The -2549 -2567 del18 Polymorphism in VEGF and Irreversible Bronchoconstriction in Asthmatics.

BACKGROUND: While the importance of vascular endothelial growth factor (VEGF) in the pathogenesis of several diseases (eg, neoplasms) has been proven, its role in asthma, especially in terms of the potential associations between genetic variants of VEGF and airway remodeling, has received relatively little attention. Objectives: This study aimed to evaluate the possible connection between a genetic factor, ie, the polymorphism del/ins in the VEGF promoter region, and airway remodeling potential in asthmatics with and without irreversible bronchoconstriction. MATERIAL AND METHODS: The study population comprised 82 patients with asthma (of whom 42 had irreversible bronchoconstriction) and a group of 40 controls. DNA was isolated from peripheral blood leukocytes. Polymerase chain reaction was used to type the VEGF (18-bp deletion/insertion) gene polymorphism at loci -2549 -2567. Other factors (ie, smoking, disease duration) were also taken into consideration. RESULTS: The del/del genotype was found in 74.39% of patients with asthma (P=.031; OR=2.38), 80.95% of patients with irreversible bronchoconstriction (P=.012; OR=3.48), and 67.5% patients with reversible bronchoconstriction (P=.251; OR=1.70). The proportion of smokers to nonsmokers was higher (P=.032) and disease duration was longer (P=.041) in patients with irreversible bronchoconstriction than in those with reversible bronchoconstriction. CONCLUSIONS: Our results showed that the risk of irreversible bronchoconstriction in asthmatics was associated with the presence of the del18 genotype at the -2549 -2567 position in the promoter region of the VEGF gene, as were disease duration and other factors such as smoking.

The -2549 -2567 del18 polymorphism in VEGF and irreversible bronchoconstriction in asthmatics

BACKGROUND: While the importance of vascular endothelial growth factor (VEGF) in the pathogenesis of several diseases (eg, neoplasms) has been proven, its role in asthma, especially in terms of the potential associations between genetic variants of VEGF and airway remodeling, has received relatively little attention. OBJECTIVES: This study aimed to evaluate the possible connection between a genetic factor, ie, the polymorphism del/ins in the VEGF promoter region, and airway remodeling potential in asthmatics with and without irreversible bronchoconstriction. MATERIALS AND METHODS: The study population comprised 82 patients with asthma (of whom 42 had irreversible bronchoconstriction) and a group of 40 controls. DNA was isolated from peripheral blood leukocytes. Polymerase chain reaction was used to type the VEGF (18-bp deletion/insertion) gene polymorphism at loci -2549 -2567. Other factors (ie, smoking, disease duration) were also taken into consideration. RESULTS: The del/del genotype was found in 74.39% of patients with asthma (P=.031; OR=2.38), 80.95% of patients with irreversible bronchoconstriction (P=.012; OR=3.48), and 67.5% patients with reversible bronchoconstriction (P=.251; OR=1.70). The proportion of smokers to nonsmokers was higher (P=.032) and disease duration was longer (P=.041) in patients with irreversible bronchoconstriction than in those with reversible bronchoconstriction. CONCLUSIONS: Our results showed that the risk of irreversible bronchoconstriction in asthmatics was associated with the presence of the del18 genotype at the -2549 -2567 position in the promoter region of the VEGF gene, as were disease duration and other factors such as smoking

ANTECEDENTES: Aunque se ha demostrado la importancia del factor de crecimiento endotelial vascular (VEGF) en la patogénesis de varias enfermedades (p. ej. neoplasias), los datos relativos al asma son escasos, especialmente los relacionados con las posibles asociaciones entre las variantes genéticas de VEGF y la remodelación de las vías respiratorias. OBJETIVOS: En este estudio se propuso evaluar la posible relación entre un factor genético como el polimorfismo del/ins en la región promotora de VEGF y el potencial de remodelación de las vías aéreas en los asmáticos con y sin broncoconstricción irreversible. MATERIALES Y MÉTODOS: en el estudio participaron 82 pacientes con asma (42 pacientes con broncoconstricción irreversible) y un grupo de 40 controles. El ADN fue extraído de leucocitos de sangre periférica. Para la tipificación del polimorfismo del gen VEGF (delección / inserción de 18 pb) en loci -2549 -2567 se utilizó el método de reacción en cadena de la polimerasa (PCR). Se consideraron también otros factores (fumar, duración de la enfermedad). RESULTADOS: El genotipo del/del se encontró en el 74,39% de pacientes con asma (p = 0,031; OR = 2,38), el 80,95% de los pacientes con broncoconstricción irreversible (p = 0,012; OR = 3,48) y el 67,5% de los pacientes con broncoconstricción reversible (p = 0,251; OR = 1,70). La proporción de fumadores con respecto a los no fumadores fue mayor (p = 0,032) y la duración de la enfermedad fue mayor en pacientes con broncoconstricción irreversible en comparación con aquellos con broncoconstricción reversible (p = 0,041). CONCLUSIONES: Nuestros resultados mostraron que la presencia del genotipo del18 en la posición -2549 -2567, en el promotor del gen VEGF, junto con la duración de la enfermedad y otros factores como fumar cigarrillos, se asocian con el riesgo de broncoconstricción irreversible en los individuos asmáticos

