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Correlation of fatty acid composition of adipose tissue lipids and serum phosphatidylcholine and serum concentrations of micronutrients with disease duration in rheumatoid arthritis.

To establish the concentrations of micronutrients in serum, fatty acid composition in serum phosphatidylcholine and in adipose tissue, and their correlation with inflammation and disease duration in rheumatoid arthritis (RA), 21 consecutive patients with recently diagnosed disease (mean duration eight months), 21 patients with longstanding disease (mean duration 15 years), and 57 controls were examined. In the patients with RA low concentrations of the essential fatty acids, linoleic acid (18:2) and linolenic (18:3) acid, and high concentrations of total saturated fatty acids, both in serum phosphatidylcholine and in adipose tissue, were found, abnormalities that increased with disease duration. The proportion of 18:2 in serum phosphatidylcholine correlated inversely with such acute phase proteins as orosomucoid and C reactive protein. It is proposed that the decreases in essential fatty acids are related to increased activity in the desaturase/elongation enzymes, increased production of eicosanoids, or metabolic changes secondary to cytokine mediated inflammatory reaction. When the micronutrients were studied it was found that serum concentrations of selenium were lower in patients than in controls, but not those of ascorbic acid, alpha-tocopherol, retinol, folic acid, or cobalamine. Ascorbic acid concentrations tended to be lower in RA, however, and correlated inversely with those of haptoglobin, orosomucoid, and C reactive protein, indicating a relation between the ascorbic acid concentration and the degree of inflammation.

Acute-Phase Proteins↗

Limited proteolysis of the alpha-macroglobulin rat alpha 1-inhibitor-3. Implications for a domain structure.

Rat alpha 1-inhibitor-3 is a 180-kDa monomeric proteinase inhibitor found in high concentration in rat plasma. By several criteria it has been shown to be a member of the family of alpha-macroglobulin proteinase inhibitors often exemplified by the tetrameric human alpha 2-macroglobulin. We have used limited proteolysis of rat alpha 1-inhibitor-3 to probe the domain structure of this family of proteins. Proteinases of different specificities, including trypsin, chymotrypsin, thermolysin, and Staphylococcus aureus V8 proteinase, were employed and a common fragmentation pattern was observed when the reaction products were examined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. These fragments were electrotransferred to polyvinylidene difluoride membranes and subjected to NH2-terminal amino acid sequence analysis in order to position them within the context of the primary structure. The fragmentation pattern may define the domain structure of alpha 1-inhibitor-3 and serve as a model for the domain organization of the family of alpha-macroglobulin proteinase inhibitors.

Acute-Phase Proteins↗

Nutritional disorders in HIV disease.

Reviewing the medical literature since 1981 show that patients with acquired immunodeficiency syndrome (AIDS) usually suffer from poor ingestion and absorption, increased excretion of nutrients, metabolic and endocrine abnormalities and immunologic abnormalities which impair nutrition. Human immunodeficiency virus (HIV) and associated opportunistic infections stimulate a broad and complex array of responses which include fever, hypermetabolism, leukocytosis, proteolysis of skeletal muscle, and synthesis, by the liver, of acute-phase reactant proteins and various intracellular enzymes. These responses increase gluconeogenesis and lipogenesis, decrease albumin synthesis, and redistribute and/or sequester various trace elements. Infection-induced depletion of body nutrients serves to weaken host resistance. The deterioration of the nutritional status of these patients is likely to have an important effect on the course of the disease. It is thus evident that comprehensive management of HIV infection must include nutritional evaluation and treatment. When oral nutrition proves to be insufficient to maintain adequate intake, alternative routes must be considered. Selection of an appropriate nutritional support formula requires an evaluation of the absorptive capacity of the gastrointestinal (GI) tract, the length of time required for nutritional repletion, costs, patient acceptance, and feasibility of at-home use. Nutritional support maximizes the ability of the AIDS patient to resist infection, may favor the response to medication by decreasing the incidence of adverse drug reactions, and may prolong the quality and productivity of life.

Acquired Immunodeficiency Syndrome↗

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↗

Evidence for lipopolysaccharide binding in human granulosa-luteal cells.

