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Endogenous mediators of the acute-phase reaction. I. Rabbit granulocytic pyrogen and its chromatographic subfractions.

LP, a saline extract of exudate-derived rabbit granulocytes, shown to be free of endotoxin contamination by sensitive LAL assay, can elicit brisk acute-phase responses in the rabbit. Following a single large intravenous dose of LP (875 mce) there is a brisk fall in serum iron at 8 hr and marked elevations in concentrations of CxRP, haptoglobin, fibrinogen, and ceruloplasmin and a lesser rise in sialic acid in the blood at 24 hr, which return toward baseline to varying degrees by 48 hr. When the crude LP solution is fractionated by column chromatography on Sephadex G75, all detectable acute-phase mediating activity elutes in a fraction (pool C) which contains all the pyrogenic activity and about 15% of the total eluted protein. Within the limitations of the methods employed, the acute phase stimulating activity and the pyrogenic activity of LP preparations appear to be closely linked.

Animals

The esterification of cholesterol in plasma after acute myocardial infarction.

The rate of plasma cholesterol esterification (LCAT activity) and the concentration of eight proteins in the plasma have been studied in the ten male patients during the course of acute myocardial infarction. Samples were drawn 22 hr, 3 days, 8 days, 2 weeks, and 7 weeks after the onset of the acute myocardial infarction. The changes of the plasma proteins were typical for the acute-phase reaction. LCAT activity decreased initially during the illness. The lowest values were found after 8 days. Concomitantly, a reducation in the plasma concentration of total and free cholesterol and cholesteryl esters was demonstrated. The rate of cholesterol esterification correlated significantly with the concentration of prealbumin, alpha-lipoprotein, and albumin. Seven weeks after onset of the infarction, the LCAT values were equal to those in a reference group. The results suggest that the synthesis of LCAT was decreased during the acute-phase reaction.

Acute Disease

Serum proteins in diseases of the liver.

In 9 groups of liver diseases, 11 serum protein parameters were studied. Prealbumin, retinol-binding protein, albumin, alpha-lipoprotein and Normotest (NT) were usually highly intercorrelated and separated best among groups with different types of functional impairment. Haptoglobin, C3 and total iron-binding capacity were probably also sometimes reduced by restricted protein synthesis but appeared to be more easily affected by other factors, alpha1-antitrypsin was often increased in different liver diseases, but a pattern compatible with the "acute-phase reaction" was regularly present only in hepatic tumors. Bile retention was often accompanied by relatively high levels of ceruloplasmin, C3, and alpha-lipoprotein and by high NT values.

Acute Disease

[Cerebrospinal fluid protein electrophoresis in non-inflammatory central nervous system diseases].

Cerebrospinal fluids (CSF) (N = 365) from patients with non-inflammatory diseases of the central nervous system were analyzed for protein distribution by agar gel microelectrophoresis. After subdivision into diagnostically well defined groups, these patients were compared with 79 normal controls. Most of the diseases investigated were found to follow the "plasma-type" pattern. In some of them the deviations from normal were so extensive that a CSF-protein pattern similar to the "acute-phase reaction" in the serum occurred. Moreover, the following characteristics were found: a considerable increase in total protein and the gamma-globulin fractions in neurinomas; a reproducible increase in the alpha1-globulins in metastases of the central nervous system; and a statistically significant difference of CSF protein findings between male and female patients with protrusion of lumbar intervertebral discs.

Albumins

Coagulation activation and hyperviscosity in infection.

A serial study of coagulation activation and whole-blood viscosity was performed on 37 patients with local or systemic bacterial infection, malaria, or a viral infection. Thrombocytopenia, without consumption of coagulation factors, was the main feature of benign tertian malaria and viral infection, whereas in septicaemia and malignant tertian malaria it was associated with activation of coagulation and fibrinolysis. Patients with evidence of intravascular coagulation showed the highest levels of factor VIII related antigen which did not correlate with fibrinogen and probably reflected vascular endothelial cell damage rather than an acute-phase protein reaction. Hyperviscosity, which has been implicated in the pathogenesis of endotoxic shock and cerebral malaria, occurred in parallel with the acute-phase rise in plasma fibrinogen. There was, however, no evidence to implicate hyperviscosity as a major causative factor in the pathogenesis of septic shock or severe infective illness.

