Up-regulation of Toll-like receptors 2, 3 and 4 in allergic rhinitis

BACKGROUND: Toll-like receptors enable the host to recognize a large number of pathogen-associated molecular patterns such as bacterial lipopolysaccharide, viral RNA, CpG-containing DNA and flagellin. Toll-like receptors have also been shown to play a pivotal role in both innate and adaptive immune responses. The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. The present study was designed to examine the expression of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with intermittent allergic rhinitis, focusing on changes induced by exposure to pollen. METHODS: 27 healthy controls and 42 patients with seasonal allergic rhinitis volunteered for the study. Nasal biopsies were obtained before and during pollen season as well as before and after allergen challenge. The seasonal material was used for mRNA quantification of Toll-like receptors 2, 3 and 4 with real-time polymerase chain reaction, whereas specimens achieved in conjunction with allergen challenge were used for immunohistochemical localization and quantification of corresponding proteins. RESULTS: mRNA and protein representing Toll-like receptors 2, 3 and 4 could be demonstrated in all specimens. An increase in protein expression for all three receptors could be seen following allergen challenge, whereas a significant increase of mRNA only could be obtained for Toll-like receptor 3 during pollen season. CONCLUSION: The up-regulation of Toll-like receptors 2, 3 and 4 in the nasal mucosa of patients with symptomatic allergic rhinitis supports the idea of a role for Toll-like receptors in allergic airway inflammation

Regulation of neutrophil senescence by microRNAs

Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease

Spontaneous preterm labor is associated with an increase in the proinflammatory signal transducer TLR4 receptor on maternal blood monocytes

<p>Abstract</p> <p>Background</p> <p>Localized inflammation and increased expression of TLR4 receptors within the uterus has been implicated in the pathogenesis of preterm labor. It remains unclear whether intrauterine inflammatory responses activate the maternal peripheral circulatory system. Therefore we determined whether increased TLR4 expression is present in the peripheral maternal white blood cells of women with spontaneous preterm labor.</p> <p>Methods</p> <p>This is a cross-sectional study of 41 preterm labor cases and 41 non-preterm controls. For each case and control sample, RNA was purified from white blood cells and TLR4 mRNA pool size was evaluated by quantitative PCR. Protein expression levels were determined by flow cytometry. Statistical evaluation using multiple linear regressions was used to determine any significant differences between the cases and controls. The purpose was to determine association prevalence of TLR4 levels and preterm labor.</p> <p>Results</p> <p>Adjusted mean TLR4 mRNA levels of 0.788 ± 0.037 (standard error) for preterm labor and 0.348 ± 0.038 for the corresponding pregnant control women were statistically significantly different <it>(P </it>= 0.002). Using the lower 95% confidence interval of the mean expression level in PTL subjects (0.7) as a cutoff value for elevated TLR4 mRNA levels, 25/41 (60.9%) of PTL patients expressed elevated TLR4 mRNA as compared to 0/41 (0%) in control subjects. The TLR4 receptor levels in the granulocyte fraction of white blood cells from preterm labor and pregnant controls were similar. However, TLR4⁺/CD14⁺monocytes were 2.3 times more frequent (70% vs. 30%) and TLR4 also had a 2.6-fold higher density (750 vs. 280 molecules per cell) in preterm labor women compared with pregnant controls. There was no difference in the levels of TLR4 in patients at term.</p> <p>Conclusions</p> <p>Patients with preterm labor exhibited elevated levels of CD14⁺maternal blood monocytes each bearing enhanced expression of TLR4, indicating that the peripheral circulatory system is activated in patients with preterm labor. Elevated leukocyte TLR4 levels may be a useful biomarker associated with preterm labor.</p

Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor

Until recently it was assumed that hereditary angioedema is a disease that results exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity and protein in plasma were described. Since then numerous patients and families with that condition have been reported. Most of the patients by far were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. Recently, in some families mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons

Identification of cardiac MRI thresholds for risk stratification in pulmonary arterial hypertension

