Acute Phase Response In Patients Research Articles

Novel combined pharmacological strategy to alleviate acute phase response following zoledronic acid treatment

SummaryBrief rationale: Zoledronic acid treatment against osteoporosis is limited by APR. Main result: Combination therapy (hydrocortisone plus non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone) reduced intolerable APR levels and provided complete symptom relief in most patients. Significance of the paper: Combination therapy can enhance patient outcomes in osteoporosis management.PurposeOsteoporosis is a common condition associated with high morbidity rates, often requiring treatment with bisphosphonates such as zoledronic acid. However, the persistence to zoledronic acid infusion is commonly limited by acute phase response (APR). This retrospective study aimed to evaluate the efficacy of a novel combination therapy in preventing APR symptoms.MethodsA retrospective case–control study was conducted on 931 patients who received their first zoledronic acid infusion between 2011 and 2021. We evaluated the efficacy of combination therapy comprising a single dose of hydrocortisone prior to the infusion and a 3-d oral regimen of non-steroidal anti-inflammatory drugs, acetaminophen, and prednisolone following the infusion. Patients were divided into protocol (receiving combination therapy) and control groups (without treatment). Baseline characteristics, APR incidence, and the efficacy of symptom control were compared between groups using Fisher’s exact test and Student’s t-test.ResultsThere was no difference in APR incidence between the protocol (n = 507) and control group (n = 407; p = 0.1442). However, the protocol group exhibited lower intolerable APR levels (3.72% vs. 16.71%; p < 0.0001) and complete symptom relief in 96.28% of cases.ConclusionThe combination therapy protocol effectively reduced intolerable APR and relieved symptoms in most patients following zoledronic acid infusion. This study highlights the importance of proactive management strategies for APR and emphasizes the potential of combination therapy in alleviating APR symptoms and reducing the occurrence of severe APR in patients undergoing osteoporosis management.

Exploring Cardio-Metabolic Effects of Liraglutide in Patients With Type 2 Diabetes Through a Proteomic Approach

Background: Diabetes is associated with complications that increase the risk of cardiovascular events in diabetic patients by 3 folds compared to healthy population. Liraglutide is a GLP-1 receptors agonist that showed cardiovascular benefits beside its glycemic advantage and weight reduction. The cardioprotective benefit of liraglutide in diabetic patients is unclear. Objective: To explore potential cardiovascular-protective and metabolic effects of Liraglutide treatment in patients with T2DM, through evaluation of alterations in circulatory proteins using a proteomics approach. To relate the altered proteins to identify pathways using bioinformatics and network pathway analysis. Methods: Twenty adult patients with T2DM were recruited with HbA1c of 8–11 %, on oral anti-diabetic agents or insulin in whom liraglutide was indicated, after obtaining the consent. At baseline: anthropometric measurements, basal blood for HBA1c, Renal function, creatinine clearance, lipid profile and urine in the fasting state. Then Liraglutide 1.8 mg subcutaneous once daily injection was initiated as prescribed by the treating physician. AT 3 months follow up visit post-treatment, similar parameters were measured. Primary endpoint was the reduction from baseline in HbA1c for ≥ 0.5 %. Results: Alterations in the abundance of urinary proteins, analyzed by Progenesis software, revealed statistically significant differential abundance in a total of 80 spots corresponding to 71 proteins, 14 up and 57 down (≥1.5-fold change, ANOVA, p ≤ 0.05) in the post treatment group. The proteins identified in our study are known to regulate processes related to acute phase response (APR), cellular metabolism and transport. The post treatment group demonstrated an increased abundance of proteins that included alpha-1-antitrypsin, alpha-1-antichymotrypsin, serotransferrin, transthyretin, plasma protease C1 inhibitor, adenosylhomocysteinase 3 and beta-2-glycoprotein 1. The proteins with a decrease in abundance following treatment included transthyretin, serotransferrin, haptoglobin, complement C3, retinol binding protein and ceruloplasmin. Bioinformatic analysis using Ingenuity Pathway Analysis (IPA) identified dysregulation of pathways related cellular compromise, inflammatory response, and neurological disease. It also identified the involvement of the inflammatory signalling pathways, NFκb, AKT, p38 MAPK via their interactions with interleukin 12 as the central nodes. Conclusion: The altered proteins identified in the present study showed an increase in the APR in patients with diabetes before treatment with liraglutide which was significantly reduced in the post treatment group. Increase in the APR is known to lead to a state of chronic inflammation predisposing individuals to cardiometabolic stress and disease.

