Effect of the compound L-mimosine in an in vivo model of chronic granuloma formation induced by potassium permanganate (KMNO4).

The plant amino acid L-mimosine has recently been suggested to inhibit cells at a regulatory step in late G phase before establishment of active DNA replication forks. In addition, L-mimosine is an extremely effective inhibitor of DNA replication in chromosomes of mammalian nuclei. In this work, the effect of L-mimosine on chronic inflammation induced by dorsal injections of 0.2 ml of a 1:40 saturated crystal solution of potassium permanganate in mice, was studied. Seven days afterwards, all mice developed a subcutaneous granulomatous tissue indicative of chronic inflammatory response at the site of infection. The intraperitoneal administration of L-mimosine (200 μg/dose) to the potassium permanganate treated mice for 5 consecutive days (the first at the same time of inoculation of the KMnO4), produced a significant decrease in size and weight of the granuloma when compared to mice not treated with L-mimosine (controls). In addition, in all mice treated with L-mimosine, there was a strong inhibition of tumor necrosis factor alpha that was revealed in the serum (P<0.05) and in the minced granulomas. Interleukin-6 was not detected in the serum of treated and untreated mice. These findings show for the first time, that L-mimosine may have an anti-inflammatory effect on chronic inflammation and an inhibitory effect on tumor necrosis factor alpha and interleukin-6 generation in supernatant fluids of minced granulomas

Prospective cohort study of procalcitonin levels in children with cancer presenting with febrile neutropenia

BACKGROUND: Febrile neutropenia (FNP) causes significant morbidity and mortality in children undergoing treatment for cancer. The development of clinical decision rules to help stratify risks in paediatric FNP patients and the use of inflammatory biomarkers to identify high risk patients is an area of recent research. This study aimed to assess if procalcitonin (PCT) levels could be used to help diagnose or exclude severe infection in children with cancer who present with febrile neutropenia, both as a single measurement and in addition to previously developed clinical decision rules. METHODS: This prospective cohort study of a diagnostic test included patients between birth and 18 years old admitted with febrile neutropenia to the Paediatric Oncology and Haematology Ward in Leeds between 1(st) October 2012 and 30(th) September 2013. Each admission with FNP was treated as a separate episode. Blood was taken for a procalcitonin level at admission with routine investigations. 'R' was used for statistical analysis. Likelihood ratios were calculated and multivariable logistic regression. RESULTS: Forty-eight episodes from 27 patients were included. PCT >2 ng/dL was strongly associated with increased risk of severe infection (likelihood ratio of 26 [95% CI 3.5, 190]). The data suggests that the clinical decision rules are largely ineffective at risk stratification, frequently over-stating the risk of individual episodes. High procalcitonin levels on admission are correlated with a greatly increased risk of severe infection. CONCLUSIONS: This study does not show a definitive benefit in using PCT in FNP though it supports further research on its use. The benefit of novel biomarkers has not been proven and before introducing new tests for patients it is important their benefit above existing features is proven, particularly due to the increasing importance of health economics

The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia

In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis. Plasma was obtained from pediatric oncology patients at presentation with febrile neutropenia (n = 43) and 24-48 h later (n = 17). The patients were classified as having or not having a bacterial infection. Plasma was also obtained of patients in the absence and in the presence of mucositis (n = 26). At presentation with febrile neutropenia, median IL-8 and PCT levels were significantly increased in patients with a bacterial infection, in contrast to CRP and sTREM-1. IL-8 was the most sensitive marker for the early detection of bacterial infection, in combination with clinical parameters or PCT the sensitivity reached 100%. After 24-48 h, only PCT was significantly elevated during bacterial infection. IL-8 levels were significantly increased during mucositis. Mucositis did not cause considerable changes in PCT levels. IL-8 is the most useful marker for the early detection of bacterial infections, compared with CRP, PCT, and sTREM-1. IL-8 in combination with clinical parameters or PCT might be even more useful. Gastrointestinal mucositis alone does not affect PCT levels, in contrast to IL-8 levels, and therefore, PCT might be more useful for the detection of bacterial infections during mucositis than IL-8

The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008

Primary immunodeficiencies (PID) are rare diseases; therefore transnational studies are essential to maximize the scientific outcome and to improve diagnosis and therapy. In order to estimate the prevalence of PID in Europe as well as to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Within 4 years, 7430 patients from 39 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity, with 1540 patients or 20.7% of all entries, followed by isolated immunoglobulin (Ig)G subclass deficiency (546 patients, 7.4%). Evaluations show that the average life expectancy for PID patients varies from 1 to 49 years (median), depending on the type of PID. The prevalence and incidence of PID remains a key question to be answered. As the registration progress is far from finished we can only calculate minimum values for PID, with e.g. France currently showing a minimum prevalence of 3.72 patients per 100,000 inhabitants. The most frequently documented permanent treatment is immunoglobulin replacement; 2819 patients (42% of all patients alive) currently receive this form of treatment

Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer

Background: Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people. Methods: This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485. Results: We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules. Conclusions: The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study