Immunosuppressive Treatment and Its Effect on the Occurrence of Pneumocystis jiroveci, Mycoplasma pneumoniae, Chlamydophila pnemoniae, and Legionella pneumophila Infections/Colonizations Among Lung Transplant Recipients.

BACKGROUND: The aim of the study was to assess the frequency of infections caused by Pneumocystis jiroveci, Chlamydophila pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae among lung transplant recipients in the context of immunosuppression. METHODS: The study group consisted of 94 patients (37 women and 57 men; mean age 42.03 years) transplanted between 2009 and 2016 at the Silesia Center for Heart Diseases (SCCS). Immunosuppressive treatment (induction and maintenance therapy) was assessed. The immunofluorescence methods were used to detect the P. jiroveci, L. pneumophila, C. pneumoniae, and M. pneumoniae antigens in samples obtained from the respiratory tract. RESULTS: Thirty-two of 94 graft recipients developed atypical or opportunistic infection. The median time of its occurrence was 178 days after transplantation. P. jiroveci was responsible for 84.38% of first infections. Five patients developed infection with P. jiroveci and C. pneumoniae. None of the infections occurred during induction of immunosuppression. An opportunistic or atypical infection developed in 19.35% of the patients treated with a tacrolimus-based regimen, and in 43.33% of patients on a cyclosporine-based regimen. CONCLUSION: Infection with P. jiroveci is a recognized problem after lung transplantation and should be monitored. The percentage of infected patients is higher in patients treated with a cyclosporine-based regimen in comparison to those treated with tacrolimus.

Bacterial Infections During Hospital Stay and Their Impact on Mortality After Lung Transplantation: A Single-Center Study.

INTRODUCTION: The aim of the study was to assess the impact of bacterial infection during hospital stay on long-term follow-up. MATERIALS AND METHODS: This was a retrospective single-center study of 97 recipients of lung transplantations performed between December 2004 and June 2016 at a single center. Information about age, sex, underlying lung disease, and date and type of procedure was gathered from patients' charts. Immunosuppressive treatment has been analyzed individually among the cohort. Microbiological evaluation included the presence of infection, bacterial species in recipients and donors, as well as type of biological material. RESULTS: During a mean hospitalization time of 57 days (range 4-398 days), 67 patients (69%) were diagnosed with bacterial infection. There were 120 episodes of infection caused by 32 species of bacteria. The most common were Pseudomonas aeruginosa (27%), Acinetobacter baumanii (21%), Klebsiella pneumoniae (10%) and Stenotrophomonas maltophilia (11%). Analysis revealed that 39 patients developed bronchiolitis obliterans syndrome (43%). Patients with A baumanii had a lower probability of survival than the rest of the population (P < .05). Patients treated with mammalian target of rapamycin inhibitors had a higher probability of survival. CONCLUSIONS: Infection with A baumanii affects lung transplant recipients' survival. Incorporating sirolimus could be beneficial for the lung transplant recipients' survival.

Aspirin does not preferentially potentiate IgE dependent basophil CD63 upregulation in patients with food-dependent exercise-induced anaphylaxis

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Nonsteroidal anti-inflammatory drug hypersensitivity syndrome: a multicenter study. II. Basophil activation by nonsteroidal anti-inflammatory drugs and its impact on pathogenesis.