Disturbances of the hemostasis system and expression of inflammatory reaction in patients with new coronaviral pneumonia.

Disorders of the hemostatic system and inflammation play a key role in the pathogenesis of new coronavirus pneumonia (NCP), determining its course and outcome. To study the dynamics of the state of the hemostasis system and the severity of the acute phase response in patients with new coronavirus pneumonia. We determined APTT, prothrombin time (PT), fibrinogen (F), D-dimers (D-d), antitrombin III (AT III), C-reactive protein (CRP), platelet count in 22 patients. In 49 patients, the viscoelastic properties of a blood clot were studied by thromboelastography (TEG) with koalin. The age of the patients ranged from 40 to 77 years. According to CT, the severity of 100% cases corresponded to CT2-CT3. Acute respiratory failure (ARF) was diagnosed in 16 patients. A control group included 25 apparently healthy subjects. During hospitalization, patients with NCP were characterized by: an increase in the concentration of D-d, CRP, Fg, lengthening of APTT and PT, ATIII activity and platelet count not differing from the normal range. 10 days after hospitalization and against the background of ongoing therapy, patients with NCP showed positive dynamics in the hemostasiological profile and the severity of the inflammatory response. Thromboelastography indices in patients with LCP did not differ from control values both at hospitalization and on day 10.Thus, in patients with novel coronavirus pneumonia, an increased prothrombotic activity and a pronounced inflammatory response are recorded. Against the background of treatment, there is a positive dynamics in both the coagulation status and the inflammatory response. Additional studies are needed to determine the diagnostic capabilities of thromboelastography in patients with NCP.

Is there a relationship between serum omentin level and acute phase response in patients with familial Mediterranean fever?

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by frequent attacks and chronic inflammation. Subclinical inflammation continues during the attack-free period. Omentin is an anti-inflammatory adipokine, which plays important roles in the adjustments of glucose metabolism, cardiovascular homeostasis and atherosclerosis. The aim is to investigate the omentin levels in FMF patients and to assess the association with markers of subclinical inflammation in FMF patients such as serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This cross-sectional study included 54 consecutive adult FMF patients (27 male, 27 female) and 28 healthy individuals (16 male, 12 female). The FMF patients were separated into 3 groups: (1) attack-free group, (2) active-attack group and (3) colchicine-resistant group. Serum omentin levels were compared between the FMF patients and the healthy control group. A significant difference was determined between the FMF patients and healthy control subjects in terms of omentin levels (108.05 (19.97-343.22) vs. 199.5 (42.98-339.41) p < 0.05). SAA values were significantly higher in the FMF patients compared with the healthy control group. When the FMF patients were examined as separate groups, serum omentin values were lower in the colchicine-resistant group than in the groups without resistance (76.64 (19.77-224.33) vs. 186.47 (28.41-343.21) p = 0.006). FMF patients with colchicine resistance are associated with decreased omentin concentrations, probably mediated by inflammation-driven mechanisms. Key Points • Omentin is a type of adipokine which has an anti-inflammatory effect by inhibiting the inflammatory cytokine network. • Decreased omentin levels are associated with increased obesity, insulin resistance and comorbidities. • We report that omentin levels fluctuate in various diseases. In addition, we have focused on the levels of omentin in patients with FMF, as it may act as a biomarker for colchicine resistance.

