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Background Massive hemoptysis is a serious complication in Cystic Fibrosis (CF), occurring commonly in older patients. Bronchial artery embolization (BAE) can be performed to stop the bleeding. BAE is generally safe and effective, but can sometimes lead to serious complications. We report the first case of temporary unilateral diaphragmatic paralysis associated to lung consolidation following BAE in a pediatric CF female patient. This complication worsened the lung function of the patient who underwent lung transplantation after 9 months. Case presentation A 14 years old female CF patient followed by the CF center of Florence presented low-grade fever, cough increase and recurrent episodes of major hemorrhages such as to carry out a BAE. Within 24 h the patient started to complain of severe thoracic pain in the right hemithorax, increased dyspnea and fever. A computed tomographic angiography and a dynamic fluoroscopic evaluation revealed the right diaphragmatic paralysis, not present before the procedure. After 4 days the clinical condition and radiological imaging had improved with restored mobility of the right hemidiaphragm. Nine months later, she required mechanical ventilation, and subsequently the initiation of extracorporeal membrane oxygenation (ECMO) for a pulmonary exacerbation with septic shock. Lung transplantation in ECMO was performed with success. Conclusion Clinicians should be aware of the possibility of phrenic nerve injury with BAE in pediatric CF patients.

Background: Novel strategies aimed to overcome trastuzumab (Tz) resistance of HER2+ breast cancer (BC) are needed. Recently, we demonstrated a novel immune evasion strategy used by BC where tumor necrosis factor alpha (TNF) induces upregulation of the transmembrane glycoprotein mucin 4 (MUC4) via NF-kB activation to impair Tz binding that prevents antibody mediated killing of BC cells. Etanercept, a non-selective inhibitor of soluble and transmembrane TNF (sTNF, tmTNF), downregulated MUC4 expression and sensitized de novo Tz-resistant BC xenografts to Tz. Moreover, we showed that MUC4 expression is an independent predictor of poor disease-free survival in patients treated with Tz in the adjuvant setting (Clin Cancer Res 2017, 23:636). Etanercept is immunosuppressive due to off-target effects on tmTNF while selective inhibition of sTNF improves the immune response to the tumor (Cancer Immunol Res 2016, 4:441). Because of the immunosuppressive properties of etanercept, we wanted study if the dominant negative-TNF protein XPro1595 (DN-TNF; also known as INB03) that neutralizes sTNF without affecting tmTNF is able to downregulate MUC4 to inhibit Tz-resistant tumor growth and improve innate antitumor immune response. Methods: To assess the effect of DN-TNF on Tz-resistant HER2+ tumor growth, JIMT-1 cells were s.c. injected in nude mice. When tumors were established, animals were treated with IgG, DN-TNF, Tz or DN-TNF+Tz, i.p. twice a week for one month. Innate immune response was determined by flow cytometry analysis of NK cells activation and degranulation and myeloid-derived suppressor cells (MDSC) subtypes in tumor microenvironment (TME) and in spleen. Tz-dependent NK cells degranulation was assessed in splenocytes using HER2+, Tz-sensitive cell line BT-474 as the target. MUC4 and phospho NF-kB expression was determined by Western blot. Results: Treatment with Tz or DN-TNF had no impact on JIMT-1 tumor growth. However, co-treatment with DN-TNF and Tz resulted in significantly less growth. At day 21st, tumor volume was 75mm3 in DN-TNF+Tz vs 300mm3 control groups. DN-TNF+Tz treatment showed a decrease in myeloid cell infiltration and MDSC phenotype was enriched in the granulocytic-MDSC vs monocytic-MDSC suggesting a less immunosuppressive TME. DN-TNF+Tz administration significantly increased activation and degranulation of tumor infiltrating NK cells. In addition, spleen NK cells from these animals exhibited enhanced Tz-dependent degranulation vs control groups. MUC4 expression was downregulated in tumors treated with DN-TNF and NF-kB phosphorylation was inhibited (all comparisons p Conclusion: These results suggest that targeting sTNF together with Tz treatment improves antitumor immune response reducing tumor burden. Activated NK cells can more effectively attack the tumor due to a less suppressive TME and decreased MUC4 expression enhancing Tz binding in Tz-resistant HER2+ BC. Patients with increased levels of TNF expressing MUC4 in their tumors could be eligible for a combined therapy with DN-TNF and Tz to overcome/avoid resistance to therapy. These results can be translated quickly into the clinic. Citation Format: Schillaci R, Bruni S, De Martino M, Mercogliano MF, Inurrigarro G, Frahm I, Proietti CJ, Elizalde PV. Neutralizing soluble tumor necrosis factor alpha overcomes trastuzumab-resistant breast cancer immune evasion by downregulating mucin 4, improving NK cell function and decreasing myeloid-derived suppressor cells in tumor microenvironment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-14.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease. © 2021 BioScientifica Ltd.. All rights reserved.

Round table debate “Transformation of political values in the EU: pros and cons” was held on February 13 2017 on the Faculty of the humanities and social sciences of Peoples’ Friendship University of Russia (RUDN University). The “Round-table” debate has been realized in the frame of the project “Transformation of the social and political values: the EU practice” (project number: 575361-EPP-1-2016-1-RU-EPPJMO-MODULE), Erasmus+ Jean Monnet Actions. Jean Monnet Module “Transformation of the social and political values: the EU practice”.