We investigated whether human granulosa-luteal (GL) cells exhibited lipopolysaccharide (LPS)-binding protein, and the response of follicular aspirate cells to LPS in vitro. Follicular aspirates taken from a human in-vitro fertilization and gamete intra-fallopian-tube transfer programme were subjected to Percoll gradients in order to isolate an enriched population of GL cells. GL cells exhibited specific LPS-binding protein, detected by autoradiography of the cellular lysate on SDS-PAGE after the cells were specifically labelled with a radioiodinated, photoactivable and reducible LPS derivative. LPS binding to the cells was also detected by the appearance of immunofluorescence associated with the cellular membrane when incubated with a fluorescent conjugated LPS receptor antibody. Ninety-four per cent of the cells exhibiting immunofluorescent LPS-binding protein were also positive for the steroidogenic enzyme 3 beta-hydroxysteroid dehydrogenase, as detected by cytochemistry. In order to detect a response to LPS, the enriched population of GL cells were cultured in vitro in the presence or absence of LPS; after 16 h of culture, tumour necrosis factor-alpha (TNF) mRNA was detected by reverse transcription-polymerase chain reaction and Southern blot analysis of the amplified cDNA. The expression of TNF mRNA was enhanced when the cells were cultured in the presence of LPS, which also significantly enhanced TNF secretion into the media during the 16-h period. These results reveal that GL cells exhibit LPS-binding protein and thus increased TNF secretion occurs in response to LPS in follicular aspirate cells. The source of ovarian TNF may be leukocytes, macrophages and/or GL cells.

3-Hydroxysteroid Dehydrogenases↗

Sequential appearance of IL-1 and IL-6 activities in rat carrageenin-induced pleurisy.

IL-1 and IL-6 activities were measured in the pleural exudate of rats during carrageenin-induced pleurisy to examine the relationship of the local production of cytokines to the inflammatory reaction. Time courses of appearance of the cytokines and inflammatory parameters in the exudate were compared. IL-1 activity and exudate volume started to increase at 1 h after the carrageenin injection, and then slightly later IL-6 activity and leukocyte number began to increase. IL-1 showed peak activity of approximately 700 U at 3 h and IL-6, of 6000 U at 5 h in the exudate, whereas exudate volume and number of polymorphonuclear leukocytes continued to increase thereafter. Furthermore, IL-6 level in the plasma of the carrageenin-injected rats showed a peak at 4 h (30 U/ml), and when rhIL-1 alpha (100,000 U) was intrapleurally injected, the more rapid increase in plasma IL-6 level was demonstrated at 1 h (30 U/ml). This latter rise was neutralized with simultaneous injection of anti-rhIL-1 alpha antibody. These facts indicate the possibility that IL-1 produced in the exudate or injected could rapidly propagate a signal to induce IL-6 production in the circulation. It took several hours to transmit an inflammatory signal that stimulated the liver to synthesize the acute-phase protein, T-kininogen. The time lag from the peak induction of IL-1 to the T-kininogen-increase in the pleurisy corresponded well to the interval for T-kininogen-increase by exogenous rhIL-1 alpha injection. These results strongly suggest that the initial inflammatory stimulus induces sequentially IL-1, IL-6, and T-kininogen production in this carrageenin inflammation.

Acute-Phase Proteins↗

Identification of a human lactoferrin-binding protein in Staphylococcus aureus.

Human lactoferrin (HLf) is an iron-binding protein with antimicrobial activity that is present in high concentrations in milk and various exocrine secretions. HLf is also an acute-phase protein secreted by polymorphonuclear leucocytes, and its binding to a large number of clinical isolates of Staphylococcus aureus has been described recently from our laboratory. We have now characterised the HLf-staphylococcal interaction in S. aureus strain MAS-89. The binding of 125I-HLf to strain MAS-89 reached saturation in less than 90 min and was maximal between pH 4 and 9. Unlabelled HLf displaced 125I-HLf binding. Various plasma and subepithelial matrix proteins, such as IgG, fibrinogen, fibronectin, collagen and laminin, which are known to interact specifically with S. aureus, did not interfere with HLf binding. A Scatchard plot was non-linear; this implied a low affinity (1.55 x 10(7) L/mol) and a high affinity (2.70 x 10(8) L/mol) binding mechanism. We estimated that there were c. 5700 HLf binding sites/cell. The staphylococcal HLf-binding protein (HLf-BP) was partially susceptible to proteolytic enzymes or periodate treatment and was resistant to glycosidases. An active HLf-BP with an apparent Mr of c. 450 Kda was isolated from strain MAS-89 cell lysate by ion-exchange chromatography on Q-sepharose. In SDS-PAGE, the reduced HLf-BP was resolved into two components of 67 and 62 Kda. The two components demonstrated a positive reaction with HLf-HRPO in a Western blot. These data establish that there is a specific receptor for HLf in S. aureus.