Zoledronate decreases CTLA-4 in vivo and in vitro independently of its action on bone resorption.

Acute phase response (APR) following intravenous zoledronate (ZOL) administration is related to activation and increased proliferation of γδ T cells, attributed to the molecular mechanism of action of nitrogen-containing bisphosphonates (N-BPs). ZOL, however, has also been reported to inhibit the proliferation of regulatory T cells in vitro and to reduce the expression of Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4), a negative regulator of T cell activation that is increased in patients with autoimmune diseases. There are, however, no data on the relationship between ZOL treatment and soluble(s)CTLA-4 either in vivo in relevant patient populations or in vitro with the use of assays relevant to the mechanism of action of N-BPs. The objectives of the present study were firstly, to characterize the ZOL-induced APR in patients with inflammatory rheumatic diseases (IRDs) and its relationship with changes in circulating sCTLA-4 and secondly, to investigate the effects of ZOL on CTLA-4 production and expression by peripheral blood mononuclear cells (PBMCs). We studied 10 postmenopausal women with IRDs treated with intravenous ZOL 5mg. Five women experienced APR (APR+) associated with significant decreases in blood lymphocytes and increases in granulocytes and serum CRP. Serum sCTLA-4 values were increased in all patients before ZOL administration and decreased significantly 72h after the ZOL infusion (from 30.0±2.9 to 6.3±1.8ng/ml; p<0.001) with no differences between APR+ and APR- patients. Consistent with the results of the in vivo study, ZOL (1μM) decreased the production of sCTLA-4 by 87% and 57% after 3 and 5days in cultures of peripheral blood mononuclear cells (PBMCs) in vitro, respectively, and inhibited the expression of both cytoplasmic and membrane-bound CTLA-4. Our results reveal a novel immunoregulatory action of ZOL that is not related to its action on bone resorption but might be associated with reported clinically significant extraskeletal outcomes of ZOL treatment.

Early-Stage Staphylococcus aureus Bloodstream Infection Causes Changes in the Concentrations of Lipoproteins and Acute-Phase Proteins and Is Associated with Low Antibody Titers against Bacterial Virulence Factors.

Systemic and quantitative investigations of human plasma proteins (proteomics) and Staphylococcus aureus-specific antibodies (immunoproteomics) provide complementary information and hold promise for the discovery of biomarkers in Staphylococcus aureus bloodstream infection (SABSI). Usually, data-dependent acquisition (DDA) is used for proteome analysis of serum or plasma, but data-independent acquisition (DIA) is more comprehensive and reproducible. In this prospective cohort study, we aimed to identify biomarkers associated with the early stages of SABSI using a serum DIA proteomic and immunoproteomic approach. Sera from 49 SABSI patients and 43 noninfected controls were analyzed. In total, 608 human serum proteins were identified with DIA. A total of 386 proteins could be quantified, of which 9 proteins, mainly belonging to acute-phase proteins, were significantly increased, while 7 high-density lipoproteins were lower in SABSI. In SABSI, total anti-S. aureus serum IgG was reduced compared with controls as shown by immunoproteomic quantification of IgG binding to 143 S. aureus antigens. IgG binding to 48 of these anti-S. aureus proteins was significantly lower in SABSI, while anti-Ecb IgG was the only one increased in SABSI. Serum IgG binding to autoinducing peptide MsrB, FadB, EsxA, Pbp2, FadB, SspB, or SodA was very low in SABSI. This marker panel discriminated early SABSI from controls with 95% sensitivity and 100% specificity according to random forest prediction. This holds promise for patient stratification according to their risk of S. aureus infection, underlines the protective function of the adaptive immune system, and encourages further efforts in the development of a vaccine against S. aureus IMPORTANCE S. aureus sepsis has a high complication and mortality rate. Given the limited therapeutic possibilities, effective prevention strategies, e.g., a vaccine, or the early identification of high-risk patients would be important but are not available. Our study showed an acute-phase response in patients with S. aureus bloodstream infection and evidence that lipoproteins are downregulated in plasma. Using immunoproteomics, stratification of patients appears to be achievable, since at the early stages of systemic S. aureus infection patients had low preexisting anti-S. aureus antibody levels. This strengthens the notion that a robust immune memory for S. aureus protects against infections with the pathogen.