BACKGROUND: Patients who are clinically hypersensitive to nonsteroidal anti-inflammatory drugs (NSAIDs) sometimes present basophil activation in vitro, and in 50% of cases a parallel response to release of sulfidoleukotrienes (cellular allergen stimulation test) is observed. These phenomena occur not only in clinically hypersensitive patients, but also in some healthy controls who tolerate NSAIDs. MATERIAL AND METHODS: We studied 16 clinically hypersensitive patients, 22 controls tolerating NSAIDs, and 29 healthy blood donors (clinical NSAID status unknown) using 2 different basophil isolation techniques (buffy coat or plasma leukocytes). RESULTS: In a population of 13 aspirin-tolerant healthy controls and 29 healthy blood donors, basophil activation with aspirin, diclofenac, and naproxen was analyzed at 4 different concentrations. The results in the 2 groups were quite similar in qualitative terms. Choosing a cutoff of 5% and a stimulation index >2, the proportion of positive results increased with the concentration. There were more positive results at all concentrations using the plasma leukocyte technique. CONCLUSIONS: The most important finding of this study is that basophil activation by NSAIDs occurs not only in clinically hypersensitive patients but also, to a very variable extent and on an individual basis, in apparently normal healthy individuals who tolerate NSAIDs. The phenomenon is clearly dose-related, and hypersensitive patients seem to react to lower NSAID concentrations.

Nonsteroidal anti-inflammatory drug hypersensitivity syndrome. A multicenter study. I. Clinical findings and in vitro diagnosis.

BACKGROUND: We present the results obtained from the largest series of in vitro diagnostic tests ever reported in patients with clinically validated hypersensitivity to acetylsalicylic acid (ASA)/nonsteroidal anti-inflammatory drugs (NSAID) compared with various categories of controls tolerating ASA/NSAIDs. This multicenter study, which was performed within the framework of the European Network for Drug Allergy (ENDA) group, showed that the basophil activation test (BAT), particularly when used with the 3 NSAIDs aspirin (ASA), diclofenac (DIC), and naproxen (NAP), allows us to confirm the diagnosis of NSAID hypersensitivity syndrome. The results of the cellular allergen stimulation test (CAST) frequently correlate with those of the BAT, although not always. An unexpected finding was that basophil activation by NSAIDs is not an all-or-nothing phenomenon restricted to clinically hypersensitive patients, but that it also occurs in a dose-related manner in some NSAID-tolerant control individuals.Therefore, NSAID hypersensitivity appears as a shift in the normal pharmacological response to NSAIDs. These findings allow us to formulate a new rational hypothesis about the mechanism of NSAID hypersensitivity syndrome, a mechanism that most authors continue to describe as "unknown." METHODS: We enrolled 152 patients with a history of hypersensitivity to NSAIDs and 136 control participants in 11 different centers between spring 2003 and spring 2006. Flowcytometric BAT was performed. RESULTS: The most noteworthy results of our study were that 57% of 140 patients presented very clear-cut positive BAT results to multiple NSAIDs, and 16% were entirely negative. In about 27% of cases, positive results were obtained with 1 or 2 concentrations of a single NSAID. There is clearly a correlation between the results of BAT and CAST. CONCLUSIONS: BAT seems particularly indicated in patients with a clinical history of NSAID intolerance, and in whom a provocation test is not advisable for ethical, clinical, or other reasons. Clear-cut positive results can be considered as confirming a history of NSAID hypersensitivity, although negative results may not exclude it.

A new variant of the basophil activation test for allergen-induced basophil CD63 upregulation. The effect of cetirizine.

OBJECTIVE: The aim of our study was to determine the diagnostic usefulness of a newly developed basophil activation test (BAT) in patients allergic to Dermatophagoides pteronyssinus and pollens. We also analyzed the influence of cetirizine on CD63 upregulation. This popular antihistamine strongly inhibits skin tests, but its impact on BAT sensitivity remains unknown and deserves at least preliminary determination. METHODS: The study sample comprised 22 patients allergic to house dust mite and pollens and 19 healthy controls. All participants underwent skin prick testing and the newly developed flow-cytometric basophil activation test. The protocol for allergen-induced basophil CD63 upregulation consisted of whole blood samples that were processed and stained with anti-CCR3/CD63 antibodies added to the buffer at the beginning of stimulation. Skin prick tests and BAT were performed twice--before and 2 hours after ingestion of 10 mg of cetirizine. RESULTS: The new BAT is characterized by its short processing time, easy basophil gating, and strong CD63 upregulation with very high sensitivity and excellent specificity. Our results suggest that allergen-induced CD63 upregulation by higher doses of allergens is not inhibited 2 hours after administration of cetirizine (unlike skin prick tests). CONCLUSION: The BAT is a very useful and precise method for the diagnosis of allergy to aeroallergens. It is not influenced by cetirizine.

Food-dependent exercise-induced anaphylaxis: possible impact of increased basophil histamine releasability in hyperosmolar conditions.