Bacterial Proteins↗

Conformational flexibility of the serum amyloid precursor SAA.

SAA is a normal acute-phase serum protein and is thought to be the precursor of amyloid protein AA which is deposited as insoluble beta-pleated sheet fibrils in secondary amyloidosis. Native SAA has a molecular weight of 160,000 and has not been isolated; it has been most frequently purified as a species (designated SAAL) of 12,500 mol. wt. by gel filtration in dissociating solutions. The conformational properties of SAA proteins in patients with and without amyloidosis have been compared in an effort to determine the factors involved in the induction of the beta-pleated sheet conformation in the amyloid SAA protein prior to fibril deposition. Amyloid and nonamyloid SAA proteins are similar in that they readily undergo conformational changes which result in the formation of heterogenous mol. wt. SAA species and in an increased exposure of antigenic determinants which cross-react with AA fibril proteins. Amyloid and nonamyloid SAA are different, however, in that amyloid SAA is more resistant to dissociation to SAAL. Amyloid SAAL, while similar to nonamyloid SAAL in immunoreactivity, shows a greater tendency toward aggregation. The relative resistance of both amyloid SAA and SAAL to complete dissociation may play an important role in amyloid fibril formation from these precursors.

Amyloid↗

The rat female protein, a pentraxin with lectinic properties.

The C-reactive protein is the major acute phase protein (APP) in humans which binds lectin-like to different membraneous structures and exerts an important function in non-specific defense. Because of a pentameric molecular symmetry CRP as well as serum amyloid P component (SAP) and hamster female protein (FP) was merged into a special protein family named pentraxins. In rats a protein was found referred to as rat FP which was close related to hamster FP with respect to hormonal regulation and APP nature as well. Based on this conformity the molecular structure of rat FP was analyzed and as the results a pentameric structure could be demonstrated for rat FP, too. Furthermore, the response of rat CRP and FP on injection of adrenal hormones, agents being involved in acute phase reaction, was investigated. Epinephrine administration led to an increase in CRP and a decrease in FP serum concentration. Dexamethasone has the same effect in case of FP and changed the CRP concentration in a biphasic way with a maximum at about 0.01 mg/kg, a minimum at 0.6 mg/kg and a return to control values at 1.8 mg/kg. Thus, the results indicate a neuroendocrine control of CRP and FP but probably in a different way. Using FITC-labelled lectin the exposition of galactose-containing membraneous structures could be demonstrated in carbon tetrachloride-injured liver tissue in contrast to controls. These binding sites are in accordance with increased FP-binding shown by immunofluorescence histochemistry. Thus, lectin-like properties may be ascribed to rat FP comparable to CRP and SAP activity. The results are discussed with respect to findings from literature that also the acetylcholine receptor seems to have a pentameric structure.

Acute-Phase Proteins↗

Modification of inflammatory processes by phenobarbital in rats.

Enzyme-inducing drugs such as phenobarbital (PB) increase serum concentrations of an acute-phase protein, alpha 1-acid glycoprotein (AGP), in man, dogs, and rats via an unknown mechanism. We studied the effects of PB on components of an acute inflammatory reaction in rats in order to determine if PB acts only on this biological marker of inflammation or is capable of altering the clinical course of inflammatory processes. Local carrageenan injection induces a similar time-dependent plantar edema and increases serum AGP levels in Sprague-Dawley (SD) and Dark Agouti (DA) rats. Pretreatment with PB for seven days modified neither parameter in SD rats while plantar edema was aggravated and serum AGP levels were increased in DA rats. The sedative-hypnotic properties of PB were not involved, since a single administration of this drug had no action in DA rats. On the other hand, chronic PB administration reduced the severity of an autoimmune disease, type II collagen-induced arthritis, in DA rats. These data indicate that PB, a potent inducer a cytochrome P-450-dependent enzymes, modifies the course of the inflammatory process. Preliminary results with macrophage transfer experiments suggest that this response to PB could be mediated by stimulated macrophages.