P168 Adjusting serum ferritin concentrations to remove the effects of acute-phase response in patients with IBD and iron deficiency: is using C-reactive protein sufficient?

P168 Adjusting serum ferritin concentrations to remove the effects of acute-phase response in patients with IBD and iron deficiency: is using C-reactive protein sufficient?

Effect of yoga and meditation based lifestyle intervention on acute phase response in patients with rheumatoid arthritis

Effect of yoga and meditation based lifestyle intervention on acute phase response in patients with rheumatoid arthritis

Surgical trauma and low-dose methylprednisolone modulate the severity of the acute-phase response induced by zoledronic acid infusion.

The aim of the present study was to investigate risk factors for the development of an acute-phase response (APR) associated with the initial zoledronic acid (ZA) infusion in patients undergoing surgery, and to assess whether its onset may be reduced by post-dose administration of low-dose methylprednisolone (MP) or acetaminophen. A retrospective study of patients with osteoporosis who attended the departments of orthopedics and endocrinology of a single hospital and received 5 mg ZA was conducted; the patients included surgical and non-surgical cases. A total of 450 ZA-naïve patients who were treated with acetaminophen following ZA infusion were stratified based on whether they suffered APR (APR+) or not (APR-). In addition, 155 of the aforementioned acetaminophen-treated patients (acetaminophen group) were compared with another 32 patients from the orthopedic department who were treated with MP immediately following ZA infusion (MP group). Inflammatory marker levels were significantly higher in APR+ patients than in APR- patients, and the odds ratios of experiencing APR following minimally invasive or open surgery were found to be 3.54 (P<0.001) and 5.71 (P<0.001), respectively, compared with non-surgical intervention after multiple adjustments. C-reactive protein levels prior to dosing were positively correlated with body temperature (r=0.023; P<0.001). The severity of APR also exhibited a negative correlation with 23-hydroxyvitamin D3 levels (r=-0.006; P<0.05). Patients treated with MP following surgery and ZA infusion had a significantly lower incidence of APR compared with those treated with acetaminophen (6.3 vs. 62.6%; P<0.05). However, no significant differences were observed in bone mineral density between the MP and acetaminophen groups at 12 months post-surgery. The results of the present study suggest that surgical trauma serves a key role in ZA-associated APR, and low-dose MP may a suitable post-dose treatment to manage the symptoms of APR in patients undergoing surgery.

Lower serum B12 vitamin concentrations are not accompanied by hyperhomocysteinaemia in chronic spontaneous urticaria.

Lower serum vitamin B12 concentrations have been observed in patients with chronic spontaneous urticaria (CSU). It is known that vitamin B12 deficiency is closely related to hyperhomocysteinaemia, which is associated with a proinflammatory state. To assess the relationship between vitamin B12 status and concentrations of homocysteine (Hcy) with acute phase response in patients with CSU. Circulating concentrations of vitamin B12, Hcy and C-reactive protein (CRP) were measured in 42 patients with CSU of varying severity, and compared with 19 healthy controls (HCs). Significantly lower concentrations of vitamin B12 and higher concentrations of CRP were observed in the serum of the patients with CSU compared with HCs (P < 0.01 and P < 0.001, respectively). However, there were no significant differences in plasma Hcy concentrations between the investigated groups. In addition, no correlations were found between the concentrations of vitamin B12, Hcy and CRP. Lower values of vitamin B12 concentration in patients with CSU were not associated with higher Hcy concentrations, suggesting that such patients do not have functional vitamin B12 deficiency.

