochondria. We designate this "Acute Phase Lipid" comparable to "Acute Phase Proteins" (C-reactive protein (CRP) and Serum Amyloid A (SAA)) in inflammatory conditions., ((Copyright ) 2008 Wiley-Liss, Inc.)

Background: Plasma haptoglobin determination is clinically used as parameter for haemolysis. To date, however, the influence of the mode of haemolysis (extravascular vs. intravascular) and of nonhaemolytic conditions on haptoglobin concentration and its reliability as a haemolysis marker remain poorly defined., Materials and Methods: In a total of 479 individuals, the influence of haemolytic and nonhaemolytic conditions on plasma haptoglobin levels was investigated., Results: All studied types of haemolytic disease (n = 16) were associated with markedly decreased plasma haptoglobin levels, without significant differences between intravascular vs. predominantly extravascular haemolysis. Diminished haptoglobin values were also observed in patients with liver cirrhosis, which normalized after liver transplantation. In contrast, markedly increased haptoglobin levels were found in patients with inflammation. In patients with haemolysis and a concomitant acute-phase response, however, haemolysis-dependent haptoglobin depletion was not attenuated. Interestingly, patients with a strongly positive direct antiglobulin test or high cold agglutinin titre but no further evidence for haemolysis had normal haptoglobin values. Likewise, anaemia owing to bone marrow failure, acute gastrointestinal or chronic diffuse blood loss, and end-stage kidney disease were associated with normal haptoglobin levels., Conclusions: Plasma haptoglobin depletion is a reliable marker for the instant diagnosis of accelerated red cell destruction irrespective of the site of haemolysis or the presence of inflammation. The capacity of this parameter to predict haemolysis appears to be limited in patients with liver cirrhosis and decreased haptoglobin production only.

The serum concentrations of serum amyloid A, haptoglobin and fibrinogen were measured in a group of horses before and at intervals after elective and non-elective surgery, and in a control group of normal horses. There was a significant, rapid and repeatable increase in the concentration of serum amyloid A in response to both elective and non-elective surgery. In the control horses its serum concentration was within the normal range, from 0 to 0.2 microg/ml. Twenty-four hours after elective surgery its mean peak concentration was 16.4 microg/ml, and after non-elective surgery it was 27.3 microg/ml. In contrast, the serum concentrations of haptoglobin and fibrinogen increased more slowly after surgery and had not decreased by 72 hours after surgery.

Background: Vestibular neuronitis (VN) is a relatively common condition characterized by the acute onset of vertigo, nausea and vomiting, in the absence of auditory or central nervous system involvement. The exact aetiology (inflammatory, viral or vascular?) remains obscure. Lipoprotein (a) [Lp(a)] is an atherogenic particle. Its serum levels are mainly genetically determined and vary widely between individuals. Whether Lp(a) is consistently a positive acute-phase reactant is controversial., Purpose: We evaluated the alterations in lipidaemic parameters and serum biological markers (including acute-phase reactants) in adult patients presenting acutely with VN., Subjects and Methods: A total of 34 consecutive VN patients (24 men and 11 women) and 37 apparently healthy controls (25 men and 12 women) were studied. Laboratory evaluation was performed during the acute episode and 6 months later (stable state)., Results: Serum Lp(a) concentrations were significantly lower at the time of presentation (median value 6.4 vs. 16.4 mg dL-1 in the stable state, P < 0.001), whereas fibrinogen levels were significantly higher during the acute episode than in the stable state (median value 293.0 vs. 202.0 mg dL-1, respectively, P < 0.0001). During the acute episode, plasma fibrinogen correlated with CRP levels (Spearman r = 0.84, P < 0.0001). By contrast, inverse correlations were noted between Lp(a) levels and CRP (Spearman r = -0.47, P = 0.007) as well as between Lp(a) and fibrinogen levels (Spearman r = -0.35, P = 0.05)., Conclusion: Vestibular neuronitis episodes are associated with evidence of an acute inflammatory response as reflected by significant elevations in plasma fibrinogen and CRP concentrations, whereas Lp(a) behaves as a negative acute-phase reactant.