Aims: Mobile Airways Sentinel NetworK (MASK) belongs to the Fondation Partenariale MACVIA-LR of Montpellier, France and aims to provide an active and healthy life to rhinitis sufferers and to those with asthma multimorbidity across the life cycle, whatever their gender or socio-economic status, in order to reduce health and social inequities incurred by the disease and to improve the digital transformation of health and care. The ultimate goal is to change the management strategy in chronic diseases. Methods: MASK implements ICT technologies for individualized and predictive medicine to develop novel care pathways by a multi-disciplinary group centred around the patients. Stakeholders: Include patients, health care professionals (pharmacists and physicians), authorities, patient's associations, private and public sectors. Results: MASK is deployed in 23 countries and 17 languages. 26,000 users have registered. EU grants (2018): MASK is participating in EU projects (POLLAR: impact of air POLLution in Asthma and Rhinitis, EIT Health, DigitalHealthEurope, Euriphi and Vigour). Lessons learnt: (i) Adherence to treatment is the major problem of allergic disease, (ii) Self-management strategies should be considerably expanded (behavioural), (iii) Change management is essential in allergic diseases, (iv) Education strategies should be reconsidered using a patient-centred approach and (v) Lessons learnt for allergic diseases can be expanded to chronic diseases. © 2019 The Author(s).

The generation of regular and irregular inflected verb-forms has been taken as a crucial test between models of inflection in the mental lexicon, namely approaches which invoke different mechanisms for regular and irregular forms (rule-based procedures vs. recovery of whole forms stored in an associative network) and accounts which postulate a single procedure for all forms. An alternative hypothesis suggests that inflectional processes are explained by membership of words to clusters, for instance, Italian inflectional classes (conjugations). In a behavioural and a rapid event-related fMRI experiment, participants overtly generated the past participle of verbs from the three Italian conjugations. Results showed that the cognitive operations and the neural substrate underlying inflectional processes rely on specific properties of inflectional classes. Different patterns of cortical activations elicited by verbs from different conjugations were detected for the first time in the left middle frontal gyrus, left pre-supplementary motor area and left anterior cingulate cortex.

Background Nontuberculous mycobacteria (NTM) are pathogens that commonly affect the paediatric population and its most frequent manifestation is a cervicofacial lymphadenopathy. With the improvement of technologies, new species have been recently identified. Case presentation We report the first case of NMT lymphadenitis in a child caused by Mycobacterium marseillense, a newly described species belonging to Mycobacterium avium complex. Conclusions Improving the identification of these newly discovered mycobacteria, further information will be available about their clinical involvement and their best treatment.

SUMMARYTo evaluate measles incidence and its relevant changes over a 14-year period (2000–2014), we analysed data from the regional hospital discharge database on children and adults hospitalized in Tuscany, Italy. A total of 181 paediatric and 413 adult cases were identified. Despite all the efforts towards regional measles elimination, we observed that the overall measles hospitalization rates for children and adults living in Tuscany globally increased from 0·45 to 0·85/100 000 during the study period (P = 0·001) showing fluctuations due to periodic measles outbreaks. Data stratified by age group showed that the hospitalization rate significantly increased in young adults over the study period, confirming an increase in susceptibility to measles in this subpopulation. Conversely, no statistically significant difference was observed in the hospitalization rate in the other age groups. However, children aged

mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary. © 2018 The Author(s).

Artemisia vulgaris L and Artemisia annua L (Chinese: qinghao) are similar plants of the Asterbaceae family. Artesunate, a semi-synthetic derivate of artemisin which is the active principle extract of the plant qinghao, has antimalarial properties. Some cases of severe allergic reactions to artesunate have been described. The purpose of this study was to evaluate the association between positive skin tests to Artemisia vulgaris L allergen and a preparation of injectable artesunate. A total of 531 children were skin prick tested with inhalants (including Artemisia vulgaris L), foods, and artesunate. Among the 59 patients positive to Artemisia vulgaris L only one child was also positive to artesunate. No child was positive to artesunate in those negative to Artemisia vulgaris L. We conclude that Artemisia vulgaris L sensitization is not associated with sensitization to artesunate; consequently, skin test to artesunate should not be carried out before using the drug considering the rare allergic reactions.

The three Americas have 46% of all the world fresh water. South America has 60% of three Americas fresh water regarding 27.6% of world fresh wa-ter. Brazil has 28% of America's fresh water and 12% of world fresh water. The existence of this huge amount of water is directly related to various situations of floods, occurring in cities and in rural areas, at fast or slows pace. Those floods, which can cause major social and economic damage, must be studied and whenever possible prevented. This work aims to illustrate the planned activity of a bilateral collaboration between two Brazil (INPE) and Italian (CNR-IMATI) Institutions aiming at identifying methodologies fostering drainage data sharing, use and re-usage at different stages of the data processing pipelines in order to create a seamless cross-sectorial data "provider/consumer" chain. In particular, it illustrates the preliminary results of the research activities aiming at making available South America drainage network data and the Amazonian basin. Such data, produced by the TerraHidro tool developed by INPE, is going to be published as Open Data, thus addressing the implementation of the Bra-zilian e-government initiative about data transparencies according to Law no. 12.527, of November 18, 2011. The strategy of Brazil and the European Commission about "free and open public access of information" are also take into account. Moreover, the Implementing Rules of INSPIRE are considered in order to meet the scientific and technological policy between Brazil and European Commission. The approach aims at producing, publishing and reusing territorial infor-mation created by INPE about drainage resources. In a medium-long term, this methodology aimed at establishing a consolidated point of access of territorial interlinked maps and geo-localized data and metadata-related information. The implemented strategy foresees: o"Documentation of data with proper metadata needed for third party application", by covering issues such as provenance, quality, versioning (e.g., GEO-DCAT-AP, W3C-DQV, W3C-PROV); o"Fostering the data publication on the Web according to the (Linked) Open Data initiative", by adopting W3C best practices for (Spatial) Data on the Web; o"Data semantic enrichment" considering Linked Data and ontology as lightweight Semantic Web tools for the semantic enrichment of the Drainage Data. The expected result is an enrichment of drainage datasets, and in particular of Amazonia with 5m resolution produced by INPE, enhancing data dissemination among the different communities working on cross-target discipline (e.g. climate change, water.

