[Show abstract][Hide abstract] ABSTRACT: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place.
In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects.
Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1.
These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to ascertain the effect of weight loss over the course of 1 year on 5-year mortality in old nursing home (NH) residents in different classes of body mass index (BMI).
A longitudinal study was conducted on 161 NH residents aged ⩾70 years at the Istituto di Riposo per Anziani, Padova, Italy. Data were collected using a comprehensive geriatric assessment at baseline and at a 1-year follow-up visit. Mortality was recorded over a 5-year follow-up. We divided our sample into four groups using as cutoffs a BMI of 25 and a weight gain or loss of 5% at 1 year (BMI ⩾25 and weight stable/gain, BMI ⩾25 and weight loss, BMI<25 and weight stable/gain and BMI <25 and weight loss).
People with a BMI ⩾25 and weight loss suffered the worst decline in activities of daily living, whereas those with a BMI <25 and weight loss had the most significant decline in nutritional status, which coincided with the worst decline in the Multidimensional Prognostic Index among the groups whose weight changed. Compared with those with a BMI ⩾25 and weight stable/gain (reference group), those with a BMI <25 were at the highest risk of dying (in association with weight loss: hazard ratio HR=3.60, P=0.005; in association with weight stable/gain: HR=2.45, P=0.01), and the mortality risk was also increased in people with a BMI ⩾25 and weight loss (HR=1.74, P=0.03).
In conclusion, weight loss increases the mortality risk in frail, disabled NH residents, even if they are overweight or obese.European Journal of Clinical Nutrition advance online publication, 11 March 2015; doi:10.1038/ejcn.2015.19.
European Journal of Clinical Nutrition 03/2015; 69(10). DOI:10.1038/ejcn.2015.19 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The Paediatric Residency Program (PRP) of Padua, Italy, developed a set of questionnaires to assess the quality of the training provided by each faculty member, the quality of the professional experience the residents experienced during the various rotations and the functioning of the Resident Affair Committee (RAC), named respectively: ¿Tutor Assessment Questionnaire¿ (TAQ), ¿Rotation Assessment Questionnaire¿ (RAQ), and RAC Assessment Questionnaire¿. The process that brought to their validation are herein presented.Method
Between July 2012 and July 2013, 51 residents evaluated 26 tutors through the TAQ, and 25 rotations through the RAQ. Forty-eight residents filled the RAC Assessment Questionnaire. The three questionnaires were validated through a many-facet Rasch measurement analysis.ResultsIn their final form, the questionnaires produced measures that were valid, reliable, unidimensional, and free from gender biases. TAQ and RAQ distinguished tutors and rotations into 5¿6 levels of different quality and effectiveness. The three questionnaires allowed the identification of strengths and weaknesses of tutors, rotations, and RAC. The agreement observed among judges was coherent to the predicted values, suggesting that no particular training is required for developing a shared interpretation of the items.Conclusions
The work herein presented serves to enrich the armamentarium of tools that resident medical programs can use to monitor their functioning. A larger application of these tools will serve to consolidate and refine further the results presented.
Italian Journal of Pediatrics 01/2015; 41(1):2. DOI:10.1186/s13052-014-0106-2 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Problematic severe asthma is a heterogeneous disease with multiple phenotypes. It is rare (<5% of children with asthma), but accounts for 30-50% of all pediatric asthma healthcare costs. This review looks into the currently used management strategies and the innovative treatments, considering both conventional medications and innovative biological therapies for targeting airway inflammation.
Patients with problematic severe asthma should be seen by pediatric asthma specialists using a stepwise approach. The first step is to exclude alternative diagnoses; the second is to consider and exclude comorbidities, and assess adherence to medication; the third step involves identifying the pattern of inflammation; and response to treatment in the fourth. Innovative biological therapies are emerging and healthcare professionals should know how to handle them. Patient phenotyping is the main step towards a targeted therapeutic strategy.
A careful management is important for children with severe asthma, who form a small but challenging group of patients. More research efforts are needed to enable a personalized medicine and a biomarker-driven approach.
