The Italian Society of Rheumatology clinical practice guidelines for the management of large vessel vasculitis.

OBJECTIVE: Since of the last publication of last recommendations on primary large-vessel vasculitis (LVV) endorsed by the Italian Society of Rheumatology (SIR) in 2012, new evidence emerged regarding the diagnosis and the treatment with conventional and biologic immunosuppressive drugs. The associated potential change of clinical care supported the need to update the original recommendations. METHODS: Using the grading of recommendations assessment, development and evaluation (GRADE)-ADOLOPMENT framework, a systematic literature review was performed to update the evidence supporting the European Alliance of Associations for Rheumatology (EULAR) guidelines on LVV as reference. A multidisciplinary panel of 12 expert clinicians, a trained nurse, and a patients' representative discussed the recommendation in cooperation with an Evidence Review Team. Sixty-one stakeholders were consulted to externally review and rate the recommendations. RESULTS: Twelve recommendations were formulated. A suspected diagnosis of LVV should be confirmed by imaging or histology. In active GCA or TAK, the prompt commencement of high dose of oral glucocorticoids (40-60 mg prednisone-equivalent per day) is strongly recommended to induce clinical remission. In selected patients with GCA (e.g., refractory or relapsing disease or patients at risk of glucocorticoid related adverse effects) the use of an adjunctive therapy (tocilizumab or methotrexate) is recommended. In all patients diagnosed with TAK, adjunctive therapies, such as conventional synthetic or biological immunosuppressants, should be given in combination with glucocorticoids. CONCLUSIONS: The new set of SIR recommendations was formulated in order to provide a guidance on both diagnosis and treatment of patients suspected of or with a definite diagnosis of LVV.

Persistence of bDMARD therapy in Rheumatoid Arthritis after first-line TNF-inhibitor failure: the RECORD study of the Italian Society for Rheumatology.

OBJECTIVE: The optimal choice of a second biological disease-modifying anti-rheumatic drug (bDMARD) after failure with first line tumour necrosis factor inhibitor (TNFi) represents a critical therapeutic challenge. This study aims to evaluate the persistence with treatment using second line bDMARDs with different mechanisms of action in rheumatoid arthritis (RA) patients with inadequate response to first line TNFi. METHOD: A retrospective cohort study on administrative healthcare databases was conducted. We analysed the relationship between different bDMARDs and persistence with treatment in RA patients who started second line bDMARD therapy according to two different strategies: cycling (second TNFi) or switching [change in mechanism of action: abatacept (ABA), tocilizumab (TCZ), and rituximab (RTX)] with or without concomitant conventional synthetic (cs) DMARDs. RESULTS: The cohort comprised 1434 patients. The mean age was 53.8 years and 1142 (79.6%) were women. Among second line bDMARDs, 969 patients (67.6%) started TNFi, 204 (14.2%) ABA, 145 (10.1%) RTX, and 116 (8.1%) TCZ. A bDMARD was prescribed as monotherapy in 359 patients (25.0%). The switching strategy showed a lower overall discontinuation rate [hazard ratio (HR) 0.72], while switching compared to cycling showed significantly better survival for ABA (HR 0.61) and RTX (HR 0.76), but no significant difference for TCZ (HR 0.82). A lower impact of better drug survival in the switching strategy occurred in patients with concurrent methotrexate. CONCLUSIONS: Among RA patients failing a first TNFi, switching is associated with marginally better persistence, in particular for ABA and RTX, with only marginal differences in patients on concurrent csDMARDs.

The Italian Society for Rheumatology recommendations for the management of axial spondyloarthritis.

