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Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR protein is known to acts as a chloride (Cl− ) channel expressed in the exocrine glands of several body systems where it also regulates other ion channels, including the epithelial sodium (Na+ ) channel (ENaC) that plays a key role in salt absorption. This function is crucial to the osmotic balance of the mucus and its viscosity. However, the pathophysiology of CF is more challenging than a mere dysregulation of epithelial ion transport, mainly resulting in impaired mucociliary clearance (MCC) with consecutive bronchiectasis and in exocrine pancreatic insufficiency. This review shows that the CFTR protein is not just a chloride channel. For a long time, research in CF has focused on abnormal Cl− and Na+ transport. Yet, the CFTR protein also regulates numerous other pathways, such as the transport of HCO3−, glutathione and thiocyanate, immune cells, and the metabolism of lipids. It influences the pH homeostasis of airway surface liquid and thus the MCC as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF., SCOPUS: re.j, info:eu-repo/semantics/published

ispartof: Journal of Allergy and Clinical Immunology vol:141 issue:1 pages:448-451 ispartof: location:United States status: published

Sweat test is the gold standard of the diagnosis of cystic fibrosis (CF). The aim of our study was to identify the indications leading to perform a sweat test and those that led to the diagnosis of CF. METHODOLOGY We collected data of all sweat tests performed between 2008, 1th of March and 2015, 28th of February. They were analyzed following Rosenstein diagnosis criteria (1998): clinical manifestations suggesting CF, positive neonatal screening (≥ 1 positive assay of immunoreactive trypsin) or familial history of CF. RESULTS We reviewed 1,208 sweat tests over this period. Patients were aged from 13 days to 79 years. Indications were: clinical events (94.0%), a positive neonatal screening (3.7%) and a family history (2.3%). Over the 20 newly diagnosed patients, a positive neonatal screening was the main indication for the sweat test (55%). A positive neonatal screening (p

Lung transplantation is assumed to normalize essential fatty acid (EFA) profile in the plasma, described as abnormal in patients with cystic fibrosis (CF). This study sought to evaluate the EFA profile in both the plasma and erythrocyte membrane according to lung status by comparing CF patients with or without a lung transplant. A total of 50 homozygous F508del patients (33 CF patients [CF group] and 17 CF patients with a lung transplant [TX CF group]) were included. In comparison with the CF group, in the plasma, the levels of total n-3, α-linolenic, eicosapentaenoic, and docosahexaenoic acids were higher and the n-6/n-3 ratio was lower in the TX CF group. Yet, these differences were not observed in the erythrocyte membrane. This study supports that lung transplantation improves the EFA profile in the plasma but not in the erythrocyte membrane by means of the different mechanisms suggested in this article., SCOPUS: ar.j, info:eu-repo/semantics/published

Sex differences are observed in the evolution of numerous inflammatory conditions. Women exhibit better clinical courses compared to men in acute inflammatory processes, yet worse prognosis in several chronic inflammatory diseases. Inflammatory markers are significantly different between prepubertal boys and girls, whose sex steroid levels are very low, suggesting genetics play a role. To evaluate the potential influence of the X chromosome, we studied cytokine production and protein phosphorylation following Toll-like receptor (TLR) activation in whole blood and purified neutrophils and monocytes of healthy adults of both sexes as well as subjects with Klinefelter syndrome. We recorded higher levels of inflammatory cytokines in men compared to both women and patients with Klinefelter syndrome following whole blood stimulation. In purified monocytes, production of inflammatory cytokines was also higher in men compared to women, while Klinefelter subjects expressed the same pattern of cytokine production as males, in contrast with whole blood analyses. These differences remained after adjusting for sex steroid levels. Our study revealed higher cytokine inflammatory responses in men than women, yet also compared to subjects with Klinefelter syndrome, who carry two copies of the X chromosome, like women, and thus potentially benefit from the cellular mosaicism of X-linked genes., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: A 3-week short-course of adjuvant-free hydrolysates of Lolium perenne peptide (LPP) immunotherapy for rhinoconjunctivitis with or without asthma over 4 physician visits is safe, well tolerated, and effective. Objective: We sought to investigate immunologic mechanisms of LPP immunotherapy in a subset of patients who participated in a phase III, multicenter, randomized, double-blind, placebo-controlled trial (clinical.gov NCT02560948). Methods: Participants were randomized to receive LPP (n = 21) or placebo (n = 11) for 3 weeks over 4 visits. Grass pollen–induced basophil, T-cell, and B-cell responses were evaluated before treatment (visit [V] 2), at the end of treatment (V6), and after the pollen season (V8). Results: Combined symptom and rescue medication scores (CSMS) were lower during the peak pollen season (−35.1%, P =.03) and throughout the pollen season (−53.7%, P =.03) in the LPP-treated group compared with those in the placebo-treated group. Proportions of CD63 + and CD203c bright CRTH2 + basophils were decreased following LPP treatment at V6 (10 ng/mL, P, SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose and Methods: The severity and prognosis of various acute inflammatory conditions, such as sepsis, differ between males and females. The mechanisms underlying these sex differences probably involve both hormonal and genetic factors. In order to evaluate a possible genetic influence, we reviewed clinical signs and biological inflammatory markers of prepubertal children with severe sepsis admitted to the pediatric intensive care unit (PICU). Findings: A total of 142 prepubertal children, 66 girls and 76 boys, suffering from severe sepsis and admitted to the PICU were included. The survival rate demonstrated a tendency to be higher in females (P = 0.14). Maximum white blood cell count (23,800 cells/mL [15,110'34,600] in girls vs. 19,025 cells/mL [12,358'26,098] in boys, P = 0.02), neutrophil count (16,944 cells/mL [10,620'27,540] vs. 13,756 cells/mL [8410'20,110], P = 0.03), and C-reactive protein level (26.2 mg/dL [15.7'33.6] vs. 18.8 mg/dL [11.1'30.0],P = 0.04) were all significantly higher in girls. Girls also exhibited significantly longer fever duration (2 days [1'6] vs. 1 day [1'3] for the boys, P, SCOPUS: ar.j, info:eu-repo/semantics/published

