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Purpose The World Health Organization recommends reduction of salt intake to Methods The study population was made of 1270 children and adolescents. Estimates of salt consumption and iodine intake were obtained by measuring 24 h urinary sodium and iodine excretion. Results The iodine intake increased gradually across quartiles of salt consumption independently of sex, age and body weight (p 10.2 g/day). We estimated that approximately 65–73% of the total iodine intake was derived from food and 27–35% from iodized salt and that iodized salt made actually only 20% of the total salt intake. Conclusion In this pediatric population, in face of an elevated average salt consumption, the use of iodized salt was still insufficient to ensure an adequate iodine intake, in particular among teenagers. In the perspective of a progressive reduction of total salt intake, the health institutions should continue to support iodoprophylaxis, in the context of the national strategies for salt reduction. In order for these policies to be successful, in addition to educational campaigns, it is needed that the prescriptions contained in the current legislation on iodoprophylaxis are made compelling through specific enforcement measures for all the involved stakeholders.

Objective: Older patients with cancer value functional outcomes as much as survival, but surgical studies lack functional recovery (FR) data. The value of a standardized frailty assessment has been confirmed, yet it's infrequently utilized due to time restrictions into everyday practice. The multicenter GOSAFE study was designed to (1) evaluate the trajectory of patients' quality of life (QoL) after cancer surgery (2) assess baseline frailty indicators in unselected patients (3) clarify the most relevant tools in predicting FR and clinical outcomes. This is a report of the study design and baseline patient evaluations. Materials & Methods: GOSAFE prospectively collected a baseline multidimensional evaluation before major elective surgery in patients (70 years) from 26 international units. Short-/mid-/Iong-term surgical outcomes were recorded with QoL and FR data. Results: 1003 patients were enrolled in a 26-month span. Complete baseline data were available for 977(97.4%). Median age was 78 years (range 70-94); 52.8% males. 968(99%) lived at home, 51.6% without caregiver. 54.4% had 3 medications, 5.9% none. Patients were dependent (ADL < 5) in 7.9% of the cases. Frailty was either detected by G8 = 2(37.4%), TUG > 20 s (5.2%) or ASAIII-IV (48.8%). Major comorbidities (CACI > 6) were detected in 36%; 20.9% of patients had cognitive impairment according to Mini-Cog. Conclusion: The GOSAFE showed that frailty is frequent in older patients undergoing cancer surgery. QoL and FR, for the first time, are going to be primary outcomes of a real-life observational study. The crucial role of frailty assessment is going to be addressed in the ability to predict postoperative outcomes and to correlate with QoL and FR. (C) 2019 Elsevier Ltd. All rights reserved.

Clinical studies based on novel rationales and mechanisms of action of chemotherapy agents and cytokines can contribute to the development of new concepts and strategies of antitumor combination therapies. In previous studies, we investigated the paradoxical immunostimulating effects of some chemotherapeutics and the immunoadjuvant activity of interferon alpha (IFN-?) in preclinical and clinical models, thus unraveling novel rationales and mechanisms of action of chemotherapy agents and cytokines for cancer immunotherapy. Here, we carried out a randomized, phase II clinical trial, in which we analyzed the relapse-free (RFS) and overall survival (OS) of 34 completely resected stage III-IV melanoma patients, treated with peptide-based vaccination (Melan-A/MART-1 and NY-ESO-1) in combination with IFN-?2b, with (arm 2) or without (arm 1) dacarbazine preconditioning. All patients were included in the intention-to-treat analysis. At a median follow-up of 4.5 years (interquartile range, 15.4-81.0 months), the rates of RFS were 52.9 and 35.3% in arms 1 and 2, respectively. The 4.5-year OS rates were 68.8% in arm 1 and 62.7% in arm 2. No significant differences were observed between the two arms for both RFS and OS. Interestingly, the RFS and OS curves remained stable starting from 18 and 42 months, respectively. Grade 3 adverse events occurred in 5.9% of patients, whereas grade 4 events were not observed. Both treatments induced a significant expansion of vaccine-specific CD8+ T cells, with no correlation with the clinical outcome. However, treatment-induced increase of polyfunctionality and of interleukin 2 production by Melan-A-specific CD8+ T cells and expansion/activation of natural killer cells correlated with RFS, being observed only in nonrelapsing patients. Despite the recent availability of different therapeutic options, low-cost, low-toxic therapies with long-lasting clinical effects are still needed in patients with high-risk resected stage III/IV melanoma. The combination of peptide vaccination with IFN-?2b showed a minimal toxicity profile and resulted in encouraging RFS and OS rates, justifying further evaluation in clinical trials, which may include the use of checkpoint inhibitors to further expand the antitumor immune response and the clinical outcome. Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/search, identifier: 2008-008211-26.

