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PubMed1980

[Mesenchymatous tumour of the thigh causing hypoglycaemia with circulating protein of high insulin activity (author's transl)].

An 87-year-old woman underwent surgery for a dermato-fibrosarcoma of the thigh, responsible for hypoglycaemic episodes. There was a high level of NSILP contrasting with a low level of NSILAs. This is the second case where such a finding has been made in a patient suffering from an extra-pancreatic tumour causing hypoglycaemia. The possible aetiological role of NSILP in extra-pancreatic tumours causing hypoglycaemia is discussed.

Aged↗
PubMedDate not supplied

Effects of D-penicillamine on circulating protein complexes in rheumatoid arthritis and primary biliary cirrhosis.

Not immunosuppressive in conventional test systems, D-penicillamine causes minor reductions in Ig levels and occasionally induces IgA deficiency. Rather limited evidence indicates actual decline in immune complexes; more data show reductions in levels of 9S IgG and alpha1-antitrypsin-IgA complexes. On the other hand, a number of instances of toxic reactions are most readily explained on the basis of autoimmunization. Changes in redox equilibrium, haptenization, and influence on T cell function are possible mechanisms.

Antibodies, Antinuclear↗
PubMed1996

Identification, quantitation, and purification of a 36 kDa circulating protein associated with active pars planitis.

PURPOSE: To establish a correlation between the presence of a 36 kDa protein in the blood of patients with pars planitis and to characterize and purify this protein. METHODS: Blood samples were obtained from patients with pars planitis and other types of uveitis and from various controls. Samples were treated with polyethelene glycol and protein A and were analyzed on 10% SDS-PAGE for the presence of a 36 kDa protein. Quantitative estimation of the level of this protein was determined by densitometric tracing of the stained gels. Polyclonal antibodies were raised by immunizing New Zealand White rabbits with a mixture of the gel fragment containing the 36 kDa protein (p-36) and complete Freund's adjuvant. These antibodies were used in the immunoaffinity purification of this protein. RESULTS: The levels of p-36 were sixfold to eightfold higher in 81% of the patients with active pars planitis than in controls (P < 0.05). Furthermore, the levels of this protein correlated with disease activity. A partial amino terminal sequence analysis revealed that p-36 may be a novel protein. It has been purified from the patient's blood using affinity chromatography. CONCLUSIONS: A 36 kDa protein (p-36) is found in elevated concentrations in the blood of many patients with active pars planitis. Its putative role in the etiopathogenesis of pars planitis is unknown.

Amino Acid Sequence↗
PubMed1984

[Effect of various antibiotics on the circulation of proteins between the blood and lymph in macro-organisms].

The effect of tetracycline, amphotericin B and kefzol on distribution of some proteins between the blood and lymph of the thoracic duct was studied on rabbits. Tetracycline was injected intramuscularly in the form of hydrochloride dissolved in 2% novocain in a dose of 25 mg/kg once or daily for 7 and 20 days. Kefzol (sodium cephazolin) was injected intramuscularly in a single dose of 100 mg/kg. Amphotericin B was injected intravenously in a dose of 1000 Units/kg once or for 5 days. The lymph samples were collected from the thoracic duct of rabbits treated with single doses of the antibiotics 1 and 24 hours after their injection. When the animals were treated with the antibiotics repeatedly the lymph samples were collected 24 hours after the last injection. The level of the total protein and the ratio of the protein fractions, i. e. albumins, alpha 1-, alpha 2-, beta- and gamma-globulins in the lymph and blood serum were determined. On the basis of these findings the protein coefficient (albumin/globulin) of the lymph and blood, the coefficients of the protein permeability of the blood vessels (R) and the constants of selective permeability of the blood capillaries (S) were calculated. It was shown that the shifts in the protein circulation between the blood and lymph had mainly the same trends independent of the antibiotics used and their retention time in the host. A significant decrease in the permeability of the blood vessel walls in respect to the total protein and gamma-globulins and a marked increase in their selectivity in passing of the protein molecules of different size were observed in all cases.

Amphotericin B↗
PubMed2000

Characterization of transgenic mice that secrete functional human protein C inhibitor into the circulation.

Protein C inhibitor (PCI) is a heparin binding serine protease inhibitor in plasma, which exerts procoagulant activity by inhibiting thrombomodulin-bound thrombin or activated protein C (APC). Since the role of PCI in vivo is largely unknown we generated genetically modified mice with expression of human PCI mRNA in hepatocytes only. Three transgenic lines have been characterized. Transgenic mice did not show gross developmental abnormalities. Two lines showed a pericentral and one line showed a periportal expression pattern of human PCI mRNA in the liver. Genetically modified mice secreted a functional transgenic protein into the circulation (3-5 microg/ml plasma in heterozygous mice and 10 microg/ml in homozygous mice), which inhibited human APC activity in the presence of heparin. Interestingly, transgenic mice in which human PCI was expressed periportally in the liver had the highest specific activity. Endogenous mouse PCI mRNA could only be detected in the male and female reproductive system, but not in the liver, indicating that endogenous PCI levels in the circulation are low or even absent in mice. These results demonstrate that the human PCI transgenic mice are a suitable model for studying the in vivo role of PCI in blood coagulation.