Current opinion in pulmonary medicine 01/2015; 21(1):16-21. DOI:10.1097/MCP.0000000000000121 · 2.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: S-nitrosoglutathione is an endogenous airway smooth muscle relaxant. Increased airway S-nitrosoglutathione breakdown occurs in some asthma patients. We asked whether patients with increased airway catabolism of this molecule had clinical features that distinguished them from other asthma patients. We measured S-nitrosoglutathione reductase expression and activity in bronchoscopy samples taken from 66 subjects in the Severe Asthma Research Program. We also analysed phenotype and genotype data taken from the program as a whole. Airway S-nitrosoglutathione reductase activity was increased in asthma patients (p = 0.032). However, only a subpopulation was affected and this subpopulation was not defined by a "severe asthma" diagnosis. Subjects with increased activity were younger, had higher IgE and an earlier onset of symptoms. Consistent with a link between S-nitrosoglutathione biochemistry and atopy: 1) interleukin 13 increased S-nitrosoglutathione reductase expression and 2) subjects with an S-nitrosoglutathione reductase single nucleotide polymorphism previously associated with asthma had higher IgE than those without this single nucleotide polymorphism. Expression was higher in airway epithelium than in smooth muscle and was increased in regions of the asthmatic lung with decreased airflow. An early-onset, allergic phenotype characterises the asthma population with increased S-nitrosoglutathione reductase activity.
European Respiratory Journal 10/2014; 45(1). DOI:10.1183/09031936.00042414 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease often originate early in life. In addition to a genetic predisposition, prenatal and early-life environmental exposures have a persistent impact on respiratory health. Acting during a critical phase of lung development, these factors may change lung structure and metabolism, and may induce maladaptive responses to harmful agents, which will affect the whole lifespan. Some environmental factors, such as exposure to cigarette smoke, type of childbirth and diet, may be modifiable, but it is more difficult to influence other factors, such as preterm birth and early exposure to viruses or allergens. Here, we bring together recent literature to analyse the critical aspects involved in the early stages of lung development, going back to prenatal and perinatal events, and we discuss the mechanisms by which noxious factors encountered early on may have a lifelong impact on respiratory health. We briefly comment on the need for early disease biomarkers and on the possible role of "-omic" technologies in identifying risk profiles predictive of chronic respiratory conditions. Such profiles could guide the ideation of effective preventive strategies and/or targeted early lifestyle or therapeutic interventions.
European Respiratory Journal 10/2014; 44(6). DOI:10.1183/09031936.00084114 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
To assess a group of adolescents with bronchopulmonary dysplasia (BPD) from a biochemical-metabolic standpoint, applying the metabolomic approach to studying their exhaled breath condensate (EBC).
Twenty adolescents with BPD (mean age 14.8 years) and 15 healthy controls (mean age 15.2 years) were recruited for EBC collection, exhaled nitric oxide measurement, and spirometry. The EBC samples were analyzed using a metabolomic approach based on mass spectrometry. The obtained spectra were analyzed using multivariate statistical analysis tools.
A reliable Orthogonal Projections to Latent Structures-Discriminant Analysis model showed a clear discrimination between cases of BPD and healthy controls (R(2) = 0.95 and Q(2) = 0.92). The search for putative biomarkers identified an altered complex lipid profile in the adolescents with BPD.
The metabolomic analysis of EBC distinguishes cases of BPD from healthy individuals, suggesting that the lung of survivors of BPD is characterized by long-term metabolic abnormalities. The search for putative biomarkers indicated a possible role of an altered surfactant composition, which may persist far beyond infancy.
Journal of Pediatrics 10/2014; 166(2). DOI:10.1016/j.jpeds.2014.08.049 · 3.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Among the risk factors for osteoporosis and fractures, gynecological history (fertile period, parity and breastfeeding) play an important part. Changes in calcium metabolism to enable an adequate mineral transfer to the milk have a prominent role in bone loss during breastfeeding. Data on the influence of breastfeeding in postmenopausal osteoporosis are inconsistent. The aim of the present study was to identify any association between duration of breastfeeding and vertebral fractures in postmenopausal women.
All patients underwent the following tests: bone mineral density measurements of the lumbar spine (L1-L4) and the total and femoral neck using dual-energy X-ray absorptiometry and antero-posterior and lateral radiography of the thoracic and lumbar spine to identify vertebral fractures.
The study involved 752 women with a mean age of 64.5±9.3; 23% of them reported vertebral osteoporotic fractures. The women with vertebral fractures had breastfed for longer periods (11.8±12.9 vs. 9.3±11.2months, p=0.03) and had more pregnancies (2.6±2.2 vs. 2.2±1.3, p=0.002). Breastfeeding for more than 18months was associated with a two-fold risk of developing vertebral fractures (OR 2.12, 95% CI 1.14-5.38, p=0.04), particularly in those without current or past use of drugs positively affecting bone.
Our study showed an association between long periods of breastfeeding and vertebral fractures, supporting a role for lengthy lactation as a risk factor for osteoporotic fractures after menopause. Bearing in mind all the benefits of breastfeeding, this finding suggests the importance of an adequate calcium and vitamin D intake during pregnancy and breastfeeding, with the aid of dietary supplements if necessary.