Adolescent

Serial changes in coagulation and viscosity during sickle-cell crisis.

Coagulation activity and whole-blood viscosity were measured in the steady state, and serially during painful crisis, in eight patients with sickle-cell anaemia. Platelet and coagulation activation occurred in the steady state and became more pronounced early in crisis. Whole-blood viscosity increased during crisis in parallel with plasma fibrinogen. Similar changes were found in a parallel study of 20 patients with localized bacterial or viral infection who did not have sickle-cell anaemia. Reports of platelet activation, hypercoagulability, and hyperviscosity during painful crisis therefore reflect secondary changes arising from vascular stasis, precipitating infection, and an acute-phase protein reaction. Although secondary, these changes may contribute to vascular occlusion by an additive effect in vessels already partially occluded by sickled cells.

Adolescent

A new function for ceruloplasmin as an acute-phase reactant in inflammation: a scavenger of superoxide anion radicals.

In summary, purified human ceruloplasmin inhibits several reactions mediated by superoxide anion in a fashion consistent with an ability to scavenge this free radical. It must be pointed out, however, that on a weight basis, the superoxide-scavenging activity of ceruloplasmin is substantially less than that of purified human erythrocyte superoxide dismutase. Nevertheless, since superoxide dismutase is almost exclusively an intracellular enzyme, ceruloplasmin probably represents the major circulating scavenger of superoxide anion radicals. The level of superoxide dismutase in human plasma has been reported to be 0.7 microgram/ml. It is not clear, however, how this was measured. We have found that concentrations of plasma exceeding 10% (v/v) interfere significantly with the assays routinely employed for detecting superoxide-scavenging activity. Consequently, we have not yet been able to quantify the superoxide-scavenging activity of either ceruloplasmin or superoxide dismutase in whole human plasma. Thus, we can only speculate that under conditions where levels of ceruloplasmin are markedly elevated, as during pregnancy, during acute infections, or in association with inflammatory diseases (such as rheumatoid arthritis), this acute-phase reactant may play a major role as a circulating scavenger of oxygen-derived free radicals.

Ceruloplasmin

Isolation of the etiologic agent of Korean Hemorrhagic fever.

Lung tissues from 73 rodents (Apodemus agrarius coreae) gave specific immunofluorescent reactions when they reacted with sera from patients convalescing from Korean hemorrhagic fever. Similar staaining was observed in the lungs of A. agrarius inoculated with acute-phase sera obtained from two patients with this disease. The unidentified agent was successfully propagated in adult A. agrarius through eight passages representing a cumulative dilution of greater than 10(-17). Experimentally inoculated rodents developed specific fluorescent antigen in the lung, kidney, liver, parotid glands, and bladder. Organs, especially lungs, were positive beginning 10 days and continuing through 69 days after inoculation. The agent could not be cultivated in several types of cell cultures nor in laboratory animals. No fluorescence was observed when infected A. agrarius lung tissues were reacted with antisera to Marburg virus, Ebola virus, and serval arenaviruses. Diagnostic increases in immunofluorescent antibodies occurred in 113 of 116 severe and 11 of 34 milder cases of clinically suspected Korean hemorrhagic fever. Antibodies were present during the first week of symptoms, reached a peak at the end of the second week, and persisted for up to 14 years. Convalescent-phase sera from four persons suffering a similar disease in the Soviet Union were also positive for antibodies.

Animals

[Acute-phase proteins in women with a copper IUD (author's transl)].

Acute-phase (AP) proteins haptoglobin, alpha1-antitrypsin and C-reactive protein were measured in 50 women before and 10 to 30 weeks after insertion of a copper T-200. No statistically significant increase in AP proteins was found. Since these proteins are synthesized in the liver, the results indicate the lack of a systemic humoral reaction of the organism in women with a copper-containing IUD.

