Serum CA 19–9 levels as a diagnostic marker in cystic fibrosis patients with borderline sweat tests

Abstract. Patients with normal or borderline sweat tests present a diagnostic challenge. In spite of the availability of genetic analysis and measurement of nasal potential difference, there is still uncertainty in diagnosing cystic fibrosis in some patients. CA 19–9 is a tumor-associated antigen whose levels were previously found to be elevated in some cystic fibrosis patients. We investigated whether serum CA 19–9 levels can contribute to establishing the diagnosis of cystic fibrosis in patients with a borderline sweat test, and evaluated the influence of different clinical variables on CA 19–9 levels. Serum CA 19–9 levels were measured in 82 cystic fibrosis patients grouped according to their genotype and in 38 healthy individuals. Group A included 50 patients who carried two mutations previously found to be associated with a pathological sweat test and pancreatic insufficiency (F508, W1282X, G542X, N1303K, and S549R). Group B included 13 compound heterozygote cystic fibrosis patients who carried one mutation known to cause mild disease with a borderline or normal sweat test and pancreatic sufficiency (3849+10kb CT, 5T). Group C included 38 normal controls. Nineteen cystic fibrosis patients carried at least one unidentified mutation. An association between CA 19–9 levels and age, pulmonary function, pancreatic status, sweat chloride, previous pancreatitis, serum lipase, meconium ileus, distal intestinal obstruction, liver disease, and diabetes was investigated. The distribution of CA 19–9 levels was significantly different between the three groups (p<0.01); high CA 19–9 levels were found in 60% (30/50) of group Apatients and in 46.6% (6/13) of group B patients, but in only 5.2% (2/38) of the controls. CA 19–9 levels were inversely related to forced expiratory volume in 1 s, while no association was found with the other clinical parameters examined. Our findings suggest that the serum CA 19–9 in cystic fibrosis patients originates in the respiratory system, and has a useful ancillary role, particularly when diagnostic uncertainty exists. Hence, the diagnosis of cystic fibrosis should be considered in patients with borderline sweat tests and high CA 19–9 levels, but normal levels do not exclude cystic fibrosis.     

Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1

Information about the stage of liver fibrosis is important for managing patients with chronic hepatitis C (CHC). The aim of this study was to evaluate 12 plasma markers for differentiating no/mild liver fibrosis from cirrhosis among patients with CHC genotype 1. Transient elastography was used to assess the stage of fibrosis for the patients included in the study. Forty patients were included (21 cirrhotic). Plasma levels of tumor necrosis factor-α (TNF-α), interleukin 8 (IL-8), interferon-γ inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), soluble urokinase-type plasminogen activator (suPAR), monokine induced by γ-interferon (MIG), human hepatocyte growth factor (HGF), insulin, interleukin 6 (IL-6), interleukin 1-β (IL-1β), leptin, and nerve growth factor (NGF) were analyzed. Concentrations of TNF-α (median 15.0 vs. 25.1 pg/ml, area under the receiver operating characteristic curve [AUC] 0.91), IL-8 (48.7 vs. 103.3 pg/ml, AUC 0.85), IP-10 (176 vs. 566 pg/ml, AUC 0.83), MCP-1 (449 vs. 735 pg/ml, AUC 0.78), suPAR (3.5 vs. 5.2 ng/ml, AUC 0.78), MIG (100 vs. 152 pg/ml, AUC 0.75), and HGF (3.69 vs. 5.58 ng/ml, AUC 0.71) were significantly higher in patients with cirrhosis. In conclusion, several of the investigated markers showed promise for differentiating cirrhosis from no/mild fibrosis among patients with CHC genotype 1.     

Macrophage Inflammatory Protein-1α in Term and Preterm Parturtition: Effect of Microbial Invasion of the Amniotic Cavity