Over the last few years, the landscape of treatments for axial spondyloarthritis (SpA) has been rapidly evolving, urging international scientific societies to draft or update existing clinical practice guidelines (CPGs) on the management of axial SpA. The Italian Society for Rheumatology (SIR) committed to provide revised and adapted evidence- and expert-based recommendations for the management of patients with axial SpA in Italy. A systematic approach to the adaptation of existing CPGs - the ADAPTE methodology - was adopted to obtain updated recommendations suitable for the Italian context. A systematic literature search was performed in Medline and Embase databases to find international CPGs and consensus statements with recommendations for the management of axial SpA published in the previous five years. A working group composed of rheumatologists with proven experience in the management of axial SpA and methodologists identified the key research questions which guided study selection and data extraction. Guideline quality was assessed using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The Italian recommendations were developed by endorsing or adapting and rewording some existing recommendations. The draft of the recommendations was sent to a multidisciplinary group of external reviewers for comment and rating. Six original CPGs were selected and used to create this SIR CPG, which includes a final set of 14 recommendations covering the management of patients with axial SpA across the following domains: assessment, pharmacological and non-pharmacological treatment, and follow-up. The dissemination and implementation of these SIR recommendations are expected to support an evidencebased clinical approach to the management of patients with axial SpA in Italy.

Role of comorbidities on therapeutic persistence of biological agents in rheumatoid arthritis: results from the RECord-linkage On Rheumatic Disease study on administrative healthcare databases.

Objectives: This study aimed to evaluate the impact of different comorbidities on thereflecting its safety profile persistence of biological disease-modifying anti-rheumatic drugs (bDMARDs) in rheumatoid arthritis (RA), taking advantage of a retrospective analysis of administrative healthcare databases (AHDs).Method: A retrospective observational study was conducted on AHDs of the Lombardy region, Italy (2004-2013). Among RA patients treated with bDMARDs, drug survival was estimated using Cox proportional hazard models [hazard ratio (HR), 95% confidence interval (CI)], crude and adjusted for prespecified confounders (gender, age, disease duration, concomitant use of non-steroidal anti-inflammatory drugs, glucocorticoids, conventional DMARDs, specific bDMARDs), in first-line and subsequent lines of treatment. The role of comorbidities in administration of specific bDMARDs was analysed through multinomial logistic models.Results: The study included 4657 RA patients. In the first-line treatment strategy, the Charlson Comorbidity Index (CCI) (RA excluded) was significantly associated with an increased rate of bDMARD failure (CCI = 1: HR 1.28, 95% CI 1.13-1.46; CCI ≥ 2: HR 1.26, 95% CI 1.03-1.53). Among selected comorbidities, chronic obstructive pulmonary disease (HR 1.38, 95% CI 1.01-1.91), diabetes (HR 1.18, 95% CI 1.01-1.37), and previous-year bacterial infections (HR 1.18, 95% CI 1.07-1.30) were slightly associated with risk of bDMARD failure, while acute myocardial infarction (HR 1.30, 95% CI 0.97-1.75), mild liver disease (HR 1.21, 95% CI 0.91-1.60), and solid tumours (HR 1.19, 95% CI 0.93-1.53) were not. In the following treatment lines, neoplasms were associated with reduced risk of failure (HR 0.64, 95% CI 0.41-0.99). Multiple comorbidities were associated with first-line abatacept and rituximab administration.Conclusions: Comorbidities affect treatment decisions in RA and influence bDMARD failure, and should be considered when analysing the persistence of biological therapy.

Providing updated guidelines for the management of rheumatic diseases in Italy with the ADAPTE methodology: a project by the Italian Society for Rheumatology.

Not available.

Early Lupus Project: one-year follow-up of an Italian cohort of patients with systemic lupus erythematosus of recent onset.

Objective To describe the clinical and serological features of a prospectively followed cohort of early diagnosed systemic lupus erythematosus (SLE) patients during a one-year follow-up period. Methods SLE patients with disease duration less than 12 months were consecutively enrolled in a multicentre, prospective study. At study entry and then every 6 months, a large panel of data was recorded. Results Of 260 patients enrolled, 185 had at least 12 months of follow-up; of these, 84.3% were female, 92.4% were Caucasians. Mean diagnostic delay was about 20 months; higher values of European Consensus Lupus Activity Measurement (ECLAM) and of organs/systems involved were both associated with shorter diagnostic delay. Clinical and serological parameters improved after study entry. However, patients' quality of life deteriorated and cardiovascular risk factors significantly increased. About one-third of patients with active disease at study entry went into remission (ECLAM = 0). Negative predictors for remission were: oral ulcers, arthritis, low C4, anti-SSB (Ro) antibodies and therapy with mycophenolate. There was a widespread use of glucocorticoids both at baseline and during follow-up. Conclusion Clinical symptoms and serological parameters improve during the first period after diagnosis. However, patients' quality of life deteriorates. The widespread use of glucocorticoids is probably the reason for the early significant increase of some cardiovascular risk factors.