BACKGROUND: Gamma-glutamyltransferase (GGT) regulates apoptotic balance and promotes cancer progression and invasion. Higher pretherapeutic GGT serum levels have been associated with worse outcomes in various malignancies, but there are no data for renal cell carcinoma (RCC). METHODS: Pretherapeutic GGT serum levels and clinicopathological parameters were retrospectively evaluated in 921 consecutive RCC patients treated with nephrectomy at a single institution between 1998 and 2013. Gamma-glutamyltransferase was analysed as continuous and categorical variable. Associations with RCC-specific survival were assessed with Cox proportional hazards models. Discrimination was measured with the C-index. Decision-curve analysis was used to evaluate the clinical net benefit. The median postoperative follow-up was 45 months. RESULTS: Median pretherapeutic serum GGT level was 25 U l(-1). Gamma-glutamyltransferase levels increased with advancing T (P

Allergic reactions associated to the use of macrolides are uncommon; in particular only two cases of anaphylaxis with erithromycin and clarithromycin have been reported to date. The aim of this study was to investigate macrolide-induced anaphylaxis. Between December 2007 and December 2011, 136 consecutive children were referred to the Allergy Unit of A. Meyer Children's Hospital because of a past history of reactions to macrolides. Allergy work-ups were carried out according to the European Network for Drug Allergy protocol. Anaphylaxis was diagnosed according to the clinical criteria proposed by Sampson et al. and graded according to Brown SGA et al. Sixty-six out of 136 patients completed the allergologic work-up and among them we investigated three cases of anaphylaxis due to azithromycin which included one child with anaphylaxis to both clarithromycin and azithromycin. In two of the children with anaphylaxis, the diagnosis was only confirmed with the skin prick test, the third was positive to the Intradermal Test. The azithromycin allergy shows a surprisingly high sensitivity to the in-vivo tests. Moreover, this study shows that cross-reactivity may occur between different macrolidic molecules; it has even been suggested that macrolide allergies are unlikely to be class allergies.

Macrophage activation syndrome is a potentially fatal clinical syndrome caused by an excessive activation and proliferation of macrophages and T cells, leading to an exaggerated inflammatory reaction. It is well known that it can complicate the course of different conditions, especially autoimmune, lympho-proliferative, infectious diseases and drugs. Many infective pathogens can trigger the syndrome but the association with malaria has rarely been described, especially in children. We report a child with severe malaria complicated by MAS, in whom the clinical appearance of this syndrome could be considered as worsening of malaria itself. Furthermore, the use of steroids as first choice drugs in this complication, but arguable in malaria, has been highlighted. Clinicians should be aware of this syndrome when malaria does not respond to conventional therapy, since early diagnosis and prompt treatment may dramatically reduce the mortality associated with this condition.

The role of interferon-gamma release assays (IGRAs) for immunologic diagnosis of tuberculosis in children is under debate. We carried out a narrative review on the studies on IGRAs in paediatric populations. A literature search was conducted using multiple keywords and standardized terminology in Medline, EMBASE and Cochrane databases, up to January 27th, 2011. Study quality was assessed using the MOOSE checklist and results of relevant studies were summarized. Sixty-seven paediatric studies (study population ranging from 14 to 5,244 children) were identified. Non-commercial ELISPOT assay (by means of ESAT-6 and CFP-10 antigens) had been carried out in 11 studies. QuantiFERON-TB Gold (QFT-G), QuantiFERON-TB Gold In-tube (QFT-G-IT), and T-SPOT.TB assays had been performed in 10, 44 and 18 studies, respectively. Most studies reported higher specificity of IGRA than tuberculin skin test (TST), but interpretation of the results is complicated by the fact that a gold standard for the diagnosis of latent TB is lacking. The reported sensitivity for active TB ranged from 51-93 percent for QFT-G/QFT-G-IT and 40-100 percent for ELISPOT assays, suggesting that a negative IGRA result may not exclude tuberculosis. Combining TST and IGRA results increased the diagnostic sensitivity. Rates of indeterminate results largely varied (0 to 35 percent). Most of the studies on young (less than 5 years) or immune-compromised children reported a proportion of indeterminate results exceeding 4 percent. Agreement among TST and IGRA, assessed by the k statistics, ranged from -0.03 to 0.87. Higher rates of discordance were reported in BCG-vaccinated than in non-BCG-vaccinated children. Studies on children less than 5 years and immunocompromised children reported conflicting results, as did studies on serial IGRA determinations. Despite the large amount of literature data, the role of IGRA in the pediatric population is still unclear, especially in young children. Combined use of TST/IGRA may increase diagnostic sensitivity but interpretation of discordant results remains a challenging issue.