The association of sialic acid levels with nitric oxide and C-reactive protein in patients with diabetic foot ulcer / Diyabetik ayak ülseri olan hastalarda sialik asit düzeylerinin nitrik oksit ve C-reaktif protein ile ilişkisi

Abstract Objective: The present study aimed to evaluate the association of serum sialic acid (SA) levels with nitric oxide (NO) and C-reactive protein (CRP) in patients with diabetic foot ulcer. Methods: This study included total 56 type 2 diabetic patients (27 of them had diabetic foot ulcer and 29 without it) and 22 healthy volunteers. Serum SA, NO and CRP levels were measured with spectrophotometric and nephelometric methods respectively. Results: Serum SA levels were higher in diabetic foot group than diabetes group (p&lt;0.05). CRP and NO levels were found to be significantly higher in diabetic foot group compared to the diabetes (p&lt;0.001 and p=0.002, respectively) and control groups (p&lt;0.001, both). Although there was no correlation between SA and NO (p&gt;0.05), serum SA levels were significantly correlated with CRP in diabetic foot group (p&lt;0.001). Conclusion: We suggest that SA could be related to acute phase response in patients with diabetic foot ulcer. Elevated serum SA and NO levels may be indicators of oxidative stress-induced vascular damage.

Lower Admission Hemoglobin Levels Are Associated With Longer Symptom Duration in Acute ST‐Elevation Myocardial Infarction

An acute-phase response in patients with acute myocardial infarction could contribute to the development of anemia. An association may exist between symptom duration, hemoglobin (Hb) concentration and serum C-reactive protein (CRP) values in patients presenting to an emergency department (ED) with acute ST-segment elevation myocardial infarction (STEMI). A retrospective analysis was conducted on consecutive male STEMI patients who were admitted to our medical center's ED from January 2008 to November 2012 and had presented within the first 12 hours after the onset of chest pain. Hemoglobin concentration and serum CRP levels were determined from blood samples taken prior to any drug or fluid administration. Analyses of variance were used to determine interactions between selected time-to-presentation cutoffs and admission Hb and CRP concentrations. Patients with other reasons known to cause elevation of inflammatory markers, anemia, or bleeding diathesis were excluded. The study population comprised 718 patients whose mean age was 61 ± 12 years (range, 27-96 years). Blood was drawn for Hb and CRP measurements directly upon admission. Patients who presented to the ED within 3 hours of symptom onset had higher Hb concentrations (P = 0.048) and lower serum CRP levels (P < 0.001) compared with those who presented after a longer interval from symptom onset. Longer symptom duration is associated with a lower admission Hb level and an early rise in the CRP level of male patients with acute STEMI.

Long-Term Effects of Amino-Bisphosphonates on Circulating γδ T Cells

The aim of this study was to explore whether desensitization to the occurrence of the acute-phase response (APR) in patients previously treated with amino-bisphosphonates (N-BPs) is due to a long-lasting reduction in the number of circulating γδ T cells. Circulating lymphocyte subpopulation counts were obtained from 63 patients with postmenopausal or senile osteoporosis at baseline and after 2 days and 12 months of the first intravenous (IV) 5 mg zoledronic acid (ZOL) infusion. At baseline both the proportion and absolute number of circulating γδ T cells were significantly higher in patients who had never used N-BPs vs. previous users, either oral or IV. A typical APR was observed in none of the patients given IV ZOL a year earlier, in 6 (22 %) of the patients previously treated with oral N-BPs, and in 13 (57 %) of the patients naive to any N-BP treatment. In patients naive to N-BPs, a significant reduction in both total lymphocytes and their subsets was observed 2 days after ZOL infusion; all these changes returned to baseline values 1 year later with the exception of γδ T cells, which remained significantly lower in terms of both proportion and absolute number. These results indicate for the first time that both IV and oral N-BP treatments are associated with a long-lasting decrease in circulating γδ T cells, and this may explain the lower incidence of APR in patients previously exposed to N-BPs. Other clinical implications of this sustained effect of N-BPs on immune-regulatory cells might be important.