No clear explanation exists to understand how sex hormones and/or chromosomes affect the immune system. In vitro studies of human lymphoid cells also show sex differences in immune function. To evaluate these differences in frequent pediatric emergencies, we analyze the expression of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, and neutrophil count) underlying inflammatory processes in children: 482 children (241 girls and 241 boys) hospitalized for pneumonia (n = 384), pyelonephritis (n = 39), or bronchiolitis (n = 59) matched for age and sex. All patients were younger than 10 years. A control population of 97 children (50 girls and 47 boys) admitted for day surgery (tonsillectomy, circumcision, or strabismus) was included. We observed highly significant differences between girls and boys: median C-reactive protein concentration of 5.45 mg/dL (range, 0.2-36.0 mg/dL) for girls and 2.6 mg/dL (range, 0.3-37.3 mg/dL) for boys (P < 0.0001), and median erythrocyte sedimentation rate of 39.5 mm/h (range, 2-104 mm/h) for girls and 24 mm/h (range, 4-140 mm/h) for boys (P < 0.005). Neutrophil counts were also significantly different: a median of 8,796 cells/microL (range, 328-27,645 cells/microL) for girls and 6,774 cells/microL (range, 600-38,668 cells/microL) for boys (P < 0.02). The duration of fever after initiating antibiotic therapy was longer in girls than in boys, but there was no difference (Fisher exact test, P < 0.06). The present study documents a relationship between sex and both the production of inflammatory markers and neutrophil recruitment. Sex difference also showed more direct clinical relevance with associations seen between sex and both duration of fever and duration of disease (bronchiolitis P < 0.0007).

Objectives: Aprotinin has been shown to have anti-inflammatory properties, but its effects on the inflammatory reaction to cardiopulmonary bypass remain controversial. This prospective, randomized, double-blind study evaluated the influence of aprotinin on various blood markers of inflammation during and after cardiopulmonary bypass. Methods: Sixty male patients underwent coronary artery bypass grafting. The patients were randomized into 3 groups: a placebo group, a second group receiving 2,000,000 KIU of aprotinin followed by an infusion of 500,000 KIU/h and 2,000,000 KIU in the pump prime, and a third group receiving half this dosage. Measurements of tumor necrosis factor, interleukin 6, interleukin 8, interleukin 10, endotoxin, histamine, complement factors, prekallikrein, and prostaglandin D 2 were obtained at baseline, 30 minutes after study drug loading, 10 minutes after the beginning of cardiopulmonary bypass, before the end of bypass, 4 hours after bypass, and on the first and second postoperative days. Results: Aprotinin had no significant effect on any of these parameters. As expected, aprotinin reduced early blood loss in both treated groups. Conclusions: These results indicate that aprotinin at doses currently used to reduce blood loss has no significant influence on the systemic inflammatory response during moderate hypothermic cardiopulmonary bypass in human subjects, as assessed by the mediators measured in this study.

Objective: Neonates undergoing cardiac surgery have a systemic inflammatory reaction with release of proinflammatory cytokines, which could be responsible for myocardial dysfunction as a result of myocardial cell damage. The purpose of this study was to test the hypothesis that the production of proinflammatory cytokines during cardiac surgery would be associated with myocardial dysfunction after the arterial switch operation in neonates. Methods: A total of 63 neonates with transposition of the great arteries were operated on with combined deep hypothermic circulatory arrest and low-flow cardiopulmonary bypass at a median age of 7 days. Perioperative plasma concentrations of interleukins 6 and 8 were correlated with myocardial dysfunction, as assessed clinically and by echocardiography within 24 hours after the operation, and with perioperative cardiac troponin T blood levels as a marker of myocardial cell damage. Results: Myocardial dysfunction was observed in 11 patients (17.5%), and 2 of them died. Durations of cardiopulmonary bypass and aortic crossclamping, but not of circulatory arrest, were correlated with myocardial dysfunction. Patients with myocardial dysfunction had significantly higher cardiac troponin T blood levels at the end of cardiopulmonary bypass and 4 and 24 hours after the operation than did patients without myocardial dysfunction. Patients with myocardial dysfunction also had higher interleukin 6 plasma concentrations after cardiopulmonary bypass and 4 hours after the operation, as well as higher interleukin 8 plasma concentrations 4 and 24 hours after the operation, than did those without myocardial dysfunction. Postoperative interleukin 6 and 8 plasma concentrations were significantly correlated with postoperative cardiac troponin T blood levels. Multivariable analysis of independent risk factors for myocardial dysfunction comprising cytokine and troponin levels and bypass duration revealed interleukin 6 levels 4 hours after the operation as significant ( P =.047). Conclusions: Cardiac operations in neonates stimulate the production of proinflammatory cytokines, which may contribute to myocardial cell damage and myocardial dysfunction. J Thorac Cardiovasc Surg 2002;124:811-20