Attitudes towards suicidal behaviour and associated factors among nursing professionals: A quantitative study.

WHAT IS KNOWN ON THE SUBJECT?: Self-confident health professionals with positive and understanding attitudes can take better care of people with suicidal behaviour, but the factors associated with these attitudes are not known. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: The majority of nursing professionals had no experience or training in mental health or suicide. They were less self-confident and had more negative attitudes. Nurses and nursing assistants who worked before in mental health services were more understanding with people with suicidal behaviour. Nurses and nursing assistants who were working in prehospital services were less self-confident to taking care of people with suicidal behaviour. Some members of the nursing team had already seriously considered committing suicide. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The practicing, support and training in mental health may improve the nurses' attitudes and emotional competencies. It is important to know why few nurses had suicide-related training, despite the relevance of this issue. Training in mental health or suicide need to include attitudinal and emotional competencies. It is important to offer emotional support to emergency nursing professionals. ABSTRACT: Background The attitudes towards suicide of emergency nurses may affect the care provided. However, the factors associated with these attitudes remain unclear. Objective To investigate attitudes towards suicidal behaviour and associated factors among nursing professionals working in emergency settings. Methods A cross-sectional observational study including 28 nurses and 118 who were nursing assistants employed at two emergency services in Brazil was conducted. Data were collected in 2015 using a self-administered sociodemographic questionnaire and the Suicide Behavior Attitude Questionnaire (SBAQ). Results The majority of participants reported having no experience or training in mental health or suicide. They reported more negative feelings towards the patient and a lower self-perception of professional competence regarding suicidal behaviours, and these attitudes seemed to reinforce each other. Nurses who worked in mental health services reported less moralistic/judgemental attitudes. Working in prehospital services was associated with having a lower self-perception of professional competence. There were professionals who reported thinking seriously about committing suicide. Conclusion When combined with support and training, practicing mental health nursing may serve as an opportunity to develop favourable attitudes and emotional competences, and these issues need to be addressed in suicide education strategies.

Seroepidemiology of HEV and HAV in two populations with different socio-economic levels and hygienic/sanitary conditions.

The epidemiological scenarios of hepatitis E virus (HEV) and hepatitis A virus (HAV) infections have changed in the last few decades, but precise epidemiological data on the prevalence of anti-HEV and anti-HAV, alone or in combination, in the general population are scanty. We investigated HEV and HAV seroprevalence comparing two population samples living in Northern (Abbiategrasso, Milan) and Southern Italy (Cittanova, Reggio Calabria), the latter being characterized by a poorer socio-economic level and hygienic/sanitary conditions. Based on census records, we randomly enrolled and tested 3,365 subjects (Abbiategrasso, n = 2,489; Cittanova, n = 876) aged 18-75 years for anti-HAV and anti-HEV. Anti-HAV (71.3 % vs 52.5 %) and anti-HEV (17.8 % vs 9.0 %) prevalence rates were higher in Southern Italy (both p < 0.001). Most anti-HEV-positive subjects also had anti-HAV. Subjects testing positive for anti-HAV, alone or with anti-HEV, were older (p < 0.001 in both populations) and showed a trend toward declining prevalence in the youngest birth cohorts. The prevalence of subjects with a positive result for anti-HEV alone did not change in birth cohorts in the two towns. Detection of anti-HEV was independently associated with anti-HAV, town, birth cohort, and education level in multivariate analysis. Low socio-economic level and hygienic/sanitary conditions are associated with high HAV and HEV seroprevalence rates in Italy. Recent improvements, especially in the South, have led to a declining prevalence of anti-HAV, alone or with anti-HEV. Seroprevalence of HEV alone is uniformly low and does not change in birth cohorts born between 1938 and 1993.