In vivo exposure to microorganisms resident in the oral cavity is considered as a possible cause of Kawasaki disease (KD), and some epitopes derived from streptococci display homology with Factor H of Complement. Additionally, calprotectin, a major calcium binding protein released by neutrophils and activated monocytes, could be directly involved in endothelial damage occurring in KD. The aim of our study is to evaluate the percentages of IFN-γ+ and/or TNF-α+ lymphocytes and double positive calprotectin/TNF-α monocytes (CD14+) after in vitro stimulation with streptococcal- and/or Factor H-derived peptides, in patients with acute KD. Peripheral Blood Mononuclear Cells (PBMCs) obtained from KD patients and febrile controls were stimulated in vitro with peptides. After culture, cells were collected, stained with fluorochrome-labelled monoclonal antibodies against CD3, CD14, calprotectin, IFN-γ and TNF-α, and cytofluorimetric analyses were performed. Our results showed increased percentages of TNF-α+/IFN-γ+ lymphocytes in KD patients in respect to controls when PBMCs were stimulated with streptococcal or Factor H-derived epitopes. In addition, also calprotectin+/TNF-α+ monocytes from KD patients were activated after PBMC in vitro stimulation. These findings lead us to speculate that some peptides, derived from oral streptococci and cross-reactive with the human Factor H of Complement, could induce lymphocyte and monocyte activation potentially involved in the pathogenesis of KD. Our results should be confirmed by further studies enrolling more patients and controls than those analyzed in our study.

Background The genetic background, transmissibility and virulence of MRSA have been poorly investigated in the cystic fibrosis (CF) population. The aim of this multicentre study was to analyse MRSA strains isolated from CF patients attending nine Italian CF care centres during a two-year period (2004–2005). All CF patients infected by MRSA were included. Method Antibiotic susceptibility testing, SCC mec typing, Panton–Valentine Leukocidin (PVL) production, and Multi Locus Sequence Typing (MLST) analysis were carried out on collected isolates (one strain per patient). Results One hundred and seventy-eight strains isolated from 2360 patients attending the participating centres were analysed. We detected 56 (31.4%) SCC mec IV PVL-negative strains, with a resistance rate of 80.3% to clindamycin and of 14.5% to trimethoprim/sulphamethoxazole. MLST analysis showed that many isolates belonged to known epidemic lineages. The largest clone grouping of 29 isolates from 6 centres had the genetic background (ST8-MRSA-IV) of the American lineages USA300 and USA500, thus demonstrating the diffusion of these strains in a population considered at risk for hospital associated infections. Conclusions Known MRSA epidemic clones such as USA600, USA800, USA1100, and UK EMRSA-3 were described for the first time in Italy. The diffusion of MRSA strains with high pathogenic potential in the CF population suggests that analysis of the MRSA strains involved in pulmonary infections of these patients is needed.

Objective To define normal values for respiratory resistance (R(rs)) and reactance (X(rs)) and bronchodilator response (BDR) in a population of healthy Italian preschool children using a commercially available forced oscillation device Methods R(rs) and X(rs) were measured in kindergartens in Viterbo Italy Regression analysis was performed taking into account height weight age gender and reference equations calculated The coefficient of repeatability (CR) between two tests performed 15 min apart was calculated in a subset of children BDR was assessed by repeating the measurements 15 min after the administration of 200 mu g of inhaled salbutamol and calculated as an absolute change in R(rs) and X(rs) at 8 Hz as a percent change in baseline and as a change in Z score calculated from the reference equations Results Lung function was attempted in 175 healthy children and successful in 163 (81 male median age 4 8 range 2 9-6 1 years) R(rs) and X(rs) at 6 8 and 10 Hz were related to height but not other variables The CR was 1 53 hPa s L(-1) for R(rs8) and 091 hPa s L(-1) for X(rs8) The 5th percentile for absolute R(rs8) BDR was -3 16 hPa s L(-1) whereas the 95th percentile for absolute X(rs8) BDR was 2 25 hPa s L(-1) These cut off values corresponded to a change in the Z score of -1 88 and 2 48 respectively Conclusions We have established reference equations for R(rs) and X(rs) in healthy Italian preschool children using forced oscillations We recommend a change in Z score of -1 88 for R(rs8) and 2 48 for X(rs8) as cut off values for a positive BDR Pediatr Pulmonol 2010, 45 1086-1094 (C) 2010 Wiley Liss Inc

We conducted a cross-sectional study on 43 Italian perinatally human immunodeficiency virus-type 1 (HIV-1) infected children receiving highly active antiretroviral therapy (HAART) and 26 age-matched healthy controls to explore CD1d-restricted NKT subsets. CD4+CD1d-rectricted natural killer (NKT) cell depletion was evidenced in 26 HIV-1 infected children with active viral replication despite HAART. Conversely, no alteration was evidenced in 17 children with undetectable viral load, suggesting full recovery in both CD4+ and CD4− CDld-rectricted NKT cell subsets. The loss of CD4+ NKT cells in unresponsive children may have clinical consequences, including autoimmune disorders or cancer development. Future therapeutic perspectives are suggested.

Objective. To describe efficacy and safety of infliximab in the treatment of childhood chronic uveitis during a long-term follow-up.Methods. Fifteen patients (median age 12 yrs, range 5-21 yrs) with chronic uveitis were enrolled. Before infliximab treatment, children had presented active uveitis despite treatment with MTX and/or CSA. All were also receiving oral prednisone (1-2 mg/kg/day) for at least 1 month. Infliximab (5 mg/kg) was administered at weeks 0, 2, 6 and then every 6-8 weeks. Later on, in patients enrolled in Florence the administration interval was progressively increased up to 10 weeks if uveitis did not flare, whilst in children from Padua the scheduled infusion rate was maintained every 6 weeks. Absence or recurrence rate of uveitis up to the last visit was recorded.Results. Median follow-up on treatment was 30 months (range 16-38 months), median number of infusions 22 (range 11-30). During the first year, 13/15 children achieved a complete remission over a median period of 10 weeks, but all relapsed thereafter. The probability of a first relapse was correlated to length of treatment, once remission was achieved (P < 0.03). The total number of relapses correlated with the duration of treatment (r s = 0.81; P < 0.002) and with the total number of infusions (r s = 0.83; P < 0.001). The total number of relapses on treatment at last follow-up was not significantly different between the two centres.Conclusions. Even if limited to a small group, infliximab appears to be an effective treatment for uveitis in children, but its efficacy seems to wane over time.