OBJECTIVE—Autoantibodies to cell membrane associated DNA are described in systemic lupus erythematosus (SLE). The specificity of these antibodies differ from antibodies to nuclear DNA. METHODS—Using indirect immunofluorescence, a specific IgG was detected giving a characteristic pattern of continuous peripheral membrane fluorescence on cultured B-lymphocytes. RESULTS—This pattern was observed in 53 of 80 serum samples of SLE patients but absent in the serum samples of the control populations: 15 rheumatoid arthritis, 38 ankylosing spondylarthritis, 17 non-inflammatory osteopenic patients, and 224 blood donors. In 34 Sjogren syndrome's patients one only showed a positive test. The cmDNA specificity of these antibodies was confirmed by pattern extinction with DNAse but not RNase or protease pre-treatment of the cells. IgG to cmDNA, separated by absorption/elution from purified cmDNA immobilised on DEAE-nitrocellulose reproduced the immunofluorescence pattern pictures. Extensive serum depletion of anti-double strand or single strand DNA antibodies by absorption to cellulose bound ds- or ss-DNA affected marginally the pericellular fluorescence revealing some minor cross reactivity with nuclear DNA. Moreover, in SLE patients without detectable antibody to ds-DNA, pericellular fluorescence could be visible. CONCLUSION—This novel rapid immunofluorescence method may serve as an identification test of SLE patients. Given its positive (97.1%) and negative (92.9%) predictive value, sensitivity (66%) and specificity (99.5%), it improves on other diagnostic tests such as the detection of antibodies to Sm. Keywords: anti-nuclear antibodies; systemic lupus erythematosus, immunofluorescence, cytoplasmic membrane associated DNA

Tumor necrosis factor-α production and products of mast cell, basophil, and eosinophil degranulation (prostaglandin D 2 , histamine, and eosinophil cationic protein) were prospectively studied in 26 children undergoing cardiac operations. The relationship between inflammatory response to cardiopulmonary bypass and transient postoperative arrhythmias was analyzed. Cardiopulmonary bypass was conducted with circulatory arrest and deep hypothermia in 10 patients and with continuous low-flow and moderate hypothermia in 16 patients. Transient postoperative arrhythmias diagnosed on standard or atrial electrocardiograms (or both) were seen in eight of the 26 examined children: accelerated junctional rhythm ( n = 3), junctional ectopic tachycardia ( n = 3), second-degree atrioventricular block ( n = 1), and third-degree atrioventricular block ( n = 1). Children with transient postoperative arrhythmias were younger than those without ( p < 0.05). Compared with baseline values, there was in all patients a significant release of histamine and eosinophil cationic protein ( p < 0.05) related to cardiopulmonary bypass, reaching peak values 4 hours after the operation. In contrast, tumor necrosis factor-α production and prostaglandin D 2 release were not significant. This suggests that activated basophils but not mast cells are the major sources of histamine liberated during and after cardiopulmonary bypass. Histamine release but not eosinophil cationic protein release correlated with circulatory arrest and deep hypothermia ( p < 0.05), suggesting the participation of physicochemical alterations of circulating basophils leading to histamine liberation. Four hours after the operation, patients with transient postoperative arrhythmias had significantly higher blood concentrations of histamine ( p < 0.02) and eosinophil cationic protein ( p < 0.05) than did those without transient postoperative arrhythmias. On the first postoperative day, four of the eight patients with transient postoperative arrhythmias had persisting elevated histamine levels, whereas in patients without transient postoperative arrhythmias histamine reached baseline values. The multivariate analysis retained histamine release and eosinophil cationic protein variations related to cardiopulmonary bypass for the emerging model to predict transient postoperative arrhythmias. The results of this study show significant histamine release related to cardiopulmonary bypass. Furthermore, they document a possible relationship between circulating histamine and transient postoperative arrhythmias. The latter may therefore be suspected among the consequences of the inflammatory response to cardiopulmonary bypass. (J THORAC CARDIOVASC SURG 1996;111:971-81)