C-Reactive Protein

Agarose gel filtration of concentrated fecal extracts containing virus-like particles associated with hepatitis A.

Virus-like particles shown to be associated with hepatitis A infection were recently visualized by immune electron microscopy in human and chimpanzee acute-phase fecal extracts. Agarose gel filtration of concentrated chimpanzee fecal extracts containing those 27-nm diameter particles separated more than 99% of the high molecular weight fecal impurities into two major peaks as determined by absorbance at 280 and 260 nm. The hepatitis A-associated particles were found between these two peaks by both immune electron microscopy and a new immunoradiometric assay.

Animals

Systematic Proteome Profiling of Maternal Plasma for Development of Preeclampsia Biomarkers.

Preeclampsia (PE) is a hypertensive disorder of pregnancy with various clinical symptoms. However, traditional markers for the disease including high blood pressure and proteinuria are poor indicators of the related adverse outcomes. Here, we performed systematic proteome profiling of plasma samples obtained from pregnant women with PE to identify clinically effective diagnostic biomarkers. Proteome profiling was performed using TMT-based liquid chromatography-mass spectrometry (LC-MS/MS) followed by subsequent verification by multiple reaction monitoring (MRM) analysis on normal and PE maternal plasma samples. Functional annotations of differentially expressed proteins (DEPs) in PE were predicted using bioinformatic tools. The diagnostic accuracies of the biomarkers for PE were estimated according to the area under the receiver-operating characteristics curve (AUC). A total of 1307 proteins were identified, and 870 proteins of them were quantified from plasma samples. Significant differences were evident in 138 DEPs, including 71 upregulated DEPs and 67 downregulated DEPs in the PE group, compared with those in the control group. Upregulated proteins were significantly associated with biological processes including platelet degranulation, proteolysis, lipoprotein metabolism, and cholesterol efflux. Biological processes including blood coagulation and acute-phase response were enriched for down-regulated proteins. Of these, 40 proteins were subsequently validated in an independent cohort of 26 PE patients and 29 healthy controls. APOM, LCN2, and QSOX1 showed high diagnostic accuracies for PE detection (AUC >0.9 and p&#xa0;<&#xa0;0.001, for all) as validated by MRM and ELISA. Our data demonstrate that three plasma biomarkers, identified by systematic proteomic profiling, present a possibility for the assessment of PE, independent of the clinical characteristics of pregnant women.

Humans

The in vitro interactions of rat pancreatic elastase and normal and inflammatory ray serum.

The partition of labelled rat pancreatic elastase (EC 3.4.21.11) between the different protease inhibitors of rat plasma was studied at different levels of saturation of the inhibitors of rat plasma was studied at different levels of saturation of the inhibitor capacity of plasma with the enzyme. The reaction mixtures were analysed by immunoelectrophoretic methods utilizing specific antisera against the different inhibitors and by gel filtration on Sephadex G-200. Rat serum was shown to contain four elastase binding proteins. alpha 1-antitrypsin, alpha 1-macroglobulin and alpha 2-acute phase protein and alpha 1-inhibitor 3 which exhibits immunologic cross-reaction with human inter-alpha-trypsin inhibitor and is of similar molecular weight. With minute amounts of labelled elastase the partition among the binding protein was alpha 1-macroglobulin 60%, alpha 1-antitrypsin 24% and alpha 1-I3 16%. The 60% value of alpha 1-M bound radioactivity in normal serum corresponds to the sum of alpha 1-M and alpha 2-AP labelling in inflammatory serum.

Acute-Phase Proteins

Effect of human cord and postoperative serum on experimental inflammation in the rat.