PROBLEM: This study was conducted to determine whether: (1) gestational age, parturition, and microbial invasion of the amniotic cavity (MIAC) are associated with changes in amniotic fluid concentrations of immunoreactive macrophage inflammatory protein-1α; (2) amniotic fluid concentrations of macrophage inflammatory protein-1α are correlated with the white blood cell count and the concentrations of interleukin-8 in amniotic fluid. METHOD: Amniotic fluid was retrieved by amniocentesis from 126 patients; 54 women with preterm labor and intact membranes (no MIAC-delivery at term, N = 21; no MIAC-preterm delivery, N = 16; MIAC-preterm delivery, N = 17); 62 patients at term (no labor, N = 19; labor-no MIAC, N = 20; labor-MIAC, N = 23); and 10 patients in the midtrimester of pregnancy. Amniotic fluid was cultured for aerobic, anaerobic and Mycoplasma species. Determinations of amniotic fluid macrophage inflammatory protein-1α and interleukin-8 were performed with immunoassays validated for amniotic fluid (sensitivity: 14.2 pg/ml and 0.3 ng/ml, respectively). Kruskal-Wallis analysis of variance (ANOVA) for censored data, Mann-Whitney U test and Spearman's rank correlation were performed for analysis. RESULTS: 1) Amniotic fluid macrophage inflammatory protein-1α was present in only 31.0% (9/29) of patients not in labor (midtrimester and term). 2) Patients with preterm labor and MIAC had higher amniotic fluid concentrations of macrophage inflammatory protein-1α than those without MIAC (no MIAC-delivery at term: median 0.0 pg/ml, range 0.0–221.2; no MIAC-preterm delivery: median 37.4 pg/ml, range 0.0–494.6; MIAC-preterm delivery: median 7171.0 pg/ml, range 402.5–37994.0; P<0.00001). 3) Among patients at term, MIAC was associated with higher concentrations of amniotic fluid macrophage inflammatory protein-1α than patients without MIAC (no labor: median 0.0 pg/ml, range 0.0–25.6; labor-no MIAC: median 16.7 pg/ml, range 0.0–161.6; labor-MIAC: median 103.8 pg/ ml, range 0.0–4349.0, P<0.001). 4) Among patients in preterm labor, a strong correlation was found between amniotic fluid concentrations of macrophage inflammatory protein-1α and interleukin-8 (r = 0.9, P<0.00001) and between amniotic fluid macrophage inflammatory protein-1α concentrations and amniotic fluid white blood cell count (r = 0.6, P<0.0001). CONCLUSIONS: (1) Macrophage inflammatory protein-1α is undetectable in most amniotic fluid samples from patients in the midtrimester of pregnancy and at term not in labor. (2) Microbial invasion of the amniotic cavity is associated with increased concentrations of immunoreactive amniotic fluid macrophage inflammatory protein-1α in both term and preterm gestations. (3) Amniotic fluid macrophage inflammatory protein-1α concentrations significantly correlate with interleukin-8 levels and white blood cell count in amniotic fluid. Our data strongly suggest a role for macrophage inflammatory protein-1α in the mechanisms responsible for the recruitment of leukocytes into the amniotic cavity during the course of intrauterine infection.     

Correlations of Urinary Biomarkers,TNF-Like Weak Inducer of Apoptosis (TWEAK), Osteoprotegerin (OPG), Monocyte Chemoattractant Protein-1 (MCP-1), and IL-8 with Lupus Nephritis

Objective  

This case-controlled study was designed to correlate urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) levels, with renal involvement in a cohort of systemic lupus erythematosus (SLE) patients to examine their diagnostic performance.     

The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508)

BACKGROUND AND METHODS. Both the clinical manifestations of cystic fibrosis and the genotypes of patients are heterogeneous, but the associations between the two are not known. We therefore studied blood samples from 293 patients with cystic fibrosis for the presence of the most common disease-causing mutation (delta F508) on chromosome 7 and compared the results with the clinical manifestations of the disease. RESULTS. The prevalence of the delta F508 allele in the cohort was 71 percent; 52 percent of the patients were homozygous for the mutation, 40 percent were heterozygous, and 8 percent had other, undefined mutations. The patients who were homozygous for the mutation had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency; pancreatic insufficiency was present in 99 percent of the homozygous patients, but in 72 percent of the heterozygous patients and only 36 percent of the patients with other genotypes. The patients with pancreatic insufficiency in all three genotype groups had similar clinical characteristics, reflected by an early age at diagnosis, similar sweat chloride values at diagnosis, similar severity of pulmonary disease, and similar percentiles for weight. In contrast, the patients in the heterozygous-genotype and other-genotype groups who did not have pancreatic insufficiency were older and had milder disease. They had lower sweat chloride values at diagnosis, normal nutritional status, and better pulmonary function after adjustment for age. CONCLUSIONS. The variable clinical course in patients with cystic fibrosis can be attributed at least in part to specific genotypes at the locus of the cystic fibrosis gene.     