Complement activation and leukocyte stimulation were prospectively studied during and after cardiopulmonary bypass in 16 children receiving sodium nitroprusside—a nitrovasodilator releasing nitric oxide—for vasodilation during the cooling and rewarming periods of extracorporeal circulation. Results were compared with those in 29 patients who were not treated with sodium nitroprusside during the operation. Patients treated with sodium nitroprusside had significantly less C3 conversion during cardiopulmonary bypass as measured by the ratio C3d/C3 (p < 0.05) and significantly less C5a liberation immediately after cardiopulmonary bypass (p < 0.005) than patients not treated with sodium nitroprusside. C4 was not overtly consumed in our series. Leukocyte count during the rewarming period of cardiopulmonary bypass, but not leukocyte elastase release during cardiopulmonary bypass, was significantly reduced in patients treated with sodium nitroprusside (p < 0.05). In vitro experiments were conducted to analyze the effect of sodium nitroprusside on complement hemolytic activity initiated by the classic and the alternate pathways and on zymosan-induced C3 conversion by the activation of the alternate pathway. The in vitro experiments clearly demonstrate inhibition of complement hemolytic activity by sodium nitroprusside in the sera tested. The 50% inhibitory concentration of sodium nitroprusside on the available complement hemolytic activity was less through the alternate pathway than through the classic one (4.2 ± 0.8 mmol/L and 14.0 ± 2.88 mmol/L, respectively). The decrease of complement hemolytic activity measured was dose-dependent and was enhanced by the sodium nitroprusside preincubation of the sera tested. This effect was related to the duration of preincubation. Sodium nitroprusside photodegradation (enhancing nitric oxide release) increased the anticomplementary effect of the drug, reducing the 50% inhibitory concentration on complement hemolytic activity to 0.24 to 0.02 mmol/L for the alternate pathway and 2.74 to 0.3 mmol/L for the classic pathway. The zymosan-induced C3 conversion was inhibited by sodium nitroprusside. Nitroglycerin and isosorbide dinitrate (other nitric oxide donors) had in vitro effects on complement hemolytic activity similar to those of nonphotodegraded sodium nitroprusside at similar concentrations (1 mmol/L). Our results suggest that sodium nitroprusside, both in vitro and in vivo, has an inhibiting effect on complement activation initiated by both classic and alternate pathways and that this effect is mediated by nitric oxide release from sodium nitroprusside. This is the first report on the anticomplementary effect of sodium nitroprusside by nitric oxide release. (J THORAC CARDIOVASC SURG 1996;111:882-92)

Background. The serine protease inhibitor aprotinin inhibits trypsin, kallikrein, and plasmin and enhances the complement hemolytic activity of the first complement component C1. We tested whether low-dose aprotinin influences the inflammatory reaction related to cardiopulmonary bypass. Methods. In an open, randomized study, 25 children undergoing cardiac operations were investigated prospectively. The treated group comprised 11 patients receiving low-dose aprotinin (20,000 kIU/kg [2.8 mg/kg]), and the control group included 14 patients. Complement activation, cytokine production, and leukocyte stimulation were analyzed before, during, and after cardiopulmonary bypass. Results. In all children, significant C3 conversion and C5a generation, interleukin-6 synthesis, and myeloperoxidase, eosinophil cationic protein, and histamine liberation occurred in relation to cardiopulmonary bypass. This was not influenced by aprotinin treatment. In contrast, neutrophil kinetic studies at the end of cardiopulmonary bypass showed a significantly lower increase in the aprotinin as compared with the control group. Conclusions. Our results suggest that low-dose aprotinin has little influence on the inflammatory reaction induced by cardiopulmonary bypass. Aprotinin affects neutrophil mobilization but not white blood cell degranulation related to cardiopulmonary bypass, and has no influence on complement activation and interleukin-6 synthesis.

Sex influences the severity and evolution of various inflammatory conditions. Although many studies have demonstrated the role of sex hormones in immune response modulation, recent clinical data revealed significant sex differences in inflammatory markers in prepubertal children, suggesting a genetic contribution. We studied several immune functions depending on X-linked genes in healthy adults of both sexes: the respiratory burst of purified neutrophils, the CD99 and CD11b expression of stimulated leukocytes as markers of adhesion and diapedesis, and the production of inflammatory cytokines in whole blood after incubation with lipopolysaccharide for 24 h. The percentage of monocytes expressing CD99 was higher in men than in women, thus confirming the higher CD99 expression reported in males using reverse transcription-polymerase chain reaction. In addition, we observed a higher tumor necrosis factor α and tendency toward higher interleukin (IL) 6 production in men after lipopolysaccharide stimulation. These differences may contribute to the higher mortality reported in men with septic shock. Tumor necrosis factor α production significantly correlated with monocyte count, with men having a higher monocyte count than women. When cytokine levels were normalized to monocyte counts, a higher IL-8 production was found in women, which may explain the higher neutrophil count observed in girls with acute inflammatory diseases, because IL-8 is a major neutrophil chemoattractant. These sex differences regarding the activation of certain X-linked genes involved in innate immunity confirm our clinical observations, thus supporting the role of sex chromosomes in inflammatory response.