Summary Neurokinin A (NKA) has been shown to exert a potent contractile action on bronchial smooth muscles both in vitro and in vivo. Although this effect seems to be due either to a direct action of this peptide on specific muscular receptors or to an indirect effect on mast cells and/or nerves, its mechanism of action in bronchial asthma is still unknown. In the present study we have investigated the airway response to inhaled NKA in 10 asthmatic subjects and the activity of the novel pyranoquinoline dicarboxylic acid drug, nedocromil sodium, on this response. Ten asthmatic patients with stable asthma took part in the study consisting of four separate visits. On the first two occasions we derived histamine and NKA PD15 values in absence of any drug treatment. On the following two visits the inhalation challenge with NKA was performed after administration of either nedocromil sodium or matched placebo administered as pressurized aerosols via metered dose inhalers in a randomized double-blind order. Inhaled NKA produced a dose-related fall in FEV1 in all the subjects studied. Inhaled nedocromil sodium had a significant effect on the FEV1 response to NKA inhalation, the geometric mean PD15 value increasing from 16.6 to 32.2 × 10−9 mol. We conclude that nedocromil sodium attenuates subsequent responsiveness to inhaled NKA in asthmatic subjects. However, further studies are necessary to investigate the exact role and the mode of action of tachykinins in human airways.

Different transcription factors have been shown to control the transition of naive T cells into T helper 1 (Th1)/Th2 subsets. The T-cell-specific transcription factor GATA-3 is known to be selectively expressed in murine developing Th2 cells and to exert a positive action on Th2-specific cytokine production. Investigating GATA-3 gene regulation in human T cells we have found that naive T cells highly express GATA-3, and during early T2 or T1 polarization, respectively, they either maintain or quickly down-regulate expression. In developing T2 cells, as well as in committed Th2 cell lines and clones, we found a positive correlation among GATA-3, interleukin (IL)-5 and IL-4 gene expression kinetics, supporting the positive action of GATA-3 on Th2-specific cytokine production. A possible relationship between GATA-3 gene expression and the down-regulation of the IL-12 receptor (beta2-chain; IL-12Rbeta2) gene was evident only in the early phases of T2 polarization (within 24 hr), and not demonstrated at later times. During T-cell commitment the presence of IL-4 in the culture was essential to maintain or enhance GATA-3 transcription, while IL-12 was not necessary for full repression of GATA-3. Finally, we showed selective GATA-3 up-regulation in human Th2 cell lines and clones and the maintainance of a low basal level of GATA-3 expression in Th1 cells upon activation.