Chemokine profiles in the cerebrospinal fluid (CSF) during the course of pyogenic and tuberculous meningitis

The concentrations of the chemokines IL-8, monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) were measured in 120 CSF samples from 23 patients with pyogenic meningitis and from 11 patients with tuberculous meningitis (TBM) and in 10 CSF from subjects with non-infectious neurological diseases. The chemokine concentrations in patients with meningitis were significantly higher than in control subjects (P < 0.0001). The highest CSF levels were found for IL-8 (median 2917 pg/ml) and MCP-1 (median 2557 pg/ml), whereas those of MIP-1α were less significantly elevated (median 24 pg/ml) (P < 0.0001). Patients with pyogenic meningitis had higher levels of IL-8 and MCP-1 than those with TBM (P < 0.0001). In serial samples from patients with pyogenic meningitis IL-8 levels declined before MCP-1 and MIP-α. In the case of TBM, IL-8, MCP-1 and MIP-1α decreased more gradually during treatment and were detectable in the CSF for several weeks, without any characteristic time course of elimination. These data indicate that patients with pyogenic meningitis and TBM show different chemokine profiles in CSF. The distinct chemokine pattern could be responsible for a differential attraction and activation of leucocytes in the CSF which is reflected in differences in the inflammatory response and clinical course of pyogenic meningitis and TBM.     

Soluble interleukin-2 receptor and interleukin-8 plasma levels during and after cardiopulmonary bypass: correlations with creatine kinase and creatine kinase MB

In this study, soluble receptor of interleukin-2, interleukin-8, creatine kinase, and creatine kinase MB isoenzyme levels were determined serially before, during, and after cardiopulmonary bypass in blood samples of 24 patients. Interleukin-2 receptor levels were 683±80 U/ml in the preoperative period and 640±60 U/ml during hyperthermia. Subsequently, these levels increased significantly at the end of the procedure (791±70 U/ml, P<0.01), remaining elevated 1 h after (882±92 U/ml, P<0.001) and reaching peak values 24 h postoperatively (1,752±200 U/ml, P<0.001). Preoperative plasma values of interleukin-8 were 230±43 pg/ml. Interleukin-8 concentrations were 185±25 pg/ml during hypothermia. The peak interleukin-8 levels were observed at the end of cardiopulmonary bypasss (754±94 pg/ml, P<0.001) and tended to decrease 1 h after the procedure (643±76 pg/ml, P<0.001), declining to preoperative values, 24 h postoperatively (273±41 pg/ml). Interleukin-2 receptor levels correlated well with creatine kinase levels during the procedure. Furhtermore, creatine kinase MB levels were correlated with interleukin-2 receptor values only at the end and 1 h after completion of cardiopulmonary bypass. We concluded that interleukin-8 and Interleukin-2 receptor levels are elevated after cardiopulmonary bypass and may contribute to myocardial injury as reflected by increased levels of creatine kinase and creatine kinase MB and correlations between interleukin-2 receptor and both creatine kinase and creatine kinase MB levels. Received: 17 July 2000 / Accepted: 12 February 2001     

Pseudomonas Pyocyanin Increases Interleukin-8 Expression by Human Airway Epithelial Cells

Pseudomonas aeruginosa, an opportunistic human pathogen, causes acute pneumonia in patients with hospital-acquired infections and is commonly associated with chronic lung disease in individuals with cystic fibrosis (CF). Evidence suggests that the pathophysiological effects of P. aeruginosa are mediated in part by virulence factors secreted by the bacterium. Among these factors is pyocyanin, a redox active compound that increases intracellular oxidant stress. We find that pyocyanin increases release of interleukin-8 (IL-8) by both normal and CF airway epithelial cell lines and by primary airway epithelial cells. Moreover, pyocyanin synergizes with the inflammatory cytokines tumor necrosis factor alpha and IL-1α. RNase protection assays indicate that increased IL-8 release is accompanied by increased levels of IL-8 mRNA. The antioxidant n-acetyl cysteine, general inhibitors of protein tyrosine kinases, and specific inhibitors of mitogen-activated protein kinases diminish pyocyanin-dependent increases in IL-8 release. Conversely, inhibitors of protein kinases C (PKC) and PKA have no effect. In contrast to its effects on IL-8 expression, pyocyanin inhibits cytokine-dependent expression of the monocyte/macrophage/T-cell chemokine RANTES. Increased release of IL-8, a potent neutrophil chemoattractant, in response to pyocyanin could contribute to the marked infiltration of neutrophils and subsequent neutrophil-mediated tissue damage that are observed in Pseudomonas-associated lung disease.     