Network-guided modeling allows tumor-type independent prediction of sensitivity to all-trans-retinoic acid.

Background: All-trans-retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia (APL) and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires the development of predictive tools allowing identification of sensitive cancer types and responsive individuals. Materials and methods: RNA-sequencing data for 10 080 patients and 33 different tumor types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was carried out using machine learning methods and network analysis. Results: We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor types for which higher ATRA-21 predictions are associated with better outcomes. Conclusions: In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor types that are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity.

Hepatitis C virus outbreak in a haemodialysis unit: learning from failures.

The investigation of an outbreak of hepatitis C virus in an Italian haemodialysis (HD) centre showed that three patients acquired infection with the same strain, affecting a chronically hepatitis C virus (HCV)-infected patient receiving HD in the same room and during the same shifts. Through our observational analysis many possible modes of transmission were identified, but none could be definitively identified as the route of HCV spread in this small cluster. This outbreak confirms that repeated opportunities for nosocomial HCV transmission may occur among HD patients due to several breaches in the standard precautions for bloodborne infections by healthcare staff.

Morfologia do estômago e do duodeno da paca (Cuniculus paca Linnaeus, 1766) / Morphology of the stomach and duodenum of paca (Cuniculus paca Linnaeus, 1766)

Considerando a importância da paca (Cuniculus paca, Linnaeus, 1766), tanto como fonte proteica alternativa para a população quanto pela possibilidade de vir a se tornar um animal de experimentação e pela falta de informações sobre a sua anatomia, objetivou-se descrever a morfologia macroscópica e histológica do estômago e do duodeno desse roedor, reconhecendo as relações, forma e posição que esses órgãos estabelecem entre si e com outros órgãos. O estômago da paca é unicavitário, está no plano médio mais voltado para o antímero esquerdo, transversalmente, na região hipocôndrica em posição ventrocaudal, interposto entre o esôfago e o duodeno. O duodeno da paca se inicia em sequência ao estômago, segue caudalmente até o nível da quinta ou sexta vértebra lombar, na altura das quais se curva e toma direção cranial, dirigindo-se até o nível da transição entre a última vértebra torácica e a primeira vértebra lombar, onde se continua como jejuno. Histologicamente, o estômago e o duodeno da paca possuem o padrão característico da arquitetura dos órgãos ocos, apresentando as seguintes túnicas: mucosa, submucosa, muscular e serosa. Da forma que se conduziu este estudo, conclui-se que o estômago e duodeno da paca, de forma geral, possuem características morfológicas macroscópicas e histológicas semelhantes às dos animais domésticos e de outros roedores selvagens.

Considering the importance of paca (Cuniculus paca, Linnaeus, 1766) as an alternative protein source for the population as well as the possibility to become an experimental model and the lack of information regarding to the anatomy of this species, the present study aims to describe the gross anatomy and the histology of the stomach and duodenum of this rodent, recognizing the relations, shape and position that these organs establish between themselves and among other organs. The paca stomach is monocavitary; it is located at the median plane, more toward the left antimere, transversally, at the hypochondriac region in a ventrocaudal position, interposed between the esophagus and duodenum. The duodenum of paca begins in sequence of the stomach, following caudally until the fifth or sixth lumbar vertebra, at this level it curves and takes the cranial direction, going until the transition level between the last thoracic vertebra and the first lumbar vertebra where it continues as jejune. Histologically, the stomach and duodenum of paca have the characteristic pattern of the hollow organs architecture, presenting the following layers: mucosa, submucosa, muscular and serous. As this study was conducted, it is possible to conclude that the stomach and duodenum of paca, in general, present gross anatomical and histological characteristics similar to the domestic animals and to the other wild rodents.