Acute Disease↗

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↗

C-reactive protein inhibits binding of platelet-activating factor to human platelets.

Serum concentration of C-reactive protein (CRP), a prototypical acute-phase protein rises dramatically in response to tissue injury or inflammation. We report here that CRP (1-20 micrograms/ml) inhibited platelet-activating factor (PAF)-induced aggregation of human platelets in time-, and dose-dependent manner. This inhibitory action of CRP was nearly completely removed by treatment with anti CRP antiserum. At higher concentrations (20-100 micrograms/ml), CRP stabilized platelet membrane against the detergent-like effect of beta-deoxy-lysolecithin. Furthermore, CRP (10 micrograms/ml) diminished specific [3H]PAF binding to platelets and displaced previously bound labeled PAF from platelets. These results suggest that by depressing the bioavailability of PAF, CRP may be an important modulator of platelet activation during acute inflammatory reactions.

Antibody Formation↗

Use of conserved sequences from hepatitis C virus for the detection of viral RNA in infected sera by polymerase chain reaction.

Three oligonucleotide primer combinations selected from the 5' noncoding, the nucleocapsid and the putative nonstructural regions of the hepatitis C virus genome were compared in a nested polymerase chain reaction assay with respect to sensitivity and specificity for the detection of viral RNA in chimpanzee-infected and human-infected sera. Sera from both the acute and the chronic phase of the infection were obtained from 13 animals inoculated with five different non-A, non-B hepatitis strains and from seven cardiac surgery patients who had non-A, non-B hepatitis develop after transfusion and who had been tested in parallel for the presence of hepatitis C virus RNA and anti-C 100-3. A total of 90% of the acute-phase and 100% of the chronic-phase sera tested positive for hepatitis C virus RNA when the 5' noncoding-derived or the nucleocapsid-derived combinations were used; only 58% and 56%, respectively, gave positive results with the putative nonstructural primers, whereas 33% and 71%, respectively, scored positive for C100-3. Thus polymerase chain reaction primers selected from either the highly conserved 5' noncoding or nucleocapsid-regions appear to provide the sensitivity and the specificity necessary to detect low levels of hepatitis C virus RNA in both chimpanzee-infected and human-infected sera.

Animals↗

Interleukin-6 and its receptor in autoimmunity.

Interleukin-6 (IL-6) is a multifunctional cytokine which acts on a wide variety of cells, regulating immune response, acute phase reaction and hematopoiesis. In accordance with its pleiotropic functions, IL-6 is indicated to be involved in the pathogenesis of several diseases including autoimmunities, lymphoid malignancies and inflammations. An elevated level of IL-6 is demonstrated in patients with rheumatoid arthritis and cardiac myxoma, which can explain symptoms of these diseases, such as autoantibody production and increase in acute phase proteins. Therefore, inhibitors of IL-6 production or IL-6 receptor-mediated signal transduction may be used for treatment of IL-6-related diseases. The IL-6 receptor system consists of two membrane proteins, a ligand-binding chain (IL-6R) and a non-ligand-binding signal transducer, gp130, both of which belong to the cytokine receptor family. Binding of IL-6 to IL-6R triggers the association of IL-6R and gp130, and gp130 in turn transduces the signal. A nuclear factor for controlling IL-6 gene expression (NF-IL6) is also involved in the transcriptional regulation of various acute-phase protein genes. IL-6-stimulation of hepatocytes, through modification of pre-existing NF-IL6 protein, leads to binding of NF-IL6 to IL-6-responsive elements and activation of acute-phase protein genes. NF-IL6 is shown to recognize the enhancer core sequence of several viruses, suggesting a possible relationship of virus infection and IL-6 expression.

Acute-Phase Proteins↗

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↗

The involvement of TNF, IL-1 and IL-6 in the immune response to protozoan parasites.

One early reaction of the host to infection with protozoan parasites is the secretion of an array of potent cytokines including tumor necrosis factor (TNF), interleukin (IL-1) and IL-6. The combined action of these cytokines causes fever, leukocytosis and the production of acute phase proteins such as C-reactive protein (CRP). These early responses contribute significantly to the outcome of infection by influencing the course of infection directly and by regulating the specific immune response to the parasite.

Acute-Phase Proteins↗

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↗