Loxosceles Spider Venom Induces the Production of α and β Chemokines: Implications for the Pathogenesis of Dermonecrotic Arachnidism

Bites from the brown recluse spider and other Loxosceles arachnids result in dermonecrotic skin lesions. Neutrophils (PMN) are essential to the development of Loxosceles-induced skin lesions, but paradoxically, in vitro PMN activation is inhibited by direct exposure to Loxosceles venom. Neutrophil activation occurs in response to a myriad of soluble mediators that include members of both the and chemokine families. Because arachnid envenomation results in the exposure of several different cell types to venom, we investigated venom-induced expression of and chemokines in both endothelial cells (human umbilical vein; HUVEC) and epithelial cells (A549 pneumocytes). Chemokine-specific capture enzyme immunoassays (EIA) were used to measure Loxosceles deserta venom-induced chemokines: interleukin-8 (IL-8), growth-related oncogene-alpha (GRO-), and chemokines: monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in cell-free conditioned media from HUVEC and A549 cell monolayers. Exposure of HUVECs (8 h) to Loxosceles venom resulted in the production of IL-8 (5.2 ± 1.30 ng/ml), MCP-1 (1.44 ± 0.11 ng/ml) and GRO- (1.97 ± 0.15 ng/ml) in a dose and time-dependent manner. Exposure of A549 cell monolayers to venom resulted in IL-8 (7.74 ± 0.30 ng/ml), and MCP-1 (2.61 ± 0.31 ng/ml), but neither GRO- nor RANTES accumulated during an 8-hour incubation period. Chemokines accumulated in a venom dose and time-dependent manner. Neither cell type secreted RANTES in response to Loxosceles venom. These data indicate that Loxosceles spider venom is a potent inducer of and chemokines in both endothelial and epithelial cell types. Based on the established roles of IL-8, MCP-1, and GRO-, in inflammation, these observations have relevance to the pathophysiology of Loxosceles-Induced dermonecrosis.     

Interrelationships between interleukin (IL)-1, IL-6 and IL-8 in synovial fluid of various arthropathies

High levels of many cytokines, including interleukin (IL)-1, IL-6 and IL-8, were found in various arthropathies suggesting that they play a role in the pathogenesis of disease, although their relationship with the type and activity of disease is still not clear. The synovial fluid (SF) of 24 patients with rheumatoid arthritis (RA), 19 with psoriatic arthritis (PA) and 33 with osteoarthritis (OA) was analyzed for IL-1, IL-6 and IL-8. The highest concentration of the three cytokines was found in the SF of RA. IL- detectable levels (>-20 pg/ml) were observed in 8/24 (33.3%) patients with RA, in one patient with PA but in no patient with OA.IL-6 (mean±SD) (1610.37±1781.65 pg/ml) was higher in RA than in PA (672.47±867.40 pg/ml,p=0.043) and OA (89.45±120.52 pg/ml,p=0.0001). IL-8 (1042.72±698.64 pg/ml) was higher in RA than in PA (660.36±625.11 pg/ml,p=0.03) and OA (89.9±45.88 pg/ml,p=0.0001). A correlation between IL-1, IL-6 and IL-8 was found in RA. In all patients a correlation between IL-6 and IL-8 levels was found; moreover, these two cytokines were associated with SF indices of inflammation, such as white blood cells (WBC) count and total protein (TP) concentration.Out findings suggest that these interrelationships play a role in the evolution of more severe erosive arthropathy such as RA.     