In 13 neonates undergoing cardiac operations for congenital cardiac defects, complement, leukocytes, and leukocyte elastase were studied during and after cardiopulmonary bypass. All but two neonates received prostaglandin E 1 before the operation. The C3d/C3 ratio rose significantly during cardiopulmonary bypass from 0.86 ± 0.55 to 1.40 ± 0.56 (mean ± standard deviation; p 9 /L to 3.21 ± 0.64 × 10 9 /L after beginning of cardiopulmonary bypass (p 9 /L to 7.19 ± 1.84 × 10 9 /L, after protamine administration ( p 9 /L to 1.46 ± 0.35 × 10 9 /L after beginning of cardiopulmonary bypass and rose at the end of extracorporeal circulation from 1.00 ± 0.31 × 10 9 /L to 4.10 ± 1.18 × 10 9 /L, after protamine administration ( p

Twenty-nine children 3 months to 17 years of age undergoing operations for congenital heart disease were included in this prospective study. Complement activation, activation of the plasma contact system, leukocytes, leukocyte elastase release, and C-reactive protein were studied during and after cardiopulmonary bypass for the first postoperative week and related to multiple system organ failure occurring in eight (27.5%) of the 29 children. During cardiopulmonary bypass complement activation via the alternative pathway as indicated by significant conversion of C3 (expressed by C3d/C3) and abnormally high C5a values at the end of cardiopulmonary bypass without consumption of C4 was shown in all children. At the end of cardiopulmonary bypass, C3 conversion was significantly higher in the eight patients with multiple system organ failure than in the others (p < 0.05), whereas no difference in C5a level was shown. All children had a significant increase in leukocyte count directly after protamine administration (p < 0.0001) and elastase release during cardiopulmonary bypass that was significantly higher in patients with multiple system organ failure than in those without (p < 0.05). Consumption of prekallikrein as an indicator of activation of the Hageman system was not detectable during cardiopulmonary bypass in any child. After cardiopulmonary bypass, in patients without multiple system organ failure, C3d/C3 decreased and reached preoperative values within the first postoperative week, whereas, in patients with multiple system organ failure, C3d/C3 increased further, reaching a maximal value on the third postoperative day. In comparison with patients without multiple system organ failure, patients with multiple system organ failure showed a severe decrease of C4 (with minimal values on the third postoperative day), suggesting consumption by activation of the classic pathway of the complement system or a hepatic synthesis deficiency. Prekallikrein values were also significantly lower in patients with multiple system organ failure than in the others, with a maximal difference on the third postoperative day (p < 0.005). C-reactive protein was significantly lower in patients with multiple system organ failure than in the others for the first 2 postoperative days (p < 0.05), probably because of severe hepatic failure in patients with multiple system organ failure. This study demonstrates that, in children, cardiopulmonary bypass induces complement activation principally via the alternative pathway. It suggests a relationship between complement activation and multiple system organ failure observed in the postoperative period. Furthermore, it points out the role of multiple system organ failure itself on the C3 conversion and on the synthesis of the markers of the inflammatory response in children after heart operations.

Background. This study is a continuation of a recent study, in which a defect in the immunoglobulin G (IgG) response to some natural antigens (bovine betalactoglobulin [BLG] from cow's milk and antigen p1 from the house dust mite Dermatophagoides pteronyssinus), usually presented at the mucosal level, was documented in lung cancer patients. The present study further characterizes this difference in terms of antibody relative functional affinity in the BLG model. Methods. Relative functional affinity was evaluated by solid-phase enzyme-linked immunosorbent assay in terms of the relationship between specific IgG retention, assessed with peroxidase-labeled protein A, and serial dilutions of IgG fractions isolated from 24 sera from lung cancer patients and 24 sera from healthy control subjects matched for their anti-BLG IgG antibody titers. The procedure was performed in the presence and absence of low concentrations of diethylamine, which was expected to prevent low-affinity antigen–antibody binding without affecting the binding of high-affinity antibodies. Anti-BLG IgG antibody affinity also was evaluated in 25 patients with early-stage lung cancer, before and after (5 ± 1 week) complete surgical excision of the tumor. Results. Results, expressed as the slope of the binding curves and their leftward shift induced by diethylamine, showed different antibody populations between the two groups. Control sera showed a heterogeneous population of anti-BLG IgG antibodies, including antibodies of higher (steeper slope) and lower (more gradual slope) functional affinity. Cancer sera exhibited a less heterogeneous population of anti-BLG IgG antibodies, mostly with lower functional affinity. No change was observed in anti-BLG IgG antibody affinity in the 25 lung cancer patients tested 5 ± 1 week after complete surgical excision of the tumor. Conclusions. These results document a persistent qualitative immunologic disturbance in patients with lung cancer, regardless of the type and extent of tumor. The potential relationship between this observation and the development of lung cancer, however, is presently unknown.

Results Two step Cluster Analysis followed by a discriminant function analysis of the lymphocyte activation assay from the first blood sample, allowed the separation of HIV-1 patients in two groups: Cluster1 (67%) and Cluster2 (33%). Clusters definition relied on the level of three T-cells subsets: a) stimulated CD4CD69 CD25, b) unstimulated CD4CD69CD25 and c) unstimulated CD4CD25. PHA stimulated CD4 CD69 CD25 subset level alone allowed to classify correctly patients with 92% sensitivity and 87% specificity. Cluster-2 expressed more CD69 and HLA-DR activation markers on CD4 and CD8 lymphocytes, less CD8 CD28 and responded less to mitogen even if viral load undetectable. Cluster-2 presented poorly clinical profile in terms of previous AIDS events, current CD4 count, viral load, length of treatment. Over the time most patients (64%) were keeping their cluster category.