Novel Diagnostic Approaches to Adamantiades-Behcet's Disease

A 10 year old boy had visual deterioration in both eyes. Visual acuity was 0.2 in the right and 0.3 in the left eye. Further ophthalmologic findings were typical of posterior uveitis. The pediatric physical examination also disclosed aphthous stomatitis and recurrent aphthous genital ulcers. At diagnosis serum levels of IL-1β, IL-6, IL-8, TNF-α, sIL-2R, MCP-1, VEGF, tADA activity in the patient with active and ABD relapse were significantly higher than those in the inactive period of the disease, suggesting that these parameters may be related to disease activity. In addition to the proinflammatory chemokines and cytokines, plasma levels of VEGF and serum tADA activity may be used for the diagnosis of ABD and for monitoring the effect of treatment, as well as the follow-up period. Also, further studies of VEGF may lead to novel therapies with antibodies or other VEGF inhibitors

Procalcitonin and Inflammatory Cytokines in Children with Asthma

Asthma is currently defined as a chronic inflammatory disorder of the airway mucosa. The resulting inflammation of the airway mucosa shows signs of an acute as well as a more chronic type of inflammation. Cytokine-mediated interactions among the inflammatory cells may play a role in the pathogenesis of bronchial asthma. The aim of this study is to assess inflammatory agents as markers of chronic inflammation in childhood asthma and as indicators for determining the state of the disease. This study included 3 groups of children. Group A consisted of 35 children with asthma and FEV1<80% of predicted values, 24 boys, 11 girls, aged (mean age ± SE) 9.3 ± 0.4 years, Group B of 70 children with asthma and FEV1≥80% of predicted values, 44 boys, 26 girls, aged 8.65 ± 0.36 years and Group C of 48 healthy children, 33 boys, 15 girls, aged 10.73 ± 0.4 years. In serum, levels of PCT were determined by immunoluminescence, CRP by nephelometry and cytokines IL-1β, IL-6, IL-4 and IL-5 by ELISA. Our results show that the mean concentration of CRP and PCT were not significantly different between groups A, B and C. The mean values of IL-1β were significantly different between groups A, B and C. The mean values of IL-6 were higher in group A than those of Groups B and C, although the difference between the groups was not statistically significant. The mean values of Th2 cytokines IL-4 and IL-5 were significantly different between groups A, B and C. In conclusion, CRP and PCT levels did not play any role in airway allergic inflammation, while strong indications were found that sera levels of inflammatory cytokines associated mainly with Th2 responses play a key role in airway allergic inflammation

Serial procalcitonin responses in infection of children with secondary immunodeficiency

Purpose: Procalcitonin has proven to be a sensitive inflammatory marker in non-neutropenic patients. The aim of this study was to determine and compare Procalcitonin with other inflammatory markers in the serum of immunosuppressed children with haematological malignancies; and to assess the predictive value of these mediators in distinguishing between bacterial and non-bacterial infection. Methods & Results: The study included 37 children with acute lymphoblastic leukaemia undergoing intensive chemotherapy. They were divided into 3 groups, A, B and C. Group A consisted of 29 neutropenic children with 94 febrile episodes, group B of 20 neutropenic children with 56 afebrile episodes and group C of 13 non-neutropenic children with 58 afebrile episodes. Serial serum levels of PCT, C-Reactive Protein, Neopterin, Interleukin-6 and NO2/NO3 were all determined on a day-to-day basis for 7 consecutive days. In serum the concentrations of CRP was determined by nephelometry, of PCT by immunoluminescence and of Neopterin, IL-6 and NO2/NO3 by ELISA method. Conclusions: According to our results the Procalcitonin concentration increased rapidly in patients with microbial infection; the response was detectable within 24 hs of the onset of fever due to microbial infections. Procalcitonin is a spesific and sensitive marker of microbial infection in patients with neutropenic fever. The markers, C-Reactive Protein, Interleukin-6 and NO2/NO3 may not help to identify infections and distinguishe the etiology of infection in neutropenic febrile children with acute lymphoblastic leukaemia

Chemokines and Their Role in Parasitic Diseases

Chemotactic cytokines (chemokines), the intercellular mediators, produced and released by a wide variety of cell types, are a group of small secreted proteins (8–10 KDa), which mediate host response to invading organisms (viruses, bacteria, parasites), trauma or tumor. The trafficking, recruiting and recirculation of leukocytes, which is essential in acute and chronic inflammation is controlled by chemokines. This review introduces the three supergene families of chemokines (CXC, CC and C), with emphasis on their adhesion mechanism, biological effects, regulation of expression and critical role in different disease states in humans and in animal models with parasitic diseases

Mediators of Inflammation in Children with Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) in children remains a challenging problem. Crohn disease and ulcerative colitis are characterized by an activation of intestinal mononuclear cells and T-cells within the inflammed lesions. In the present study, we determined whether circulating inflammatory mediators, such as interleukins and adhesion molecules, may represent useful markers of immune activation in vivo. Serum concentrations of IL-2, IL-6, IL-8, IL-10, sIL-2R, sICAM-1 and sVCAM-1 were measured by a quantitative enzyme-linked immunosorbent assay (ELISA) in 18 patients with IBD and 25 healthy subjects matched for age and sex (control group). According to our results, all the inflammatory mediators are significantly increased in patients with IBD as compared to the control group. Pro-inflammatory mediators (IL-6, IL-8, IL-10) are elevated in the serum of patients with active disease, suggesting that they act as naturally occuring initiators of the acute inflammatory process. Increased IL-2 and sIL-2R levels reflect T-cell activation. Increased circulating sICAM-1 and sVCAM-1 levels may reflect increased adhesiveness and signal transmission across cells, probably as a result of shedding of the parent molecule during local cellular immunoresponses in vivo . The measurement of inflammatory mediators may be a useful adjunct to the clinical assessment and to the routine laboratory testing of IBD pediatric patients