Pre-treatment with topical capsaicin is known to induce neuropeptide depletion from sensory nerve endings and it is a useful pharmacological tool to evaluate the contribution of these nerves to skin injury and inflammation. To investigate the relative contribution of sensory neural stimulation to the action of bradykinin and histamine, a randomized, double-blind study has been undertaken evaluating the effect of topical capsaicin pre-treatment on the responses to intradermal injections of both agonists in 12 healthy volunteers. Capsaicin pre-treatment caused significant inhibition of the immediate mean flare responses (95% CI) to both bradykinin (from 51.5 [39.7-63.3] mm2 to 16.2 [8.0-24.5] mm2) (P < 0.01) and histamine (from 108.4 [80.4-136.4] mm2 to 52.3 [37.1-67.1] mm2) (P < 0.01). Topical capsaicin elicited a significant inhibition of the weal response induced by histamine, the mean weal area being reduced from 14.8 (12.6-17.0) mm2 to 12.1 (10.1-14.1) mm2 (P < 0.05). In addition, the effect of topical capsaicin was to completely inhibit the bradykinin induced weal response compared to control, the mean weal area (95% CI) being reduced from 13.4 (11.4-15.4) mm2 to 8.2 (5.3-11.0) mm2 (P < 0.01). Our findings show that repeated topical application with capsaicin led to a significant reduction of the skin responses to intradermal injections with both agonists, and particularly with bradykinin. The weal responsiveness to bradykinin may entirely follow neuropeptide release from sensory nerves within the skin and the same applies to the flare response, although this is not completely inhibited by topical application with capsaicin.

Several studies have demonstrated that neuropeptides are present in bronchial tissue. The aim of this study was to evaluate in vivo the influence of antihistamine in comparison to an anticholinergic drug on bronchospasm induced by inhalation of substance P (SP). Seven moderate asthmatic patients (mean age = 34.4 +/- 8.9), five being female, were studied. The acetate salt of SP was prepared in 0.9% saline to produce a dose range of 23 to 184 x 10(-6) mol. Patients were studied on three separate days with an interval of 3 weeks between challenges. On the first day the dose of SP producing a 20% change in FEV1 was calculated from the individual semilogarithmic dose-response curve. On subsequent days, in a randomized double-blind manner, the patients were treated either with astemizole (20 mg BID for three days) and placebo ipratropium bromide or with placebo of astemizole (twice a day for three days) and with pressurized aerosol of ipratropium bromide (IB) (40 micrograms 20 minutes before the challenge). Two way analysis of variance was used for statistical analysis. Our results demonstrated that inhaled SP is able to produce a dose-response curve of bronchoconstriction with a geometric mean of PD20 of 50.51 x 10(-6) moles (37.38 to 68.19 x 10(-6) mol). Treatment with astemizole induced a geometric mean PD20 of 65.51 x 10(-6) mol (33.02 to 130.21 x 10(-6) mol) and the premedication with the IB induced a significant (P less than .05) shift of dose-response curve to SP (geometric mean PD20 = 109.1 x 10(-6) mol; 58.67 to 204.05 x 10(-6) mol). Our results demonstrated that bronchoconstriction induced by SP could be attributed to a weak cholinergic activation and not to histamine release.

Adenosine, when administered as an aerosol to asthmatic subjects, provokes a prompt dose-dependent bronchoconstriction. The aim of this study was to establish whether tachyphylaxis in response to repeated inhalations with adenosine occurs in asthmatic subjects. Eight asthmatic patients were studied on three separate days (days A, B, and C) at the same time of day for each subject. Three inhalation tests were performed, separated by one hour, on each study day. The study was conducted in a double-blind fashion and performed in random order. On day A, three adenosine inhalation tests were performed to assess adenosine tachyphylaxis. On day B, a saline inhalation test was carried out between two adenosine challenges to assess the time course of the adenosine tachyphylaxis. On day C, three methacholine inhalation tests were performed to confirm that tachyphylaxis does not occur to methacholine. Repeated inhalation with adenosine, but not methacholine, produced a progressive loss of responsiveness to the nucleoside, which was particularly manifest with the third challenge.

The prophylactic effectiveness of the phthalazinone derivative, azelastine was compared with ketotifen. A total of 111 patients, aged 18 – 65 years, from 10 centres was entered into this randomized, double-blind study. All patients had reversible asthma. After 1 week on placebo, patients were allocated to either 8 mg/day azelastine once or twice daily, or to 1 mg ketotifen, twice daily, for a further 12 weeks. Azelastine was more effective in improving respiratory function (forced expiratory flow in 1 s and peak expiratory flow rate) when given in the once daily regimen, whereas clinical measures (number of weekly asthma attacks) were most improved by twice daily dosing. There was no significant difference between the effectiveness of azelastine and that of ketotifen. Treatments were equally well tolerated and a low incidence of side-effects was reported. In conclusion, 8 mg/day azelastine, in either a single or twice daily dosage regimen may be regarded as providing effective prophylaxis against bronchial asthma.