In humans and animal models, females express higher immune reactivity and more robust inflammatory responses. We analyzed the expression of current inflammatory markers in 149 children (74 girls and 75 boys) with three chronic inflammatory diseases: 50 with asthma, 47 with cystic fibrosis, and 52 with sickle cell anemia to evaluate the potential differences in clinical response according to sex. Data including temperature, neutrophil count (NC), and C-reactive protein were recorded for each patient at several time points according to his/her disease. In asthma, NC was higher in girls than in males (P < 0.02), as were doses of cortisone (P < 0.04) or inhaled bronchodilators (P < 0.01) received at recovery. In cystic fibrosis, NC became significantly higher in girls at age 5 years (P < 0.003), whereas episodes of infection and antibiotic administration were already significantly more frequent in girls at age 2 years (P < 0.02 and P < 0.05, respectively). In sickle cell anemia, the number of crises since diagnosis and number of acute chest syndrome episodes were significantly higher in girls (P < 0.01 and P < 0.05, respectively). Our study extends the documentation of a relationship between sex, inflammatory markers, and clinical outcome in prepubescent children, suggesting a genetic predetermination is more likely than hormonal influence.

Diaphragm thickness is increased in cystic fibrosis (CF), but it shows a marked variability between patients. The variable response of the diaphragm to loading may reflect the combined and opposite effects of training by the respiratory disease and systemic inflammation.To assess the impact of systemic inflammation on diaphragm and limb muscle strength and bulk in adult patients with CF.In 38 stable patients with CF and 20 matched control subjects, we measured fat-free mass (FFM), inspiratory muscle strength, diaphragm thickness, quadriceps and biceps strength and cross-sectional area, and circulating levels of leukocytes, C-reactive protein, IL-6, IL-8, IL-17, tumor necrosis factor-alpha, tumor necrosis factor-alpha soluble receptors, and immunoglobulin G.Patients had increases in several inflammatory markers that correlated with the severity of lung disease and nutritional depletion. Compared with control subjects, patients with CF had increased diaphragm thickness and inspiratory muscle strength and showed a trend toward a reduction in limb muscle strength and bulk. Multiple regression analyses identified FFM and airway resistance as independent predictors of diaphragm thickness, but systemic inflammation had no (or only a minor) predictive effect on FFM, inspiratory muscle strength, diaphragm thickness, and limb muscle strength and bulk.In patients with CF, the intensity of systemic inflammation does not account significantly for the variance of FFM and diaphragm or limb muscle strength and bulk. Training of the diaphragm in CF occurs despite the presence of systemic inflammation.

Purpose: To investigate the expression of CD69 on CD4 and CD8 lymphocytes of patients with autoimmune uveitis Methods: Peripheral blood from 14 patients with severe autoimmune uveitis and 15 healthy controls was directly cultured in RPMI for 3 days. T lymphocytes were thereafter analysed by flow cytometry for the expression of CD25, CD69 or CD28, CD69 on CD4+ or CD8+ T cells respectively. Results: The expression of CD69 by CD4+ lymphocytes of patients with uveitis was significantly higher than in control subjects (p=0.029). This difference was more pronounced when CD69 expression was analysed on CD4+CD25++ lymphocytes (p=0.016) and lost for CD4+CD25+ T cells. Besides, the number of CD4+CD25++ lymphocytes was increased in the uveitis group (p=0.01). However, we did not observed any correlation between the level of CD69 on CD4+ lymphocytes and the severity or aetiology of the disease. No differences were found when the expression of CD69 was studied on CD8+ lymphocytes. Conclusions: Our results suggest that some patients with autoimmune uveitis have a spontaneous activation of their CD4+CD25 ++ lymphocytes.

Clinical symptoms and lung function of CF may be influenced by correcting essential fatty acids (EFA) deficiency. Nevertheless, the value of EFA supplementation in CF remains controversial. Objectives The aim of this longitudinal randomized double-blind placebo-controlled clinical trial was to assess the benefits of an oral supplementation with omega-3 on clinical and nutritional status, lung function and exercise tolerance. Methods A supplementation with a triglyceride source of omega-3 (Omega 3 Premium®, Laboratoires Ponroy, France) at a daily dose of 60 mg/kg during 1 year was administered to ΔF508 homozygous CF patients above 5 years of age. Patients were assessed at 3, 6, 9 and 12 months. Lung function was performed at each visit and an exercise test before and at the end of study. Results Of the 16 patients included, 13 completed the study. Six received omega-3 and 7 the placebo. Compared to the control group the cumulative duration of antibiotic therapy decreased in the intervention group at 9 months (24.5 days vs 46.0 days, p=0.02) and at 12 months (26.5 days vs 65.0 days, p Conclusions This longitudinal randomized placebo-controlled study shows some clinical benefits of long-term omega-3 supplementation in CF patients. However, additional studies with larger populations are needed. Supported by a grant from the Belgian Cystic Fibrosis Association.