Despite the importance of noninfectious joint diseases in equine medicine, little is known about the acute phase response which may be elicited if the local inflammatory process of noninfectious arthritis is sufficiently strong, Therefore the aim of this study was to monitor the systemic inflammatory response during experimentally-induced noninfectious arthritis by studying the dynamics in serum of the acute phase proteins serum amyloid A (SAA), haptoglobin, fibrinogen and alpha2-globulins. Twenty-four Standardbred horses, age 3-7 years, found healthy on thorough clinical, radiological, haematological and serum biochemical examination, were injected aseptically into the right midcarpal joint with amphotericin B. Blood samples were drawn before induction of arthritis (0 h), and at 8, 16, 24, 36 and 48 h postinduction and then on Days 3, 4, 5 and 15 postinduction. All horses developed lameness with joint effusion and joint heat as well as increased respiratory rate, heart rate and body temperature. The lameness started to decline after 24-36 h and, in most animals, systemic signs disappeared on Day 2 postinjection. The concentration of the acute phase proteins increased following induction of arthritis. The SAA concentrations were higher than baseline concentrations from 16 h postinduction and were maximal at 36-48 h (227 times baseline concentration). The haptoglobin concentrations were higher than baseline concentrations from 24 h and were maximal at 48-96 h (1.14 times baseline concentration). The maximal concentrations of fibrinogen were seen between 36-72 h postinjection and increased on average 0.87 times from baseline concentrations. The fibrinogen concentrations were higher than baseline concentrations from 24 h postinjection. Alpha2-globulins concentrations showed a minor increase and increased 0.55 times from baseline concentrations. The markers had returned to baseline concentrations by Day 15. Our results demonstrate that amphotericin B-induced arthritis in a single joint gives rise to a systemic acute phase response measurable as increased concentrations in serum SAA, haptoglobin, fibrinogen and alpha2-globulins during the first 2 weeks of the condition and, thereby, that such an increase need not be indicative of infectious arthritis. Further research should be aimed at determining whether chronic noninfectious arthritis in the horse gives rise to increased acute phase protein concentrations in serum.

The acute-phase response is an immediate reaction of the host against invading microorganisms. We show here that oligodeoxynucleotides (ODNs) containing a CpG motif rapidly induce the major murine acute-phase proteins in vivo, i.e. serum amyloid A (SAA) and serum amyloid P (SAP). Serum levels of these proteins are elevated within 12 h and peak at 24 h after the injection of CpG-ODN or endotoxin. Liver cells produce the proteins with the same kinetics. Injection of interleukin 6 (IL-6), IL-1beta and tumour necrosis factor alpha (TNF-alpha) induces SAA and SAP in vivo, but the CpG-ODN-mediated induction does not depend on the presence of the TNF receptor p55, as the acute-phase response in TNF receptor p55-deficient mice does not differ from that of wild-type mice. Aside from CpG-ODN, bacterial genomic DNA also induces the acute-phase response in LPS-resistant C3H/Hej mice. The induction of the major acute-phase proteins SAA and SAP is blocked by the simultaneous injection of CpG-ODN together with D-galactosamine (D-GalN). As D-GalN sensitizes the host for the toxic effects of TNF-alpha, a possible mechanism could be the prevention of synthesis of the major acute-phase proteins SAA and SAP.

Peroxidation by peripheral blood leucocytes was measured in 15 patients in acute septic shock and 15 uninfected controls, using the probe dichloroflorescein. Mortality in septic subjects was 40%. In 14 of 15 patients from whom serial samples were analysed, periods of increased oxidative activity were detected. Increased peroxidation occurred early in the sequence of clinical changes, at the same time as increases in temperature, blood pressure and C-reactive protein. Peak peroxide production preceded increases in acute phase reactants and changes in leucocyte distribution. Mean peroxide production in leukocytes from patients who died was significantly higher (P < 0.001) than paired controls, and greater (P < 0.05) than peroxide production in patients who survived. The in vitro oxidative response to endotoxin was upregulated in infected patients. This supports the hypothesis that systemic mediators and leucocyte-derived reactive oxygen are involved in the vascular and organ damage associated with fatal septic shock.

Antiserum against rat alpha 1-macroglobulin (alpha 1MG) was produced in rabbits. Antiserum against rat pregnancy-associated alpha 1-glycoprotein (PAG) was obtained by immunization with a partly purified PAG preparation and absorption of the serum with male rat serum. Acute inflammation was produced in non-pregnant female rats by a single intramuscular injection of turpentine. The concentrations of both macroglobulins in the serum and in tissue extracts were measured by rocket immunoelectrophoresis at various times up to 7 days after injury. Inflammation produced in the rats resulted in moderately elevated serum levels of these proteins soon after injury. At first, alpha 1MG levels in a number of tissues (heart, lung, kidney, spleen, pancreas, uterus and ovary) were depressed markedly; they then stabilized. The elevated serum concentrations of alpha 1MG remained unchanged during inflammation. The store of PAG in the tissues was rapidly depleted and its serum level decreased to a normal value 7 days after injury. Our findings indicate that alpha 1MG plays a more important role in maintenance of the proteinase inhibitory potential in the rat than does PAG.