This study was performed in a randomized double-blind manner on 6 separate days in 10 asthmatic patients to investigate the effect of a sustained theophylline on baseline bronchial hyperreactivity to histamine in relation to the theophylline serum levels and the degree of bronchodilatation produced. No significant bronchodilatation was seen after theophylline administration at every time of evaluation. An improvement of PD20 values of histamine was observed after 4 h (p less than 0.05), 8 h (p less than 0.01) and 12 h (p less than 0.05) from theophylline administration versus respective PD20 values obtained with placebo at the same times. No significant correlation was found between serum theophylline levels and percentage change of PD20 values after drug administration (r = 0.250). We observed an improvement of PD20 mean values in relation to the maximal serum theophylline concentration but our study failed to correlate the degree of protection with serum concentration.

There is now considerable evidence in favor of vasoactive intestinal peptide (VIP) as a neurotransmitter of nonadrenergic noncholinergic nerves in the airways. The purpose of our study was to evaluate the influence of inhaled VIP on bronchomotor tone after a beta-adrenergic- and cholinergic-receptor blockage. The study was performed in six patients with asthma in 4 days. On the first day, a propranolol provocative dose producing a 20% change in FEV1 (PD20) was determined from the individual semilogarithmic dose-response curve. On the other days, the propranolol challenge was performed after inhalation of ipratropium bromide (40 micrograms), VIP (70 micrograms), and both drugs in randomized double-blind order. Statistical analysis was performed by two-way analysis of variance. The results demonstrated that mean propranolol PD20 was 0.14 mg (geometric mean + SD = 1.22). Ipratropium bromide administration, like VIP administration, significantly raised the PD20 value. The administration of both drugs elicited a further remarkable increase of mean propranolol PD20. The results demonstrated that inhaled VIP influences bronchomotor tone and that this effect is independent of the cholinergic blockage.

The exact mechanism of adenosine-induced bronchoconstriction in patients with asthma is unknown. Adenosine contraction of guinea pig trachea was antagonized by inhibitors of cyclooxygenase. The aim of this study was to investigate the effect of indomethacin (100 mg/day) on adenosine-induced bronchoconstriction in 14 asymptomatic patients with asthma. Airway response was evaluated as FEV1, and adenosine was administered as an aerosol diluted in 0.9% saline to produce a concentration range of 0.125 to 4 mg/ml. The dose of adenosine producing a 20% change in FEV1 (PD20) was calculated from the individual semilogarithmic dose-response curve; the results of PD20 were converted to log values for statistical analysis (Student's paired t test). The study was performed on 3 separate days. On the first day, the adenosine challenge was performed, and on subsequent days patients were pretreated with either placebo or indomethacin in a randomized, double-blind manner. Inhaled adenosine caused bronchoconstriction with a geometric mean PD20 of 0.71 mg (95% confidence limits, 0.44 to 1.16). After placebo, a geometric mean PD20 of 0.91 mg (95% confidence limits, 0.53 to 1.58) was obtained. Indomethacin pretreatment decreased adenosine hyperresponsiveness and shifted the dose-response curves of adenosine challenge to the right with a geometric mean PD20 of 1.28 mg (95% confidence limits, 0.64 to 2.56). The effect of indomethacin on adenosine bronchoconstriction (p less than 0.01 versus baseline; p less than 0.05 versus placebo) suggests an indirect mechanism of adenosine on inducing release of arachidonic acid derivatives. Inflammatory mediators inhibited by indomethacin may be involved in adenosine bronchoconstriction, even if this mechanism is not relevant.(ABSTRACT TRUNCATED AT 250 WORDS)