The Acute-phase Response Is Not Predictive for the Development of Arthritis in Seropositive Arthralgia – A Prospective Cohort Study

To evaluate whether markers of the acute-phase response in patients presenting with arthralgia and positive anticitrullinated protein antibodies (ACPA) and/or immunoglobulin M rheumatoid factor (IgM-RF) could be predictive for the development of arthritis. In total, 137 ACPA- and/or IgM-RF-positive patients were included. Patients were followed annually for the development of arthritis, defined as presence of 1 or more swollen joints at clinical examination. High-sensitivity C-reactive protein (hsCRP), procalcitonin (PCT), secretory phospholipase A2 (SPLA2), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-12p70, IL-10, and interferon-γ (IFN-γ) were measured in baseline serum samples. Gene expression focusing on a predefined panel of genes coding for inflammatory molecules was measured by multiplex ligation-dependent probe amplification. Thirty-five patients (26%) developed arthritis within a median time of 11 months (interquartile range 3.7-18 mo). Circulating levels of cytokines, SPLA2, hsCRP, and PCT were not different between patients with progression to clinical arthritis and those without progression. However, a trend for IL-12p70, TNF-α, IL-10, IL-6, and SPLA2 was observed. No correlation between messenger RNA (mRNA) expression levels of inflammatory genes and progression to arthritis was found. Subgroup analysis of patients with early progression to arthritis showed higher levels of mRNA expression of poly(A)-specific ribonuclease and polycomb complex protein BMI-1 compared to patients without progression to arthritis. Although low-grade inflammation is present before onset of clinical arthritis in large cohorts and can be detected using consecutive measurements, a single measurement of acute-phase reactants seems to have limited value for prediction of development of arthritis in individual patients.

Enteral or parenteral nutrition in traumatic brain injury: a prospective randomised trial.

Few studies have evaluated the route of nutritional therapy in patients with head trauma. We aimed at investigating whether early enteral (EN) or parenteral nutrition (TPN) may differ in protein/ calorie supply, serum glucose modifications, and acute phase response in patients with traumatic brain injury (TBI). Twenty two patients with moderate TBI (Glasgow score between 9-12) were randomized to receive isocaloric and isonitrogeneous either EN (n=12) or TPN (n=10). The daily amount of calories and nitrogen (N) supplied, the nitrogen balance, and the daily serum level of glucose, C-reactive protein, and albumin were collected for 5 consecutive days. Clinical endpoints as length of stay and mortality were also compared. Mortality was 9.1% (two cases) with one case in each group. A progressive caloric deficit occurred in both groups (p=0.001) without difference between them. The mean serum glucose level in TNP patients (134.4, 95% CI=122.6 to 146.2 mg/dl) was significantly higher than in the EN group (102,4; 95% CI 91.6 to 113.2 mg/dL) (p<0.001). There was a trend (p=0.06) of 24 h urinary N loss to be greater in TPN group which received higher amounts of N than the NE group (p<0.05). However, nitrogen balance was similar in the two groups. There was no difference in either the clinical outcome variables or the acute phase response. Both routes were able to supply increasing provision of calories to brain injured patients. TPN provided significantly greater amount of nitrogen but losses were also greater. Nitrogen balance was similar with both types of therapy. Parenteral compared to enteral nutrition lead to greater hyperglycemia. There was no influence of the route in both the early inflammatory response and clinical outcome.