We present a case of anaphylactic shock induced by exercise following celery ingestion. The possible mechanism of food-dependent exercise-induced anaphylaxis (FDEIA) and the laboratory tests for its diagnosis are discussed. We evaluated spontaneous, celery-allergen-induced, and anti-FcepsilonRI-antibody-induced histamine release from basophils obtained from the patient, 2 celery-allergic controls, and 3 healthy controls. Buffers of increasing osmolarity were used to mimic conditions of vigorous physical exercise. Only the patient's basophils showed an increase in spontaneous, anti-FcepsilonRI antibody-induced and allergen-induced histamine release under physiological conditions and with slightly increased medium osmolarity. To our knowledge, this is the first report on the possible role of increased histamine releasability in the pathogenic mechanism of FDEIA. We suggest that FDEIA results from increased histamine releasability triggered by physical effort after exposure to a sensitizing food allergen.

Production of leukotriene C4 by peripheral blood leukocytes stimulated with anti-fcepsilonRI antibody, PMA, and fMLP does not correlate with irreversible airway obstruction in asthmatics.

BACKGROUND: Airway remodeling has recently emerged as a major problem in an increasing percentage of patients with asthma. Reasons for great diversity in the progression of irreversible bronchoconstriction among asthmatics remain unclear. OBJECTIVE: The aim of this study was to assess whether the potential ability of leukocytes to produce cysteinyl leukotrienes in response to various stimuli is correlated with magnitude of irreversible airway obstruction in asthmatics. MATERIALS AND METHODS: The study sample comprised 76 asthmatics (34 males, mean +/- SD age 52 +/- 13 years), and 35 healthy controls (18 males, 38.2 +/- 15 years). Each subject underwent 2 pulmonary function tests: before and after bronchodilator administration. In addition, approximate annual decline in forced expiratory volume in 1 second (FEV1) (% of predicted) was calculated. Leukotriene C4 (LTC4) production was assessed combining a cellular antigen stimulation test and enzyme-linked immunosorbent assay using Bulhmann Laboratories AG kits. Leukocytes isolated from peripheral blood were stimulated with anti-FcepsilonRI antibody, N-formyl-methionyl-leucyl-phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA). In separate tubes each subject's leukocytes were tested for spontaneous LTC4 production. Finally, stimulated LTC4 production was expressed in pg/mL after subtraction of values of spontaneous production. RESULTS: In asthmatics, baseline FVC% and FEV% values ranged from 24.4% to 122.4% (mean, 75.5%) and from 23.4% to 126.6% (mean, 74.4%), respectively. There were no significant differences between asthmatics and controls in LTC4 production stimulated by anti-FcepsilonRI antibody (P = .79), fMLP (P = .33) or PMA (P = .86). We found no correlation between stimulated LTC4 production and spirometric parameters at baseline or after bronchodilator administration or annual decline in FEV1%. CONCLUSION: Our results do not confirm the hypothesis that airway remodeling in asthma might be related to enhanced ability of leukocytes to produce cysteinyl leukotrienes in response to various stimuli.

[Pathogenesis of exercise induced asthma]. / Patogeneza astmy wysilkowej.

Exercise induced asthma is an exaggerated airway response to airway dehydration and the following mediators release from the inflammatory cells. The airway narrowing is primarily caused by bronchial smooth muscle contraction, but in milder form mucus production, airway edema and cough can be observed. In this study we have described some previously and currently proposed hypotheses which may explain pathomechanism of this form of bronchial hyperreactivity.

[Influence of long-term low molecular weight heparin nebulization on selected clinical parameters and course of allergic inflammation in patients with bronchial asthma]. / Wplyw heparyny niskoczasteczkowej w przewleklej nebulizacji na wybrane parametry kliniczne i przebieg zapalenia alergicznego u pacjentów z astma oskrzelowa.

Bronchial asthma is a chronic condition with an inflammatory background--allergic inflammation. In recent years several observations have been published documenting activity of low molecular weight heparin (LMWH) in chronic inflammatory diseases of respiratory tract. This study was set up to evaluate the effect of nebulized LMWH on spirometric parameters and selected markers of allergic inflammation in bronchial asthma. Twenty patients diagnosed with mild or moderate asthma entered the study. At the beginning and at the end of the experiment every patient underwent bronchoscopy with BAL and in 15 of them bronchial biopsy was performed. Blood was drawn for ECP evaluation. LMWH was administered in nebulization in a dose 5000 U Xa/day for two weeks. BALf cellularity was evaluated as well as BALf IL-5 concentration. Further ELAM-1 and VCAM-1 expression in bronchial mucosa was examined in immunohistochemistry. We demonstrated that heparin treatment significantly enhanced FEV1 from 76.02 +/- 21.7% nominate value before to 92.4 +/- 21.8% after treatment (p < 0.005). Cellular profile of BALf changed, showing significant drop in percentages of eosinophils--from 7% to 6% (p < 0.05), macrophages--38 to 32% (p < 0.05) and neutrophils--32 to 28% (p < 0.05). Surprisingly we did not notice any change in ECP concentration in blood serum or IL-5 in BALf. Also adhesion molecules expression in bronchial mucosa remained unchanged. We conclude that chronic LMWH nebulization is a valuable treatment ameliorating asthmatic condition clearly due to anti-inflammatory properties of heparin. Both dose of LMWH used and the time of therapy have to be further investigated in order to develop treatment able to influence more of the elements of allergic inflammation.

