IRAK-M is involved in the pathogenesis of early-onset persistent asthma.

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.

The usefulness of 99mTc-tetrofosmin SPECT in monitoring the response to chemotherapy in lung cancer patients.

We evaluated the usefulness of 99mTc-tetrofosmin (TF) scintigraphy in monitoring chemotherapy response in 31 inoperable lung cancer (LC) patients, 24 NSCLC and 7 SCLC. In all cases after 740 MBq 99mTc-TF i.v. injection both planar and SPECT images were acquired, before and after 3 cycles of chemotherapy; SPECT was analysed both qualitatively and semiquantitatively by calculating tumor/background ratio (T/B). Scintigraphic data were always related to CT findings, according to which patients were classified into 2 groups after therapy: responders (with >or=50% reduction in tumor size) and non-responders (with an increase or no change/no significant reduction in tumor size). Four patients were rechecked for the third time, during long-term follow-up. SPECT images, positive before therapy in all cases, were concordant with CT in assessing treatment response in 13/13 responders and in 18/18 non-responder patients, showing tumor reduction in the former and an increase or no change/no significant reduction in the latter. Planar imaging failed to give additional information but also led to disease down-staging in some cases. T/B ratio significantly decreased after therapy (1.67+/-0.39 vs. 3.02+/-0.87, p<0.005) in responders

The control of asthma in Italy. A multicentre descriptive study on young adults with doctor diagnosed current asthma.

BACKGROUND: Few data are available on the management of asthma in the general population. The aim of this study was to evaluate the level of asthma control in Italian patients, a decade after the publication of the international guidelines. MATERIALS AND METHODS: Within the framework of a multicentre, population-based study on people aged 20-44 years, 18 873 subjects replied to a postal screening questionnaire (response rate = 72.7%) on the presence of asthma symptoms and exacerbations, and their impact on daily life. All subjects reporting having ever had a doctor diagnosis of asthma and either taking medicine for asthma when interviewed or having had an asthma attack in the last 12 months, were considered current asthmatics. RESULTS: Of the screened subjects, 649 (3.4%) were current asthmatics. Of these, only 14% did not report exacerbations or had been symptom-free in the last 12 months. More than 20% of current asthmatics had their daily life activities seriously impaired and 54 patients (8%) had at least one hospital/emergency department admission as a result of asthma exacerbation in the last 12 months. The life impairment and the rates of hospitalization significantly increased as the control of the symptoms worsened. The use of asthma drugs was quite common in current asthmatics: 586 (90.2%) reported having been under pharmacological treatment in the last 12 months. Only 63 patients (10%) had the disease under control (neither symptoms nor life impairment): they had a significantly higher percentage of drug use (100%vs 89%) and of daily use prescriptions (50%vs 36%) than non/moderately controlled asthmatics. Poorly controlled asthmatics had a significantly higher percentage of women (63%vs 44%), of patients with the coexistence of chronic cough and phlegm (47%vs 30%) than moderately/well-controlled asthmatics. The comparison between our data and similar data collected in 1991 in Italy showed that the use of asthma drugs increased by about 12%, while the control of symptoms did not improve in the last decade. CONCLUSION: Despite the high percentage of drug users, the control of symptoms and exacerbations was overall poor in Italy and resulted in a heavy individual and social burden, pointing out that the guideline goals have far from been reached in Italy.

The usefulness of 99mTc-tetrofosmin SPECT in the detection of intrathoracic malignant lesions.

To evaluate the usefulness of 99mTc-tetrofosmin (TF) SPECT in the detection of intrathoracic malignant lesions, we studied 304 patients, 261 with malignant and 43 with benign lesions; 196 of the former had non-treated primary tumors, 193 lung cancer (LC) and 3 mesotheliomas, 11 had LC recurrences and 54 had metastases from different kinds of tumors. Twenty-nine patients with primary tumors were re-checked after chemotherapy or surgery. In all patients, after 740 MBq TF injection, both planar and SPECT images were acquired and analysed qualitatively, SPECT images also semiquantitatively. Scintigraphy was always compared to CT. SPECT showed higher sensitivity, specificity and accuracy values than CT (98.1, 90.7 and 97 vs. 96.2, 81.4, and 93.9%, respectively), their combined use achieving 100% sensitivity and 98.8% accuracy. Planar did not give more information than SPECT, showing a significantly lower sensitivity (63.2%) and accuracy (67.4%). SPECT showed higher accuracy values than CT and planar (86.9 vs. 78.3 and 69.6%) in NSCLC mediastinal lymph node staging. Moreover, SPECT was concordant with CT in correctly evaluating the response to chemotherapy or surgery in all monitorized primary tumors cases, except in one in whom only SPECT detected residual tumor. The semiquantitative analysis added useful information in differentiating malignant from benign lesions and in monitoring the response to chemo-therapy. TF SPECT appears a highly accurate diagnostic method in the detection of intrathoracic malignant lesions, in lungs and pleura, as well as in NSCLC mediastinal lymph node staging and in monitoring treatment effectiveness, playing a complementary role to CT in selected cases.