Rationale: Pulmonary arterial hypertension (PAH) is a life-shortening condition. The European Society of Cardiology and European Respiratory Society and the REVEAL (North American Registry to Evaluate Early and Long-Term PAH Disease Management) risk score calculator (REVEAL 2.0) identify thresholds to predict 1-year mortality. Objectives: This study evaluates whether cardiac magnetic resonance imaging (MRI) thresholds can be identified and used to aid risk stratification and facilitate decision-making. Methods: Consecutive patients with PAH (n = 438) undergoing cardiac MRI were identified from the ASPIRE (Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Center) MRI database. Thresholds were identified from a discovery cohort and evaluated in a test cohort. Measurements and Main Results: A percentage-predicted right ventricular end-systolic volume index threshold of 227% or a left ventricular end-diastolic volume index of 58 ml/m2 identified patients at low (10%) risk of 1-year mortality. These metrics respectively identified 63% and 34% of patients as low risk. Right ventricular ejection fraction >54%, 37–54%, and <37% identified 21%, 43%, and 36% of patients at low, intermediate, and high risk, respectively, of 1-year mortality. At follow-up cardiac MRI, patients who improved to or were maintained in a low-risk group had a 1-year mortality <5%. Percentage-predicted right ventricular end-systolic volume index independently predicted outcome and, when used in conjunction with the REVEAL 2.0 risk score calculator or a modified French Pulmonary Hypertension Registry approach, improved risk stratification for 1-year mortality. Conclusions: Cardiac MRI can be used to risk stratify patients with PAH using a threshold approach. Percentage-predicted right ventricular end-systolic volume index can identify a high percentage of patients at low-risk of 1-year mortality and, when used in conjunction with current risk stratification approaches, can improve risk stratification. This study supports further evaluation of cardiac MRI in risk stratification in PAH

Tracing Personalized Health Curves during Infections

By concentrating on the relationship between health and microbe number over the course of infections, most pathogenic and mutualistic infections can be summarized by a small alphabet of curves, which has implications not only for basic research but for how we might treat patients

Expression of Toll-like Receptor 9 in nose, peripheral blood and bone marrow during symptomatic allergic rhinitis

BACKGROUND: Allergic rhinitis is an inflammatory disease of the upper airway mucosa that also affects leukocytes in bone marrow and peripheral blood. Toll-like receptor 9 (TLR9) is a receptor for unmethylated CpG dinucleotides found in bacterial and viral DNA. The present study was designed to examine the expression of TLR9 in the nasal mucosa and in leukocytes derived from different cellular compartments during symptomatic allergic rhinitis. METHODS: The study was based on 32 patients with seasonal allergic rhinitis and 18 healthy subjects, serving as controls. Nasal biopsies were obtained before and after allergen challenge. Bone marrow, peripheral blood and nasal lavage fluid were sampled outside and during pollen season. The expression of TLR9 in tissues and cells was analyzed using immunohistochemistry and flow cytometry, respectively. RESULTS: TLR9 was found in several cell types in the nasal mucosa and in different leukocyte subpopulations derived from bone marrow, peripheral blood and nasal lavage fluid. The leukocyte expression was generally higher in bone marrow than in peripheral blood, and not affected by symptomatic allergic rhinitis. CONCLUSION: The widespread expression of TLR9 in the nasal mucosa along with its rich representation in leukocytes in different compartments, demonstrate the possibility for cells involved in allergic airway inflammation to directly interact with bacterial and viral DNA

Number of siblings and the risk of solid tumours: a nation-wide study

We analysed the effects of number of siblings on the risk of solid tumours using the Swedish Family-Cancer Database, including population-based information on over 11 million individuals and more than 178 000 cancer patients diagnosed between 1958 and 2004. Incidence rate ratios (RRs), estimated by Poisson regression models, were adjusted for age, sex, birth cohort, area of residence and socioeconomic status. Having eight or more siblings vs none increased the risk of stomach cancer (RR=1.83, 95% confidence interval (CI), 1.44–2.34). Anal cancer diagnosed before age 40 showed the strongest association with the total siblings (RR=3.27, 95% CI, 2.04–5.26 for five or more siblings vs none). Endometrial (RR=0.76, 95% CI, 0.70–0.82), testicular (RR=0.71, 95% CI, 0.62–0.82), skin cancer (RR=0.82, 95% CI, 0.69–0.97) and melanoma (RR=0.72, 95% CI, 0.65–0.79) showed strong decreased risks for five or more siblings vs none. Prostate cancer risk for those with five or more older siblings vs none was 1.38 (95% CI, 1.23–1.55). Having five or more younger siblings was most strongly associated with stomach cancer (RR=1.59, 95% CI, 1.29–1.95) and melanoma (RR=0.68, 95% CI, 0.59–0.79). We conclude that sibship characteristics are strong correlates of cancer risk at several sites; plausible interpretations include socioeconomic status

Macrophage phenotype is associated with disease severity in preterm infants with chronic lung disease.

The etiology of persistent lung inflammation in preterm infants with chronic lung disease of prematurity (CLD) is poorly characterized, hampering efforts to stratify prognosis and treatment. Airway macrophages are important innate immune cells with roles in both the induction and resolution of tissue inflammation