Background: Varicella zoster virus (VZV) vasculopathy produces stroke secondary to viral infection of cerebral arteries. Not all patients have rash before cerebral ischemia or stroke. Furthermore, other vasculitides produce similar clinical features and comparable imaging, angiographic, and CSF abnormalities. Methods: We review our 23 published cases and 7 unpublished cases of VZV vasculopathy. All CSFs were tested for VZV DNA by PCR and anti-VZV IgG antibody and were positive for either or both. Results: Among 30 patients, rash occurred in 19 (63%), CSF pleocytosis in 20 (67%), and imaging abnormalities in 29 (97%). Angiography in 23 patients revealed abnormalities in 16 (70%). Large and small arteries were involved in 15 (50%), small arteries in 11 (37%), and large arteries in only 4 (13%) of 30 patients. Average time from rash to neurologic symptoms and signs was 4.1 months, and from neurologic symptoms and signs to CSF virologic analysis was 4.2 months. CSF of 9 (30%) patients contained VZV DNA while 28 (93%) had anti-VZV IgG antibody in CSF; in each of these patients, reduced serum/CSF ratio of VZV IgG confirmed intrathecal synthesis. Conclusions: Rash or CSF pleocytosis is not required to diagnose varicella zoster virus (VZV) vasculopathy, whereas MRI/CT abnormalities are seen in almost all patients. Most patients had mixed large and small artery involvement. Detection of anti-VZV IgG antibody in CSF was a more sensitive indicator of VZV vasculopathy than detection of VZV DNA ( p GLOSSARY: EIA = enzyme immunoabsorbent assay; VZV = varicella zoster virus.

Objective: To compare transthoracic impedance (TTI/ECG) and pulse oximetry alarm traces detected during home monitoring in infants at risk of apnoea, bradycardia and hypoxaemia. Study design: A retrospective evaluation of the monitor downloads of 67 infants who had undergone either TTI/ECG or pulse oximetry home monitoring using a device which can detect both parameters. Methods: The patients were categorised as: apparent life-threatening events (n = 39), preterm infants (n = 21) and miscellaneous (n = 7). TTI/ECG and pulse oximetry alarm traces were scored as either true or false alarms. Classification criteria were based on visual analysis of the impedance and plethysmographic waveforms captured by the memory monitor every time alarm thresholds were violated. Results: 5242 alarms occurred over 3452 days of monitoring: 4562 (87%) were false and 680 (13%) true. The mean duration of monitoring was 51 days (range 5–220 days). There were 2982 TTI/ECG false alarms (65% of the total) and 1580 pulse oximetry false alarms (35%) (p = 0.0042). Of the 680 true alarms, 507 (74%) were desaturations not attributable to central apnoea and 173 (26%) were true TTI/ECG alarms (p = 0.0013). Conclusions: Comparison of pulse oximetry and TTI/ECG alarm traces shows that true events were mostly attributable to desaturations, while false alarms were mainly provoked by TTI/ECG. The total number of false alarms is lower than reported in other studies using TTI/ECG only, thus indicating that monitoring using both pulse oximetry and TTI/ECG is suitable for home use. When the combination of both techniques is not feasible or not required, we recommend the use of motion resistant pulse oximetry alone.

The upper eyelashes in vernal keratoconjunctivitis (VKC) patients have been reported to be longer than in healthy age- and gender-matched subjects. Eyelash length positively correlated to the severity of the disease and negatively to the employment of cyclosporine eye drops, suggesting that specific humoral factors could be involved in both ocular inflammation and elongation of the eyelashes. The aim of the present study is to evaluate a possible relationship between eyelash length and the duration of topical cyclosporine treatment. The length of the upper eyelashes of 34 VKC patients never treated with topical cyclosporine (Cyc-NT) was matched with that of 58 VKC patients treated with cyclosporine (Cyc-T). The latter group was divided into three subgroups, depending on the duration of therapy: 1–6 months (group 1; 21 subjects), 7–12 months (group 2; 19 subjects), >12 months (group 3; 19 subjects). Cyc-NT patients' eyelashes were significantly longer than those of VKC patients treated for 1–6 months (group 1). No significant difference was found between Cyc-NT and Cyc-T patients in group 2 and group 3. The differences between Cyc-T patients and group 1 and 2, group 2 and 3, and group 1 and 3 were not statistically significant. The eyelash shortening observed seems directly related to the rapid improvement of ocular symptoms induced by the treatment. A receptor down-regulation by mediators of ocular inflammation may explain this data, although different cytokines, hormones or other humoral mediators could be expressed on the ocular surface at different stages of the disease, mainly in periods of rapid change of the clinical course.