The effects of aseptic abscesses induced by subcutaneous injections of turpentine (5 mL/kg body weight) on the acute-phase protein response (alpha 2-macroglobulin, alpha 2-M) and on the circulating albumin and total protein concentrations were assessed in young rats that were made malnourished by restricting dietary intake to an extent that either impaired growth (60% of normal intake) or caused weight loss (0% to 45% of normal intake). The measurements were obtained daily during a period of 4 days in malnourished rats that had lost about 25% body weight but had maintained a stable weight thereafter, or in rats that had lost about 12% body weight and were continuing to lose weight at various rates at the time of the turpentine injection. In animals that were injected while they maintained a stable weight after losing about 25% body weight, the alpha 2-M response was attenuated fourfold to eightfold compared with control animals (the area under the 4-day alpha 2-M curve in control rats was 23.3 +/- 2.3 g/L/d). In the depleted animals that were injected while they were actively losing weight (approximately 12.5% weight loss), the attenuation of the alpha 2-M response was related to the rate of weight loss or to the extent of dietary restriction (area under the 4-day alpha 2-M curve ranged from 5.7 +/- 1.4 g/L/d in animals receiving 15% restricted diet to 15.6 +/- 1.5 g/L/d in animals receiving the 45% restricted diet).(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: Administration of interleukin-6 partially reproduces the inhibitory effects of the acute-phase response on cytochrome P450-dependent drug metabolism. The aim of the study was to determine whether endogenous cytokine has such an effect in patients treated by cyclosporine, which is metabolized by the cytochrome P4503A subfamily., Methods: Blood cyclosporine and serum interleukin-6 levels were determined in six patients undergoing bone marrow transplantation, as long as they received cyclosporine by continuous infusion. Two serum acute-phase proteins, C-reactive protein and alpha 1-acid glycoprotein, and two cyclosporine metabolites, AM1 and AM9, were also determined., Results: At the time of marrow infusion, levels of specific markers of inflammation were low. A peak in interleukin-6 level was then observed a mean of 10.8 days after transplantation, closely associated with variations in C-reactive protein levels. A parallel twofold increase in AM1 concentrations was observed, followed by a three-fold increase in cyclosporine levels, which peaked 4.8 days after interleukin-6. The times of peak cyclosporine and AM1 levels correlated with the time of peak interleukin-6 levels. AM9 was detectable in three patients but concentrations fell when interleukin 6 became detectable., Conclusions: An inflammatory reaction could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytochrome P4503A-dependent enzyme activities by endogenous interleukin-6. Blood AM1 accumulation might be explained by a secondary metabolic step that is highly sensitive to the inhibitory effect of interleukin-6.

Animal experiments demonstrate that interleukin-1 beta (IL-1 beta) is beta-cell cytotoxic in vitro and inhibits insulin secretion in vivo. However, it is unknown if IL-1 beta affects beta-cell function in man. Since IL-1 beta and other cytokines are main mediators of the acute phase response, the objectives of the present study were to examine beta-cell function in patients with major burn injuries, and to test if changes in beta-cell function correlated to systemic levels of IL-1 beta and tumour necrosis factor alpha (TNF alpha). We established and validated an IL-1 beta assay measuring free and protein bound IL-1 beta; protein bound IL-1 beta was detached from the IL-1 beta specific binding protein by acidification, rendering it accessible for the employed antibody. The IL-1 beta specific binding protein (43-60 kDa) was found in serum and plasma from all tested patients and normal subjects. Survivors of burn injuries had a stimulated beta-cell function, whereas non-survivors had an impaired beta-cell function as indicated by an increased plasma concentration of proinsulin, and an increased proinsulin/insulin ratio. In addition, non-survivors had significantly increased plasma levels of IL-1 beta. However, we could not demonstrate any correlation between C-peptide, proinsulin, insulin or proinsulin/insulin ratio and plasma concentration of IL-1 beta. In conclusion, beta-cell function abnormalities are evident in patients with major burn injuries, and a high plasma level of IL-1 beta correlates with a fatal outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of the study was to examine the cause of the increased serum ferritin post-partum observed previously. B-hemoglobin, B-leucocytes, S-ferritin, erythrocyte protoporphyrin and S-orosomucoid were determined in the blood of 21 pregnant women in the 39th week of pregnancy, two to four days and six weeks after delivery. The S-ferritin was increased from 12.1 micrograms/l at the 39th week of pregnancy to 30.1 micrograms/l post-partum. The probable reason for this increment is an acute phase reaction since a rise in the concentration of S-orosomucoid and B-leucocytes were concurrently observed.

In order to assess the usefulness of haptoglobin as a measure of the acute phase response in cattle, the concentration of serum haptoglobin was estimated in the non-infectious conditions of milk fever and ketosis, and in the infectious conditions of severe mastitis, acute severe metritis, retained placenta and chronic endometritis. Mean haptoglobin concentrations were normal in cattle with non-infectious conditions and chronic endometritis but significantly increased in cattle with infectious conditions.