Effect of recombinant IFN-gamma on igE-dependent leukotriene generation by peripheral blood leukocytes in patients with pollinosis and asthma.

Interferon gamma (IFN-gamma) is considered one of the causative and intensifying factors in inflammation. The reaction to allergens releases IFN-gamma, an immunomodulatory cytokine known to inhibit IgE synthesis and Th cell proliferation. The aim of the study was to evaluate the influence of IFN-gamma on leukotriene (LT) release in vitro, from human leukocytes of atopic patients with pollinosis and asthma. Thirty-eight patients were enrolled in the study: 15 with pollinosis and 23 asthmatics. In the presence of IL-3, leukocytes were stimulated with specific allergens. Other samples of leukocytes were preincubated with different concentrations of IFN-gamma for 15 min before allergen stimulation. The concentration of LT in supernatants was measured according to the CAST-ELISA procedure. We stated that IFN-gamma had significantly diminished LT release in a dose-dependent mode from the leukocytes of pollinotics. IFN-gamma did not change LT release in the asthmatic group, although, in leukocytes the small and medium basic production of LT, IFN-gamma caused a statistically significant fall in LT generation.

[Allergy to nickel, chromium and cobalt after osteosynthesis]. / Alergia na nikiel, chrom i kobalt po zespoleniu kosci za pomoca laczników metalowych.

Metals are known as a common cause of contact allergies. The prevalence of sensitisation to the composite metals makes for a potential risk of osteosynthesis complications in patients suffering from long bones fractures. In the study the prevalence of delayed allergy to nickel sulphate, potassium dichromate and cobalt was estimated as well as the relation to the osteosynthesis complications. The atopy prevalence was estimated too. Persons under examination were divided into 3 groups. I--treated with osteosynthesis without complications (n = 20), II--treated with osteosynthesis with synostosis complications (n = 16) and III--negative controls (n = 34). We estimated 5% prevalence of delayed allergy to nickel in group I, 6.25% in group II and 5.8% in group III. In patients exposed to chromium we observed delayed allergy prevalence of 5.8% in group I and 3% in group III. No allergy to chromium in group II was revealed. No allergy to cobalt in all groups was revealed. The prevalence of atopy in group II was rare (6.35%) when in group I it was 45% and in controls 32%. The more frequent occurrence of type IV allergy to metals in atopic patients was not confirmed. There was no difference between the prevalence of delayed allergy to metals in groups I and II. Only one case of secondary allergy to chromium was observed.

[Bronchial hyperreactivity to histamine and levels of serum eosinophil cationic protein in patients with non-atopic asthma]. / Nadreaktywnosc oskrzeli na histamine a stezenie eozynofilowego bialka kationowego w surowicy chorych na astme oskrzelowa nieatopowa.

Pathogenesis of non-atopic bronchial asthma remains still an open question. Until now there have been very few studies concerning relationship between eosinophil activation and nonspecific bronchial hyperreactivity to histamine in this form of asthma. Sixteen subjects with mild nonatopic bronchial asthma entered the study. Evaluations of PC 20 for histamine and serum eosinophil cationic protein (ECP) concentration have been performed in all patients. In spite of fact that all patients were considered as mild asthmatic we have observed wide range of PC 20 and serum ECP concentration. Moreover we were able to find statistically significant inverse correlation between PC 20 for histamine and serum eosinophil cationic protein concentration: r = -0.498, p < 0.05. We conclude that eosinophil activation plays an important role in pathophysiology of nonspecific bronchial hyperreactivity in nonatopic bronchial asthma.

[The evaluation of concentration myeloperoxidase and interleukin-8 in blood serum of pregnant women with or without pregnancy induced hypertension]. / Ocena stezen mieloperoksydazy i interleukiny-8 w surowicy krwi ciezarnych z nadcisnieniem indukowanym ciaza oraz w ciazach fizjologicznych.

In the serum of woman during the pregnancy with and without PIH the activity of interleukin-8 and myeloperoxydase was measured. 40 pregnant woman with PIH and 16 normal pregnant woman were included in the study. We have not found significative difference between examined populations.