Human cord and postoperative serum depressed the oedema provoked by mediators of the inflammatory reaction such as bradykinin, histamine, serotonin and prostaglandin E2 and also the experimental inflammation caused by carrageenin. Normal human and pregnancy serum did not have such an effect. In two cases of open neural tube defect, one of anencephaly and another of spina bifida, human amniotic fluid also had a strongly depressing effect on the experimental oedema provoked by serotonin. Human amniotic fluid from normal pregnancies did not inhibit this experimental inflammation. A protein-fraction of mol. wt 30,000--100,000 has been isolated from the inhibiting sera and shows the anti-inflammatory activity to be dose-related towards all the oedema-provoking substances used. Immunological studies showed that the inhibiting factor could be a protein in the pre-albuminic region, while alpha-foetoprotein did not appear to be responsible for the anti-inflammatory activity. Our conclusion is that human serum contains a protein of foetal origin with an acute-phase character and strong anti-inflammatory activities analogous to rat alpha 2-macrofoetoprotein.

Amniotic Fluid

Acute-phase proteins from the liver and enzymes from myocardial infarction; a quantitative relationship.

In 14 patients with acute myocardial infarction (M.I.) not having any other disease, the possible quantitative relationship between enzymes from M.I. and changes in concentration of acute phase reactants coming from the liver were studied. The patients were followed up until 1 1/2 years after M.I. and comparison of baseline-protein values took place using a control group of 18 healthy individuals. Quantitation of protein changes was done by planimetric determination of the area under the concentration curve and by taking peak values. The myocardial infarction was quantitatively estimated by mathematical analysis of the time course of alpha-hydroxybutyrate dehydrogenase (alpha-HBDH) plasma concentrations and by taking peak values. A quantitative relationship with enzymatic infarct size was found for haptoglobin, alpha1-acid glycoprotein, alpha1-antitrypsin, C-reactive protein, fibrinogen and E.S.R. Albumin and transferrin did not show a negative quantitative relationship with enzymatic infarct size. Humoral factors originating from the site of tissue injury and evoking in proportion a positive acute phase reaction by the liver are probably the basis for this observed quantitative relationship.

Acute Disease

Saliva versus lesion swabs for PCR diagnosis of acute-phase clade Ib mpox in Uganda: a prospective matched hospital cohort study.

BACKGROUND: As clade Ib mpox expands through HIV-affected populations in east and central Africa, diagnostic specimen selection should balance accuracy, accessibility, and operational feasibility in outbreak settings. Here, we aimed to compare the diagnostic performance of matched plasma, saliva, genital, anal, and skin specimens during the acute rash phase of clade Ib mpox to identify clinically practical and high-yield sampling approaches for outbreak response and clinical care. METHODS: We conducted a prospective cohort study of 155 adults (median age 30 years, IQR 25-36) hospitalised at Uganda's national mpox referral hospital. The specimens were collected between March 3 and April 10, 2025, during the clade Ib outbreak. All participants were admitted with suspected mpox and were subsequently confirmed by MPXV PCR. We collected 836 clinical specimens (acid citrate dextrose plasma, saliva, genital swabs, anal swabs, and skin swabs) during the acute phase (visit 1; 14 days [SD 2] after systemic symptom onset) and at approximately 3 months (visit 2). A matched acute-phase subset (n=80) provided concurrent plasma, saliva, genital, and skin specimens for within-participant comparisons. MPXV DNA was quantified by F3L real-time quantitative PCR, and cycle threshold (Ct) values were compared using paired Wilcoxon signed-rank tests. Whole-genome sequencing of selected acute specimens confirmed clade assignment. FINDINGS: In the matched subset at visit 1, PCR positivity was high in saliva (78 [98%] of 80), skin swabs (78 [98%] of 80), and genital swabs (77 [96%] of 80). Results for the saliva closely mirrored genital and skin swab results, supporting saliva as a high-yield alternative when lesion sampling is painful, operationally difficult, or unacceptable. Plasma had substantially lower sensitivity (34 [43%] of 80) and showed poor agreement with mucocutaneous compartments. At 3 months, persistent MPXV DNA was rare (ten [9%] of 109) and clustered among people with HIV, including the only two participants with persistent plasma positivity. All sequenced genomes clustered within clade Ib. INTERPRETATION: During the established rash phase (14 days [SD 2] after onset), saliva provides diagnostic yield similar to that provided by lesion swabs for clade Ib mpox in this hospitalised cohort. These findings are restricted to this sampling window; further studies are needed to define performance in prodromal, pre-rash, and asymptomatic infection. FUNDING: CEPI through its Centralised Laboratory Network.