The aim of this study was to determine the effects of n-3 fatty acids on acute-phase proteins and response. Healthy male volunteers were submitted to standard bicycle ergometry once without supplementation and a second time after 3-weeks supplementation with highly purified n-3 fatty acids (1.75 g eicosapentaenoic acid and 1.05 g docosahexaenoic acid per day). Acute-phase proteins (immunoglobulin M, complement C4, haptoglobin, C-reactive protein, alpha 2-macroglobulin, coerulopasmin, fibrinogen, alpha 1-glycoprotein) were measured before, immediately after, 24 and 72 h after exercise. There were significantly lower values of immunoglobulin M (pre-exercise and at 72 h) and alpha 2-macroglobulin (pre-exercise) when cross-sectionally comparing the baseline data with and without n-3 supplementation. Longitudinal comparisons show that the ergometric test induced a discrete acute-phase reaction, which is evident with and without n-3 fatty acids. Yet the kinetics of the response seem to be altered by n-3 supplementation. The relative increase of most acute-phase proteins is numerically larger and the rise persists longer, which is particularly evident for fibrinogen and alpha 1-glycoprotein. The findings suggest that n-3 fatty acids lower acute-phase proteins at baseline and alter the pattern of change following acute exercise.

Serum amyloid A and high density lipoprotein (HDL) interrelationships were evaluated in 11 normal men during an acute phase response induced by the inflammatory steroid etiocholanolone. Compared with baseline, HDL-cholesterol levels were significantly elevated at 30 h but not at 50 h (P less than 0.05) after etiocholanolone. A-apoprotein concentrations were unchanged at 30 h but were reduced at 54 h (P less than 0.01). Four subjects were sampled every 6-8 h for 5 days. Two men had peak SAA concentrations of 30 and 33 mg dl-1. Their A-apoprotein levels declined as SAA rose and remained low even after SAA levels had returned to baseline. High density lipoprotein cholesterol levels did not fall, however, when SAA was increasing, and fell only after SAA levels declined. No changes in HDL-cholesterol or protein were observed in two subjects whose peak SAA concentrations were 10 and 12 mg dl-1. These observations suggest that a threshold level of acute phase response is required before HDL reductions occur. Column chromatography of SAA-rich plasma did not demonstrate the presence of either SAA or A-apoproteins that were unassociated with lipoproteins. Serum amyloid A, moreover, demonstrated little capacity to displace A-proteins from HDL at SAA concentrations typically observed during the acute phase response. We infer from these studies that SAA may substitute for the A-apoproteins and temporarily maintain HDL-cholesterol levels; but that low HDL levels during the acute phase response are likely due to reduced A-protein synthesis rather than displacement by SAA.

A sensitive and precise immunoassay for equine serum amyloid A protein (SAA) was established and used to determine, for the first time, the circulating concentration of this protein in health and disease. As in other species, equine SAA was present only at trace levels in healthy animals but behaved as an extremely sensitive and rapidly responding acute phase reactant following most forms of tissue injury, infection and inflammation, objectively reflecting the extent and activity of disease. Measurements of SAA should make a significant contribution to diagnosis and management of viral and bacterial infection in horses, and routine serial assays could provide an objective criterion for monitoring prospectively the general health of horses in training and racing.

An acute phase reaction was elicited in four horses to which Freund's adjuvant was administered intramuscularly. The localised inflammation was accompanied by changes in the plasma concentrations of copper, iron and zinc. The plasma copper concentration, the plasma ceruloplasmin copper concentration and the ceruloplasmin oxidase activity in the plasma steadily increased to a maximum 24 days after the administration of the adjuvant. At this time, the plasma copper concentration was 2.2 micrograms/ml, a 90 per cent increase over the baseline concentration. The ratio of the concentration of plasma ceruloplasmin copper to plasma copper remained constant, indicating that the non-ceruloplasmin bound copper component of the plasma is also an acute phase reactant in the horse. The plasma zinc and iron concentrations decreased to 59 per cent and 30 per cent of their respective baseline concentrations and the severity of the inflammation appeared to influence the plasma concentrations of each metal. Weak correlations between the plasma fibrinogen concentration and the plasma copper and zinc concentrations of 25 horses with plasma fibrinogen concentrations of 5 g/litre or greater indicated that a single measurement of plasma copper concentration is not useful in the diagnosis of non-specific inflammatory disorders of the horse. However, the results suggest that the plasma copper concentrations in serial samples may be used to monitor the resolution of inflammatory disorders in the horse.