Nutrición enteral o parenteral en lesión traumática cerebral: un estudio prospectivo y randomizado

Introduction - Few studies have evaluated the route of nutritional therapy in patients with head trauma. Objective – We aimed at investigating whether early enteral (EN) or parenteral nutrition (TPN) may differ in protein/ calorie supply, serum glucose modifications, and acute phase response in patients with traumatic brain injury (TBI). Methods – Twenty two patients with moderate TBI (Glasgow score between 9-12) were randomized to receive isocaloric and isonitrogeneous either EN (n=12) or TPN (n=10). The daily amount of calories and nitrogen (N) supplied, the nitrogen balance, and the daily serum level of glucose, C-reactive protein, and albumin were collected for 5 consecutive days. Clinical endpoints as length of stay and mortality were also compared. Results – Mortality was 9.1% (two cases) with one case in each group. A progressive caloric deficit occurred in both groups (p = 0.001) without difference between them. The mean serum glucose level in TNP patients (134.4, 95% CI = 122.6 to 146.2 mg / dl) was significantly higher than in the EN group (102,4; 95% CI 91.6 to 113.2 mg / dL) (p <0.001). There was a significant trend (p = 0.06) of 24h urinary N loss to be greater in TPN group which received higher amounts of N than the NE group (p<0.05). However, nitrogen balance was similar in the two groups. There was no difference in either the clinical outcome variables or the acute phase response. Conclusion – Both routes were able to supply increasing provision of calories to brain injured patients. TPN provided significantly greater amount of nitrogen but losses were also greater. Nitrogen balance was similar with both types of therapy. Parenteral compared to enteral nutrition lead to greater hyperglycemia. There was no influence of the route in both the early inflammatory response and clinical outcome.

Biological variations of MASP-3 and MAp44, two splice products of the MASP1 gene involved in regulation of the complement system

The lectin pathway of complement is part of the innate immune system. The complement-activating pattern-recognition molecules (for which we suggest the abbreviation CAPREMs) mannan-binding lectin (MBL) and the three ficolins (H-, L- and M-ficolin) circulate in complexes with MBL-associated serine proteases (MASP-1, -2 and -3) and two additional proteins (MAp19 and MAp44, also termed sMAP and MAP-1, respectively). When MBL or ficolins recognize a microorganism or altered self components, activation of the MASPs ensues, leading to the activation of the complement system. MASP-1, MASP-3 and MAp44 are all three encoded by the MASP1 gene. MASP-1 and -3 share five domains (constituting the so-called A-chain), but have unique protease domains (B-chains). MAp44 shares the first four domains with MASP-1 and MASP-3, followed by 17 unique C-terminal amino acid residues. Thus, assays for the protease domain of MASP-3 and for the 17 C-terminal amino acids of MAp44 are required to measure these proteins specifically and here we present such assays for MASP-3 and MAp44. MASP-3 was captured with a monoclonal antibody (5F5) reacting with a common domain of the three proteins (CCP1) and the assay was developed with a monoclonal antibody (38.12.3) specific for the C-terminal part of the MASP-3 protease domain. MAp44 was captured with a monoclonal antibody (2D5) reacting with the C-terminus of MAp44 followed by assay development with a monoclonal anti-CCP1 antibody (4H2). Using Superose 6 gel permeation chromatography of serum, MASP-3 and MAp44 were found in complexes, which eluted in positions corresponding to 600–800kDa and 500–700kDa, respectively. The level of MASP-3 in donor sera (N=200) was log-normally distributed with a median value of 5.0μg/ml (range: 1.8–10.6μg/ml), and the corresponding value for MAp44, also log-normally distributed, was 1.7μg/ml (range: 0.8–3.2μg/ml). For MASP-3, the inter-assay coefficients of variation of low, intermediate and high level internal controls were 4.9%, 6.9% and 3.9% (N=12). For MAp44, the corresponding inter-assay CVs were 7.6%, 6.2%, and 7.0% (N=12). MASP-3 levels were low at birth and reached adult levels within the first 6months, whereas MAp44 levels fell slightly during the first 6months. Concomitant with the acute phase response in patients undergoing major surgery, levels of both proteins fell slightly over 1–2days, but whereas MASP-3 recovered to baseline values over another 2days, MAp44 only reached baseline values at around day 30. Thus, neither of the two proteins behaves as a classical acute phase protein.