Basic life support knowledge of first-year university students from Brazil

We aimed to evaluate knowledge of first aid among new undergraduates and whether it is affected by their chosen course. A questionnaire was developed to assess knowledge of how to activate the Mobile Emergency Attendance Service - MEAS (Serviço de Atendimento Móvel de Urgência; SAMU), recognize a pre-hospital emergency situation and the first aid required for cardiac arrest. The students were also asked about enrolling in a first aid course. Responses were received from 1038 of 1365 (76.04%) new undergraduates. The questionnaires were completed in a 2-week period 1 month after the beginning of classes. Of the 1038 respondents (59.5% studying biological sciences, 11.6% physical sciences, and 28.6% humanities), 58.5% knew how to activate the MEAS/SAMU (54.3% non-biological vs 61.4% biological, P=0.02), with an odds ratio (OR)=1.39 (95%CI=1.07-1.81) regardless of age, sex, origin, having a previous degree or having a relative with cardiac disease. The majority could distinguish emergency from non-emergency situations. When faced with a possible cardiac arrest, 17.7% of the students would perform chest compressions (15.5% non-biological vs 19.1% biological first-year university students, P=0.16) and 65.2% would enroll in a first aid course (51.1% non-biological vs 74.7% biological, P<0.01), with an OR=2.61 (95%CI=1.98-3.44) adjusted for the same confounders. Even though a high percentage of the students recognized emergency situations, a significant proportion did not know the MEAS/SAMU number and only a minority had sufficient basic life support skills to help with cardiac arrest. A significant proportion would not enroll in a first aid course. Biological first-year university students were more prone to enroll in a basic life support course.

Basic life support knowledge of first-year university students from Brazil.

We aimed to evaluate knowledge of first aid among new undergraduates and whether it is affected by their chosen course. A questionnaire was developed to assess knowledge of how to activate the Mobile Emergency Attendance Service - MEAS (Serviço de Atendimento Móvel de Urgência; SAMU), recognize a pre-hospital emergency situation and the first aid required for cardiac arrest. The students were also asked about enrolling in a first aid course. Responses were received from 1038 of 1365 (76.04%) new undergraduates. The questionnaires were completed in a 2-week period 1 month after the beginning of classes. Of the 1038 respondents (59.5% studying biological sciences, 11.6% physical sciences, and 28.6% humanities), 58.5% knew how to activate the MEAS/SAMU (54.3% non-biological vs 61.4% biological, P=0.02), with an odds ratio (OR)=1.39 (95%CI=1.07-1.81) regardless of age, sex, origin, having a previous degree or having a relative with cardiac disease. The majority could distinguish emergency from non-emergency situations. When faced with a possible cardiac arrest, 17.7% of the students would perform chest compressions (15.5% non-biological vs 19.1% biological first-year university students, P=0.16) and 65.2% would enroll in a first aid course (51.1% non-biological vs 74.7% biological, P<0.01), with an OR=2.61 (95%CI=1.98-3.44) adjusted for the same confounders. Even though a high percentage of the students recognized emergency situations, a significant proportion did not know the MEAS/SAMU number and only a minority had sufficient basic life support skills to help with cardiac arrest. A significant proportion would not enroll in a first aid course. Biological first-year university students were more prone to enroll in a basic life support course.

Lessons learnt over two decades of vaccination against hepatitis B in Italy.

This article reviews topics covered and discussed at the Meeting: "Vaccini e vaccinazioni. Migliorare l'oggi e preparare il domani", held in Genoa, Italy, on 12 September 2014. Data presented at the meeting, clearly showed that: 1) hepatitis B vaccination can confer long-term protection and there is no need for booster in immunocompetent vaccinees; 2) vaccination is highly effective in protecting population from clinical acute or chronic HBV infections, including hepatocellular carcinoma; 3) children vaccinated as infants with hexavalent vaccines maintain immunological memory 5 years after priming, but further studies are needed to assess whether immunity persists during the adolescence and adulthood when risk of exposure to HBV becomes higher; 4) the emergence of vaccine-escape mutants and Pol-gene mutants during antiviral therapy - which can result in changes in the S-gene - is of some concern, but at present there is no evidence that such mutants may pose a threat to the established programs of vaccination.

Characterization of novel akermanite:poly-ϵ-caprolactone scaffolds for human adipose-derived stem cells bone tissue engineering.