Introduction Neonatal cardiac surgery is associated with a systemic inflammatory reaction that might compromise the reactivity of blood cells against an inflammatory stimulus. Our prospective study was aimed at testing this hypothesis. Methods We investigated 17 newborn infants with transposition of the great arteries undergoing arterial switch operation. Ex vivo production of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), of the regulator of the acute-phase response IL-6, and of the natural anti-inflammatory cytokine IL-10 were measured by enzyme-linked immunosorbent assay in the cell culture supernatant after whole blood stimulation by the endotoxin lipopolysaccharide before, 5 and 10 days after the operation. Results were analyzed with respect to postoperative morbidity. Results The ex vivo production of TNF-α and IL-6 was significantly decreased (P < 0.001 and P < 0.002, respectively), whereas ex vivo production of IL-10 tended to be lower 5 days after the operation in comparison with preoperative values (P < 0.1). Ex vivo production of all cytokines reached preoperative values 10 days after cardiac surgery. Preoperative ex vivo production of IL-6 was inversely correlated with the postoperative oxygenation index 4 hours and 24 hours after the operation (P < 0.02). In contrast, postoperative ex vivo production of cytokines did not correlate with postoperative morbidity. Conclusion Our results show that cardiac surgery in newborn infants is associated with a transient but significant decrease in the ex vivo production of the pro-inflammatory cytokines TNF-α and IL-6 together with a less pronounced decrease in IL-10 production. This might indicate a transient postoperative anti-inflammatory shift of the cytokine balance in this age group. Our results suggest that higher preoperative ex vivo production of IL-6 is associated with a higher risk for postoperative pulmonary dysfunction.

Aprotinin has been shown to have anti-inflammatory properties, but its effects on the inflammatory reaction to cardiopulmonary bypass remain controversial. This prospective, randomized, double-blind study evaluated the influence of aprotinin on various blood markers of inflammation during and after cardiopulmonary bypass.Sixty male patients underwent coronary artery bypass grafting. The patients were randomized into 3 groups: a placebo group, a second group receiving 2,000,000 KIU of aprotinin followed by an infusion of 500,000 KIU/h and 2,000,000 KIU in the pump prime, and a third group receiving half this dosage. Measurements of tumor necrosis factor, interleukin 6, interleukin 8, interleukin 10, endotoxin, histamine, complement factors, prekallikrein, and prostaglandin D(2) were obtained at baseline, 30 minutes after study drug loading, 10 minutes after the beginning of cardiopulmonary bypass, before the end of bypass, 4 hours after bypass, and on the first and second postoperative days.Aprotinin had no significant effect on any of these parameters. As expected, aprotinin reduced early blood loss in both treated groups.These results indicate that aprotinin at doses currently used to reduce blood loss has no significant influence on the systemic inflammatory response during moderate hypothermic cardiopulmonary bypass in human subjects, as assessed by the mediators measured in this study.

In their recent paper on the resurgence in mumps virus infections in Ireland ([2][1]), Carr et al. observed a strong ( P < 10−32) bias for acute mumps virus infection in males compared to females that was independent of vaccination status. The authors extrapolated to natural infections the gender

This study examined the hypothesis that core temperature (T(o)) during cardiopulmonary bypass (CPB) influences the perioperative systemic inflammatory response and post-operative organ damage. Twenty-four pigs were assigned to a T(o) regimen during CPB: normothermia (T(o) 37 degrees C; n = 8), moderate hypothermia (T(o) 28 degrees C; n = 8), or deep hypothermia (T(o) 20 degrees C; n = 8). Perioperative leukocyte activation, endotoxin release, and production of tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL10) were examined with regard to post-operative organ damage, which was scored at histological examination of tissue probes of heart, lungs, liver, kidney, and ileum, taken 6 h after CPB. Total blood leukocyte count and TNFalpha plasma levels during CPB were significantly lower and IL10 levels were significantly higher in the moderate hypothermic group than in both other groups. Elastase activity, leukotriene B4-, and endotoxin levels were not affected by T(o) regimen. Moderate hypothermia was associated with the lowest histological organ damage score and normothermia with the highest. In all animals organ damage score for heart, lungs, and kidneys correlated significantly with TNFalpha levels at the end of CPB. Our data demonstrate a clear relationship between TNFalpha production during cardiac operations and post-operative multiple-organ damage. Moderate hypothermia, by stimulating IL10 synthesis and suppressing TNFalpha production during CPB, might provide organ protection.