Bone 08/2014; 68. DOI:10.1016/j.bone.2014.08.001 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High serum levels of insulin-like growth factor-1 (IGF-1) seem to coincide with higher rates of some types of cancer and the risk of all-cause mortality in old people. Eating vegetables seems to reduce IGF-1 levels because they are rich in micronutrients such as vitamins. This study investigates the possible association between vitamin intake and IGF-1 levels in a representative group of healthy elderly women with Mediterranean dietary habits.
This cross-sectional study included 124 healthy women with a mean age of 71.3±4.2years and a mean body mass index (BMI) of 27.37±3.48kg/m(2) attending a mild fitness program twice a week at public gyms in Padova. The main parameters considered were IGF-1 (measured by chemiluminescence) and diet, assessed on the basis of a 3-day record and a questionnaire on the frequency with which they usually ate certain foods.
The mean IGF-1 level for the sample as a whole was 136.2±38.9μg/l, and was significantly lower in women with a higher folate intake (p=0.04). On simple linear analysis, the vitamins found associated with serum IGF-1 levels were: folates (r: -0.25; p=0.003); vitamin E (r: -0.21; p=0.01); vitamin D (r: -0.17; p=0.03); and riboflavin (r: -0.16; p=0.03). After removing the effect of calorie, protein, carbohydrate and fat intake, and other known potential confounders (age, BMI, alcohol intake), only folate intake correlated with IGF-1 levels (r=-0.17; p=0.04).
A folate-rich diet could have the effect of lowering circulating IGF-1 levels in elderly women.
Growth hormone & IGF research: official journal of the Growth Hormone Research Society and the International IGF Research Society 09/2013; 23(6). DOI:10.1016/j.ghir.2013.09.003 · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy. From a clinical standpoint BPD subjects are characterized by recurrent respiratory symptoms, which are very frequent during the first years of life and, although becoming less severe as children grow up, they remain more common than in term-born controls throughout childhood, adolescence and into adulthood. From a functional point of view BPD subjects show a significant airflow limitation that persists during adolescence and adulthood and they may experience an earlier and steeper decline in lung function during adulthood. Interestingly, patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations during childhood and later on, suggesting that also prematurity per se has life-long detrimental effects on pulmonary function. For the time being, little is known about the presence and nature of pathological mechanisms underlying the clinical and functional picture presented by BPD survivors. Nonetheless, recent data suggest the presence of persistent neutrophilic airway inflammation and oxidative stress and it has been suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD. This hypothesis is intriguing but more pathological data are needed. A better understanding of these pathogenetic mechanisms, in fact, may be able to orient the development of novel targeted therapies or prevention strategies to improve the overall respiratory health of BPD patients.
Early human development 08/2013; 89. DOI:10.1016/j.earlhumdev.2013.07.015 · 1.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In order to help assess resident performance during training, the Residency Affair Committee of the Pediatric Residency Program of the University of Padua (Italy) administered a Resident Assessment Questionnaire (ReAQ), which both residents and faculty were asked to complete. The aim of this article is to present the ReAQ and its validation.
The ReAQ consists of 20 items that assess the six core competencies identified by the Accreditation Council of Graduate Medical Education (ACGME). A many-facet Rasch measurement analysis was used for validating the ReAQ.
Between July 2011 and June 2012, 211 evaluations were collected from residents and faculty. Two items were removed because their functioning changed with the gender of respondents. The step calibrations were ordered. The self evaluations (residents rating themselves) positively correlated with the hetero evaluations (faculty rating residents; Spearman's rho = 0.75, p < 0.001). Unfortunately, the observed agreement among faculty was smaller than expected (Exp = 47.1%; Obs = 41%), which indicates that no enough training to faculty for using the tool was provided.
In its final form, the ReAQ provides a valid unidimensional measure of core competences in pediatric residents. It produces reliable measures, distinguishes among groups of residents according to different levels of performance, and provides a resident evaluation that holds an analogous meaning for residents and faculty.