Animals↗
PubMed2006

Soluble thrombomodulin is antithrombotic in the presence of neutralising antibodies to protein C and reduces circulating activated protein C levels in primates.

We studied whether there was a relationship between the anticoagulant effects of recombinant human soluble thrombomodulin (rhsTM) and activation of protein C in a primate model of acute vascular graft thrombosis in 11 baboons (Papio species). Baboons were pretreated with 0.1, 1 and 5 mg/kg of rhsTM, with or without co-injection of a neutralising monoclonal antibody to protein C (HPC4) in the 1 mg/kg rhsTM group. Subsequently, thrombogenic polyester grafts were deployed for 3 h into chronic exteriorised arteriovenous shunts. Thrombus growth in the graft, plasma-activated protein C (APC) levels, coagulation and thrombosis markers were determined. In untreated baboons, baseline circulating APC levels more than doubled and graft thrombi propagated until reaching equilibrium in about 1 h. Treatment with rhsTM reduced thrombus propagation rates, prolonged the clotting and bleeding times, decreased thrombin-antithrombin complex, beta-thromboglobulin and fibrinopeptide A levels, and, surprisingly, also decreased systemic APC levels, in a dose-dependent manner. In the presence of HPC4 antibody to inhibit APC generation, the acute antithrombotic activity of rhsTM on graft thromboses was not attenuated for up to 80 min, but sustained thrombus accumulation was observed over a 180-min period. These findings suggest that, in contrast to the prevailing hypotheses, the primary antithrombotic activity of rhsTM is independent of protein C, at least in this primate model. Direct inhibition of thrombin's prothrombotic activity upon complex formation with rhsTM might explain the molecular mechanism of the observed antithrombotic effect.

Animals↗
PubMed2004

Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk.

Endothelial cell protein C receptor (EPCR) enhances the generation of activated protein C (APC) by the thrombin-thrombomodulin complex. A soluble form of EPCR (sEPCR), which is generated by metalloprotease activity, is present in plasma. The distribution of sEPCR levels in healthy populations is bimodal. Previously, we described two polymorphisms in exon 4 of the EPCR gene, 4600A/G that encodes the substitution of Ser219 by Gly in the transmembrane region of EPCR and 4678G/C in the 3'-UT region. The aim of this study was to investigate the relationship between these two polymorphisms and plasma sEPCR and APC levels and risk of venous thrombosis. We genotyped 401 healthy controls from the Spanish population and measured their plasma sEPCR and APC levels. Carriers of the 4600AG genotype had significantly higher sEPCR levels than those with the AA genotype, while the 4678CC genotype was associated, to a lesser extent, with elevated APC levels. To assess the effect of these polymorphisms on the risk of thrombosis, we genotyped 405 patients with venous thromboembolism. The frequency of the 4600AG genotype was very similar in patients and controls (p=0.975), whereas the 4678CC genotype was significantly more frequent in controls than in patients (p=0.008). In multivariate analysis, carriers of the 4678CC genotype had a decreased risk of thrombosis (OR=0.61, p=0.009). These data indicate that individuals carrying the 4600AG genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism.

Adult↗
PubMed1981

Placental protein 5: circulating levels in twin pregnancy and some observations on the analysis of biochemical data from multiple pregnancy.

Blood was collected from 344 subjects with singleton pregnancy between 28 and 40 wk gestation, together with 70 samples from 24 subjects with twin pregnancy of comparable gestation. Circulating placental protein 5 (PP5) in singleton pregnancy rose from a median of 26 microgram/l at 28 wk to reach a plateau with a median of 38 microgram/l at 36 wk. The median PP5 levels in twin pregnancy were 50 microgram/l at 28 wk rising to 65 microgram/l at 38 wk. The ratio of the medians of PP5 levels in twin and singleton pregnancies fell from 1.94 at 28 wk to 1.62 at 38 wk. An "action line' for low levels of PP5 in twin pregnancy was defined by applying a multiple of the median for twin pregnancy.

Analysis of Variance↗
PubMed1990

A circulating exogenous protein can enter enteric nervous tissue in the rat.