ANF-Konzentrationen und Drücke im kleinen Kreislauf unter Belastung vor und nach Koronardilatation

Summary According to several reports of close correlations between pulmonary artery pressure and ANF plasma levels it would be convenient to replace invasive pressure monitoring by ANF determination.Mean pulmonary artery and right atrial pressures and pulmonary artery as well as peripheral venous ANF plasma concentrations were measured in 24 patients before and after coronary angioplasty (PTCA) continuously at rest and during exercise: At rest, both pressure and ANF-values remained unchanged before and after PTCA. At exercise, there was a decrease of mean pulmonary artery pressure (from 41.3±8.6 to 31.5±7.4 mmHg,p<0.001), mean right atrial pressure (from 11.9±3.0 to 9.0±2.3 mmHg,p< 0.001), pulmonary artery (282.5±191.0 to 207.3±157.2 pg/ml,p<0.05) and peripheral venous (112.7±48.0 to 97.1±53.2 pg/ml, n.s.) ANF concentration after PTCA. We found no correlation between PTCA-induced changes of right arterial pressures and ANF concentrations, while changes of pulmonary artery pressures were significantly correlated to changes of peripheral venous (r=0.79,p<0.001) as well as pulmonary artery (r=0.59,p<0.01) ANF concentrations at exercise. In 6 of the 24 patients, however there was an inverse relationship between changes of pulmonary artery pressures and ANF concentrations. — Our data demonstrate a significant correlation between changes of ANF plasma level and pulmonary artery pressure values at exercise after PTCA. In the individual case however invasive pressure monitoring cannot be replaced by determination of ANF plasma levels.

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Abkürzungsverzeichnis ANF Atrialer natriuretischer Faktor - PTCA Perkutane transluminale Koronarangioplastie - PPa mittlerer pulmonalarterieller Druck - PPc mittlerer pulmonalcapillärer Druck - PRA mittlerer rechtsatrialer Druck Herrn Prof. Dr. med F. Scheler zum 65. Geburtstag gewidmet     

Effect of anticonvulsant drugs on interleukins-1, -2 and -6 and monocyte chemoattractant protein-1

In order to evaluate whether treatment with valproic acid or carbamazepine can modify interleukins and monocyte chemoattractant protein-1, we studied 40 epileptic children and adolescents. We evaluated the patients before and after 1 year of therapy. At the end of follow-up, the patients showed a significant increase of the production of interleukin-1α, interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1; interleukin-2 production was significantly higher only in patients receiving carbamazepine. In conclusion, antiepileptic drugs can influence the immune system by modifying interleukin and chemokine concentrations; these changes seem to be independent of the serum concentrations of these drugs. Received: 16 February 2001 / Accepted: 18 September 2001     

Vitamin B12 and folic acid deficiency in chronic pancreatitis: a relevant disorder?

Summary Vitamin B12 malabsorption was reported earlier to occur in patients with exocrine pancreatic insufficiency, and pancreatic extracts were shown to improve the absorption of vitamin B12. We investigated serum levels of vitamin B12 and serum folate in patients with chronic pancreatitis and different degrees of pancreatic insufficiency.137 patients (84 males, 53 females, age 34–72 years) with chronic pancreatitis (C.P.) were included in the study. 123 of 137 (89.8%) patients had a pathologic pancreatic function test result, classified into mild (n=24), moderate (n=61) or severe (n=38) insufficiency. The normal range of serum vitamin B12 and folic acid was established in 58 healthy controls and was found to be 190–1020 pg/ml for serum vitamin B12 and 2.4–16.1 ng/ml for folic acid. 7 patients (5.7%) with C.P. had vitamin B12 serum levels below 190 pg/ml; 4 of these had severe and 3 had mild or moderate exocrine pancreatic insufficiency. However there was no overall correlation between the degree of pancreatic insufficiency and vitamin B12 values. Serum levels of Vitamin B12 were 512±48 pg/ml in mild, 493±52 pg/ml in moderate and 428±45 pg/ml in severe exocrine insufficiency. Serum folic acid below 2.4 ng/ml were present in 5 patients (3.6%). Folic acid serum levels were 8.34±0.76 ng/ml in mild, 6.34±0.52 ng/ml in moderate and 7.45±0.53 ng/ml in severe exocrine insufficiency. We conclude that vitamin B12 deficiency is a rare finding in chronic pancreatitis and does not strictly depend on the degree of exocrine pancreatic insufficiency. In clinical practice enzyme supplementation in patients with severe pancreatic insufficiency is obviously sufficient for normal vitamin B12 absorption. Folic acid deficiency is also unfrequently found in chronic pancreatitis.     