In this study, three different akermanite:poly-ϵ-caprolactone (PCL) composite scaffolds (wt%: 75:25, 50:50, 25:75) were characterized in terms of structure, compression strength, degradation rate and in vitro biocompatibility to human adipose-derived stem cells (hASC). Pure ceramic scaffolds [CellCeram™, custom-made, 40:60 wt%; ß-tricalcium phosphate (ß-TCP):hydroxyapatite (HA); and akermanite] and PCL scaffolds served as experimental controls. Compared to ceramic scaffolds, the authors hypothesized that optimal akermanite:PCL composites would have improved compression strength and comparable biocompatibility to hASC. Electron microscopy analysis revealed that PCL-containing scaffolds had the highest porosity but CellCeram™ had the greatest pore size. In general, compression strength in PCL-containing scaffolds was greater than in ceramic scaffolds. PCL-containing scaffolds were also more stable in culture than ceramic scaffolds. Nonetheless, mass losses after 21 days were observed in all scaffold types. Reduced hASC metabolic activity and increased cell detachment were observed after acute exposure to akermanite:PCL extracts (wt%: 75:25, 50:50). Among the PCL-containing scaffolds, hASC cultured for 21 days on akermanite:PCL (wt%: 75:25) discs displayed the highest viability, increased expression of osteogenic markers (alkaline phosphatase and osteocalcin) and lowest IL-6 expression. Together, the results indicate that akermanite:PCL composites may have appropriate mechanical and biocompatibility properties for use as bone tissue scaffolds.

Hepatitis B immunity in teenagers vaccinated as infants: an Italian 17-year follow-up study.

We assessed the persistence of hepatitis B surface antigen antibody (anti-HBs) and immune memory in a cohort of 571 teenagers vaccinated against hepatitis B as infants, 17 years earlier. Vaccinees were followed-up in 2003 and in 2010 (i.e. 10 years and 17 years after primary vaccination, respectively). When tested in 2003, 199 vaccinees (group A) had anti-HBs <10 mIU/mL and were boosted, 372 (group B) were not boosted because they had anti-HBs ≥10 mIU/mL (n = 344) or refused booster (n = 28) despite anti-HBs <10 mIU/mL. In 2010, 72.9% (416/571) of participants had anti-HBs ≥10 mIU/mL (67.3% in group A vs. 75.8% in group B; p 0.03). The geometric mean concentrations (GMCs) were similar in both groups. Between 2003 and 2010, anti-HBs concentrations in previously boosted individuals markedly declined with GMC dropping from 486 to 27.7 mIU/mL (p <0.001). Fifteen vaccinees showed a marked increase of antibody, possibly due to natural booster. In 2010, 96 individuals (37 of group A and 59 of group B) with anti-HBs <10 mIU/mL were boosted; all vaccinees of the former group and all but two of the latter had an anamnestic response. Post-booster GMC was higher in group B (895.6 vs. 492.2 mIU/mL; p 0.039). This finding shows that the immune memory for HBsAg persists beyond the time at which anti-HBs disappears, conferring long-term protection.

Hepatitis E: a puzzling double-faced disease.

Viral hepatitis type E is highly endemic in many developing countries, where large water-borne epidemics caused by viral genotype 1 and - to a lesser degree - by genotype 2 cyclically occur, resulting in high morbidity and mortality, especially among pregnant women. In developed countries, the disease is usually diagnosed in travelers coming back from endemic countries, but an increasing number of sporadic locally acquired hepatitis cases caused by genotype 3 and 4 have recently been reported. The wide-spread distribution of HEV3 and HEV4 in domestic pigs, wild boars, deer, as well as in other mammals, suggests that infections caused by these genotypes may have a zoonotic source. HEV3 infection can evolve to chronic infection in immunosuppressed patients; in addition, it may be associated with neurological disorders and extrahepatic manifestations. Two recently developed recombinant vaccines have proved to be safe and effective. One of such vaccines has recently been licensed for use in China.

Characterization and differential expression analysis of complete coding sequences of Vitis vinifera L. sirtuin genes.