Adult

Hepatitis "C" antigen in non-A, non-B post-transfusion hepatitis.

Evidence for a new hepatitis-specific antigen has been obtained from double immunodiffusion assays between acute and convalescent sera obtained from patients with non-A, non-B post-transfusion hepatitis. The designation hepatitis C (HC) antigen is proposed. HC was found in the acute-phase sera of all 13 non-A, non-B post-transfusion hepatitis patients with longer incubation and duration periods (type 2) tested, but only transiently in 4 out of 10 acutephase sera obtained from patients with type 1 non-A, non-B hepatitis, with shorter incubation and duration periods. The antigen was also detected in 2 out of 16 single specimens obtained during the acute phase from acute hepatitis patients who had not received a blood-transfusion. This suggests presence of a carrier state. No patients with alcoholic hepatitis and no healthy blood-donor carried HC antigen. The antigen seems distinct from those of hepatitis A and B (surface and core). It migrated in the serum beta-globulin region and had a buoyant density of 1.30 and a molecular weight between 100 000 and 300 000. Antibodies against HC antigen were found in only 30% of the type-2 non-A, non-B post-transfusion hepatitis patients and did not persist for long. However, these antibodies were directed specifically against HC antigen and moved in a manner similar to 7S globulin on rate-zonal centrifugation.

Acute Disease

Cell-mediated immunity to Epstein-Barr-virus-transformed lymphoblastoid cells in acute infectious mononucleosis.

Mononuclear peripheral blood leukocytes from 21 patients with infectious mononucleosis and 16 healthy controls were tested in a 51Cr-release assay for cytotoxicity against two human lymphoblastoid cell lines derived from the same donor. One line contained the Epstein-Barr virus (EBV); the other did not. Acute-phase leukocytes were significantly more cytotoxic against the EBV-infected cell line than were control leukocytes. Mean (+/- S.E.) lysis at a leukocyte-target-cell ratio of 100:1 was 10.6 +/- 1.6 per cent for patients and 3.4 +/- 0.6 per cent for controls (P less than 0.0005). Cytotoxicity correlated with the percentage of atypical lymphocytes. Cells of three patients with acute mononucleosis-like illnesses failed to show killing activity above those of normal controls. Cytotoxicity against the EBV-negative line was not significantly different for each group. The finding of cytotoxic cells in infectious-mononucleosis patients with atypical lymphocytes suggests that these cells operate in vivo to limit the proliferation of altered EBV-transformed B lymphoblasts.

Acute Disease

Localization of hepatitis A antigen in marmoset organs during acute infection with hepatitis A virus.

Twelve marmosets (Saguinus mystax) were inoculated intravenously (iv) with hepatitis A virus (HAV). One died early (day 12); seven were sacrificed at the time of elevation in level of alanine aminotransferase (serum glutamic-pyruvic transaminase), and four without elevation were not sacrificed but seroconverted. In the seven marmosets sacrificed during the acute stage of illness, hepatitis A antigen (HA Ag) was detected in the liver by immunofluorescence in all cases, by immune electron microscopy in four, and by enzyme-linked immunosorbent assay (ELISA) in three. The HA Ag appeared by immunofluorescence as very fine granules in the cytoplasm of hepatocytes and Kupffer cells. The HA Ag could not be detected by immunofluorescence in biopsy specimens taken from the duodenum, jejunum, ileum, or transverse colon in any of eight marmosets in which necropsy was performed during the acute or preacute stage of illness. These findings suggest that the gut is not involved during the acute phase of HAV infection following iv inoculation into marmosets. The ELISA results showed that only three of 12 marmoset livers obtained during the acute phase of HAV infection could be used as an antigen source in serologic testing for antibody to HA Ag. Thus, marmoset livers were no better as a source of HA Ag than acute-phase stools from patients with type A hepatitis.

Acute Disease