The diagnosis of latex allergy is made on clinical history, but a confirmatory skin prick test (SPT) or a serological assay based on a commercial latex extract is always recommendable. Different raw materials can be used in the preparation of commercial latex extracts. Such extracts can consequently show both different qualitative profiles and a different diagnostic potential. Therefore, the selection of a proper latex extract is essential for in vitro and in vivo diagnosis of latex allergy. In the present study three different latex extracts, prepared from different raw materials (ammoniated -AL-, serum -SL-, or rubber particles -RPE- latex), are compared by in vitro techniques using sera from twenty patients with latex allergy. SDS-PAGE technique was used to compare the antigenic profile of the three latex extracts. Subsequently, their allergenic profiles were evaluated by immunoblotting technique using the individual sera from the twenty latex allergic patients. The diagnostic potential of the three latex extracts was also evaluated using direct Radio-Allergo-Sorbent Test (RAST) as well as skin prick tests (SPTs). In order to establish the more appropriate latex extract in a perspective of in vivo diagnosis of latex sensitization, the same latex extracts were subsequently compared by an in vivo SPT involving ten of the above subjects. The SDS-PAGE profiles of the three latex extracts examined were quite different. SL extract showed numerous bands comprised between 10–100 kDa. RPE extract was characterized by two intense bands at 14 and 20 kDa while AL extract showed the poorer antigenic composition. Analogously, immunoblotting analysis evidenced a different profile in relation to both different patients and extracts. For only two out of the twenty sera, direct RAST results showed a same positive class in relation to the different latex extracts used. SPT with SL extract showed, in respect to the other extracts (AL, RPE), a significantly higher wheal. This study showed that SL extract is able to express the best in vitro and in vivo diagnostic potential. Thus, its use should be preferred for the diagnosis of patients affected by latex allergy.

Gleich's syndrome is characterized by recurrent localized angioedema, hypereosinophilia, elevated levels of IgM, rapid weight gain, itchy urticaria and fever. Little is known about the pathogenesis of this disease. Increased serum levels for IL5, IL6 and C5a have been reported before and during clinical exacerbations. In order to better understand the role of the T cells in Gleich's syndrome we analyzed the intracellular cytokine expression in CD3+ cells of a patient affected by the disease. As hypereosinophilia was documented, we asked whether IL-4 and IL-5 levels were increased, and the intracytoplasmatic expression of these Th2-cytokines was determined. The percentage of T lymphocytes (CD3-gated cells) of both CD8− and CD8+ phenotype expressing different cytokines showed an unusually high percentage of Th2-related cytokine (IL-4, IL-5 and IL-13) expressing T lymphocytes. The two new variants (myeloproliferative and lymphoproliferative) seem to account for hypereosinophilia in patients with hypereosinophilic syndrome (HES). In the lymphroliferative variant, the presence of a clonal CD3-CD4+ Th2 like lymphocyte secreting IL-4 and IL-5 in peripheral blood, may explain the hypereosinophilia and the hyper-IgE. In our study we show that the patient had a lymphoproliferative variant and her T cell had a Th2 type phenotype. Moreover, we suggest that Th2 lymphocytes may play a role in the pathogenesis of Gleich's syndrome. Further studies are needed to evaluate the possibility that a polyclonal aspecific activation of Th2 type cells can lead to hypereosinophilia, IgE production and the other manifestations typical of Gleich's syndrome.

Regulation of the immune response to self-antigens is a complex process that involves maintaining self-tolerance while preserving the capacity to exert an effective immune response. The primary mechanism that leads to self-tolerance is central tolerance. However, potential pathogenic autoreactive lymphocytes are normally present in the periphery of all individuals. This suggests the existence of mechanisms of peripheral tolerance that prevent the initiation of autoimmune diseases by limiting the activation of autoreactive lymphocytes. If these mechanisms of peripheral tolerance are impaired, the autoreactive lymphocytes may be activated and autoimmune diseases can develop. Several processes are involved in the maintenance of peripheral tolerance: the active suppression mediated by regulatory T cell populations, the different maturation state of antigen-presenting cells presenting the autoantigen to autoreactive lymphocytes, inducing tolerance instead of cell activation, the characteristics of B cell populations. A deeper comprehension of these mechanisms may lead to important therapeutic applications, such as the development of cellular vaccines for organ-specific autoimmune diseases. In addition, autoimmunity does not always have pathological consequences, but may exert a protective function, as suggested by several observations on the beneficial role of autoreactive T cells in central nervous system injury.

The aim of the study was to describe the recent trends in antiretroviral treatment in late pregnancy and the sociodemographic changes among pregnant women with HIV over the last 6 years. Data from the National Program on Surveillance on Antiretroviral Treatment in Pregnancy in Italy were grouped per calendar year, and changes in antiretroviral treatment, population characteristics, maternal immunovirologic status and newborn clinical parameters were analyzed. A total of 981 HIV-infected mothers who delivered between 2002 and 2008 were evaluated. The proportion of women receiving at least three antiretroviral drugs at delivery increased significantly from 63.0% in 2002 to 95.5% in 2007-2008, paralleled by a similar upward trend in the proportion of women who achieved complete viral suppression at third trimester (from 37.3 in 2002 to 80.9 in 2007-2008; p < 0.001). The co-formulation of zidovudine plus lamivudine remained the most common nucleoside backbone in pregnancy, even if a significant increase in the use of tenofovir plus emtricitabine was observed in more recent years. Starting from 2003, nevirapine prescription declined, paralleled by a significant rise in the use of protease inhibitors (PI), which were present in more than 60% of regimens administered in 2007-2008. Nelfinavir was progressively replaced by ritonavir-boosted PIs, mainly lopinavir. No significant changes in preterm delivery, Apgar score, birth weight, and birth defects were observed during the study period, and the rate of HIV transmission remained below 2%. These data demonstrate a significant evolution in the treatment of HIV in pregnancy. Constant improvements in the rates of HIV suppression were observed, probably driven by the adoption of stronger and more effective regimens and by the increasing options available for combination treatment