The sirtuin/Sir2 (Silent information regulator 2) family of NAD+-dependent deacetylases and mono-ADP-ribosyltransferases plays an important role in several cellular processes including gene silencing, cell cycle regulation and life span extension in yeast and animals. Compared to other eukaryotes, plants have relatively fewer SIR2 related genes encoding only two putative SIR2 family proteins. Recently, two putative sirtuin genes were identified also in the grapevine genome. Starting from the predicted coding sequences present in the database, we have been able to obtain two truly expressed coding sequences from the start to the stop codon for both sirtuin genes that were named VvSRT1 and VvSRT2. The search for the expressed coding sequences was performed by comparing the predicted sequences with the recently available grape RNA seq database with the aim to develop the primers to be used in reverse transcriptase PCR reactions to amplify the genes of interest. Finally, in order to better understand the physiological role of both sirtuins, we investigated the expression of these genes in young leaves, mature leaves, and berries sampled at different growing stages. In leaves, usually it has been observed that VvSRT1 is less expresses than VvSRT2, moreover in young leaves VvSRT2 showed the higher expression during setting while in mature leaves during the flowering time. No particular variations have been observed concerning VvSRT1. In berries the two genes showed more similar expression level, and they showed the highest expression during the flowering time. Finally, the expression of VvSRT2 in berries is smaller than in leaves.

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA.

All-trans retinoic acid (ATRA), the only clinically available cyto-differentiating agent, has potential for the therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoid-based protocols. Here, we demonstrate that 23-32% of the human ERBB2(+) breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the retinoic acid receptor, RARα. This represents a novel subtype of breast cancer characterized by remarkable sensitivity to ATRA and RARα agonists, regardless of positivity to the estrogen receptor, a known modulator of retinoid sensitivity. In estrogen-receptor-negative cellular models showing coamplification of ERBB2 and RARA, simultaneous targeting of the corresponding gene products with combinations of lapatinib and ATRA causes synergistic growth inhibition, cyto-differentiation and apoptosis. This provides proof-of-principle that coamplification of ERBB2 and RARA can be exploited for the stratified and targeted therapy of a novel subtype of breast cancer patients, with an approach characterized by tumor cell selectivity and low predicted toxicity. The available cellular models were exploited to define the molecular mechanisms underlying the antitumor activity of combinations between lapatinib and ATRA. Global gene expression and functional approaches provide evidence for three components of the antiproliferative/apoptotic responses triggered by lapatinib+ATRA. Induction of the retinoid-dependent RARRES3 protein by ATRA stabilizes the effect of lapatinib inhibiting ERBB2 phosphorylation. Upregulation and activation of the transcription factor FOXO3A integrates ATRA-dependent transcriptional and lapatinib-dependent posttranscriptional signals, controlling the levels of effector proteins like the antiapoptotic factor, BIRC5. Stimulation of the TGFß pathway by ATRA mediates other components of the apoptotic process set in motion by simultaneous targeting of ERBB2 and RARα.

Is avian influenza virus A(H5N1) a real threat to human health?

The A(H5N1) influenza remains a disease of birds with a significant species barrier: in the presence of some tens million cases of infection in poultry--with a wide geographical spread--, only a few hundreds cases have occurred in humans. To date, human cases have been reported in 15 countries--mainly in Asia--and all were related to the onset of outbreaks in poultry. A peak of H5N1 human cases was recorded in 2006, then decreasing in subsequent years. Despite this trend, the H5N1 virus still represents a possible threat to human health, considering that more than half of human cases of H5N1 have been fatal. Moreover, despite the drop in the number of cases, the risk of a novel pandemic cannot be excluded, since H5N1 continues to circulate in poultry in countries with elevated human population density and where monitoring systems are not fully appropriate. In addition, there is a major global concern about the potential occurrence of a reassortment between the 2009 pandemic H1N1 and the highly pathogenic H5N1 influenza viruses following a co-infection in a susceptible host. Therefore, the implementation of appropriate surveillance and containment measures is crucial in order to minimize such risk. In conclusion, H5N1 avian influenza is still a rare disease in humans but its clinical severe outcome requires a careful monitoring of the virus's ability to evolve and to trigger a new pandemic.