Previous studies of the permeation of circulating protein tracers yielded conflicting results in the enteric nervous system. We show that within 5 min of intravenous injection, horseradish peroxidase (HRP) enters all the extracellular spaces of the ganglia and connecting strands of the submucous and myenteric plexuses of the rat's small intestine, including the clefts between neuroglial cells and neurons. The tracer is still there after 10 min, but is nearly all gone 30 min after injection. Enteric neurons, like others with somata in peripheral ganglia, are therefore probably accessible to plasma proteins and to substances with smaller molecules that are protein-bound when circulating in the blood.

Animals↗
PubMed1985

Sequential changes in circulating total protein and albumin masses after abdominal vascular surgery.

Sequential changes in total circulating protein (TCP) and total circulating albumin (TCA) masses after different blood replacement regimens were investigated in a prospective study involving 40 patients undergoing reconstructive abdominal aortic surgery. Group I (13 patients) had 80 gm of albumin during operation and 60 gm of albumin during the following 3 days. Blood loss was replaced milliliter for milliliter by whole blood. Group II (14 patients) had the same blood substitution but no albumin. In group III (13 patients), 800 ml of blood loss was replaced by salt water. Maximum decrease in TCP (group II: 17%, group III: 29%) was found 4 hours after the operation. On postoperative day 1, protein mobilization to plasma equalling 10% of TCP had occurred. On day 4, TCP and plasma colloid osmotic pressure had not changed in group I, indicating an unchanged TCA/TCP ratio. In groups II and III, a significant decrease in TCP was followed by complete recovery of TCP. This also entailed a decrease in the TCA/TCP ratio, indicating an enhanced synthesis of acute-phase proteins. Based on these findings, a depression of globulin synthesis by supplemental albumin administration is proposed.

Aorta, Abdominal↗
PubMed1984

Levels of immunoreactive aldolase C, creatine kinase-BB, neuronal and non-neuronal enolase, and 14-3-3 protein in circulating human blood cells.

Five proteins found in the human nervous system have been measured by radioimmunoassay in human red cells, platelets, and lymphocytes. Two neuronal proteins (neurone-specific enolase and 14-3-3 protein) occur in platelets at levels equivalent to their concentration in brain, and in erythrocytes at levels approximately 10% of the level in brain. Two proteins characteristic of astrocytes in the cerebral cortex (creatine kinase BB and aldolase C) occur at low levels in platelets and are virtually undetectable in erythrocytes and lymphocytes. The more widely distributed non-neuronal enolase is present in erythrocytes, platelets and lymphocytes. The neurone-specific enolase and 14-3-3 protein immunoreactivities found in circulating blood cells have been characterised in terms of molecular mass, charge, and dilution characteristics in the respective radioimmunoassay and in each case appears to represent the intact protein. Controlled lysis of erythrocytes releases neurone-specific enolase and 14-3-3 protein in parallel with haemoglobin. The occurrence of brain proteins in circulating blood cells (which appears to be a species-dependent phenomenon) has the practical clinical consequence that minor degrees of especially red cell lysis can produce high serum levels of immunoreactivity. This represents a pitfall in the measurement of these proteins in serum as tumour markers or as indices of damage to the central nervous system.

14-3-3 Proteins↗
PubMedDate not supplied

[Intensity of protein synthesis in different sections of the brain of rats after arrest of systemic circulation].

Protein synthesis intensity in the tissue of various portions of the brain of rats pre-exposed to 10 min systemic circulation arrest was studied with the use of 3H-leucin, a protein synthesis labeled precursor, and compared with that in intact animals. Protein synthesis intensity in the brain of resuscitated animals was found to correlate with the degree of their neurologic status recovery. In rapidly recovering animals a significant intensification of protein synthesis is observed on day 4 after resuscitation in the sensorimotor cortex, hippocampus, and cerebellum. In the animals whose resuscitation was not so smooth this process develops only in the hippocampus and the intermedial and lateral portions of the cerebellum. In patients with disturbed neurologic status protein synthesis intensity was unchanged in all the examined portions of the brain. The authors suggest that protein synthesis activation phase is an obligatory stage in full-value neurologic recovery of resuscitated animals.

Animals↗
PubMed1985

Eosinophil involvement in rheumatoid arthritis as reflected by elevated serum levels of eosinophil cationic protein.