Plasma levels of atrial natriuretic peptide are raised in essential hypertension during low and high sodium intake

Summary Plasma levels of -human atrial natriuretic peptide (hANP) were measured in 17 patients with primary hypertension (11 females, 6 males, aged 22–61; blood pressure systolic 154±7 mmHg, diastolic 92±4 mmHg) and in 9 normotensive controls (4 males, 5 females, aged 20–71; blood pressure systolic 117±4 mmHg, diastolic 76±2 mmHg) during unrestricted sodium diet, at the 4th day of a low sodium intake (40–60 mEq/day) and at the 6th day of sodium loading (280–320 mEq/day) both after an overnight rest and after 4 h of upright posture. In the controls, plasma levels of hANP at 8:00 a.m. were lowered from 73±11 to 49±7 pg/ml during low sodium diet and increased to 128±37 pg/ml after high salt intake. Plasma ANP levels were significantly lower after 4 h of upright posture during unrestricted, low and high sodium intake. In the hypertensive group, plasma ANP levels were elevated during unrestricted diet (203±43 pg/ml), during the low sodium period (139±31 pg/ml), and after high sodium intake (267±63 pg/ml) compared to the controls. All levels were lowered by upright posture. The absolute decrease was more pronounced compared to the normotensives, the relative decline was similar in both groups. In the hypertensives, plasma ANP levels significantly correlate with systolic and diastolic blood pressure (r=0.468,r=0.448,P<0.05) and with urinary aldosterone during unrestricted diet (r=0.536,P<0.05). There was an inverse correlation between plasma ANP levels and plasma renin concentration during low and high sodium intake (r=–0.469,r=–0.496,P<0.05).These studies demonstrate raised circulating plasma ANP levels in patients with essential hypertension. The modulation of ANP by different sodium intake and by upright posture is maintained similar to the changes in plasma ANP in normotensive controls. Raised ANP levels in the hypertensives are correlated with low renin secretion and high aldosterone excretion. High ANP levels, therefore, might indicate sodium retention in essential hypertension.Abbreviation ANP atrial natriuretic peptide Supported by a grant from Ministerium für Wissenschaft und Forschung, NRW     

Differential expression of binding sites for chemokine RANTES on human T lymphocytes

The C-C chemokine RANTES, a T lymphocyte chemoattractant, is considered an important mediator of inflammation, allergy, and host defense against HIV-1 infection. In this study, we investigated the modulation of binding of RANTES to T lymphocytes. Human peripheral blood CD3+ T cells, when freshly isolated from buffy-coat blood, expressed a considerable number of high-affinity binding sites for RANTES. These cells also showed significant chemotactic migration in response to RANTES in vitro. After 6–15 h incubation at 37°C, the binding of RANTES, but not of macrophage inflammatory protein-1α (MIP-1α) or of monocyte chemotactic protein-3 (MCP-3), consistently increased. Scatchard analyses indicated that the number of binding sites for RANTES increased about threefold by 15 h without any change in the affinity. The increase in RANTES binding was no longer detected by 24 h. This increase in the specific binding was mainly attributable to CD4⁺ T cells and was not associated with increased chemotactic activity of these cells in response to RANTES. Incubation with anti-CD3 antibody for 15 h markedly reduced the binding capability of T cells for RANTES and was associated with decreased chemotactic activity. On the other hand, when T cells were incubated with interleukin-2 (IL-2) for 1 week, the specific binding for all three C-C chemokines, RANTES, MIP-1α, and MCP-3 was markedly increased in comparison to cells cultured in the absence of IL-2. These results suggest that the expression of binding sites on T cells for RANTES is differentially modulated, indicating the existence of novel receptors for RANTES that do not bind MIP-1α.     

Chemokines IL-8, GROα, MCP-1, IP-10, and Mig Are Sequentially and Differentially Expressed During Phase-Specific Infiltration of Leukocyte Subsets in Human Wound Healing

Healing of cutaneous wounds requires a complex integrated network of repair mechanisms, including the action of newly recruited leukocytes. Using a skin repair model in adult humans, we investigated the role chemokines play in sequential infiltration of leukocyte subsets during wound healing. At day 1 after injury, the C-X-C chemokines IL-8 and growth-related oncogene α are maximally expressed in the superficial wound bed and are spatially and temporally associated with neutrophil infiltration. IL-8 and growth-related oncogene α profiles also correlate with keratinocyte migration and subsequently subside after wound closure at day 4. Macrophage infiltration reaches the highest levels at day 2 and is paralleled by monocyte chemoattractant protein-1 mRNA expression in both the basal layer of the proliferative epidermis at the wound margins and mononuclear cells in the wound area. Other monocyte-attracting chemokines such as monocyte chemoattractant protein-3, macrophage inflammatory protein-1α and -1β, RANTES, and I309 are undetectable. At day 4, perivascular focal lymphocyte accumulation correlates with strong focal expression of the C-X-C chemokines Mig and IP-10. Our results suggest that a dynamic set of chemokines contributes to the spatially and temporally different infiltration of leukocyte subsets and thus integrates the inflammatory and reparative processes during wound repair.     

Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure

Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations were measured in patients with dialysis-dependent chronic renal failure and in patients with coronary artery disease exhibiting normal or elevated left ventricular end-diastolic pressure (LVEDP) (n = 30 each). Blood samples were obtained from the arterial line of the arteriovenous shunt before, 2 h after the beginning of, and at the end of hemodialysis in patients with chronic renal failure. In patients with coronary artery disease arterial blood samples were collected during cardiac catheterization. BNP and ANP concentrations were determined by radioimmunoassay after Sep Pak C₁₈ extraction. BNP and ANP concentrations decreased significantly (P < 0.001) during hemodialysis (BNP: 192.1 ± 24.9, 178.6 ± 23.0, 167.2 ± 21.8 pg/ml; ANP: 240.2 ± 28.7, 166.7 ± 21.3, 133.0 ± 15.5 pg/ml). The decrease in BNP plasma concentrations, however, was less marked than that in ANP plasma levels (BNP 13.5 ± 1.8%, ANP 40.2 ± 3.5%; P < 0.001). Plasma BNP and ANP concentrations were 10.7 ± 1.0 and 60.3 ± 4. 0 pg/ml in patients with normal LVEDP and 31.7 ± 3.6 and 118.3 ± 9.4 pg/ml in patients with elevated LVEDP. These data demonstrate that BNP and ANP levels are strongly elevated in patients with dialysis-dependent chronic renal failure compared to patients with normal LVEDP (BNP 15.6-fold, ANP 2.2-fold, after hemodialysis; P < 0.001 or elevated LVEDP (BNP 6.1-fold, ANP 2.0-fold, before hemodialysis; P < 0.001), and that the elevation in BNP concentrations was more pronounced than that in ANP plasma concentrations. The present results provide support that other factors than volume overload, for example, decreased renal clearance, are also involved in the elevationin BNP and ANP plasma levels in chronic renal failure. The stronger elevation in BNP concentrations in patients with chronic renal failure and in patients with elevated LVEDP and the less pronounced decrease during hemodialysis suggest a different regulation of BNP and ANP plasma concentrations.[/ p]Abbreviations ANP atrial natriuretic peptide - BNP brain natriuretic peptide - LVEDP left ventricular end-diastolic pressure Correspondence to: C. Haug     

Use of inflammatory molecules to predict the occurrence of fever in onco-hematological patients with neutropenia

Febrile neutropenia remains a frequent complication in onco-hematological patients, and changes in the circulating level of inflammatory molecules (IM) may precede the occurrence of fever. The present observational prospective study was carried out to evaluate the behavior of plasma tumor necrosis factor alpha (TNF-α), soluble TNF-α I and II receptors (sTNFRI and sTNFRII), monocyte chemoattractant protein-1 [MCP-1 or chemokine (c-c motif) ligand 2 (CCL2)], macrophage inflammatory protein-1α (MIP-1α or CCL3), eotaxin (CCL11), interleukin-8 (IL-8 or CXCL8), and interferon-inducible protein-10 (IP-10 or CXCL10) in 32 episodes of neutropenia in 26 onco-hematological patients. IM were tested on enrollment and 24-48 h before the onset of fever and within 24 h of the first occurrence of fever. Eight of 32 episodes of neutropenia did not present fever (control group) and the patients underwent IM tests on three different occasions. sTNFRI levels, measured a median of 11 h (1-15) before the onset of fever, were significantly higher in patients presenting fever during follow-up compared to controls (P = 0.02). Similar results were observed for sTNFRI and CCL2 levels (P = 0.04 for both) in non-transplanted patients. A cut-off of 1514 pg/mL for sTNFRI was able to discriminate between neutropenic patients with or without fever during follow-up, with 65% sensitivity, 87% specificity, and 93% positive predictive value. Measurement of the levels of plasma sTNFRI can be used to predict the occurrence of fever in neutropenic patients.