Italian Journal of Pediatrics 07/2013; 39(1):41. DOI:10.1186/1824-7288-39-41 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Food allergy is an increasingly prevalent problem all over the world and especially in westernized countries, and there is an unmet medical need for an effective form of therapy. During childhood natural tolerance development is frequent, but some children with cow's milk or hen's egg allergy and the majority of children with peanut allergy will remain allergic until adulthood, limiting not only the diet of patients but also their quality of life. Within the last several years, the usefulness of immunotherapy for food allergies has been investigated in food allergic patients. Several food immunotherapies are being developed; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. The approach generally follows the same principles as immunotherapy of other allergic disorders and involves administering small increasing doses of food during an induction phase followed by a maintenance phase with regular intake of a maximum tolerated amount of food. Oral immunotherapy seems to be a promising approach for food allergic patients based on results from small uncontrolled and controlled studies. Diet containing heated milk and egg may represent an alternative approach to oral immunomodulation for cow's milk and egg allergic subjects. However, oral food immunotherapy remains an investigational treatment to be further studied before advancing into clinical practice. Additional bigger, multicentric and hopefully randomized-controlled studies must answer multiple questions including optimal dose, ideal duration of immunotherapy, degree of protection, efficacy for different ages, severity and type of food allergy responsive to treatment.
Current pharmaceutical design 05/2013; 20(6). DOI:10.2174/13816128113199990053 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor and uncoupler of nitric oxide synthase. By promoting the formation of peroxynitrite, ADMA is believed to contribute to several aspects of asthma pathogenesis (ie, airway inflammation, oxidative stress, bronchial hyperresponsiveness, and collagen deposition). The aim of the present study was to compare this mediator in healthy children and children with asthma using the completely noninvasive exhaled breath condensate (EBC) technique.
We recruited 77 children with asthma (5-16 years of age) and 65 healthy children (5-15 years of age) who underwent EBC collection and spirometry. Serum ADMA levels and fractional exhaled nitric oxide levels were measured on the same day in a subgroup of children with asthma. EBC was collected using the Turbo-Deccs (Medivac). ADMA levels were measured using the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique.
ADMA could be detected in the EBC of 71 subjects with asthma and 64 healthy subjects. ADMA levels in the EBC of children with asthma were significantly higher than in the healthy control subjects (median, 0.12 [interquartile range, 0.05-0.3] vs 0.07 [0.05-0.12]; P = .017), whereas no difference emerged between the children with asthma who were or were not receiving inhaled steroid treatment. No correlation was found between serum and EBC ADMA levels (P > .5).
We measured ADMA in EBC by UPLC-MS/MS, a reference analytical technique. Higher ADMA levels were found in children with asthma, supporting a role for this mediator in asthma pathogenesis. This oxidative stress-related mediator also seems to be scarcely affected by steroid therapy. We speculate that ADMA might be a target for new therapeutic strategies designed to control oxidative stress in asthma.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Exhaled breath condensate (EBC) is a biofluid collected non invasively that, enabling the measurement of several biomarkers, has proven useful in the study of airway inflammatory diseases, including asthma, COPD and cystic fibrosis. To the best of our knowledge, there is no previous report of any analytical method to detect ADMA in EBC. OBJECTIVES: Aim of this work was to develop an online sample trapping and enrichment system, coupled with an UPLC-MS/MS method, for simultaneous quantification of seven metabolites related to "Arginine-ADMA cycle", using the isotopic dilution. METHODS: Butylated EBC samples were trapped in an online cartridge, washed before and after each injection with cleanup solution to remove matrix components and switched inline into the high pressure analytical column. Multiple reaction monitoring in positive mode was used for analyte quantification by tandem mass spectrometry. RESULTS: Validation studies were performed in EBC to examine accuracy, precision and robustness of the method. For each compound, the calibration curves showed a coefficient of correlation (r(2)) greater than 0.992. Accuracy (%Bias) was <3% except for NMMA and H-Arg (<20%), intra- and inter-assay precision (expressed as CV%) were within ±20% and recovery ranged from 97.1 to 102.8% for all analytes. Inter-day variability analysis on 20 EBC of adult subjects did not demonstrate any significant variation of quantitative data for each metabolite. ADMA and SDMA mean concentrations (μmolL(-1)), measured in EBC samples of asthmatic adolescents are significantly increased (p<0.0001) than in normal controls (0.0040±0.0021 vs. 0.0012±0.0005 and 0.0020±0.0015 vs. 0.0002±0.0001, respectively), as well the ADMA/Tyr (0.34±0.09 vs. 0.12±0.02, p<0.0001) and the SDMA/Tyr ratio (0.10±0.04 vs. 0.015±0.004, p<0.0001). CONCLUSIONS: The proposed method features simple specimen preparation, maintenance of an excellent peak shape of all metabolites and reduced matrix effects as well mass spectrometer noise. Moreover, the possibility to perform different cycles of enrichment, using large injection volumes, compensated for the low concentration of analytes contained in EBC, leading to a good analytical sensitivity. Preliminary data obtained from asthmatic and healthy adolescents, demonstrated that the analytical method applied to EBC seems suitable not only for research purposes, but also for clinical routinely analysis.