We studied the inflammatory reaction related to cardiopulmonary bypass in 24 neonates (median age 6 days) undergoing the arterial switch operation for simple transposition of the great arteries, with respect to the development of postoperative capillary leak syndrome. Complement proteins, leukocyte count, tumor necrosis factor-α, and histamine levels were determined before, during, and after cardiopulmonary bypass. Additionally, protein movement from the intravascular into the extravascular space during cardiopulmonary bypass was assessed by the measurement of plasma concentrations of proteins with molecular weights ranging from 21,200 to 718,000. Capillary leak syndrome developed in 13 of the 24 neonates. Patients with capillary leak syndrome, as compared with those without, had preoperatively higher C5a levels (C5a, 3.0 ± 0.6 μg/L vs 0.9 ± 0.2 μg/L) (mean ± standard error of the mean) ( p < 0.05) and higher leukocyte counts (leukocytes, 17.9 ± 2.1 × 103 cells/ml versus 11.7 ± 0.8 × 10 3 cells/ml) ( p < 0.05), suggesting in these neonates a preoperative inflammatory state. Preoperative clinical and operative data were identical in both patient groups. Before cardiopulmonary bypass, serum protein concentrations were similar in all patients. Ten minutes after institution of cardiopulmonary bypass, protein concentrations fell to significantly lower values in patients with capillary leak syndrome than in those without: albumin (19% ± 1.5% vs 30% ± 6% of the prebypass value, p < 0.05), immunoglobulin G (17% ± 1.5% vs 29% ± 5.5%, p < 0.001), and α 2 -macroglobulin (15% ± 1.2% vs 25% ± 4%, p < 0.02). During cardiopulmonary bypass, albumin concentrations remained significantly lower in patients with capillary leak syndrome than in those without, whereas hematocrit values were similar in both groups. During cardiopulmonary bypass, patients with capillary leak syndrome also had lower concentrations of complement proteins C3 and C4 but not C1 inhibitor. C3d/C3 ratio and C5a levels were similar in both patient groups. In contrast, histamine liberation during cardiopulmonary bypass was significantly more pronounced in patients with capillary leak syndrome than in those without (725.2 ± 396.7 pg/ml vs -54.1 ± 58.4 pg/ml, p < 0.05). Tumor necrosis factor-α levels after protamine administration were also significantly higher in patients with capillary leak syndrome (38.1 ± 10.0 pg/ml vs 15.3 ± 3.4 pg/ml, p < 0.05). Leukocyte count during and after cardiopulmonary bypass was similar in both patient groups. This study demonstrates increased protein leakage as early as 10 minutes after initiation of cardiopulmonary bypass in patients having clinical signs of postoperative capillary leak syndrome. Patients with capillary leak syndrome displayed more pronounced histamine liberation and tumor necrosis factor-α liberation than patients without capillary leak syndrome, suggesting a relationship between cardiopulmonary bypass–related inflammatory reaction and perioperative capillary damage. A preoperative inflammatory state in patients with capillary leak syndrome could have enhanced the inflammatory response to cardiopulmonary bypass. (J THORAC CARDIOVASC SURG 1996;112:687-97)

A retroplacental serum factor responsible for the downregulation of the MHC class II antigen expression has been described [1]. We found that maternal serum had the same property. The HLA class II modulating activity is however diminished in the presence of maternal serum as compared to retroplacental serum suggesting that the IA like inhibiting factor is released at the fetomaternal interface. After a 3-day incubation period of unrelated lymphocytes and mononuclear cord blood cells in a maternal serum pool, it was shown that the HLA Dr, the HLADp, and more significantly, the HLADq molecules were modulated. This phenomenon was more pronounced among cord blood cells. When third party lymphocytes and mononuclear cord blood cells were stimulated by Candidine or unrelated mononuclear cells in the presence of retroplacental serum, only the cellular subpopulation belonging to the CD4+ subset showed an HLADq downregulation. The molecular constituents of the MHC class II antigen expression characterizing cells belonging to other subsets remained unchanged. When the same stimulation assay was performed in the presence of a control medium (nulliparous serum), we found no changes in the MHC class II molecular constituents. When unrelated mononuclear cells and mononuclear cord blood cells were PHA stimulated in the presence of maternal and nulliparous serum, the HLADq expression of the CD8+ subset showed a significant downregulation in the maternal serum mediated stimulation assay as compared to the control stimulation test. The molecular expression of the HLA class II antigen related to the other subpopulation (CD4+, CD3+) stimulated by a mitogenic lectin remained unchanged. It is suggested that these molecular MHC class II modulations are due to a factor included in the maternal IgG reaction. Retroplacental IgG contains the highest concentration of this factor.

Introduction Neonatal cardiac surgery is associated with a systemic inflammatory reaction that might compromise the reactivity of blood cells against an inflammatory stimulus. Our prospective study was aimed at testing this hypothesis.

It was of objective of this study to investigate clinical and laboratory risk factors for myocardial dysfunction (MD) in neonates after arterial switch operation for transposition of the great arteries.

To confirm that sleeplessness in infants can be related to an undiagnosed allergy to cow's milk proteins, 71 infants were studied. Group I consisted of 20 infants referred for chronic insomnia that had appeared in the early days of life. Group II was made up of 31 infants admitted for skin or digestive symptoms attributed to cow's milk intolerance; 13 of these infants were shown to sleep as poorly as the infants of group I. Group III consisted of 20 infants with no history of sleep disturbance or milk allergy. The three groups of infants were comparable for sex and age. Laboratory tests revealed immunologic reactions to milk in all the infants in groups I and II. The sleep of the insomniac infants (group I, and the 13 "poor sleepers" in group II) became normal after cow's milk was eliminated from the diet. Insomnia reappeared when the infants in group I were challenged with milk. We conclude that infants with clinically evident milk allergy may suffer from sleeplessness and that when no evident cause for a chronic insomnia can be found in an infant the possibility of milk allergy should be given serious consideration.