Circulating levels of eosinophil cationic protein (ECP), an eosinophil specific granule protein, and numbers of peripheral eosinophils were determined in 42 patients with rheumatoid arthritis. At the time of the investigation the patients were without drug treatment. They had normal blood counts of eosinophils but on average a five-fold increase of the serum ECP values compared with healthy subjects. The intracellular content of ECP in eosinophils isolated from 14 patients was normal. High serum levels of ECP were particularly observed in patients with a disease of rather short duration but with a more aggressive course. Other factors associated with high ECP values were blood eosinophil counts in the upper normal range, high rheumatoid factor titre and increased inflammatory activity as defined by elevated serum haptoglobin and blood platelet counts. No relation was found between serum ECP and circulating immune complexes or serum total IgE. Synovial fluids obtained from 14 patients with rheumatoid arthritis contained very high concentration of ECP; on average nine times higher than those in the circulation of the patients. During corticosteroid but not NSAID therapy serum ECP decreased on average about 50% compared with pre-treatment values. Although eosinophils are not a notable feature of the synovial membrane infiltrate or cellular joint exudate, data obtained indirectly indicates their participation in the inflammatory reaction in RA.

Anti-Inflammatory Agents↗
PubMed1994

Ferric iron potentiates cell depolarization by a circulating shock protein.

OBJECTIVE: To determine whether or nor iron affects the depolarizing activity of a circulating shock protein that appears in plasma after hemorrhage. DESIGN: Randomized design. SETTING: University laboratory. ANIMALS: Healthy male Sprague-Dawley rats weighing 300 to 400 g with femoral artery and vein cannulas placed 4 days before hemorrhage. INTERVENTION: A 20-mL/kg hemorrhage and plasma collection. MAIN OUTCOME MEASURES: Depolarizing activity was measured as the increased fluorescence of an oxonol dye in the presence of Fe3+, Fe2+, or the iron chelator deferoxamine mesylate and was titrated against increasing concentrations of circulating shock protein or iron. Circulating shock protein was derived from plasma and was purified in two steps: stepwise ammonium sulfate precipitation followed by denaturing ion-exchange chromatography and refolding. RESULTS: At physiologic concentrations, Fe3+ but not Fe2+ potentiated the depolarizing activity of plasma after ammonium sulfate. Addition of deferoxamine abolished activity. Denaturing chromatography removed nearly all the depolarizing activity; however, Fe3+ restored activity to this fraction. Fe3+ increased total activity and decreased the concentration at which 50% activity was observed. CONCLUSION: These data indicate that physiologic concentrations of Fe3+ may act to modulate the depolarizing activity of circulating shock protein that in turn mediates the intracellular accumulation of salt and water in shock.

Animals↗
PubMed2001

Protein Z circulates in plasma in a complex with protein Z-dependent protease inhibitor.

Protein Z (PZ) is a vitamin K-dependent plasma protein that forms a Ca++-dependent complex with factor Xa at phospholipid surfaces. This interaction between PZ and factor Xa enhances by >1,000-fold the inhibition of factor Xa by the serpin called protein Z-dependent protease inhibitor (ZPI). These experiments show that PZ also binds ZPI in a process that does not require Ca++ or phospholipids. In pooled normal plasma, which contains excess ZPI relative to PZ, all the PZ appears to be bound in a complex with ZPI. The binding of PZ to ZPI reduces the rate and extent of factor XIa inhibition produced by ZPI. During the course of these studies, it was noted that a PZ purification procedure, that included NaSCN (2.0 M) elution of PZ from an immunoaffinity column, produced aggregated, inactive forms of PZ.

Blood Protein Electrophoresis↗
PubMed2025

Circulating inflammatory proteins as causal drivers and therapeutic targets in asthma: insights from genetic and pathway-based analyses.

OBJECTIVE: To identify circulating inflammatory proteins with potential causal roles in asthma development through integrated genetic and pathway-based analyses, and to evaluate their potential as therapeutic targets. METHODS: We used genetically anchored instrumental variables from 180 protein quantitative trait loci (pQTLs) to assess the causal effects of 91 circulating inflammatory proteins on asthma risk, using large-scale GWAS datasets. Analytical robustness was evaluated through pleiotropy and heterogeneity testing. Functional enrichment and literature-based pathway analyses were performed to support biological plausibility and validate findings. RESULTS: Four proteins showed significant causal effects on asthma: CCL19 and LIFR were protective (OR = 0.89 and 0.91, p&#x2009;&#x2264;&#x2009;6.8E-03), while ARTN and IL6 were associated with increased risk (OR = 1.15 and 1.18, p&#x2009;&#x2264;&#x2009;1.1E-04). We also identified reverse causal effects of asthma on 11 cytokines, including MMP10, TGFB1, IL33, and IL18R1. Most of these proteins were enriched in pathways related to cytokine signaling and immune response (p&#x2009;<&#x2009;0.001). All identified proteins had prior literature support linking them to asthma or airway inflammation. CONCLUSIONS: Our findings highlight a subset of circulating inflammatory proteins that are likely causal in asthma pathogenesis and may serve as promising targets for therapeutic intervention. These results offer novel insights into the immunological mechanisms underlying asthma and support the utility of genetic causal inference in target prioritization.

Asthma↗