Background Few prospective data have been published on the comparison of bone density and quality in homogeneous groups of patients with juvenile systemic lupus erythematosus (JSLE) and juvenile idiopathic arthritis (JIA). Objective and hypothesis The objective of this study is to perform a longitudinal evaluation of the prevalence and the characteristics of bone mass and quality and to evaluate the differences on the bone parameters, using DXA, pQCT and QUS. Population and/or methods Forty-three JSLE patients (35 females, 8 males, median age 18.8, range 14.0–34.1 years) have been studied with DXA, pQCT and QUS scans and compared with 138 JIA patients (112 females, 26 males, median age 18.9, range 13.4–33.2 years), and 79 controls (59 females, 20 males; median age 19.3, range 13.5–36.5 years). Of these, 39 patients (32 females and 7 males, median age 20.3, range 16.6–36.8 years) with JSLE were followed longitudinally and compared with 131 patients (108 females, 23 males median age 20.7, range 15.8–37.1 years) with JIA and 63 controls (48 females, 15 males; median age 21.9, range 15.5–38.3 years). Results JSLE patients have a higher bone cortical density (CrtBMD) than controls and JIA patients ( p Conclusions The evaluation of bone density and structure parameters in JSLE patients highlights significant differences compared with JIA patients and controls. These data might indicate a different pathogenesis of bone damage in the two entities, and suggest a different diagnostic and therapeutic approach to improve the peak bone mass.

The Chauvet-Pont d'Arc Cave is one of the most important sites for the study of the earliest manifestations and development of prehistoric art at the beginning of the Upper Paleolithic. Different dating techniques have been performed thus far (AMS 14C, U/Th TIMS, 36Cl dating) to model the chronological framework of this decorated cave. The cave yielded several large charcoal fragments, which enabled the opportunity for obtaining multiple dates; thus, a First Radiocarbon Intercomparison Program (FIP) was initiated in 2004 using three charcoal pieces. The FIP demonstrated that those cross-dated samples belonged to a time period associated with the first human occupation. One of the statistical interests of an intercomparison program is to reduce the uncertainty on the sample age; thus, to further assess the accuracy of the chronological framework, the Second Intercomparison Program (SIP) involving 10 international 14C laboratories was carried out on two pieces of charcoal found inside two hearth structures of the Galerie des Mégacéros. Each laboratory used its own pretreatment and AMS facilities. In total, 21 and 22 measurements were performed, respectively, which yielded consistent results averaging ∼32 ka BP. Two strategies have currently been developed to identify statistical outliers and to deal with them; both lead to quasi-identical calibrated combined densities. Finally, the new results were compared with those of the FIP, leading to the important conclusion that five different samples from at least three different hearth structures give really tightened temporal densities, associated with one short human occupation in the Galerie des Mégacéros.

SUMMARY HIV-1 in adults changes the proportion of mitogen-stimulated lymphocytes expressing the CD69 activation molecule, but little is known about this molecule expression on lymphocytes of HIV-1-infected (HIV-1+) children. Freshly isolated CD3+, CD4+, CD8+ and CD19+ and phytohaemagglutinin (PHA)-stimulated CD3+, CD4+ and CD8+ lymphocytes co-expressing CD69 were investigated cross-sectionally (adopting a MoAb double-staining technique) in 24 HIV-1+ children with severe disease and given anti-retroviral therapy and in 24 age-matched healthy children. CD69 results in HIV-1+ children were correlated with plasma HIV-1 RNA load prospectively determined. HIV-1+ compared with healthy children had higher frequencies of freshly isolated CD3+CD69+ (2.4 ± 2.2% versus 0.9 ± 0.5%; P = 0.002) and CD8+CD69+ (1.5 ± 1.1% versus 0.5 ± 0.2%; P

SUMMARYEighty-six children fed human milk were followed prospectively from birth to 12 months of age to assess the effect of milk 90K, a secreted glycoprotein with immune-stimulatory properties, on development of acute respiratory infections (ARI). The level of human milk 90K was inversely related to episodes of ARI (r = − 0.34; P = 0.001). The average 90K level in human milk fed to children who did not develop ARI was significantly higher than in milk fed to children in whom infection occurred on multiple occasions (156.6 ± 144.8 μg/ml versus 70.9 ± 92.3 μg/ml; P = 0.001). These data suggest that the protective effects of human milk against ARI may be due in part to immune maturation effects by secreted 90K.

On 31 May 2013, the first case of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection in Italy was laboratory confirmed in a previously healthy adult man, who developed pneumonia with moderate respiratory distress after returning from a holiday in Jordan. Two secondary cases were identified through contact tracing, among family members and colleagues who had not previously travelled abroad. Both secondary cases developed mild illness. All three patients recovered fully.

Vaccines have eradicated or controlled many infectious diseases, saving each year millions of lives and quality of life of many other millions of people. In spite of the success of vaccines over the last two centuries, parents (and also some health care workers) gloss over the devastating consequences of diseases, which are now avoided thanks to vaccines, and direct their attention to possible negative effects of immunization. Three immunological objections are raised: vaccines cause antigenic overload, natural immunity is safer and better than vaccine-induced immunity, and vaccines induce autoimmunity. The last point is examined in this review. Theoretically, vaccines could trigger autoimmunity by means of cytokine production, anti-idiotypic network, expression of human histocompatibility leukocyte antigens, modification of surface antigens and induction of novel antigens, molecular mimicry, bystander activation, epitope spreading, and polyclonal activation of B cells. There is strong evidence that none of these mechanisms is really effective in causing autoimmune diseases. Vaccines are not a source of autoimmune diseases. By contrast, absolute evidence exists that infectious agents can trigger autoimmune mechanisms and that they do cause autoimmune diseases.