Serum 25-hydroxyvitamin D levels modulate the acute-phase response associated with the first nitrogen-containing bisphosphonate infusion

The acute-phase response (APR) is the most frequent side effect after the first dose of intravenous nitrogen-containing bisphosphonates (N-BPs). It has been demonstrated in vitro that N-BPs stimulate gammadelta T-cell proliferation and production of cytokines and that vitamin D is able to modulate them. Therefore, we have studied the relationship between bone metabolism parameters, particularly for 25-hydroxyvitamin D [25(OH)D], and APR in patients treated with 5 mg zoledronic acid intravenously. Ninety N-BP-naive osteoporotic women (63.7 +/- 10.6 years of age) were stratified for the occurrence of APR (APR(+)) or not (APR(-)) and quantified by body temperature and C-reactive protein (CRP). The APR(+) women had significantly lower 25(OH)D levels than the APR(-) women. Levels of 25(OH)D were normal (>30 ng/mL) in 31% of APR(+) women and in 76% of APR(-) women. The odds ratio (OR) to have APR in 25(OH)D-depleted women was 5.8 [95% confidence interval (CI) 5.30-6.29; p < .0002] unadjusted and 2.38 (95% CI 1.85-2.81; p < .028) after multiple adjustments (for age, body mass index, CRP, calcium, parathyroid hormone, and C-telopeptide of type I collagen). Levels of 25(OH)D were negatively correlated with postdose body temperature (r = -0.64, p < .0001) and CRP (r = -0.79, p < .001). An exponential increase in fever and CRP has been found with 25(OH)D levels lower than 30 ng/mL and body temperature less than 37 degrees C, whereas normal CRP was associated with 25(OH)D levels above 40 ng/mL. The association between post-N-BPs APR and 25(OH)D suggests an interesting interplay among N-BPs, 25(OH)D, and the immune system, but a causal role of 25(OH)D in APR has to be proven by a randomized, controlled trial. However, if confirmed, it should have some practical implications in preventing APR.

Significance and impact of bisphosphonate-induced acute phase responses

Bisphosphonates are synthetic analogs of inorganic pyrophosphates with high avidity for bone, where they bind to hydroxyapatite crystals. Bisphosphonates are effective in decreasing bone resorption, the incidence of skeletal-related events, and pain from bone metastases. These agents have recently become incorporated into the treatment regimen of patients with osteolytic and osteoblastic metastatic bone disease. Although relatively well tolerated, the initial dose(s) of intravenous aminobisphosphonates can be associated with an acute phase response, a nonspecific physiologic reaction associated with increased levels of inflammatory cytokines, fever, and flu like symptoms including fatigue, nausea, and myalgia. The purpose of this article is to provide an updated review of the literature in this field. A search of PubMed was performed using the key terms bisphosphonate, acute phase response, and cancer, and limited to publications in English. The published literature on acute phase response with bisphosphonate therapy was reviewed. Approximately 40% of patients receiving aminobisphosphonates experience an acute phase response, which generally occurs only on first exposure to the drug and typically last <72 h. Not all bisphosphonates induce acute phase responses to the same extent. This article reviews acute phase response in patients with metastatic bone disease treated with aminobisphosphonates.

VASOPRESSORS IN CARDIAC SURGERY: THE ROLE OF THE ADRENAL GLAND

PURPOSE: Serum total cortisol level has been used for the diagnosis of adrenal insufficiency. However, more than 90% of circulating cortisol is protein-bound and this can affect the assessment of adrenal gland reserve in cardiac surgery patients, because the binding protein levels fall substantially during the postoperative acute phase response. To evaluate cortisol levels and their relationship to albumin levels in the context of severe stress and the acute phase response in patients undergoing cardiac surgery and to assess if the cortisol/albumin (C/A) ratio can be used to predict the need for vasopressors postoperatively.