Data regarding the use of Interferon-gamma release assays (IGRAs) for tuberculosis diagnosis are accumulating. We systematically searched PubMed, EMBASE and Cochrane and performed pooled estimates of sensitivity and specificity of QuantiFERON-TB Gold In Tube (QFT-G-IT) and T-SPOT. TB compared to tuberculin skin test (TST). For studies assessing sensitivity, children had to have active tuberculosis. Specificity data were derived from children classified as non-infected. Eleven studies were included in the sensitivity analysis for TST, 10 for QFT-G-IT, and 9 for T-SPOT.TB. Eight studies were included in specificity analysis for TST, 8 for QFT-G-IT, and 7 for T-SPOT.TB. Pooled QFT-G-IT sensitivity was 0.79 (95%CI:0.70–0.89) pooled T-SPOT.TB sensitivity was 0.74 (95%CI:0.59–0.90) and pooled TST sensitivity was 0.82 (95%CI:0.72–0.93). Pooled QFT-G-IT and T-SPOT.TB specificities were 0.95 (95%CI:0.93–0.97) and 0.96 (95%CI:0.93–1.00), respectively. Pooled TST specificity was significantly lower 0.83 (95%CI:0.74–0.92). IGRA performance in children showed no better sensitivity than TST, but higher specificity.

Eighteen pigs weighing a mean 19 ± 4 kg, were divided into group 1 (n = 2), that underwent resection of the left lateral lobe, group 2 (n = 2), resection of the left median and right median lobes; and group 3 (n = 18), resection of the left lateral, left median, right median, and right lateral lobes. All animals were followed for 5 days. Liver failure (n = 8) leading to animal death within 3 days after surgery was observed in 65% of group 3, whereas no group 1 or 2 animal experienced liver insufficiency. Multivariate analysis revealed that the extent of liver resection expressed as a percentage of total body weight 1.6 as postoperative day 2, serum bilirubin > 4.2 on postoperative day 2, and serum lactates > 9 mmol/L after resection were independent predictors of liver failure (P < .05). The number of resected liver lobes was not a good predictor of liver failure in swine, whereas the extent of resection expressed as a percentage of total body weight was an independent predictor of early liver failure. A resected liver-to-body weight ratio >2.3% was associated with a 65% probability of developing liver insufficiency. This parameter may be useful when developing a model of liver failure after extended liver resection in swine.

Type 1 diabetes (T1D) is a heterogeneous disorder characterized by destruction of pancreatic beta cells, culminating in loss of insulin secretion. Data from large epidemiologic studies worldwide indicate that during the last decades the incidence of T1D has increased significantly, reaching percentages of 2-5% annually. This increase suggests that there is a significant environmental contribution impacting the development of the disease, since genetic factors alone can hardly explain the rapid increase. Studies regarding T1D epidemiology in diverse populations aim to identify the disease causal factors and new targets for intervention. Viruses are one of the environmental factors implicated in the development of T1D in susceptible individuals. Recent studies suggest an association of T1D with H1N1 influenza. We would like to comment on this association and report our experience. Prospective studies are necessary to assess whether H1N1 infection is involved in T1D pathogenesis and provide directions on how to deal with viral infections in diabetes-susceptible individuals.

In vivo exposure to microorganisms resident in the oral cavity is considered as a possible cause of Kawasaki disease (KD), and some epitopes derived from streptococci display homology with Factor H of Complement. Additionally, calprotectin, a major calcium binding protein released by neutrophils and activated monocytes, could be directly involved in endothelial damage occurring in KD. The aim of our study is to evaluate the percentages of IFN-gamma+ and/or TNF-alpha+ lymphocytes and double positive calprotectin/TNF-alpha monocytes (CD14+) after in vitro stimulation with streptococcal- and/or Factor H-derived peptides, in patients with acute KD. Peripheral Blood Mononuclear Cells (PBMCs) obtained from KD patients and febrile controls were stimulated in vitro with peptides. After culture, cells were collected, stained with fluorochrome-labelled monoclonal antibodies against CD3, CD14, calprotectin, IFN-gamma and TNF-alpha, and cytofluorimetric analyses were performed. Our results showed increased percentages of TNF-alpha+/IFN-gamma+ lymphocytes in KD patients in respect to controls when PBMCs were stimulated with streptococcal or Factor H-derived epitopes. In addition, also calprotectin+/TNF-alpha+ monocytes from KD patients were activated after PBMC in vitro stimulation. These findings lead us to speculate that some peptides, derived from oral streptococci and cross-reactive with the human Factor H of Complement, could induce lymphocyte and monocyte activation potentially involved in the pathogenesis of KD. Our results should be confirmed by further studies enrolling more patients and controls than those analyzed in our study.

Background: To date, no reliable serum marker for clear cell renal cell carcinoma (CCRCC) is available. The aim of this study was to evaluate the putative significance of circulating 20S proteasome levels. Methods: Preoperative 20S proteasome serum levels were determined in 113 CCRCC patients and 15 healthy controls by a sandwich enzyme-linked immunosorbent assay. Associations with CCRCC, pathological variables, disease-specific survival (DSS), and response to sunitinib were evaluated. Results: Median 20S proteasome levels were higher in CCRCC patients than in healthy controls (4.66 vs 1.52 μg ml−1, P